Review Article
Alginate: Current Use and Future Perspectives in
Pharmaceutical and Biomedical Applications
Marta Szekalska,
1
Agata PuciBowska,
1
Emilia SzymaNska,
1
Patrycja Ciosek,
2
and Katarzyna Winnicka
1
1
Department of Pharmaceutical Technology, Medical University of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland
2
Department of Microbioanalytics, Warsaw Univers ity of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
Correspondence should be addressed to Marta Szekalska; marta.szekalska@umb.edu.pl
Received September ; Revised November ; Accepted December
Academic Editor: Muhammet U. Kahveci
Copyright © Marta Szekalska et al. is is an open access article distributed under the Creative Commons Attribution License,
which per mits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Over the last decades, alginates, natural multifunctional polymers, have increasingly drawn attention as attractive compounds in the
biomedical and pharmaceutical elds due to their unique physicochemical properties and versatile biological activities. e foc us
of the paper is to describe biological and pharmacological activity of alginates and to discuss the present use and f uture possibilities
of alginates as a tool in drug formulation. e recent technological advancements with using alginates, issues related to alginates
suitability as matrix for three-dimensional tissue cultures, adjuvants of antibiotics, and antiviral agents in cell transplantation in
diabetes or neurodegenerative diseases treatment, and an update on the antimicrobi al and antiviral therapy of the alginate based
drugs are also highlighted.
1. Introduction
Alginates (ALG) are a group of naturally occurring anionic
polysaccharides derived from brown algae cell walls, includ-
ing Macrocystis pyrifera, Laminaria hyperborea, Ascoph yllum
nodosum [, ], and several bacteria strains (Azotobacter,
Pseudomonas) []. is term usually referred to alginic acid
and its salts, but it can also be used for all derivatives of alginic
acid. ALG are linear biopolymers consisting of ,-linked
𝛽-D-mannuronic acid (M) and , 𝛼-L-guluronic acid (G)
residues (Figure ) arranged in homogenous (poly-G, poly-
M) or heterogenous (MG) block-like patterns [–]. With
regard to the initial source material, commercial ALG may
dier in composition and the sequence of G- and M-blocks.
ALG extraction process from seaweeds is uncomplicated
but multistage procedure, which usually starts with treating
the dried raw materia l using diluted mineral acid. Aer
further purication, the obtained alginic acid is converted
into water-soluble sodium salt in the presence of calcium
carbonate, which is next transformed back into acid or its
expected salt (Figure ) [, ].
Commercial ALG are exclusively possessed from
algal sources, although alternative production by microbial
fermentation has been recently explored in order to provide
ALG with more dened physicochemical properties [].
Among various ALG, sodium alginate is one of the
most widely investigated ones in the pharmaceutical and
biomedical eld and its monograph is included into both the
European Pharmacopeia and the U nited States Pharmacopeia
[, ]. e current pharmacopoeial requirements regarding
sodium alginate are presented in Table .
2. General Properties of ALG
Currently used ALG possess a high degree of physico-
chemical heterogeneity which inuences their quality and
determines potential applicability. ALG are commercially
available in various grades of molecular weight, composition,
and distribution pattern of M-block and G-block, the factors
responsible for their physicochemical properties such as
viscosity, sol/gel transition, and water-uptake ability. e
molecular weight, expressed as an average of a ll the molecules
present in the sample, of commercial ALG varies between
and g/mol. ALG extracted from dierent
sourcesdierinMandGresiduesaswellasthelengthof
Hindawi Publishing Corporation
International Journal of Polymer Science
Volume 2016, Article ID 7697031, 17 pages
http://dx.doi.org/10.1155/2016/7697031
International Journal of Polymer Science
O
O
OH
O
OH
O
O
O
OH
−
OOC
−
OOC
1,4𝛼-L-Guluronic acid 1,4𝛽-D-Mannuronic acid
(a)
O
O
O
O
O
O
O
O
O
O
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
−
OOC
−
OOC
−
OOC
−
OOC
−
OOC
−
OOC
M G MM GG
O
O
O
(b)
MGMG GGGG MMMM MGMG
MG-block MG-blockM-blockG-block
(c)
F : e structure of ALG: monomers (a), chain conformation (b), and blocks distribution (c).
