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IJP 13963 1–13 International Journal of Pharmaceutics xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

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Mini review

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Application of gellan gum in pharmacy and medicine

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Tomasz Osmałek * , Anna Froelich, Sylwia Tasarek

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 60-780, Poland The Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Grunwaldzka 6, Poznan

A R T I C L E I N F O

A B S T R A C T

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

Over the past few decades, microbial polysaccharides have been under intense investigation due to their advantageous physicochemical properties. A great structural diversity of these biomolecules has led to multiple applications in food industry, personal care products, pharmacy and medicine. Currently, one of the most widely studied and fully described member of this group is gellan. It is a linear polymer produced by Sphingomonas elodea. A polymer chain of gellan consists of a tetrasaccharide repeating unit of L-rhamnose, D-glucose and D-glucuronate. So far most of the studies have been focused on the application 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 on gellan. Various formulations have been studied including oral, ophthalmic, nasal and other. Recent reports suggest that gellan-based materials can also be used in regenerative medicine, stomatology or gene transfer technology. ã 2014 Published by Elsevier B.V.

Keywords: Gellan gum Polysaccharides Controlled release Hydrogels Tissue engineering

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1. Introduction

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The unique properties, biocompatibility, widespread availability and low production costs led to the application of natural gums in various areas of our life. This class of compounds consists of polysaccharides obtained from plant tissues (gum acacia, gum ghatti, gum tragacanth etc.), seeds (guar gum, konjac gum etc.), seaweeds (agar–agar gum, alginates, carregeenans etc.) or microorganisms (gellan gum, xanthan gum, rhamsan gum, welan gum etc.). Primarily, gums were used mainly as additives for food products (Francois et al., 1986; Bayarri et al., 2001; Totosaus and Pérez-Chabela, 2009; Imeson, 2010; Banerjee and Bhattacharya, 2011). Simultaneously, natural gums or their derivatives have been broadly investigated as excipients for pharmaceutical or biomedical purposes (Dumitriu, 2002; Rehm, 2010). Matrix tablets (Sujja et al., 1999; Toti et al., 2004; Vendruscolo et al., 2005; Mundargi et al., 2007b; Asghar et al., 2009; Rasul et al., 2010; Vijan et al., 2012), soft or cross-linked hydrogels (Shalviri et al., 2010), floating beads (Alhaique et al., 1996; Santucci et al., 1996; Verma and Pandit, 2011), pellets (Santos et al., 2004), microspheres (Sullad et al., 2011; Kajjari et al., 2012), in situ forming systems (Miyazaki et al., 1999) or transdermal films (Mundargi et al., 2007a) are the common examples.

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

One of the most extensively studied and described member of bacterial polysaccharides is gellan gum. It was discovered in 1978 (Kaneko and Kang, 1979; Morris et al., 2012) and is commercially provided by C.P. Kelco in USA and Japan. Gellan is produced by the bacteria 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 of a-L-rhamnose, b-D-glucose, and b-D-glucuronate, in the molar ratios 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). Alkaline hydrolysis is used to remove both of the residues and gives deacetylated gellan, also called low-acetyl or low-acyl (Kang et al., 1982). Both native and low-acyl gellan form hydrogels in the presence of mono-, di- (Shimazaki et al., 1995; Ohtsuka and Watanabe, 1996; Tang et al., 1996, 1997; Mao et al., 2000) and trivalent cations (Maiti et al., 2011). The process is temperature dependent. Initially, to obtain a clear water solution, heating to at least 70  C is needed. Subsequent cooling leads to conformation changes of the polymer chains which induce coil-to-helix transition. Native gellan gives soft, easily deformable gels, while the deacetylated one forms rigid and brittle gels. Various analytical techniques have been used to determine the properties of gellan solutions and gel formation mechanism. 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), texture analysis (Sworn et al, 1995; Mao et al., 1999a,b; Huang et al., 2003;

http://dx.doi.org/10.1016/j.ijpharm.2014.03.038 0378-5173/ ã 2014 Published by Elsevier B.V.

