Application of gellan gum in pharmacy and medicine

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International Journal of Pharmaceutics xxx (2014) xxx–xxx

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Mini review

Application of gellan gum in pharmacy and medicine

Tomasz Osmałek *, Anna Froelich, Sylwia TasarekThe Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Grunwaldzka 6, Pozna�n 60-780, Poland

A R T I C L E I N F O

Article history:Received 28 October 2013Received in revised form 17 March 2014Accepted 18 March 2014Available online xxx

Keywords:Gellan gumPolysaccharidesControlled releaseHydrogelsTissue engineering

A B S T R A C T

Over the past few decades, microbial polysaccharides have been under intense investigation due to theiradvantageous physicochemical properties. A great structural diversity of these biomolecules has led tomultiple applications in food industry, personal care products, pharmacy and medicine. Currently, one ofthe most widely studied and fully described member of this group is gellan. It is a linear polymerproduced by Sphingomonas elodea. A polymer chain of gellan consists of a tetrasaccharide repeating unitof L-rhamnose, D-glucose and D-glucuronate. So far most of the studies have been focused on theapplication of gellan as a food ingredient. However, due to the unique structure and beneficial properties,gellan is currently described as a potent multifunctional additive for various pharmaceutical products.Specific gelling properties in different media led to the development of controlled release forms based ongellan. Various formulations have been studied including oral, ophthalmic, nasal and other. Recentreports suggest that gellan-based materials can also be used in regenerative medicine, stomatology orgene transfer technology.

ã 2014 Published by Elsevier B.V.

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsev ier .com/locate / i jpharm

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1. Introduction

The unique properties, biocompatibility, widespread availabili-ty and low production costs led to the application of natural gumsin various areas of our life. This class of compounds consists ofpolysaccharides obtained from plant tissues (gum acacia, gumghatti, gum tragacanth etc.), seeds (guar gum, konjac gum etc.),seaweeds (agar–agar gum, alginates, carregeenans etc.) or micro-organisms (gellan gum, xanthan gum, rhamsan gum, welan gumetc.). Primarily, gums were used mainly as additives for foodproducts (Francois et al., 1986; Bayarri et al., 2001; Totosaus andPérez-Chabela, 2009; Imeson, 2010; Banerjee and Bhattacharya,2011). Simultaneously, natural gums or their derivatives have beenbroadly investigated as excipients for pharmaceutical or biomedi-cal purposes (Dumitriu, 2002; Rehm, 2010). Matrix tablets (Sujjaet al., 1999; Toti et al., 2004; Vendruscolo et al., 2005; Mundargiet al., 2007b; Asghar et al., 2009; Rasul et al., 2010; Vijan et al.,2012), soft or cross-linked hydrogels (Shalviri et al., 2010), floatingbeads (Alhaique et al., 1996; Santucci et al., 1996; Verma andPandit, 2011), pellets (Santos et al., 2004), microspheres (Sulladet al., 2011; Kajjari et al., 2012), in situ forming systems (Miyazakiet al., 1999) or transdermal films (Mundargi et al., 2007a) are thecommon examples.

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54* Corresponding author. Tel.: +48 618546661; fax: +48 618546666.E-mail addresses: [email protected], [email protected] (T. Osmałek).

http://dx.doi.org/10.1016/j.ijpharm.2014.03.0380378-5173/ã 2014 Published by Elsevier B.V.

Please cite this article in press as: Osmałek, T., et al., Application of gellandoi.org/10.1016/j.aca.2013.12.001

One of the most extensively studied and described member ofbacterial polysaccharides is gellan gum. It was discovered in 1978(Kaneko and Kang, 1979; Morris et al., 2012) and is commerciallyprovided by C.P. Kelco in USA and Japan. Gellan is produced by thebacteria Sphingomonas (formerly Pseudomonas) elodea (Kang et al.,1982; Nampoothiri et al., 2003; Bajaj et al., 2007). It is a linear,anionic exopolysaccharide, with the repeating unit consisting ofa-L-rhamnose, b-D-glucose, and b-D-glucuronate, in the molarratios 1:2:1 (Fig. 1) (Jansson and Lindberg, 1983; Milas et al., 1990).Native form of gellan contains two types of acyl substituents,namely L-glyceryl and acetyl (Chandrasekaran et al.,1992). Alkalinehydrolysis is used to remove both of the residues and givesdeacetylated gellan, also called low-acetyl or low-acyl (Kang et al.,1982).

Both native and low-acyl gellan form hydrogels in the presenceof mono-, di- (Shimazaki et al., 1995; Ohtsuka and Watanabe,1996;Tang et al.,1996,1997; Mao et al., 2000) and trivalent cations (Maitiet al., 2011). The process is temperature dependent. Initially, toobtain a clear water solution, heating to at least 70 �C is needed.Subsequent cooling leads to conformation changes of the polymerchains which induce coil-to-helix transition. Native gellan givessoft, easily deformable gels, while the deacetylated one forms rigidand brittle gels. Various analytical techniques have been used todetermine the properties of gellan solutions and gel formationmechanism. These include rheological measurements (Izumi et al.,1996; Miyoshi et al., 1996; Nakamura et al., 1996b; Jampen et al.,2000; García et al., 2011; Flores-Huicoche et al., 2013), textureanalysis (Sworn et al, 1995; Mao et al., 1999a,b; Huang et al., 2003;

gum in pharmacy and medicine, Int J Pharmaceut (2014), http://dx.