Milling ExtractionSodium carbonateMineral acid
Brown algae
Algal material
Alginic acid
Sodium alginate
Puried
Sodium alginate
F:eprocedureofsodiumalginateextractionfrombrownalgae[].
each block. Generally, by raising the ALG G-block content or
molecular weight, more stronger and brittle ALG gels may be
achieved []. Alginic acid is insoluble in water and organic
solvents, whereas ALG monovalent salts and ALG esters are
water-soluble forming stable, viscous solutions [–]. e
% w/v aqueous solution of sodium alginate has a dynamic
viscosity – mPa⋅sat
∘
C. ALG solubility is limited by
the solvent pH (a decrease in pH below pKa .–. may
lead to polymer precipitation), ionic strength, and the content
of “gelling ions” [, ]. ALG with more heterogeneous
structure (MG-blocks) are soluble at low pH compared to
poly-M or p oly-G ALG molecules, which precipitate under
these conditions [, ]. Apart from molecular weight,
the ALG capability of creating viscous solutions may vary
according to their concentration, solvent pH (a maximum pH
is reached around .–.), temperature, and the presence of
divalent ions [–, ].
ALG can be easily formed into diverse semisolid or solid
structures under mild conditions because of their unique
ability of sol/gel transition. erefore, ALG are commonly
used as viscosity increasing agents, thickeners, and suspen-
sion and emulsion stabilizers in food and pharmaceutical
industry (Table ).
ALG gelation can be induced in the presence of divalent
ions, which cross-link the polymer chains through the “egg-
box” model [, , ] or by lowering the pH value below
the pKa of ALG monomers using lactones like d-glucono-𝛿-
lactone [, ]. I t should be noted that calcium chloride, most
frequently used source of Ca
2+
ions, is responsible for rapid
anduncontrollableALGgelation.egelationrateisacritical
International Journal of Polymer Science
T : Sodium alginate characteristic recommended by the European Pharmacopeia (Eur. Ph.) and United States Pharmacopeia (USP)
[, ].
Parameter Eur. Ph. . USP -NF
A ppearance of solid product White or pale yellowish-brown powder n.d.
Content n.d. .%–.% of dried basis
Packaging and storage n.d. preserved in tight containers
Solubility Slowly soluble in water, practically insoluble in ethanol % n.d.
A ppearance of solution
Not more opalescent than reference formazin suspension in water
and not more intensely coloured than intensity of the range of
reference solutions of the most appropriate colour
n.d.
Heavy metals ≤ ppm ≤.%
Chlorides ≤.% n.d.
Calcium ≤.% n.d.
Arsenic n.d. ≤. ppm
Loss on drying ≤.% ≤.%
Total ash n.d. .%–.%
Sulfated ash .%–.% n.d.
Microbial limits
TAMC: ≤ cfu/g
≤ cfu/g
TYMC: ≤ cfu/g
Absence of specied
microorganisms
Salmonella sp ., Escherichia coli Salmonella sp., Escherichia coli
n.d.: not determined, TAMC: total aerobic microbial count, and TYMC: total yeast/moulds count.
T : e use of alginic acid and its salts in food and pharmaceutical industry.