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Fig. 1. The structure of native (A) and low-acyl (B) form of gellan gum. 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71

Picone and Cunha, 2011), tensile testing (Teratsubo et al., 2002), circular dichroism (Miyoshi et al., 1995; Ogawa et al., 2002), differential scanning calorimetry (Mazen et al., 1999; Picone and Cunha, 2011), confocal laser scanning microscopy (Pérez-Campos et al., 2012), nuclear magnetic resonance (Matsukawa and Watanabe, 2007; Tako et al., 2009; Shimizu et al., 2012), polarization modulation spectroscopy (Horinaka et al.,2004), atomic force microscopy (Ikeda et al., 2004; Funami et al., 2009). It was stated that in case of native gellan, the acetyl and glyceryl groups located on the periphery of the helix, hamper the polymer chain association and contribute to less effective packing (Morris et al., 1996; Mazen et al., 1999). After deacetylation, the cations can easily form bridges between polymer chains. The process leads to generation of a branched network (Fig. 2) (Grasdalen and Smidsrød, 1987; Chandrasekaran et al., 1988; Quinn and Hatakeyama, 1993; Ikeda et al., 2004; Morris et al., 2012).

The gelling temperature, gel strength, texture, clarity and the rate of gel formation strongly depend on the pH value (Horinaka et 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 (Dai et al., 2010). The specific gelling properties in different media led to the development of controlled release forms based on gellan. Various pharmaceutical solid, semi-solid and liquid formulations have 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 rectal administration (El-Kamel and El-Khatib, 2006). Moreover, gellanbased 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

Fig. 2. Gradual transformation of gellan gum from aqueous solutions (modified from Miyoshi et al., 1996).

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

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

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2. Applications of gellan gum in the pharmaceutical technology

2.1.1. Solid dosage forms Gellan 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 (Vijan et al., 2012; Franklin-Ude et al., 2007). Both applications are based on swelling behavior but the concentration of gellan is crucial for the effect. The fast drug release tablets require low content of the polymer (Emeje et al., 2010), while the prolonged release tablets usually contain higher amounts of gellan (Franklin-Ude et al., 2007). The rate and extent of swelling is significantly higher in simulated 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 the medium pH (Emeje et al., 2010). To prolong the release of

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2.1. Oral drug delivery

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The active compound is only a part of the formulation which must 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 (Rathbone et al., 2003). It was shown that drug release from natural hydrophilic polymer matrices is a result of complex interaction between swelling, diffusion and erosion (Ferrero et al., 2010). In the aqueous environment polymeric gums hydrate from the periphery toward the centre and form a swollen, mucilaginous mass which further prevents penetration of the fluid into the tablet. As a result,

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

API

Theophylline Theophylline Propranolol hydrochloride Theophylline Paracetamol Cephalexin Ephedrine hydrochloride Amoxicillin Metformin hydrochloride Metoclopramide hydrochloride Amoxicilin Gellan macrobeads 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 complex Gellan beads gelated by Al3+ and cross-linked by glutaraldehyde Glipizide Gellan beads Rifabutin Gellan beads Cefpodexime proxetil Acrylamide-grafted gellan gum tablets Metformin hydrochloride Carboxymethyl gellan beads Metformin Ophtalmic formulations In situ gelling ophthalmic solution Sustained delivery ophthalmic system Soluble bioadhesive ocular insert Albumin nanoparticles with gellan for ophthalmic use In situ gelling ophthalmic solution In situ gelling ophthalmic solution In situ gelling ophthalmic solution In situ gelling ophthalmic solution In situ gelling ophthalmic solution In situ gelling ophthalmic solution In situ gelling ophthalmic solution Ocular insert In situ gelling ophthalmic solution In situ gelling ophthalmic solution In situ gelling ophthalmic solution

Sezolamide, dorzolamide Methylprednisolone Gentamicin Pilocarpine Pilocarpine Timolol maleate Indomethacin Carteolol hydrochloride Pefloxacin mesylate Piroxicam Gatifloxacin sesquihydrate Ciprofloxacin hydrochloride Timolol maleate Gatifloxacin Matrine

In situ gelling ophthalmic nanoemulsion

Terbinafine hydrochloride

Nasal formulations In situ nasal gel In situ nasal gel

Fluorescein dextran Scopolamine hydrobromide

In situ nasal gel based on thiolated gellan Gellan microspheres

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Oral formulations Gellan capsules and beads Gellan beads Gellan beads In situ gelling system In situ gelling system Gellan beads Gellan granules In situ gelling floating gellan system Gum cordia/gellan beads Immediate release gellan tablets

In situ nasal gel Intranasal microparticles

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Momethasone furoate Metoclopramide hydrochloride Dimenhydrinate Sildenafil citrate