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Fig. 1. The structure of native (A) and low-acyl (B) form of gellan gum.

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cone and Cunha, 2011), tensile testing (Teratsubo et al., 2002),rcular dichroism (Miyoshi et al., 1995; Ogawa et al., 2002),fferential scanning calorimetry (Mazen et al., 1999; Picone andnha, 2011), confocal laser scanning microscopy (Pérez-Campos

al., 2012), nuclear magnetic resonance (Matsukawa andatanabe, 2007; Tako et al., 2009; Shimizu et al., 2012),larization modulation spectroscopy (Horinaka et al.,2004),omic force microscopy (Ikeda et al., 2004; Funami et al.,09). It was stated that in case of native gellan, the acetyl andyceryl groups located on the periphery of the helix, hamper thelymer chain association and contribute to less effective packingorris et al., 1996; Mazen et al., 1999). After deacetylation, thetions can easily form bridges between polymer chains. Theocess leads to generation of a branched network (Fig. 2)rasdalen and Smidsrød, 1987; Chandrasekaran et al., 1988;inn and Hatakeyama, 1993; Ikeda et al., 2004; Morris et al.,12).

Fig. 2. Gradual transformation of gellan gum from aqu

Please cite this article in press as: Osmałek, T., et al., Application of gelladoi.org/10.1016/j.aca.2013.12.001

The gelling temperature, gel strength, texture, clarity and therate of gel formation strongly depend on the pH value (Horinakaet al., 2004; Picone and Cunha, 2011), presence of sugars(Whittaker et al., 1997; Bayarri et al., 2002; Kasapis, 2006;Evageliou et al., 2010, 2011), type and concentration of cations (Daiet al., 2010). The specific gelling properties in different media led tothe development of controlled release forms based on gellan.Various pharmaceutical solid, semi-solid and liquid formulationshave been studied for oral (Miyazaki et al., 1999; Kubo et al., 2003),buccal (Remuñán-López et al., 1998), ophthalmic (Carlfors et al.,1998; Kesavan et al., 2010; Dickstein et al., 2001; Liu et al., 2010),nasal (Cao et al., 2009; Mahajan and Gattani, 2009) or rectaladministration (El-Kamel and El-Khatib, 2006). Moreover, gellan-based materials are investigated in the field of tissue regeneration(Cencetti et al., 2011; Shin et al., 2012), dental care (Chang et al.,2012), bone repair (Chang et al., 2010), gene delivery (Goyal et al.,2011) or biosensor synthesis (Wen et al., 2008). The available

eous solutions (modified from Miyoshi et al., 1996).

n gum in pharmacy and medicine, Int J Pharmaceut (2014), http://dx.



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T. Osmałek et al. / International Journal of Pharmaceutics xxx (2014) xxx–xxx 3

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reports concerning the pharmaceutical gellan-based formulationsare summarized in Table 1.

2. Applications of gellan gum in the pharmaceutical technology

2.1. Oral drug delivery

The active compound is only a part of the formulation whichmust be delivered to the desired region of the body (Dumitriu,2002). Because of the convenience and easiness of administration,oral route is currently the most extensively studied one (Rathboneet al., 2003). It was shown that drug release from naturalhydrophilic polymer matrices is a result of complex interactionbetween swelling, diffusion and erosion (Ferrero et al., 2010). In theaqueous environment polymeric gums hydrate from the peripherytoward the centre and form a swollen, mucilaginous mass whichfurther prevents penetration of the fluid into the tablet. As a result,

Table 1Oral, ophthalmic and nasal formulations based on gellan gum.

Formulation type API

Oral formulationsGellan capsules and beads Theophylline

Gellan beads Theophylline

Gellan beads Propranolol hydrocIn situ gelling system Theophylline

In situ gelling system Paracetamol

Gellan beads Cephalexin

Gellan granules Ephedrine hydrochIn situ gelling floating gellan system Amoxicillin

Gum cordia/gellan beads Metformin hydrochImmediate release gellan tablets Metoclopramide

hydrochlorideGellan macrobeads Amoxicilin

Gellan gum tablets Metronidazole

Gellan beads coated with chitosan Amoxicilin

Oil filled gellan buoyant beads blended by carbopol 934 or HPMC Clarithromycin

In situ gelling floating gellan system Clarithromycin

Microcapsules of gellan gum and egg albumin Dilitiazem – resin cGellan beads gelated by Al3+ and cross-linked by glutaraldehyde Glipizide

Gellan beads Rifabutin

Gellan beads Cefpodexime proxeAcrylamide-grafted gellan gum tablets Metformin hydrochCarboxymethyl gellan beads Metformin

Ophtalmic formulationsIn situ gelling ophthalmic solution Sezolamide, dorzolSustained delivery ophthalmic system MethylprednisolonSoluble bioadhesive ocular insert Gentamicin