Code Ingredient Application in food industry Application in pharmaceutical industry
E Alginic acid [] Emulsier, formulation aid, stabilizer, thickener
Tablet binder and disintegrant, sustained release and
release-modifying agent, taste masking agent, thickener,
suspending and viscosity incr easing agent, stabilizer
E
Sodium alginate
[]
Texturizer, stabilizer, t hickener, formulation aid,
rming agent, avour adjuvant, emulsier, sur face
active agent
Suspending and viscosity increasing agent, tablet and
capsule disintegrant, tablet binder, stabilizer, sustained
release agent, diluent in capsule formulation, thickener
E
Ammonium
alginate []
Stabilizer, thickener, humectant Color diluent, emulsier, lm former, humectant
E
Calcium alginate
[]
Stabilizer, thickener Tablet disintegrant
E
Propylene glycol
alginate
[]
Emulsier , avoring adjuvant, formulation aid,
stabilizer, sur factant, thickener
Stabilizer, emulsier, suspending and viscosity
increasing agent
parameter in controlling gelation process. Slow gelation
provides creating uniform gel structures with mechanical
integrity []. One approach to reducing the rate of gel
forming process is to apply to phosphate buers (e.g., sodium
hexametaphosphate). In the reaction with ALG carboxylate
groups, phosphate groups present in the buer compete with
calcium ions and as a result ALG gelation process is retarded
[]. Additionally, calcium sulfate and calcium carbonate
with lower solubility also prolong the gel formation. e
gelati on rate is also dependent on temperature; at lower
temperatures, the reactivity of Ca
2+
is reduced []. Recently,
a freeze-thaw technique has been examined as an advance d
controlled method for ALG hydrogels formation []. Gelling
properties are strongly associated with ALG structure and
prop ortions of M-, G-, and MG-blocks [, , ]. In
addition, ALG gels with an increased amount of repeating G-
block units are regarded as stier, brittle, and mechanically
more stable [, ]. In contrast, ALG characterized by
high proportion of M-blocks form gradually so and more
elastic gels. However, MG-blocks in ALG gel determine its
shrinkage and higher exibility []. Nevertheless, ALG with
predominated M-block content, as a result of high water
absorption, exchange ions more easily in comparison to ALG
with hig her amount of G-block residues [, , , ].
Itshouldbenotedthatanumberofstudiesrevealedthat
ALG solution/gel transition occurred under physiological
conditions, for example, in the presence of divalent ions and
under acidic environment of body uids []. For instance,
nonwoven dressings of calcium alginate capable of exchange
ions with the wound uid have been commonly utilized
International Journal of Polymer Science
−5
−4
−3
−2
−1
0
1
2
3
4
024
−4−6 −2−8
REF
ALG
RNT
RNT + 1% ALG
RNT + 2% ALG
F : Potentiometric electronic tongue plot showing taste clusters of reference solution (. M Ca(NO
3
)
2
, . M NaCl) (REF),
pure ranitidine hydrochloride (RNT), microspheres placebo (ALG), and microspheres prepared with using % and % ALG solution (RNT +
ALG % and RNT + ALG %, resp.). Samples were placed in mL of deionized water ; measurement time was min with signal acquisition
every s. e data were processed using Principal Component Analysis (PCA) with autoscaling (author’s original unpublished data).
for the treatment of exuding injuries or infected surgical
wounds [–]. Formation of a highly absorbent soluble
gel eectively maintains a physiologically moist environment
and aids healing process through facilitating growth of fresh
epidermis [, ]. Due to mechanical stability and proper
viscoelastic behavior, ALG are also applied as structural
supporting biomaterials for tissue (teeth, bo ne, and cartilage)
reconstruction [].
e fact that ALG may undergo in situ gelation makes
ALG materials promising tools for a wide range of app li-
cations, including injectable vehicles for tissue engineering
or topical drug delivery systems [, , ]. Moreover,
due to gelling properties, ALG have been investigated as
taste masking agents [, ]. Studies performed with using
potent iometric electronic tongue [] have proved that spray-
dried microspheres with sodium alginate hid the bitter
taste of ranitidine hydrochloride through physical gel-barrier
formation (Figure ). Figure presents nal chemical image,
which shows that for all samples distinctive clusters are easily
observable.eyareformedbychemicalimagesofsamples
of various types, where ALG microspheres with ranitidine
hydrochloride are easi ly discernable from pure drug, which
indicates masking eect obtained with the use of sodium
alginate.
Greatly porous three-dimensional ALG hydrogel struc-
ture displays favorable swelling properties arising from the
presence of hydrophilic functional groups []. ALG ability
of hydration and gel formation gives the opportunity to
prolongreleaseoftheactivesubstanceattheadministration
site. Hence, these polymers have been extensively studied
for prolonged or controlled release drug delivery systems
[, ].
In addition, owing to the mild conditions during gel
formation, ALG (especially calcium alginate) appear to be
favorable tools for cell entrapment used in tissue engineering
or regeneration [–]. ALG barrier protects immobilized
material toward physical stress (maintaining its viability dur-
ing long-term culture) and enables avoiding immunological
reactions with the host. Currently, ALG microparticulate
systems are also being developed for the treat ment of a variety
of diseases, including cancer, diabetes, or Parkinson’s dise ase
[, ].
