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Drug Development and Industrial Pharmacy, 28(6), 621630 (2002)

REVIEW
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Alginate in Drug Delivery Systems


Hanne Hjorth Tnnesen and Jan Karlsen*

Institute of Pharmacy, University of Oslo, P.O. Box 1068 Blindern,


0316 Oslo, Norway

ABSTRACT

Alginates are established among the most versatile biopolymers, used in a wide
range of applications. The conventional use of alginate as an excipient in drug
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products generally depends on the thickening, gel-forming, and stabilizing proper-


ties. A need for prolonged and better control of drug administration has increased
the demand for tailor-made polymers. Hydrocolloids like alginate can play a
signicant role in the design of a controlled-release product. At low pH hydration
of alginic acid leads to the formation of a high-viscosity acid gel. Alginate is
also easily gelled in the presence of a divalent cation as the calcium ion. Dried
sodium alginate beads reswell, creating a diusion barrier decreasing the migra-
tion of small molecules (e.g., drugs). The ability of alginate to form two types of
gel dependent on pH, i.e., an acid gel and an ionotropic gel, gives the polymer
unique properties compared to neutral macromolecules. The molecule can be
tailor-made for a number of applications. So far more than 200 dierent alginate
grades and a number of alginate salts are manufactured. The potential use of the
various qualities as pharmaceutical excipients has not been evaluated fully, but
alginate is likely to make an important contribution in the development of poly-
meric delivery systems. This natural polymer is adopted by Ph.Eur. It can be
obtained in an ultrapure form suitable for implants. This review discusses the
present use and future possibilities of alginate as a tool in drug formulation.

Key Words: Alginate; Controlled release; Drug delivery

INTRODUCTION steadily during the last 50 years. In most cases the


purpose is to make a product that maintains a pro-
The interest in formulated dosage forms, where longed therapeutic eect at a reduced dosing fre-
the drug release can be controlled, has increased quency. Although a large number of substances
*Corresponding author.

621

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622 Tnnesen and Karlsen

demonstrate pharmacological eects in vitro, the acids. The alginic acid can then be converted to a
active principle must reach the site of action in a salt of which sodium alginate is the major form cur-
concentration large enough to initiate a pharmaco- rently used. Alginic acid is a linear polymer consist-
logical response to be useful as a compound in ing of D-mannuronic acid and L-guluronic acid
human medicine. The amount of the drug delivered residues that are arranged in the polymer chain in
to the site of action will depend on the administra- blocks. These homogeneous blocks (composed of
tion dose, the rate and extent of absorption, and either acid residue alone) are separated by blocks
the distribution throughout the body. The clinical made of random or alternating units of mannuronic
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eect will last until the drug concentration falls and guluronic acids (1). Alginates have been
below a minimum level due to excretion and meta- reported to undergo proton-catalyzed hydrolysis,
bolism. Drugs are almost never administered to a which is dependent on time, pH, and temperature.
patient in an unformulated state. A dosage form Alginates from dierent sources vary in their pro-
generally consists of one or more active principles portions of blocks. Hydration of alginic acid leads
together with a varying number of other substances to the formation of a high-viscosity acid gel due
(excipients) that have been added to the formula- to intermolecular binding. After gelation the water
tion in order to facilitate the preparation and molecules are physically entrapped inside the
administration, promote the consistent release and alginate matrix, but are still free to migrate. This is
bioavailability of the drug, and protect it from of great importance in many applications (e.g.,
degradation. These excipients strongly inuence the alginate gels for cell immobilization/encapsulation).
physicochemical characteristics of the nal prod- The water-holding capacity of the gel is due to
ucts. Excipients were considered to be inert in that capillary forces. Heat-stable gels can develop at
they should not exert any therapeutical or biologi- room temperature.
cal action or modify the biological action of the Monovalent metal ions form soluble salts with
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drug substance. It is now recognized that excipients alginate whereas divalent and multivalent cations
can potentially inuence the rate and/or extent of (except Mg2) form gels or precipitates. The various
absorption of a drug (e.g., by complex formation). cations show dierent anity for alginate, and
The successful formulation of a stable and eective selective ion binding is the basis for the ability of
dosage form therefore depends on the careful selec- alginate to form ionotropic hydrogels. Alginates
tion of excipients. In this context it should be men- with a high content of guluronic acid blocks give
tioned that the use of polymers as a formulation gels of considerably higher strength compared to
aid in controlled drug delivery systems has over the
years become an important area of research and
development.
The present trend points to an increasing interest
in the use of natural ingredients in food, drugs, and
cosmetics. The naturally occurring alginate poly-
mers have a wide potential in drug formulation due
to their extensive application as food additives and
their recognized lack of toxicity. Alginates can be
tailor-made to suit the demands of applicants in
both the pharmaceutical and biomedical areas. This
group of polymers possesses a number of character-
istics that makes it useful as a formulation aid, both
as a conventional excipient and more specically as
a tool in polymeric-controlled drug delivery.
Alginates are natural polysaccharide polymers
isolated from brown seaweed (Phaeophyceae)
(Fig. 1). The seaweed is extracted with a dilute alka-
line solution which solubilizes the alginic acid pres-
ent. Free alginic acid is obtained on treatment of Figure 1. Alginate block types: G guluronic acid,
the resulting thick and viscous mass with mineral M mannuronic acid.
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Alginate in Drug Delivery Systems 623