Albumin nanoparticles with gellan for ophthalmic use Pilocarpine

In situ gelling ophthalmic solution Pilocarpine

In situ gelling ophthalmic solution Timolol maleate

In situ gelling ophthalmic solution Indomethacin

In situ gelling ophthalmic solution Carteolol hydrochloIn situ gelling ophthalmic solution Pefloxacin mesylatIn situ gelling ophthalmic solution Piroxicam

In situ gelling ophthalmic solution Gatifloxacin sesquiOcular insert Ciprofloxacin hydroIn situ gelling ophthalmic solution Timolol maleate

In situ gelling ophthalmic solution Gatifloxacin

In situ gelling ophthalmic solution Matrine

In situ gelling ophthalmic nanoemulsion Terbinafine hydroc

Nasal formulationsIn situ nasal gel Fluorescein dextranIn situ nasal gel Scopolamine hydro

In situ nasal gel Momethasone furoIntranasal microparticles Metoclopramide

hydrochlorideIn situ nasal gel based on thiolated gellan Dimenhydrinate

Gellan microspheres Sildenafil citrate


the diffusion of the drug molecules into the surrounding medium ishampered (Colombo et al., 1985, 1995; Talukdar and Kinget,1995).

2.1.1. Solid dosage formsGellan gum has been used in oral drug delivery mainly as a

disintegrating agent in immediate release tablets (Shiyani et al.,2009) or a matrix-forming excipient for sustained release (Vijanet al., 2012; Franklin-Ude et al., 2007). Both applications are basedon swelling behavior but the concentration of gellan is crucial forthe effect. The fast drug release tablets require low content of thepolymer (Emeje et al., 2010), while the prolonged release tabletsusually contain higher amounts of gellan (Franklin-Ude et al.,2007). The rate and extent of swelling is significantly higher insimulated intestinal fluid (SIF) than in simulated gastric fluid (SGF).However, water uptake is not based on a diffusion mechanism,as it proceeds with a constant velocity independently of themedium pH (Emeje et al., 2010). To prolong the release of

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Application References

Phosphodiesterase inhibitor Alhaique et al. (1996)Phosphodiesterase inhibitor Santucci et al. (1996)

hloride Beta-blocker Kedzierewicz et al. (1999)Phosphodiesterase inhibitor Miyazaki et al. (1999)Analgesic, antipyretic Kubo et al. (2003)Antibiotic Agnihotri et al. (2006)

loride Sympathomimetic Franklin-Ude et al. (2007)Antibiotic Rajinikanth et al. (2007)

loride Antidiabetic Ahuja et al. (2009)Antiemeticgastroprokinetic

Shiyani et al. (2009)

Antibiotic Babu et al. (2010)Antibacterial Emeje et al. (2010)Antibiotic Narkar (2010)Antibiotic Tripathi and Singh (2010)Antibiotic Bhimani (2011)

omplex Antihypertensive Kulkarni et al. (2011)Type 2 diabetes mellitus Maiti et al. (2011)Antibiotic Verma and Pandit (2011)

til Antibiotic Utkarsch (2012)loride Antidiabetic Vijan et al. (2012)

Antidiabetic Ahuja et al. (2013)

amide Anti-glaucoma Gunning et al., (1993)e Sanzgiri et al. (1993)

Antibiotic for veterinary use Gurtler et al. (1995)Anti-glaucoma Zimmer et al. (1995)Anti-glauzoma Meseguer et al. (1996)Glaucoma Rozier et al. (1997)Anti-inflammatory Balasubramaniam et al. (2003)

ride Anti-glaucoma El-Kamel et al. (2006)e Antibiotic Sultana et al. (2006)

Anti-inflammatory Hîncu et al., (2007)hydrate Antibiotic Kalam et al., (2008)chloride Bacterial conjuctivitis Kumar et al. (2009)

Anti-glaucoma Singh et al. (2009)Bacterial conjunctivitis Kesavan et al. (2010)Anti-inflammatorybacterial conjuctivitisbacterial keratitis

Liu et al. (2010)

hloride Fungal keratitis Tayel et al. (2013)

Epithelial uptake testing Jansson et al. (2005)bromide Nausea, motion sickness

preventionCao et al. (2007)

ate Anti-inflammatory Cao et al. (2009)Antiemetic Mahajan et al. (2009)

Motion sickness prevention Mahajan and Gattani (2009)Erectile dysfunction Shah et al. (2010)




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etformin, Vijan et al. (2012) used acrylamide-grafted-gellan gumA-g-GG). The release profile in phosphate buffer (pH 6.8)llowed the Higuchi kinetic model and the release mechanismas governed by Fickian diffusion. Total drug release wasolonged up to 8 h. Slightly different effects were observed forrd gelatin capsules containing gellan or carboxymethycelluloseanules with ephedrine hydrochloride (Franklin-Ude et al., 2007).e formulations were examined in different media, namely: 0.1 Ndrochloric acid (pH 1.2), simulated gastric juice (pH 1.5) andulated intestinal fluid (pH 7.5). The release profile followed first

der kinetics and the Fickian release mechanism. Slower druglease was observed in the acidic environment. Shiyani et al.009) compared the disintegrant properties of gellan gum in therm of an untreated powder and after previous swelling in water,bsequent drying and further milling. The authors stated that theecial treatment contributed to more effective swelling anddration of the tablets which resulted in faster drug release.wever, when compared to other popular disintegrants like Ac--Sol1, PolyplasdoneTM XL, Explotab1 and agar, gellan gumrned out to be the least effective.

