Alginate is a natural polysaccharide that is widely used as a
component of pharmaceuticals and in food industry. Alginate
particles can be used for encapsulation of substances with the necessity
of prolonged release. They can also provide appropriate
microenvironment for cells. Here the methods of the synthesis of
alginate beads, micro- and nanoparticles are reviewed with special
attention to the calcium alginate ones. The results from publications
that did not deal with alginate particles but, to our opinion,
could be applied in this field are also included in order to give an
outline for possible future research. The suggested applications of
the particles are mentioned as well. The two main methods for the
synthesis of calcium alginate particles are internal and external
gelation, but the external gelation techniques can be themselves
subdivided into several subtypes. Currently, a technique being able
to produce alginate nanoparticles with any desirable size does not
exist. We analyze the possibilities of employing aerosolization
method for this purpose. The potentials to overcome the problem of burst
release of the encapsulated substances by means of
cyclodextrin inclusion complexes and employing additional crosslinking
agents are also discussed. The clinical application of
alginate nanoparticles is still limited because of the burst release of
encapsulated drugs and the poor size control of the particles
formed. Further research must concentrate on overcoming these problems
and on topical application of alginate particles without
entering bloodstream rather than on investigation of model drug release in vitro without taking the above-mentioned problems
into account.
Keywords: Calcium alginate; Alginate beads; Alginate microparticles; Alginate nanoparticles; Drug encapsulation; Particle size
control; Aerosol
Introduction
Alginates are polysaccharides. The commercially available
ones come from brown algae. They are linear copolymers of
(1→4)-linked units of β-D-mannuronic acid and α-L-guluronic
acid. The molar ratio between them and their distribution along
the commercial polymer depend on the algal source, its location,
age, collection season and extraction technique. Guluronic acid
residues can form so-called egg-box complexes with calcium ions or
some other divalent metal cations leading to gel formation (Figure
1). The name ‘egg-box’ is used because, if depicted schematically,
the cations look like eggs situated inside puckered boxes formed
by four guluronic acid residues of two superimposed chains.
Mannuronic acid residues have much less affinity to metal ions [1].
Barium ions have more affinity to alginate than the calcium ones. If
reacted with calcium alginate at lower concentrations, they create
new gelling junctions. At higher concentrations, barium ions also
displace calcium ions from existing junctions [2].
Figure 1: The egg-box model.
To extract alginate, algae are usually washed with organic
solvents and water, dried and milled. After acid pretreatment,
alginate is solubilized with Na2CO3
. The crude extract is
concentrated, dialyzed against water and then freeze-dried or
precipitated with ethanol. Acidification or treatment with Ca2+ can
be used instead. Brown algae are abundant in nature; however, the
possibility of cultivating them exists as well [1].
The viscosity of aqueous sodium alginate solution rapidly
increases with its concentration. For example, the addition of
10% of alginate to water leads to a ~100-fold increase in viscosity.
But the poly electrolyte nature of alginate has little effect on its
hydration, and in the above example less than 3.7% of the water
molecules present in solution is involved in alginate hydration.
Such a large viscosity increase is determined by the polysaccharide
network, with large bulk-like water pools present between the
polysaccharide chains [3].
Sodium alginate may act as a mucoadhesive polymer. A
comparative study of adhesion between buccoadhesive compacts
and pig buccal mucosa or sodium alginate solution revealed that
the results were of similar performance [4]. Sodium alginate was
proposed as a mucoadhesive component of a nasal gel [5] or in
buccal patches containing salbutamol sulfate [6]. Sodium alginate
conferred in situ gelling mucoadhesive properties and retarded
drug release from liquid rectal suppositories. These suppositories
were successfully tested on Guinea pigs to alleviate symptoms of
histamine-induced bronchospasm [7]. Sodium alginate was also
evaluated as an excipient in salbutamol sulfate sublingual films
[8] and tablets [9]. However, drug release was found to be too
slow in the films [8] or too rapid in tablets [9]. Only salbutamol
sulfate tablets formulated from granules containing mastic and
sodium alginate excelled commercial tablets in the terms of drug
release when tested on rabbits [10]. In combination with hydroxy
propyl methyl cellulose and propylene glycol sodium alginate was
used in the formulation of terbutaline sulfate sublingual films
[11]. Sodium alginate could be also used as a component of plugs
for water-soluble parts of crosslinked gelatin capsules containing
pellets with encapsulated salbutamol sulfate. The plug absorbed
the surrounding fluid, and began to release the drug through the
swollen matrix and was finally ejected out of the capsule by erosion
of the material. The usability of the system was shown on rabbits
[12].