Application

References

Phosphodiesterase inhibitor Phosphodiesterase inhibitor Beta-blocker Phosphodiesterase inhibitor Analgesic, antipyretic Antibiotic Sympathomimetic Antibiotic Antidiabetic Antiemetic gastroprokinetic Antibiotic Antibacterial Antibiotic Antibiotic Antibiotic Antihypertensive Type 2 diabetes mellitus Antibiotic Antibiotic Antidiabetic Antidiabetic

Alhaique et al. (1996) Santucci et al. (1996) Kedzierewicz et al. (1999) Miyazaki et al. (1999) Kubo et al. (2003) Agnihotri et al. (2006) Franklin-Ude et al. (2007) Rajinikanth et al. (2007) Ahuja et al. (2009) Shiyani et al. (2009)

Anti-glaucoma

Gunning et al., (1993) Sanzgiri et al. (1993) Gurtler et al. (1995) Zimmer et al. (1995) Meseguer et al. (1996) Rozier et al. (1997) Balasubramaniam et al. (2003) El-Kamel et al. (2006) Sultana et al. (2006) Hîncu et al., (2007) Kalam et al., (2008) Kumar et al. (2009) Singh et al. (2009) Kesavan et al. (2010) Liu et al. (2010)

Antibiotic for veterinary use Anti-glaucoma Anti-glauzoma Glaucoma Anti-inflammatory Anti-glaucoma Antibiotic Anti-inflammatory Antibiotic Bacterial conjuctivitis Anti-glaucoma Bacterial conjunctivitis Anti-inflammatory bacterial conjuctivitis bacterial keratitis Fungal keratitis

Babu et al. (2010) Emeje et al. (2010) Narkar (2010) Tripathi and Singh (2010) Bhimani (2011) Kulkarni et al. (2011) Maiti et al. (2011) Verma and Pandit (2011) Utkarsch (2012) Vijan et al. (2012) Ahuja et al. (2013)

Tayel et al. (2013)

Epithelial uptake testing Nausea, motion sickness prevention Anti-inflammatory Antiemetic

Jansson et al. (2005) Cao et al. (2007)

Motion sickness prevention Erectile dysfunction

Mahajan and Gattani (2009) Shah et al. (2010)

Cao et al. (2009) Mahajan et al. (2009)

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metformin, Vijan et al. (2012) used acrylamide-grafted-gellan gum (AA-g-GG). The release profile in phosphate buffer (pH 6.8) followed the Higuchi kinetic model and the release mechanism was governed by Fickian diffusion. Total drug release was prolonged up to 8 h. Slightly different effects were observed for hard gelatin capsules containing gellan or carboxymethycellulose granules with ephedrine hydrochloride (Franklin-Ude et al., 2007). The formulations were examined in different media, namely: 0.1 N hydrochloric acid (pH 1.2), simulated gastric juice (pH 1.5) and simulated intestinal fluid (pH 7.5). The release profile followed first order kinetics and the Fickian release mechanism. Slower drug release was observed in the acidic environment. Shiyani et al. (2009) compared the disintegrant properties of gellan gum in the form of an untreated powder and after previous swelling in water, subsequent drying and further milling. The authors stated that the special treatment contributed to more effective swelling and hydration of the tablets which resulted in faster drug release. However, when compared to other popular disintegrants like AcDi-Sol1, PolyplasdoneTM XL, Explotab1 and agar, gellan gum turned out to be the least effective. 2.1.2. Low-acyl gellan beads and capsules Beads and capsules based on natural polymers have recently a, gained much attention (Shiraishi et al., 1993; Sezer and Akbug 1995; Kulkarni et al., 2012; Assifaoui et al., 2013). Both are obtained by ionotropic gelation technique. Beads are formed when a solution of gellan is introduced dropwise by a needle into an aqueous solution of ions, under constant stirring (Fig. 3A) (Patil et al., 2012). The polymer chains are rapidly cross-linked and a three-dimensional network is formed. In most cases, Ca2+ ions are used (Smrdel et al., 2008a,b). Depending whether the drug was previously dissolved in the polymer or ion solution, it can be located in the core of the bead or in the outer layer, respectively. Gellan capsules are formed when a solution of ions and API is instilled to the polymer dispersion. Each droplet is rapidly surrounded by a gel coating (Fig. 3B). Capsules or beads are usually washed with water and dried prior to use. Subsequent immersion in water leads to reswelling. The properties and parameters of beads and capsules depend on the formulation conditions. Size, shape and surface relate