.2. Low-acyl gellan beads and capsulesBeads and capsules based on natural polymers have recentlyined much attention (Shiraishi et al., 1993; Sezer and Akbu�ga,95; Kulkarni et al., 2012; Assifaoui et al., 2013). Both are obtained ionotropic gelation technique. Beads are formed when alution of gellan is introduced dropwise by a needle into anueous solution of ions, under constant stirring (Fig. 3A) (Patil

al., 2012). The polymer chains are rapidly cross-linked and aree-dimensional network is formed.In most cases, Ca2+ ions are used (Smrdel et al., 2008a,b).pending whether the drug was previously dissolved in thelymer or ion solution, it can be located in the core of the bead or

the outer layer, respectively. Gellan capsules are formed when alution of ions and API is instilled to the polymer dispersion. Eachoplet is rapidly surrounded by a gel coating (Fig. 3B). Capsules orads are usually washed with water and dried prior to use.bsequent immersion in water leads to reswelling.The properties and parameters of beads and capsules depend

the formulation conditions. Size, shape and surface relate

. 3. Production of gellan beads (A) and capsules (B) with the use of calcium saltlution.


mainly to the needle size, pumping rate, temperature, polymerconcentration, stirring rate, pH, concentration of counter-ions,hardening time and drying parameters (Babu et al., 2010; Vermaand Pandit, 2011). Agnihotri et al. (2006) showed that gellan beadsprepared in acidic media display a porous structure, while inalkaline smooth surface is obtained (Fig. 4). Narkar et al. (2010)concluded that cross-linking of gellan in alkaline conditions (pH9.0) led to a higher drug entrapment, contrary to the acidicconditions (pH 5.0). Moreover, gellan beads and capsules showevidence of pH sensitivity, as they are stable in acidic media anddisintegrate in basic (Quigley and Deasy, 1992; Miyazaki et al.,1999). According to Alhaique et al. (1996) and Santucci et al. (1996),a drug release rate depends strongly on the solubility and theamount of the API. Alhaique et al. (1996) observed that capsuleswith higher hydrophobic drug concentration showed fast releaseat the beginning followed by the near zero order kinetics.Dissolution testing in different media showed that in the acidicenvironment a competition between H+ and Ca2+ occurs and leadsto modification of the gel structure. As a result, faster drug releaseis observed. In order to sustain the drug release, clay or oil (linseed,peanut) may be added to the formulation. Moreover, Kedzierewiczet al. (1999) reported that gelation may be altered by the presenceof cationic drugs. Such compounds reveal a tendency to mask the

Fig. 4. SEM images of beads produced in: pH 9 (a) and pH 5 (b) media (Agnihotriet al., 2006).




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anionic groups in the polymer chains, making them less availablefor counter-ions. Futhermore, the authors suggested that therelease of the active substance from uncoated gellan beads maybe too fast for pharmaceutical purposes.

A simple method to stabilize beads and modify drug release iscoating or mixing with other polymers (Tripathi and Singh, 2010).According to Narkar et al. (2010), the uncoated beads released 80% ofamoxicilin during the first hour, whereas the chitosan layer clearlyextended the release of the drug up to 7 h. Additionally, chitosancontributed to higher mucoadhesivity. Ahuja et al., 2010 showed thatsustained release from beads can be obtained by combination ofgellan with strongly mucoadhesive gum cordia. The experimentsrevealed that the release of metformin HCl was prolonged up to 24 h.The Plackett–Burman screening design, based on % of drugentrapment and % of the drug release, showed that the optimalproperties of the beads were achieved with lower levels of calciumchloride, lower concentration of the drug, shorter hardening timeand higher hardening temperature. Maiti et al. (2011) investigatedthe possible application of Al3+ ions as gelling agents. The obtainedbeads were further chemically cross-linked with glutaraldehyde.Such treatment increased the stability of the beads in the alkalinemedia and prolonged the release of glipizide. Kulkarni et al. (2011)evaluated the properties of microcapsules based on an inter-penetrating polymer network (IPN) containing diltiazem hydrochlo-ride. The network has been obtained by ionotropic gelation of gellanand egg albumin and subsequent covalent cross-linking withglutaraldehyde. Additionally, the drug was complexed with theion-exchange resin (Indion 2541). Authors stated that suchformulation reduced the bitter taste of the drug and provided anamorphous dispersion. The release time of the drug from resinatecomplex was more than three times longer than in case of purediltiazem. Ahuja et al., 2013 obtained carboxymethylated gellan(CMGG) beads with metformin. The polymer was modified by thereaction with monochloroacetic acid. As a result, almost 3-foldincrease of mucoadhesive properties was observed. Simultaneously,the cation-induced gelation was diminished, thus the drug entrap-ment was higher than in case of an untreated gellan.