suspending and thickening agent in water-miscible


gels, lotions, and creams, and as a stabilizer for
emulsions. The potential lies, however, in the devel-
opment of alginate-controlled drug delivery systems.

THE APPLICATION OF ALGINATE IN


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ORAL DOSAGE FORMS WITH


Figure 2. Probable binding mode between the calcium ion SYSTEMIC EFFECT
and two G residues.
Tablets and capsules are by far the most fre-
quently used oral dosage forms. The products are
alginates rich in mannuronate, as the G residues often designed as immediate-release type, i.e.,
exhibit a stronger anity for divalent ions than the immediate release of drug for rapid absorption.
M residues (Fig. 2) (2,3). Coating of the units can lead to sustained-release
Transmittancy, swelling, and viscoelasticity of products, i.e., the release of the therapeutic agent is
alginate gel membranes are highly aected by the retarded. Controlled-release drug delivery systems
M/G ratio (4,5). The calcium alginate gels are the are designed to give a reproducible and kinetically-
most extensively studied. The ability of alginate to predictable release of drug substance. Alginates may
form two types of gel dependent on pH, i.e., an be utilized in dosage forms designed for either type
acid gel and an ionotropic gel, gives the polymer of drug release.
unique properties compared to neutral macromole- Traditionally, sodium alginate has been used as a
cules. The physicochemical properties of the poly- tablet binding agent, while alginic acid is used as a
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mer system and the swelling process to activate the tablet disintegrant in compressed tablets designed
release of drugs will be dependent on the type of gel for immediate drug release (8). The eect of sodium
formed. alginate on tablet properties is, however, dependent
Alginic acid and its sodium and calcium salts are on the amount incorporated in the formulation and
regarded as generally non-toxic and biocompatible in some cases the alginate salt can promote disinte-
(6). These products are commercially available and gration.
over 200 dierent alginate grades, in addition to
alginic acid and a number of corresponding salts,
are manufactured. Alginates are widely used in the Development of a Controlled-Release System
pharmaceutical, cosmetic, and food industry (7,8).
However, since alginates are obtained from a nat- The oral dosage forms are often made according
ural source, a variety of impurities may potentially to one of the following principles: the entire drug
be present. These include heavy metals, proteins, dose is in the same physical unit or the dose is con-
and endotoxins. For pharmaceutical applications, tained in an assembly of small sub-units. In the
particularly for parenteral administration, these latter case the sub-units are lled into a capsule or
impurities should be removed. A monograph for compressed into a tablet. The formulations employ
alginic acid is included in the European Pharmaco- a chemical or physical barrier to provide a con-
poeia (Ph.Eur.). Alginate approved by Ph.Eur. can trolled release of the drug. Many formulation tech-
now be obtained. Ultrapure grades of alginates niques have been used to build the barrier into the
have a controllable level of pyrogenicity and may peroral dosage form, e.g., the coating of a core con-
be used as implants in combination with drugs. taining the active ingredient or the embedding of
Compounds used as excipients will often nd the active ingredient in a polymer matrix.
more than one application, and that is also the case Hydrocolloids like alginate can play a signicant
for alginic acid and its salts. Their application gen- role in the design of a controlled-release product.
erally depends on the thickening, gel-forming, and The alginate molecule will undergo an almost
stabilizing properties. As examples it can be men- immediate hydration to create a hydrocolloidal
tioned that sodium alginate can be used as a bind- layer of high viscosity. This makes up a diusion
ing and disintegrating agent in tablets, as a barrier decreasing the migration of small molecules
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624 Tnnesen and Karlsen