Chitosan-alginate complex was proposed as an excipient for
orodispersible tablets, and their disintegration time was so short
that it was even referred to as a ‘super dis-integrant’ [13]. One
optimized formulation containing the excipient for 5-fluorouracil
tablets, suitable for trans buccal and rectal drug delivery, contained
this chitosan-alginate complex along with the same components
un-complexed in order to avoid burst release and to improve the
mucoadhesive properties [14].
Sodium alginate itself also has a therapeutic effect. When
admixed to foods for diabetic human patients, it decreased gastric
emptying rate and rises glucose in blood, serum insulin and
plasma C-peptide levels [15]. Orally administered, sodium alginate
significantly alleviated small intestinal enteritis in rats, caused by
treatment with the anti-inflammatory drug indomethacin, and this
relief seemed to be independent of the sodium alginate viscosity
administered [16]. Oral disposal of sodium alginate to rats with
colitis led to a significant reduction of colonic damage, decreased
lesion formation [17,18] and inhibited mucosal injury [17].
Orally administered alginate oligosaccharide obtained from
hydrolysis of sodium alginate by Bacillus subtilis improved
histopathological and biochemical parameters of mice having
ovalbumin-induced asthma in a dose-dependent manner [19]. Rats
fed with sodium alginate drank more water, and their urine volume
and pH rose sharply. In contrast, calcium alginate caused very little
changes in the same parameters [20].
Commercially available calcium alginate swabs were used
for sampling nasal flora for subsequent DNA extraction [21]. The
mucoid exopolysaccharide produced by the pathogenic bacterium
Pseudomonas aeruginosa is alginate, but it has low immunogenicity
if it is not conjugated with a carrier protein. Even in the form of
conjugate it is non-toxic if administered intraperitoneally to mice
or guinea pigs and non-pyrogenic if administered intravenously to
rabbits [22]. When alginate beads with encapsulated tumor cells
were implanted to mice, a process of angiogenesis was observed
in the implants zone. The beads were prepared from commercially
available alginate [23]. It may be considered as a further proof of
alginate biocompatibility.
Sodium alginate was also shown to be beneficial for agriculture.
Being administered as dietary supplement to the white shrimp
Litopenaeus vannamei, it acted as an immunostimulant and
improved its resistance against the attack of Vibrio alginolyticus
bacterium [24]. Sodium alginate digested with alginate lyase
promoted root elongation of rice, carrot [25], lettuce [26] and
barley plants [27,28] even under hypoxic conditions [28]. It was
hypothesized that digested alginate might initiate some signal
transduction pathway [27,28]. Under hypoxic conditions digested
alginate also caused enhancement of the activity of the enzymes
regenerating NAD+
[28].
Alginate oligomers promoted the germination of unhulled rice
and Komatsuna seeds as well as tobacco callus differentiation.
The mixture of oligomers was assumed to contain so-called
oligosaccharine, an oligosaccharide inducing unusual proliferation
and/or differentiation of plant cells. There are several kinds of
oligosaccharines. They act as a chemical signal for the stimulation
of hormone synthesis [29]. The promoting effect of alginate
oligosaccharides on root formation and growth in rice was mediated
by endogenous indole-3-acetic acid [30].