2.1.3. Oral in situ gelling systemsThe ability of low-acyl gellan to undergo sol–gel transition in

the acidic environment led to the idea of oral in situ forming gels.Easy-to-swallow formulations seem to be suitable for pediatric orgeriatric patients. Oral administration of liquid gellan results information of sustained release form in stomach (Miyazaki et al.,1999, 2001). On the other hand, self-structuring gellan gels can bealso applied as stomach filling to reduce appetite in obesitytreatment (Norton et al., 2011). In order to delay gelling beforeadministration, sodium citrate may be added to complex free Ca2+

ions prior to use (Miyazaki et al., 1999). A comparative study forxyloglucan, gellan and alginate solutions loaded with cimetidinewas performed by Miyazaki et al. (2001). Dissolution experimentsshowed that increasing concentrations of the polymers decreasedthe drug release rate. In vivo experiments were conducted by Kuboet al. (2003). The authors evaluated gellan gels with paracetamol.The drug release in the rabbit and rat stomach appeared to bediffusion-controlled with total release time up to 6 h. Floating insitu gelling system of amoxicillin for eradication of Helicobacterpylori was assessed by Rajinikanth et al. (2007). Floating propertieswere obtained by addition of calcium carbonate. After theimmersion in simulated gastric fluid, immediate gelation withsimultaneous production of carbon dioxide was observed.

2.2. Ophthalmic formulations

Limited permeability of the cornea contributes to low absorp-tion of ocular drugs (Carlfors et al., 1998). Addition of various


polymers to the ophthalmic formulations is a common method toimprove bioavailability (Zimmer et al., 1995; Rupenthal et al.,2011a,b). Traditional ophthalmic solutions or suspensions are easyto administer and thus well tolerated by the patients. Unfortu-nately, one has to consider that within a short time afterinstillation dilution takes place and the active substance is rapidlyremoved by a tear liquid from the corneal surface. Blinkingeliminates the drug to the lachrymal duct and nasal cavity,therefore, only a small amount of the medication is delivered andmaintained in the place of action (Gurtler et al.,1995). As a result ofsuch limitations, higher concentrations of API are required toobtain the desired efficiency. Taking into account particularsensitivity of the ocular region toward high drug concentrations,it seems desirable to design novel in situ gelling systems with theprolonged drug release (Kumar et al., 2009; Thakur and Kashiv,2011). Gellan may be successfully applied in such formulations as athickening and gelling agent. It is well tolerated and can be usedwithout the risk of any toxic effects (Singh et al., 2009). The mostpopular gellan-based formulation, already marketed and wellrecognized, is Timoptic XE1. In comparison with the standardtimolol solution, Timoptic XE1 applied to the rabbits corneaenhances the bioavailability of the drug by three- to four-fold(Rozier et al., 1989). According to Shedden et al. (2001), theundesired systemic effects are less frequent in the case of TimopticXE1. Similar effects were observed for gellan in situ gelling systemswith indomethacin (Balasubramaniam et al., 2003). Gellan gumhas been also investigated as a component of complex ocularformulations. Kesavan et al. (2010) evaluated the properties ofmucoadhesive systems composed of gellan alone or in combina-tion with sodium alginate and carboxymethylcellulose. Gatiflox-acin in a concentration of 0.3% was used as a model drug. Theformulated systems provided in vitro sustained release of the drugfor over 12 h. Liu et al. (2010) studied different combinations ofGelrite1/alginate mixtures containing matrine. In vivo precornealretention studies indicated that the applied polymers areappropriate to prolong the retention of the active substance.Rheological tests revealed that all of the formulations displayedshear-thinning behaviour in the presence of an artificial tear fluid.This feature is favorable for ophthalmic formulations in terms ofapplication and distribution of the formulation on the eye surface.Tayel et al. (2013) designed a microemulsion-based system todeliver terbinafine hydrochloride. The viscosity tests for gels aloneand combined with mucine revealed the possible interactionbetween gellan and mucine chains. This indicates the presence ofadhesive forces between gellan and biosurfaces.

2.3. Nasal formulations

Nasal cavity is used mainly for the local treatment of nasalcongestion, infections or allergic symptoms (Illum, 2012). How-ever, intranasal route may be suitable to achieve the systemicaction, especially for drugs that are quickly metabolized or notefficiently absorbed in the GI tract (Jansson et al., 2005). Targetingto the nasal cavity is easy and generally well tolerated. Theabundance of blood vessels in the mucosa contributes to drugabsorption rates almost equal to intravenous injections (Rathboneet al., 2003). Bioadhesive polymers play an important role in theintranasal drug delivery by controlling drug release and providingclose adherence to the mucus layer (Nakamura et al., 1996a;Ugwoke et al., 2005). Jansson et al. (2005) studied the trans-mucosal uptake of high molecular weight fluorescein dextran.Gellan improved the epithelial transport more effectively thanisotonic D-mannitol solution. Moreover, the residence time in thenasal cavity was up to 4 h and no harmful side effects wereobserved. Cao et al. (2007) evaluated the properties of in situ gelscontaining 0.2%, 0.5%, and 1.0% of gellan as carriers for scopolamine




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drochloride. The experiments showed that bioavailability fromllan gels was higher than after oral or subcutaneous adminis-ation of the drug. A different technique was proposed by Mahajand Gattani (2009). The authors prepared gellan microparticlesith metoclopramide hydrochloride. After application, a sponta-ous gel formation was observed. Therefore, the drug release wasstained and followed anomalous, non-Fickian release mecha-sm. Similar experiments with microspheres containing sildenafiltrate were performed by Shah et al. (2010). However, contrary toe data presented by the previous authors, the drug releasepeared to be Fickian. Another study presented by Mahajan et al.009) concerned the comparison between nasal formulationssed on untreated gellan and thiolated gellan. Dimenhydrinate, antihistaminic agent, was used as a model drug. The reason forch modification was to improve gelation strength and to increaseucoadhesive properties of the polymer.