(e.g., drugs). So far, alginate has mainly been retarding drugs at higher alginate concentrations
applied in systems based on diusion. (14,15) and when the alginates are rich in guluronic
acid (14,16). The guluronic acid conformation gives
a high degree of coordination of the calcium, and
Diusion Systems
thereby forms more rigid gels that are less prone to
Diusion systems based on alginate can be swelling and erosion. By increasing the mannuronic
divided into two main categories. In the polymer acid content the gels become softer, more elastic, but
membrane system the drug formulation is encapsu- less porous and they dissolve more easily. The situa-
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lated within a drug reservoir compartment. The tion may be dierent for drug molecules that
drug formulation may exist as a solid or suspension, strongly interact with alginate. Gentamicin sulfate
or in a solution. The drug release is controlled by was found to interact selectively on the mannuronic
the polymeric encapsulating membrane having a residues of alginate without competition with cal-
specic permeability. The encapsulation of drug is cium ions involved in the polymer gelation. In this
accomplished by various techniques, e.g., spray- case a higher mannuronic acid content would lead to
coating or microencapsulation. Alginate has been a higher binding capacity for drug molecules, and
applied in the preparation of gel capsules. In one mannuronic-rich alginates may be preferred (17).
study, the compound theophylline was encapsulated The molecular weight and viscosity of the alginates
and the drug release rate was signicantly reduced did not aect the drug release of nicardipine HCl in
compared to the matrix-type alginate gel beads (9). neutral medium (16). Interestingly, the release of the
The release rate became lower as the coat thickness basic drug pindolol was, however, demonstrated to
increased. The release followed zero-order kinetics be dependent on the alginate molecular size (18).
as expected. A further decrease in release rate The slowest in vitro release rate of pindolol (at neu-
can be obtained by incorporating additives such tral pH) was observed for the beads prepared by
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as carnauba wax into the drug reservoir. This alginate of low molecular weight, although this
is demonstrated for indomethacin, a non-steroidal showed the fastest in vivo absorption rate. The dru-
anti-inammatory drug which is highly irritating g:alginate ratio and calcium chloride concentration
to the mucosa in the upper gastrointestinal (GI) aect the drug release. The release of nicardipine
tract (10). from alginate particles prepared in a ratio of 1:1 was
In the polymer matrix system the drug is homoge- delayed more than that from 1:2 particles (19). A
neously dispersed in a rate-controlling polymer high calcium content is favorable (14,1921). The
matrix. The nal product may be in the form of curing time seems to be of minor importance in some
swellable microspheres or conventional tablets. When systems (19), while a long gelling time is favorable
such systems are exposed to the dissolution medium, under other experimental conditions (14,20,21). The
drug release is modulated by diusion through cross-linker type and concentration seem to have a
matrix swelling and dissolution/erosion at the matrix pronounced inuence on the drug release (2123).
periphery (11). The swellingdissolutionerosion Calcium alginate beads displayed prolonged release
process is highly complex. In systems based on proles when compared to alginate beads prepared
sodium alginate cross-linked with calcium chloride, from other cross-link agents like Ba2 and Sr2 (24).
the osmotic pressure gradient that exists between the It is interesting to notice that even calcium bound
alginate gel and the environment comprises an with the G block was displaced by monovalent
important factor in the swelling process. Under cations at high salt concentration (>0.2 M), result-
acidic conditions (e.g., in the stomach) swelling of ing in an increased swelling (3). Variation in bead
the calcium alginate beads scarcely occurs. A drug is size may be used as a formulation principle to
likely to be released by diusion through the insolu- change the release time onset. Release of dextran in
ble matrix. Under neutral conditions (e.g., intestine) a pulsative fashion is obtained by mixing dierent
the beads will swell and the drug release depend on bead sizes (25). This may be of importance in the
the swelling and erosion process. The swelling beha- design of drug delivery systems intended to follow
vior of calcium alginate has been thoroughly the circadian rhythm in the body.
exploited for the development of a multiple-unit, Drug release from polymer matrix systems can
controlled-release drug delivery system (12,13). be modulated by varying the material for encapsula-
Alginate gel beads seem to be most eective in tion. Cross-linking with glutaraldehyde decreased
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Alginate in Drug Delivery Systems 625