ALG possess good mucoadhesive proper ties resulting
from the presence of free carboxyl groups allowing the
polymer to interact with mucin by hydrogen and electrostatic
bonding. Environmental pH has a st rong impact on ALG sol-
ubility and consequently on their mucoadhesive character as
only ionized carboxyl groups are capable of interacting with
mucosal tissue. In addition, soluble ALG facilitate solvent
penetration through polymer matrix resulting in formation
of more viscous and cohesive gel structure responsible for
strengthening the mucoadhesive bonds. In contrary, too
excessive hydration of ALG matrix in physiological uids
might weaken mucoadhesiveness as a result of attenuation
of ALG functional groups available for interact i ons with
mucosal tissue [–].
Owing to mucoadhesive properties, ALG are regarded as
prop er polymer excipients to prepare buccal [–], nasal
[, ], ocular [, ], and gastrointestinal dosage forms
[–]. Recently, se veral studies have shown favourable
mucoadhesiveness of ALG-based applications in contact with
vaginal mucosa tissue [, ]. Furthermore , an increased
drug residence ti me at the ocular mucosal surface and
prolonged release of active agents from microparticulate
International Journal of Polymer Science
5𝜇m
(a)
10 𝜇m
(b)
5𝜇m
(c)
F : SEM images of alginate microspheres obtained by the spray drying method with metronidazole under magnication ×
(a), ranitidine hydrochloride under magnication × (b), and metformin hydrochloride under magnication × (c) (author’s
unpublished images).
delivery systems with ALG were displayed []. Due to large
surface area, which may favour an intimate contact between
the polymer and mucin, multiunit dosage forms with sodium
alginate are also explored as gastroretentive drug carriers
(Figure ), especially for substances, which are unstable or
degraded in the alkaline pH [, ].
ALGhavebeenextensivelyevaluatedasvaccineadjuvants
or coadjuvants as these polymers were displayed to enhance
bioavailability and immunogenicity of antigens aer nasal
and oral administration [, , ].
3. ALG Modification for Drug Delivery
Systems and Biomedical Devices
ALG can be easily modied through chemical or physical
cross-linkinginordertoformALGhydrogelsandimprove
physicochemical properties and/or biological activity. Many
methods have been described for ALG cross-linking, which
includes ionic cross-linking, covalent cross-linking, cell
cross-linking, phase transition (t hermal gelation), “ click”
reaction, and free radical p olymerization []. An alteration
of the M- to G-block proportion or an enrichment of polymer
backbone in M-, G-, or MG-blocks is being practiced by
modication through enzymatic epimerisation catalysed by
mannuronan C- epimerases. is enzyme, isolated from
the soil bacterium Azotobacter vinelandii and expressed in
Escherichia coli, converts mannuronic acid residues into
guluronicacidresiduesinthepolymerbackbonewithout
breaking of the glycosidic bond [, , ]. Additionally,
from ALG backbone, oligosaccharides might be isolated,
which are polymer fragments containing three to ten of
simple monosaccharides. ere are two methods, which
might be used to prepare ALG oligosaccharides: enzymatic
depolymerization and acid hydrolysis []. e common
chemical modication of ALG hydroxyl groups includes
oxidation, sulfation, gra copolymerization, acetylation, and
phosphorylation process [, ]. Modication of the car-
boxyl g roups may be achieved by esterication and amidation
[, , ]. A list of the commonly used chemical changes
of ALG structure for biomedical and pharmaceutical applica-
tion is presented in Table . ALG solubility might be changed
by modication of hydroxyl groups (in positions C and C)
or the carboxyl groups (in C position) through covalent
attachment of long alkyl chains or aromatic groups to the
polymer backbone. Increasing ALG hydrophobicity provides
decreasing polymer dissolution and erosion. Additionally,
there are many studies, which include production of ALG
derivatives by graing w ith dierent substances such as poly-
acrylamide, methacrylate, galactose, lectin, sulfate, cysteine,
cyclodextrins, propylene glycol, and dodecylamine [–].
4. ALG Biological Activity and Application in
Pharmaceutical Products
ALG are regarded as biocompatible, nonimmunogenic, and
nontoxicmaterials[].AlthoughALGgelisnotdegradablein
mammalian digestive tract (alginase/lyase enzyme involved
in depolymerization of ALG is present only in prokaryotic