4. Other gellan-based formulations

Various novel drug delivery systems based on chemicallyodified gellan are currently widely explored. Interesting experi-ents were presented by Matricardi et al. (2009). The chemicaldrogels were obtained by linking gellan chains with L-lysinehyl ester moieties. Such modification kept the polymer network a disordered state and contributed to the explicit increase ofater uptake ability. The swelling parameter was comparable toat of super-absorbent materials. D‘Arrigo et al. (2012) showedat the chemical cross-linking of gellan chains may be used forhancing the bioavailability of poorly water soluble drugs. Thethors conjugated prednisolone with carboxylic moieties of thelymer. The material revealed a tendency to self aggregate ine aqueous media and to form biocompatible nanohydrogels withe average size of 300 nm. Mundargi et al. (2010) obtainedermo-responsive microparticles consisting of two semi-terpenetrating ionic-crosslinked polymer networks, i.e. gellanm and poly(N-isopropylacrylamide), with incorporated atenolol.e matrices released the drug in a controlled, temperature-pendent manner. It was shown that at 25 �C the atenolol releasecreased in comparison with 37 �C, which was attributed to pIPAAm) swelling at lower temperatures and possible precipita-n at higher. The observed property allowed to obtain a pulsatillen-off” release profile with the use of temperature fluctuations.upei et al., 2006 used a simple solvent evaporation method toepare composite membranes consisting of gellan and poly(N-nylimidazole). In the acidic media, interpolymer complexationas observed. Regardless of the composition, the obtainedatrices showed stability in the acidic medium and were soluble

the alkaline. Hamcerencu et al. (2008) obtained a series ofsaturated esters by functionalization of gellan with acrylic acid,ryloyl chloride or maleic anhydride. Such treatment led tormation of easily polymerizable derivatives. Hydrogels prepared

further co-polymerization of the esters with N-isopropylacry-mide revealed pH and thermosensitive properties. Yadav et al.,14 investigated the possibility to increase gellan mucoadhesiveoperties. The polymer chains were esterified with thioglycolicid. The obtained conjugate retained biocompatibility, however,e sensitivity toward ion gelation decreased.

Biomedical applications of gellan gum

. Tissue engineering

Gellan gum has been recently investigated in the field of tissuegineering, mostly as a material for cartilage reconstruction. It isportant to note that the ability of cartilage to self-repair aftergeneration or mechanical damage is limited. Therefore, novel


biomaterials with the potential to replace the damaged tissue or toinduce regeneration are of great importance. Gellan-basedstructures are currently explored as injectable carriers for variousautologous cells i.e. chondrocytes, bone marrow cells, articularchondrocytes or chondrogenic and non-chondrogenic adiposestem cells (Smith et al., 2007; Oliveira et al., 2009, 2010a,b,c). Theresults are very promising. In most cases, cells showed goodviability during storage in the polymer matrix. Moreover, theformation of cell clusters was observed and hypotheticallyatributed to cell proliferation (Smith et al., 2007; Oliveira et al.,2010a). In vivo experiments concerning histological and biochemi-cal response after subcutaneous administration of gellan con-firmed its great biocompatibility and a tendency to integrate withthe surrounding tissues. The presence of extracellular matrixcomponents within the implants suggested that gellan was welltolerated (Oliveira et al., 2009). The mechanical properties of thescaffolds before and after implantation were similar although theirmass decreased. This phenomenon can be explained by a possibleresorption of the polysaccharide and migration of the cells to thesurrounding tissues. Experiments concerning gellan injectablesystems for the delivery of rabbit autologous cells showed that 1, 4and 8 weeks after injection all of the implants stayed at the site ofapplication, although animals were not prevented from moving.After 8 weeks, all damaged zones were filled. Adipose stem cellsdisplayed the best total outcome, including progression, integrityand quality of the tissue (Oliveira et al., 2010b,c).

It is important to note that simple gellan gels have poormechanical properties, e.g. hardness, brittleness and low mechan-ical strength. High gelling temperature is also unfavorable. Theseproblems can be solved by introduction of another polymer, eitheras a blended or chemically-bonded component. Gong et al. (2009)successfully modified the gelation point by cleaveage of gellanchains into smaller fragments with an oxidative agent – sodiumperiodate. The gelation temperature was dependent on theconcentration of NaIO4 and reaction time. The histologicalinvestigation of the modified material with encapsulated chon-drocytes revealed that most of the cells stayed viable, had normalmorphology and proliferated well during 150 days of theexperiment. However, Tang et al. (2012) observed that oxidationdamaged the crosslinking points in gellan network and contribut-ed to increased water absorption and faster degradation. Theauthors proposed an additional crosslinking of gellan withcarboxymethyl chitosan (Fig. 5) to stabilize the gel structure.