the swelling of alginate microspheres while the load- beads. Drug release from hydrophilic matrix tablets
ing of the water-soluble drug nimesulide increased is controlled by the formation of a hydrated viscous
(26). Ironcross-linked hydroxamated alginic acid layer around the tablet, which acts as a barrier to
has proved to be successful in prolonging drug drug release by opposing penetration of water into
release of a number of compounds (27). The drug the tablet, and also the movement of dissolved
release proles of calcium alginate microspheres solutes out of the matrix. A compressed alginate
loaded with sulfaguanidine were aected by addi- tablet will have a very closed structure compared to
tion of various copolymers (28,29). It was demon- a gel bead, and the degree of sustained release eect
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strated that some cellulose derivatives produced a will therefore be higher in the tablet. Water-soluble
marked aggregation of the microspheres. Of the cel- drugs are released primarily by diusion of dis-
lulose derivatives only ethyl cellulose and hydroxy- solved drug molecules across the gel layer, whilst
propyl cellulose resulted in a decrease in drug poorly water-soluble drugs are released predomi-
release rate (2831). For these preparations the nantly by erosion mechanisms. In a preparation
retardation in drug release was attributed to the made by direct compression of drugalginate blends
aggregate formation. Addition of pectinate to algi- it has been demonstrated that drugs of high water
nate makes the coating more brittle (32). Alginate solubility are released signicantly faster in simu-
forms strong complexes with polycations like chito- lated gastric uid than in simulated intestinal uid,
san. Chitosan-treated alginate beads have been whereas the opposite eect is observed for drugs of
developed as an attempt to suppress the gel matrix poor solubility (44). This is explained in terms of
erosion of alginate beads (33). The alginate beads the dierent hydration kinetics in these two media.
are coated with chitosan by ionic interaction during Cationic drugs (e.g., lidocaine HCl) seem to be
preparation. A retarded release of highly-soluble released more slowly than anionic drugs (e.g.,
drugs like nitrofurantoin and timolol maleate or a sodium salicylate), possibly because of the negative
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prodrug was observed with the chitosan-treated charge of the matrices (45). By incorporating a pH-
beads (3436). An enteric protection of a prepara- independent hydrocolloid gelling agent (e.g., cellu-
tion with the drug diclofenac was demonstrated by lose polymers) in the tablet the release rate of a
mixing the alginate with chitosan (37). The resulting basic drug can be made independent of pH (46).
alginatechitosan beads showed a release behavior Spray-dried composite particles of lactose and
dependent on pH. The chitosan polymer is poorly sodium alginate used as a ller of tablets can also
soluble in water. In acidic medium, protonation of modify the release properties. The release of acet-
the amine groups improves solubility. The interpoly- aminophen from tablets containing spray-dried
meric complex between alginate and chitosan exists lactosealginate particles was found to be slower in
in a gel form at low pH. At neutral pH the viscous an acidic solution and more rapid in a neutral solu-
complex will swell and the gel formed will slowly tion than release from a conventional sodium
disintegrate, releasing the drug. The release rate is a alginate matrix tablet (47). One explanation could
function of the degree of cross-linking between both be that the spray-dried particles had a much smaller
polymers. An interaction between chitosan and the particle size than an average sodium alginate parti-
drug molecule was also observed (37,38). Other cle, leading to a more eective gel network and
coatings like Eudragit will also modify the release thereby a more eective barrier. As the pH
of drugs from alginate beads (39,40). increases the lactose was more rapidly dissolved
Combinations of liposomes and alginate have than the sodium alginate and a faster erosion
been investigated in order to modify the release of occurred. In order to obtain specic delivery to the
drugs from such phospholipid vehicles and to stabi- colon, lactosesodium alginate particles were
lize the products. Alginate either served as a vehicle applied as the coating ller of dry-coated tablets.
for the liposomes (41) or formed a gel inside the Addition of chitosan to the mixture further pro-
liposome (42) leading to stabilization and a delayed longed the induction period in the drug release pro-
drug release respectively. Alginates are demonstrated cess (48). Dry-coated tablets with alginate in the
to have antioxidative activity and will thereby coating or alternatively alginate in the tablet core
further stabilize the liposome preparation (43). and a calcium-containing salt in the coating also
Alginate-based polymeric matrix systems can also showed a slow release rate (49,50). Gelatin capsules
be prepared as compressed tablets rather than coated with alginate are demonstrated to remain
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626 Tnnesen and Karlsen