But proliferation of the microalga Chlamidononas reinhardtii
was repressed by the same oligomers [29]. It should be noted that
only digested sodium alginate shows this effect. And the possibility
of alginate degradation by the lyases of soil bacteria is assumed
[28]. Therefore, it is speculated that these active substances can be
formed from alginate under natural conditions.
Another notable advantage of alginate is its ability to bind
micronutrients. Some important Mn, Cu, Zn and Mo fertilizers are
MnCl2
, CuSO4
·5H2O, ZnCO3
and Na2
MoO4
·2H2O, respectively [31].
Manganese can be complexed with alginate by addition of MnCl2
to
the gelling solution of CaCl2
or BaCl2
, and slow release of manganese
ions from the beads into physiological saline has been reported [32]
because the affinity of alginate to Ca2+ is higher than to Mn2+ [33].
The beads containing Ba and Mn could be used for manganeseenhanced magnetic resonance imaging and were tested on rats
[32]. The use of CuSO4
[34] or CuCl2
[35] as a gelling solution led
to copper alginate hydrogel being able to release copper ions into
simulated body fluid [34] or into phosphate buffer (pH 6) [35] in a
prolonged manner. The use of basic zinc carbonate for zinc alginate
hydrogel formation using internal gelation method has also been
reported. The hydrogel was active against E. coli [36]. Molybdenum
can be adsorbed by preformed calcium alginate beads preferably
in the form of H2[MoO4] or [Mo(H2O)6]3+ at pH 2 and released back
up to 50% into 0.1M HCl. If radioactive molybdenum is used, the
method is suitable for radiotherapy [37]. Copper ions from CuCl2
may also be adsorbed onto preformed calcium alginate beads [38].
Copper alginate shows activity against Staphylococcus aureus,
Staphylococcus epidermidis, Staphylococcus pyogenes and E. coli
[34].
The biodegradability of unmodified alginate particles, their
ability to bind micronutrients and the beneficial effect of alginate
make them promising carriers of agrochemicals. This is especially
important because in a recent review [39] the authors expressed
great concerns regarding the use of nanoparticles in agriculture
because of the negative impact of metal and oxide nanoparticles on
soil microorganisms, earthworms and even on cultivated plants.
Alginate beads can also have industrial applications:
• Wastewater treatment. The beads with encapsulated
horseradish peroxidase could be reused up to 3 times, although
the encapsulation decreased enzyme activity in comparison
with the free enzyme [40]. In another report, the efficiency of
phenol removal by encapsulated horseradish peroxidase was
demonstrated by reducing to half the initial phenol quantity
after only 5 reaction cycles [41].
• Food industry. Xylanase immobilized in alginate beads
may be used for fruit juice clarification [42]. Lactobacillus
helveticus and Streptococcus thermophilus immobilized in
alginate beads were intended for use as lactic starters in milk
fermentation [43]. Alginate particles with encapsulated healthy
nutrients can also be used as components of functional foods.
• Enzyme production by cells immobilized in alginate
beads. A good example is glucoamylase [44]. In this case fungus
Thermomucor indicae-seudaticae was immobilized in alginate
beads, and cane molasses was used as a cheap medium [44].
In all these applications alginate is exploited because of its
natural origin, i.e. it cannot be a harmful admixture if separated
incompletely. Beads (and not nanoparticles) are chosen because
they can be easily separated by sedimentation. As could be seen
above, not only enzymes themselves but also enzyme-producing
bacteria can be immobilized in alginate beads.
In contrast to metal nanoparticles, alginate particles can be
modified either before or after their synthesis. In the former case,
bulk alginate is modified and then used to prepare the particles.
This way is usually preferable from the two options because it
avoids the leak or destruction of encapsulated substance during
the modification. The chemical modification of alginate is reviewed
widely in [45].