Gellan is also considered as a material suitable for the treatmentof intervertebral disc disorders related to the disfunction anddeformation of nucleus pulposus, the central part of the interverte-bral disc. This painful disorder strongly impairs patients’ quality oflife. Moreover, standard therapies with anelgesic drugs or surgicaltreatment are often ineffective.

However, it must be taken into account that simple gellan gumimplants gradualy dissolve in physiological fluids. This problem isattributed to non-covalent bonds between the polymer chains.Nevertheless, a comparative study concerning the behavior ofgellan gum and two other polymers of natural origin, i.e. pectin andalginate in cell culture environment revealed that gellan possessedthe most pronounced tendency to retain its original rheologicalcharacteristics (Jahromi et al., 2011). Pereira et al. (2011) designedimplants consisting of gellan microparticles immersed in gellanmatrix. Unfortunately, storage and loss moduli were different fromthose of human intervertebral disc. However, it turned out thatswelling and degradation behaviour of the implants can beregulated by adjusting the concentration of low- and high-acylgellan. Several methods have been proposed to improve themechanical parameters of gellan by introduction of covalent bonds(Coutinho et al., 2010, 2012). The studies of photo-crosslinkedmethacrylated gellan indicate that the density remarkably




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Fig. 5. Schiff-base formation between amino groups of CM-chitosan and aldehyde groups of oxidized gellan gum (A). In gellan chains, cis-dihydroxyl of rhamnose wasoxidized to dialdehyde, the addition of Ca2+ introduced ionic bonds between the carboxyl groups of gellan via electrostatic interaction, subsequently aldehyde groups andamino groups of CM-chitosan formed the second network via the Schiff-base reaction. The crosslinking mechanism of complex hydrogel (B). Gellan gum chains formed doublehelix conformations with Ca2+, and then CM-chitosan chains link the aldehyde zones to the formation of a three dimensional network, that created the gel (Tang et al., 2012).


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increased after the modification (Silva-Correia et al., 2011). Thevalue of Young’s modulus was similar to the value reported forhuman nucleus pulposus (Leahy and Hukins, 2001). It was alsoshown that methacrylated gellan prevented nucleus pulposus byacting as a barrier for angiogenesis (Silva-Correia et al., 2012). Shinet al. (2012) designed hydrogels for the encapsulation of humanfibroblasts consisting of two interpenetrating networks ofmethacrylated gellan gum and methacrylated gelatin. Theobtained hydrogels were subjected to photocrosslinking (Fig. 6).Unfortunately, cell viability was worse than in the single networkhydrogels, mostly because of the aggressive conditions duringphotocrosslinking. Nevertheless, more than 70% of encapsulatedcells survived three days of incubation.

Gellan gum constructs can also be applied in the guided boneregeneration (GBR). In this kind of treatment, a bone fracture isisolated from the surrounding tissues in order to avoid thedevelopment of an unwanted connective tissue in the damagedarea. Materials used for isolation are usualy films made of variouspolymers, both degradable and non-degradable. The latter need tobe removed after bone recovery. Wang et al. (2008) prepared gellangum microspheres grafted with gelatin and designed to deliverliving cells to the damaged tissue (Fig. 7). Gelatin displays high


similarity to collagen and contains receptor sites for proteins likefibronectin. Therefore, it was applied to improve the affinity of themicrospheres to the cells implemented on their surface. Bothhuman dermal fibroblasts and human fetal osteoblasts used in thisstudy attached well to the surface of the spheres. Moreover, goodcell viability, morphology and proliferation were observed in bothcases. Alkaline phosphatase assay and von Kossa stainingperformed for microcarriers with osteoblasts revealed the signsof osteogenesis (Fig. 8).

Shin et al. (2014) used the photocrosslinking reaction to obtainstiff microgels consisting of gellan. The product was immersed in amodified gelatin solution which was also photocrosslinked. Thematerial displayed significantly higher mechanical strength thansimple physical double-network gel. Mouse proteoblasts viabilitywas better whenever the cells were placed in gelatin instead ofgellan solution. It is noteworthy that the material can be applied asan injectable system and photocrosslinked in situ. Chang et al.(2010) proposed gellan bio-absorbable film for GBR. Artificiallyinduced bone defects in rats were covered with the film for twomonths. The presence of the polymer film prevented an unwantedconnective tissue penetration into the damaged areas. It isnoteworthy that the material revealed the desired biodegradability




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Fig. 6. Synthesis scheme of (A) gellan gum methacrylate (GGMA) (pictured as above for simplicity, although methacrylic anhydride can react with any hydroxyl group ingellan gum) and (B) gelatin methacrylamide (GelMA) (pictured as above for simplicity, although minor reactions occurred with other reactive groups than amine groups ofgelatin). (C) Fabrication of DN hydrogels through a two-step photocrosslinking process (Shin et al., 2012).

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d the surrounding tissues displayed no signs of inflammation.llan can also be applied to improve poor mechanical properties

other materials applied in bone reconstruction. Barbani et al.012) used gellan to increase the mechanical strength of complexnocomposite scaffolds containing hydroxyapatite and gelatin.ecific interaction between gellan carboxylate groups and amidesidues of gelatin resulted in more dense microstructure andcreased Young’s modulus of the obtained sponges. Spectral

. 7. Morphological observation and size analysis of gellan gel-based microspherescroscopy (scale bar = 500 mm). (b) Main distribution (frequency of each 50 mm segme2%, 550–600 mm (Wang et al., 2008).


analysis confirmed the presence of gellan–gelatin and alsogelatin–hydroxyapatite interactions resulting in formation ofmatrix similar to natural bone.