intact as long as they are retained in the stomach, Modulation of Gastrointestinal Transit Time
allowing for drug delivery selectively to the intestine
(51). In one study acrylic polymer microspheres A variation in gastric emptying time may
containing a highly water-soluble drug (acebutolol strongly inuence the absorption of drugs, espe-
hydrochloride) were powder-coated with sodium cially of compounds with an absorption window
alginate and formulated into capsules or tablets or with poor bioavailability from the lower regions
(5254). This caused a prolonged release because of of the digestive tract. A buoyant capsule formula-
the gelled matrix structures formed during dissolu- tion has been prepared for the pH-independent
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tion. The same eect has also been demonstrated controlled release of a basic drug. This is obtained
when the drug substance (indomethacin) is cross- by the preparation of a powder consisting of the
linked with sodium alginate and compressed into drug substance in combination with alginate and a
tablets (55). pH-independent hydrocolloid gelling agent (e.g.,
An oral sustained-delivery formulation based on hydroxypropylmethyl cellulose). The powder is lled
in situ gelation of sodium alginate has been into hard gelatin capsules (62). The preparation
reported (56). The formulation depends for its does not contain calcium ions. Neither does it
action on in situ gelling induced by the sequential involve gas generation. In the stomach, water pene-
administration of two solutions, the rst containing trates the capsule shell, initiating surface hydration
sodium alginate immediately followed by adminis- of the pH-independent polymer, leading to the for-
tration of a solution containing calcium ions in a mation of a gel layer. Air is trapped inside the less
complexed form. The acidic environment in the dense powder bulk to account for the buoyant
stomach causes the calcium ions to be released, behavior of the capsule. At this low pH, alginic acid
allowing the gellation to take place. This formula- is formed from alginate and this further modies
tion principle leads to a signicant increase in the the gel layer. Erosion of the gel layer gradually
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bioavailability of theophylline compared to a pro- exposes more dry matrix that hydrates at the same
prietary oral sustained-release formulation, although time as drug dissolves in the gel and diuses out to
no increase in the mean residence time could be the surrounding aqueous environment. After buoy-
observed. ancy is lost the dosage form is emptied from the
Drug molecules with low water solubility can stomach followed by an increase in pH. The gelled
show poor bioavailability when formulated into powder plug changes structure and becomes more
solid dosage forms. Low-molecular alginate, i.e., porous as the alginic acid turns into a more soluble
hydrolysis products of the polymer, may be used as salt. The drug can diuse more readily through the
a carrier to enhance the dissolution rate of acidic, matrix and this compensates for the lower dissolu-
basic, or neutral drugs. Kneaded mixtures of var- tion of basic substances at higher pH.
ious drug substances and low-molecular alginate Another potential approach to extend the gastro-
were investigated, and a signicant increase in disso- intestinal residence time is to prepare a bio(muco)-
lution rate was observed (57,58). This may be due adhesive drug delivery system. Specialized cells
to an improvement of wettability and to changes of located in the stomach, duodenum, and transverse
the crystallinity, microcrystal size, and shape. colon continuously secrete a large amount of
Alginate coating of the drug substance prior to mucin-containing mucus to protect the surface
compression is another approach to make the parti- epithelium against the acidic environment and
cles more hydrophilic (59). Microcrystalline cellu- protein-splitting enzymes present in the GI tracts.
lose coprocessed and partly surface-coated with an Mucin consists of an oligosaccharide chain with
alginate calcium/sodium salt complex (Avicel AC- terminal sialic acid (pKa 2.6). The drug delivery sys-
815) provides excellent suspending agents for water- tems should contain a mucoadhesive component
insoluble drugs (60). Highly lipophilic drugs can be that binds to mucin. It appears that polyanions,
incorporated into alginate microspheres by use of a especially polymers containing carboxylic groups
multiple-phase emulsion technique (61). The drug is and with a high charge density, are highly active.
dissolved in an oil (e.g., soybean oil) and the result- Alginate is demonstrated to have excellent bio-
ing alginate microspheres contain immobilized drug- adhesive properties. The addition of a chitosan
containing oil microdroplets. The microspheres can coating to alginate beads increased the adhesive
be coated further, allowing a pH-dependent release. properties signicantly (13,63). Both the coated
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Alginate in Drug Delivery Systems 627