Alginate microparticles and nanoparticles are usually used to
encapsulate and carry various substances, and the goal of many
studies is to achieve sustained release of them. It should be noted,
however, that the results of experiments dealing with the release
of poorly water-soluble drugs might often be misinterpreted,
because the drug not found in the solution is assumed to remain
encapsulated in the particles. However, it may decompose after
the release or simply precipitate out. Supersaturated solutions
with varying extent of supersaturation can also be formed, making
the results irreproducible. Special care must be taken in the case
of putting the particles into a dialysis bag, because the films act
as an additional diffusion barrier. If centrifugation is used for
separation of the medium with the released substance from the
nanoparticles, the pressure generated during the process can
disturb the equilibrium. It can also make difficult resuspending the
nanoparticles in the fresh portion of medium for further incubation
[46].
For consistency, throughout this review we will use the
following terms (even if different names for them were used in the
respective publications):
• Encapsulation efficiency: the percentage of the substance
that was encapsulated (i.e. not lost).
• Loading efficiency (expressed in percent): the ratio of the
weight of the successfully encapsulated substance regarding to
the total weight of the particle. Some authors calculate loading
efficiency using different formulae, but we will give their values
without a special discussion. We have rounded encapsulation
and loading efficiencies as well as zeta potentials to the nearest
integer values.
• Nanoparticles are considered smaller than 1µm.
Microparticles have size from 1 to 1000µm. Beads have size
in a millimeter range. We have rounded bead size to the first
decimal place.
Also, some authors term their particles ‘microcapsules’.
However, we will use this term only if they have demonstrated or
at least assumed the presence of a liquid core in their particles. In
other cases, we will refer them to as microparticles.
Alginate-chitosan particles
Since alginate is a polyanion and chitosan is a polycation, they
can form a polyelectrolyte complex upon mixing, provided both of
them are charged, i.e. at suitable pH. This mixture can spontaneously
form particles. The pKa
of alginate carboxyl group is close to 5, and
that of the ammonium group of chitosan is about 6.2 [1].
Alginate-chitosan nanoparticles were prepared by dropwise
addition of a chitosan solution containing glutathione into
an alginate solution at pH 4, under stirring. If prepared at
0.75 alginate: chitosan ratio, the formed nanoparticles with
encapsulated glutathione had the following characteristics: size
361nm, polydispersity index 0.33, zeta potential 27mV [47,48]. At
1.5 alginate: chitosan ratio, the values were 212nm, 0.4 and 23mV,
respectively, although the storage stability decreased, making these
nanoparticles less suitable for application. In the same way, the
pH increase from 5.0 to 6.5 and further caused aggregation [48].
The encapsulation efficiency was 27% [47] or 80% at ratio 0.75
and fell to 1% at ratio 1.5 [48]. The respective investigations were
aimed to achieve the synthesis of mucoadhesive nanoparticles
with an encapsulated NO donor needed for treat important
diseases because of the multifaceted role of NO in vivo. Therefore,
encapsulated glutathione was nitrosated inside the nanoparticles
by adding sodium nitrite to the solution. S-nitrosoglutathione
decomposition at 400µM was delayed by its encapsulation in the
nanoparticles. At 18µM encapsulated S-nitroso glutathione was not
cytotoxic to cultured Chinese hamster lung fibroblast cells (V79),
whereas free S-nitroso glutathione was slightly cytotoxic at the
same concentration. This assay could enable the use of these anti
microbial nanoparticles in pharmaceutical applications such as
wound healing without severe side effects [47,48].
Later, the same technique was used by the same group to
encapsulate mercaptosuccinic acid and nitrosate it inside the
particles. In this case, the hydrodynamic size of the nanoparticles
was ~750nm. The encapsulation efficiency was 89%. Burst release
of NO in aqueous solution was followed for 4 hours, although the
release in the normal mode continued for 6 hours more. These
nanoparticles were assayed for topical application for bovine
mastitis. The minimal inhibitory concentration of the nanoparticles
for Staphylococcus aureus determined in vitro was 125-250µg/ml.