3.2. Surgery and wound healing

Recent studies revealed that due to biocompatibility and non-toxic properties, gellan gum can be used as a component of novel

. (a) Microspheres prepared by emulsion method with good integrity under opticalnt >10%) of diameters of microspheres: �14%, 450–500 mm; �18%, 500–550 mm; and




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Fig. 9. Morphology of the 1.5% GG-DF: (a) front view and (b) side view.

Fig. 8. Proliferation and osteogenesis of human fetal osteoblasts (hFOB 1.19) on TriG microspheres. Under proliferative conditions: (a) optical microscopic observationhighlighting the cell population and the cell growth-induced inter-microspherical conglutination, and (b) cell viability indication with the fluorescent “Live/Dead” assay (scalebar = 500 mm). Under differentiation conditions: (c) alkaline phosphatase (ALP) production varies from day 3 to 14, Q4and (d) von Kossa indication of osteogenic mineralizationat day 14 (calcium deposition highlighted by red arrows and circles, scale bar = 200 mm) (Wang et al., 2008) (For interpretation of the references to colour in this figure legend,the reader is referred to the web version of this article).


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wound dressings designed to inhibit postsurgical adhesion andprevent scar formation. Lee et al. (2010) prepared a series of 26 mmthick, water insoluble films of low-acyl gellan, cross-linked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). No toxicitytoward blood and fibroblast cells was observed. The filmspossessed antiplatelet (antiadhesive) properties. In vivo assayson rats showed a slight inflammation after surgical skin excisionbut long term effects turned out to be satisfactory. A different typeof antiadhesive material was designed by Lee et al. (2012).Cinnamate moieties were grafted on gellan chains to achievephotosensitivity and perform the crosslinking process, but also toobtain the anti-inflammatory effect. Cencetti et al., 2011 studiedthe properties of biocompatible hydrogels composed of low-acylgellan (2%) and sulphated hyaluronic acid (3%).

The aim of the work was to evaluate the suitability of the gels inpostsurgical epidural scar prevention. The materials showedremarkable elastic properties and maintained stable up to 12months of storage time. No haemolytic effect was observed.Cencetti et al., 2012 examined antimicrobial wound dressingsdesigned for slow silver release. Nonwoven gellan-Hyaff1 (benzylderivative of hyaluronic acid) patches were used as a matrix. Inorder to enhance silver entrapment and prolong its release, a PVA/borax system was applied. The prepared patches revealed strongantimicrobial activity toward Staphyloccocus aureus and Pseudo-monas aeruginosa.

3.3. Other biomedical applications of gellan

The number of reports concerning the application of gellan gumin the different areas of medicine is still emerging. Some of themare particularly worth noting. Gellan has been considered as amaterial for preparation of dental cavitiy fillings after toothextraction (Chang et al., 2012). Various concentrations of gellan inthe range of 0.75–1.75% were tested. The obtained solutions were


lyophilized to form sponges (Fig. 9) which were additionallycrosslinked by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidefor 24 h. It was observed that the pore diameter increased with thecontent of gellan. The material revealed high in vitro stability withsuperior blood absorption rate, higher than fillings already presenton the market (Fig. 10).

Gellan sulfate materials turned out to be promising candidatesfor rheumatoid arthritis treatment, as they have a tendency forselective binding of fibronectin molecules (Miyamoto et al., 2001).Another potential application of an immobilized gellan sulfatesystem is the development of cell-hybrid materials for artificialveins design (Miyamoto et al., 2002). Due to an anticoagulantactivity of such derivatives, the thrombous reaction can be avoided(Miyamoto et al., 2010). Goyal et al. (2011) demonstrated thatgellan can be used as a component of gene delivery devices.Branched polyethylenimine (PEI) molecules were applied as non-viral transfection agents. Gellan was added to reduce the positivecharge, and the new material was used to prepare nanocomposites.Blending with the polymer contributed to more efficient transfec-tion and provided better protection of DNA against enzymalcleavage.




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Fig. 10. Hemoglobin leak from the Teruplug1 (a) and 1.5% GG-DF (b).


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Conclusions

Gellan gum is one of the most extensively studied polysaccha-e of natural origin, employed as multifunctional excipient inany various dosage forms. Its advantageous properties, e.g.odegradability, non-toxicity, rapid gelation in the presence oftions, high water holding capacity or mucoadhesive potential,ake it a useful component of multiple oral, ophthalmic, nasal andher formulations. Moreover, it has been successfully employed inomedical areas as an absorbing material in wound healing andomatology and also as a cell carrier in tissue engineering. Due to arge variety of potential applications of gellan gum, severalviews have been prepared (Giavasis et al., 2000; Bajaj et al., 2006;orris et al., 2012; Prajapati et al., 2013). So far, none of them havecused on the particular role of gellan in the field of pharmacy andedicine. It is noteworthy that almost all of the described gellan-sed formulations are still under laboratory investigation.

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Reitmeier et al. (2012)

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Application of gellan gum in pharmacy and medicine