and the uncoated microcapsules showed the stron- polymer (79). Protein diusion within alginate gels
gest anity for the stomach mucosa. The adhesive is demonstrated to be greatest for gels prepared
properties increased with an increase in homo- from sodium alginate of low guluronic acid content
geneity of the beads. Alginate/chitosan tablets (80). Magnetically triggered delivery of insulin from
have been prepared for adhesion to human cheek a formulation based on alginate spheres has been
mucosa (64,65). evaluated (81). The magnetic eld characteristics
and the mechanical properties of the polymer
matrix were factors of great importance in control-
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THE APPLICATION OF ALGINATE IN ling the release rate. A higher release rate was
DELIVERY SYSTEMS FOR observed for less rigid matrices.
BIOMOLECULES The mucoadhesive feature of alginate may aid in
its utility as a potential delivery vehicle for biomole-
Alginate has several unique properties that have cules to mucosal tissues (other than the GI tract),
enabled it to be used as a matrix for the entrapment thereby improving overall drug eectiveness and
and/or delivery of biomolecules like DNA, proteins, bioavailability. Attachment of lectins to the surface
and cells. A relatively mild gelation process free of of spermine-modied alginate beads allows for adhe-
organic solvents enables biomolecules and cells to sion to epithel rather than mucosa (82). Adhesion
be incorporated into the matrices with the retention to surfaces is important in the development of non-
of the three-dimensional structure (i.e., full biologi- parenteral vaccines, e.g., oral, intranasal, or vaccines
cal activity) (66). The aqueous environment within to the upper respiratory tract. Recent work has
the matrix is quite inert, and may consist of distilled shown promising results for intranasal or oral
water or sucrose solutions (67,68). The porosity of administration of antigens, or delivery of BCG virus
the gel allows for acceptable diusion rates of to the lung by inhalation (74,83). Encapsulation
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macromolecules or low molecular weight drugs of cells or DNA in the alginate matrix is another
bound to macromolecules (69). The diusion rate eld of growing interest. So far, a number of
can be further controlled by coating of the beads cells and DNA have successfully been encapsulated
(70). Alginate gels are stable in the temperature in alginate matrices, which may be of importance
range 0100 C and may be autoclaved under special in the treatment of a number of chronic diseases
conditions (71). Freeze-drying of alginate beads (e.g., diabetes, Parkinsons disease, cystic brosis,
containing cells or biomolecules is a possibility to cancer) (71,72,74,8487). The application of algi-
keep their secondary structure and to ensure their nate in parenteral preparations, e.g., a subcuta-
stability during storage (72). neous injection for chemotherapy, has also been
Biocompatibility or/and immunogenicity of algi- evaluated (88).
nate is demonstrated to vary with factors like M/G
ratio and mitogenic impurities. Capsules composed
of G-rich alginates in combination with polylysine THE APPLICATION OF ALGINATE IN
proved to induce a severe inammatory response PREPARATIONS FOR LOCAL
(73), but in general the G-rich alginates seem to ADMINISTRATION
possess a higher biocompatibility than the M-rich
polymers (74). It is however apparent that other Alginate-based raft-forming formulations have a
factors like form and size of the beads, and smooth- wide application in the treatment of heartburn and
ness, composition, and viscosity of the membrane esophagitis (89). The foam makes a barrier against
can inuence alginate immunogenicity. reux and adds to the mucosa, providing a protec-
A large number of proteins have been encapsu- tive coating against stomach acid. The raft-forming
lated in alginate microbeads (7478). Positively formulations can be used in combination with ant-
charged proteins can potentially compete with acids or cimetidin (H2 blocker). Recently, a liquid
calcium ion for available carboxylic acid sites on preparation of sodium alginate in combination with
the alginates, resulting in a reduction in diusion a calcium-containing solution has been evaluated
rate or protein inactivation. It may therefore be for eradication of Heliobacter pyroli (HP), a bacter-
necessary to include additives (e.g., polyacrylic acid) ium closely associated with chronic gastritis and
which protect the active agent from the alginate peptic ulcers. Although HP is highly sensitive to
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628 Tnnesen and Karlsen