The number of colony forming units was 10-fold and 1000-fold
lower after bacteria were incubated with nitrosated nanoparticles
at 500µg/ml for 4 and 7 hours, respectively, compared with
bacteria growth in the presence of empty nanoparticles at the same
concentration and time. The CFU drastically decreased further
upon the addition of a second dose of nitrosated nanoparticles. For
E. coli the minimal inhibitory concentration exceeded 2000µg/ml,
i.e. these nanoparticles were inefficient against this bacterium.
The 50% cytotoxicity concentration of the nanoparticles for
cultured HEp-2 cells was 640µg/ml. Chitosan nanoparticles without
alginate at the same concentrations of the acid released more NO
at higher rates. Nevertheless, it was concluded that NO-releasing
nanoparticles might be used to combat bacteria for treating and
preventing bovine mastitis [49].
Spherical alginate-chitosan beads with encapsulated
lemongrass oil having size of 1.8-2.1mm displayed significant
antibacterial and antioxidant activity. For unencapsulated oil the
same activity was observed only at higher concentration. This
beneficial action was attributed to the strong interaction between
chitosan and the oil. This kind of beads has potential applications as
a greener agent for medical purposes [50].
The following advantages of alginate-chitosan particles can be
underlined:
• Chitosan can enhance drug bioavailability by its capacity
of infiltration into the mucus layer of the small intestine with
subsequent opening of tight junctions of epithelial cells [51].
• Unlike calcium alginate, alginate-chitosan polyelectrolyte
complex cannot be disintegrated by chelatoring agents.
Their main disadvantage could be the necessity to use an acidic
solution of chitosan because of its insolubility at neutral pH.
Preparation of alginate particles without employing
gelation
Now we describe the techniques for preparation of particles
from bulk sodium alginate or its solution as well as spontaneous
formation of particles of modified alginic acid in water. The resultant
particles are usually intended to be ready to use. However, dry
sodium alginate particles can be later treated with CaCl2
solution in
order to convert them to calcium alginate particles.
There exists a patented technique for producing alginate,
cellulose, starch or collagen particles from bulk substances by ball
milling with the possibility to control particle size from 100nm
to 50µm. The resultant nanoparticles containing therapeutic
proteins have shown efficacy in treating solid tumors, single
dose vaccination, and oral delivery. For instance, tumor-bearing
mice that received these nanoparticles containing Texas red and
cisplatin showed significant tumor size diminishing. If the same
nanoparticles were coupled to dendritic cell-binding peptide and
contained encapsulated pneumococcal surface protein A, together
with an adjuvant, they were effective to combat the bacterial load of
the mice that was reduced (in the terms of infected tissue volume)
after exposition to nanoparticles. The nanoparticles produced
by the same milling technique were also used to induce passive
immunity against anthrax toxin in mice by means of oral delivery of
monoclonal antibodies developed versus anthrax toxin [52].
Another technique consists in dropwise addition of pure ethanol
or acetone to 1% sodium alginate in water containing drug solution
in dimethyl formamide. Mixing [53] and cooling down to 3-5 °C is
needed during the process. At low mixing speed aggregation was
observed [54]. These microparticles can be separated by filtration,
washed with the same solvent and dried on air, in a heating oven
[53] or in a desiccator [54]. Using nitrofurazone as an example
of an encapsulated drug, the loading efficiency and yield of
microparticles decreased as the particle size increased from 5 to
30μm with ethanol dripping rate increasing. The presence of 0.1%
ammonia [54] (pH 8-9) and of a surfactant was needed in order
to avoid particle aggregation in the case of nitrofurazone. Other
drugs, viz. acridone, tetracycline, dibazole and metronidazole were
encapsulated in the same way (but without ammonia), although the
encapsulation conditions needed to be optimized for every drug
separately. The yield varied from 31% for metronidazole to 77.5%
for tetracycline, and the loading efficiency varied from 2% for
metronidazole to 43% for nitrofurazone [53]. In a later publication,
the same group reported that in the case of nitrofurazone the yield of microparticles was 81% with a loading efficiency of 34%.