most antibiotics, it is dicult to obtain minimum CONCLUSION


inhibitory concentrations in the gastric mucus, in
which HP colonizes, by systemic treatment. The Alginates have a wide application as rate-control-
alginate preparation will spread in the stomach and ling excipients in drug delivery systems, as a matrix
release the incorporated drugs to the gastric wall for biomolecules, and as an excipient in pharmaceu-
rather than the gastric lumen by gel formation on tical preparations for local administration. Critical
the surface of the preparation (90). considerations of pharmaceutical excipients are com-
Alginates are used in various types of wound patibility, physicochemical properties, toxicology,
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dressings, e.g., powder-, lm-, or ber-based (8,91). and formulation issues (e.g., sterilization, bulk ow,
The hydrocolloid may be used on dry wounds pro- compressibility, stability). This specic polymer can
vided that the dressing is premoistened with saline. be prepared in a neutral or charged form, which
Alginates are, however, best suited for moist exuda- makes it compatible with a broad variety of sub-
tive wounds. Sodium from the wounds exudate and stances. The ability to form two types of gel depend-
calcium from the alginate undergo ion exchange, ing on the pH of the medium results in a large
forming a soluble sodium alginate gel. The genera- variation in physicochemical properties. It is suitable
tion of free calcium ion amplies the clotting cas- for freeze-drying and direct compression (tablets).
cade, endowing the dressing with signicant Alginate has been widely used in food products for
hemostatic properties. The dressing is non-adherent several decades and is generally non-toxic. The
to the wound. The gel can also serve as a vehicle acceptable daily intake (ADI) is not specied,
for drugs. Further, alginate bers can be used in which is the highest possible classication for food
woven, non-woven, and gauze-type dressings. additives. Being polysaccharides, alginates are sus-
Alginates high in guluronic acid form highly absor- ceptible to hydrolysis or degradation in strong acid
bent gels, while mannuronic acid-rich alginates or alkali, especially at elevated temperatures. Under
For personal use only.

make softer bers which form less absorbent gels. neutral conditions alginate is generally quite stable
The bioavailability of ocular administered drugs at room temperature. Standard alginate grades will
is low (13%) due to dilution and a high drainage precipitate in acid conditions. The excipient can be
rate. Macromolecular excipients oer the possibility obtained in an ultrapure form. Sterilization may be
of prolonging the contact time on the cornea by an performed by sterile ltration or by heat treatment
increase in viscosity and by mucoadhesion. Sodium under special conditions. Alginate is further adopted
alginate is demonstrated to undergo in situ gelation by Ph.Eur. The pharmacopeial requirements may
in the eye without the addition of calcium ions (92). change in the future according to specic applica-
Instant gel formation was observed from alginates tions of a polymer. This may lead to several alginate
with G contents more than 65%. Pilocarpine incor- monographs, and thereby ocial status for new algi-
porated into the gel was released over a period of nate grades. The molecule can be tailor-made for a
24 hr. A decrease in gel viscosity was, however, number of applications. Polymer-controlled drug
observed in contact with tear uid (93). delivery is still in the developmental stage. A new
approach in the eld is the development of systems
that are capable of adjusting drug release according
OTHER APPLICATIONS OF to physiological needs (e.g., pH-responsive systems
ALGINATES AS DRUG EXCIPIENTS based on polymer swelling, magnetically triggered
delivery systems). Alginate would also possess the
Many drug substances have a bitter or unplea- physicochemical properties required to make it an
sant taste that makes them unsuitable for certain important contributor to this area of future research.
oral dosage forms. Sodium alginate has been used
in tablets to mask the bitter taste of amiprilose
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