Spray drying instead of filtration was recommended to increase
the yield [54]. The stability of nitrofurazone-loaded microparticles
resuspended in water was reported to increase with pH [53]. At 1%
and 2% of particles (nitrofurazone concentration was 0.34% and
0.68%, respectively) these solutions were more active against E.
coli, P. aeruginosa, P. vulgaris, S. aureus and B. subtilis than aqueous
nitrofurazone solution having drug concentration less than 0.02%
because of its insolubility. In the case of Candida albicans the
same solutions of microparticles excelled in antifungal activity
nitrofurazone solutions in DMSO with the concentrations of 1%
and 2% [54]. The ability of the particles to form stable suspensions
and to enhance drug solubility in water broadens the field of drug
application [53,54]. The encapsulated drugs are expected to be
more stable under ambient conditions [53].
Spray drying the sodium alginate solution containing
the payload (caffeine-loaded peptidic nanoparticles) yielded
microparticles having size of about 4μm. The crosslinking with
CaCl2
solution increased their mean size to 7.4µm but decreased
their shrinkage and slowed down the release of caffeine into
simulated gastric fluids. The particles are potentially bioactive
because of the presence of antioxidant peptides [55]. Spray drying
the solution containing sodium alginate, pectin and gentamicin
sulfate at inlet temperature of 90 ºC was used for wound dressing
preparation. The volume diameter at the 50th percentile (spanning
from 310 to 1003nm for various samples), the width of particle size
distribution, water content and drug release rate increased with
nozzle spray mesh diameter and with feed solution concentration
at constant ratio of the components. Flowability of the powders,
the adhesive strength of the gel formed from them in contact
with simulated wound fluid as well as its activity at 0.25mg/ml of
gentamicin sulfate against Staphylococcus aureus and Pseudomonas
aeruginosa showed the opposite tendency. Antimicrobial activity
was expressed as the diameter of the zones of clearance around the
two samples spotted on agar plates with the spread bacterial culture
after incubation for 24 hours. For Staphylococcus aureus the activity
of two samples was also tested in culture medium after 3, 6, 9 and 12
days of incubation. The particles were mainly spherical, but other
shapes appeared when either feed concentration or mesh nozzle
increased, and further increase led to large collapsed particles. All
the particles were composed of smaller aggregated particles. The
encapsulated drug was being released in simulated wound fluid in
Franz-type diffusion cells for up to 5 days. Loading efficiency was
around 24-27% with an encapsulation efficiency between 70 and
83%, and for all the samples initial burst release was observed. At
40 °C and 75% relative humidity drug content was preserved for
6 months with only slight increase in water content. Swelling rate
in contact with simulated wound fluid depended on particle size.
The yield increased with feed solution concentration but decreased
with nozzle spray mesh diameter. The nanoparticulate powder
may be used as a self-consistent formulation having great potential
application in the treatment of both acute and chronic infected
wounds [56].
Low molecular weight alginic acid prepared by acid hydrolysis
of sodium alginate formed nanoparticles itself (without calcium
ions) when its hydroxyl groups were functionalized with oleoyl
residues. The nanoparticles were loaded with vitamin D3
by
addition of its solution to the reconstituted solution of vacuumdried
nanoparticles. Loading efficiency increased with the vitamin
concentration from 0.3 to 0.9%, but the encapsulation efficiency
also decreased from 68% to 46%. Mean nanoparticle hydrodynamic
diameter also decreased from 559nm to 305nm, and particle
formation rate was sped up when substitution degree increased.
An unimodal particle size distribution was revealed. In simulated
gastric fluid they retained spherical shape and released ~40% of
the encapsulated vitamin for 3 hours. But in simulated intestinal
fluid they became irregularly shaped, their hydrodynamic diameter
was 757nm and burst release of 40% of the vitamin occurred, with
60% of the vitamin released after 7 hours. The nanoparticles can be
used as oral carriers for liposoluble nutraceuticals [57].
The great disadvantage of sodium alginate particles is the very
limited possibility of prolonged drug release because of sodium
alginate solubility leading to fast disintegration of the particles. The
particles of modified alginic acid offer convenient manipulation,
but the need of its prior chemical functionalization limits the
applicability of the technique for non-specialized, e.g. biomedical
laboratories.
Production of Alginate Particles Using Other
Particles as Cores
In this method, sodium alginate is physically adsorbed or
covalently linked to the surface of other particles. The particles
can also be formed already capped with alginate. In some cases
subsequent gelation with CaCl2
is carried out. For CaCO3
particles
there is a possibility of their generation simultaneously with
alginate gelation.
Dropwise addition of chitosan nanoparticles with encapsulated
bovine serum albumin modified with rhodamine isothiocyanate to
sodium alginate solution at controlled pH yielded negatively charged
nanoparticles having hydrodynamic diameter of several hundred
nanometers depending on the solution composition. The highest
diameters were registered in water. The nanoparticles successfully
delivered the protein into cultured cells, with the localization
depending on cell type. Significant increase in peroxide production
by HCEC cells was observed at 300 and 600µg/ml of empty
nanoparticles after exposure for 4 hours. However, there was almost
no superoxide production after either 4 or 24 hours of exposure. The
metabolic activity of LN229 and MCF-7 cells remained unchanged
for up to 72 hours of incubation with the empty nanoparticles. But
MDA-MB-231 and HCEC cells displayed significantly decreased
metabolic activity at nanoparticle concentration above 180µg/ml
after 72 hours of exposure, but not after 24 hours. Similar survival
decrease at these concentrations of nanoparticles was observed
for A549 cells. Dose dependencies acquired after 24 or 72 hours
of exposure were almost the same. Survival of HT29 and CaCO2
cells was significantly increased only after exposure to 600µg/ml
of the nanoparticles for 72 hours. The nanoparticles have potential
applicability as nanocarriers in cancer therapy [58]. A similar
technique was used for enoxaparin encapsulation. The proposal was to
evaluate nanoparticles loaded with this low molecular weight
heparin for its oral delivery, controlled and prolonged release in
order to improve patient compliance. In this, chitosan nanoparticles
were covered with sodium alginate (applied in phosphate buffer)
and treated with CaCl2
. Parameters of the optimized formulation
were as follows: average size 335nm, spherical, polydispersity
index 0.37, zeta potential –31mV, encapsulation efficiency >70%,
drug release in simulated gastric fluid for 2 hours 2%, in simulated
intestinal fluid for 14 hours ~60%. Degradation and erosion of
nanoparticles was identified as a possible drug release mechanism.
The pharmacokinetic parameters of the drug given orally to fasted
rats through cannula in a dose of 50mg/kg body weight were
improved. Nevertheless, those of intravenously administered free
enoxaparin at 1mg/kg were better. 75% of the encapsulated drug
applied at 2mg/ml reached across the intestine to the serosal fluid
for 90 minutes, as shown in vitro by means of everted intestinal sac
model. 900 IU of orally administered encapsulated drug reduced
thrombus formation by 59% compared with buffer. Significant
uptake of the nanoparticles by the intestinal mucosa for 1 hour was
shown by administration of nanoparticles loaded with fluorescein
isothiocyanate instead of the drug through gastric cannula to
fasted rats. Therefore, the nanoparticles proved their utility as
oral delivery vehicle for enoxaparin. Such a vehicle is a foremost
requirement for non-invasive and non-hospitalized treatment of
vascular disorders (deep vein thrombosis, pulmonary embolism
and venous thromboembolism). But subcutaneously injected free
drug was even better [51].
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