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

mainly to the needle size, pumping rate, temperature, polymer concentration, stirring rate, pH, concentration of counter-ions, hardening time and drying parameters (Babu et al., 2010; Verma and Pandit, 2011). Agnihotri et al. (2006) showed that gellan beads prepared in acidic media display a porous structure, while in alkaline smooth surface is obtained (Fig. 4). Narkar et al. (2010) concluded that cross-linking of gellan in alkaline conditions (pH 9.0) led to a higher drug entrapment, contrary to the acidic conditions (pH 5.0). Moreover, gellan beads and capsules show evidence of pH sensitivity, as they are stable in acidic media and disintegrate 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 the amount of the API. Alhaique et al. (1996) observed that capsules with higher hydrophobic drug concentration showed fast release at the beginning followed by the near zero order kinetics. Dissolution testing in different media showed that in the acidic environment a competition between H+ and Ca2+ occurs and leads to modification of the gel structure. As a result, faster drug release is observed. In order to sustain the drug release, clay or oil (linseed, peanut) may be added to the formulation. Moreover, Kedzierewicz et al. (1999) reported that gelation may be altered by the presence of 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 (Agnihotri et al., 2006).

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anionic groups in the polymer chains, making them less available for counter-ions. Futhermore, the authors suggested that the release of the active substance from uncoated gellan beads may be too fast for pharmaceutical purposes. A simple method to stabilize beads and modify drug release is coating or mixing with other polymers (Tripathi and Singh, 2010). According to Narkar et al. (2010), the uncoated beads released 80% of amoxicilin during the first hour, whereas the chitosan layer clearly extended the release of the drug up to 7 h. Additionally, chitosan contributed to higher mucoadhesivity. Ahuja et al., 2010 showed that sustained release from beads can be obtained by combination of gellan with strongly mucoadhesive gum cordia. The experiments revealed that the release of metformin HCl was prolonged up to 24 h. The Plackett–Burman screening design, based on % of drug entrapment and % of the drug release, showed that the optimal properties of the beads were achieved with lower levels of calcium chloride, lower concentration of the drug, shorter hardening time and higher hardening temperature. Maiti et al. (2011) investigated the possible application of Al3+ ions as gelling agents. The obtained beads were further chemically cross-linked with glutaraldehyde. Such treatment increased the stability of the beads in the alkaline media and prolonged the release of glipizide. Kulkarni et al. (2011) evaluated the properties of microcapsules based on an interpenetrating polymer network (IPN) containing diltiazem hydrochloride. The network has been obtained by ionotropic gelation of gellan and egg albumin and subsequent covalent cross-linking with glutaraldehyde. Additionally, the drug was complexed with the ion-exchange resin (Indion 2541). Authors stated that such formulation reduced the bitter taste of the drug and provided an amorphous dispersion. The release time of the drug from resinate complex was more than three times longer than in case of pure diltiazem. Ahuja et al., 2013 obtained carboxymethylated gellan (CMGG) beads with metformin. The polymer was modified by the reaction with monochloroacetic acid. As a result, almost 3-fold increase of mucoadhesive properties was observed. Simultaneously, the cation-induced gelation was diminished, thus the drug entrapment was higher than in case of an untreated gellan. 2.1.3. Oral in situ gelling systems The 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 or geriatric patients. Oral administration of liquid gellan results in formation of sustained release form in stomach (Miyazaki et al., 1999, 2001). On the other hand, self-structuring gellan gels can be also applied as stomach filling to reduce appetite in obesity treatment (Norton et al., 2011). In order to delay gelling before administration, sodium citrate may be added to complex free Ca2+ ions prior to use (Miyazaki et al., 1999). A comparative study for xyloglucan, gellan and alginate solutions loaded with cimetidine was performed by Miyazaki et al. (2001). Dissolution experiments showed that increasing concentrations of the polymers decreased the drug release rate. In vivo experiments were conducted by Kubo et al. (2003). The authors evaluated gellan gels with paracetamol. The drug release in the rabbit and rat stomach appeared to be diffusion-controlled with total release time up to 6 h. Floating in situ gelling system of amoxicillin for eradication of Helicobacter pylori was assessed by Rajinikanth et al. (2007). Floating properties were obtained by addition of calcium carbonate. After the immersion in simulated gastric fluid, immediate gelation with simultaneous production of carbon dioxide was observed.

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2.2. Ophthalmic formulations

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

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polymers to the ophthalmic formulations is a common method to improve bioavailability (Zimmer et al., 1995; Rupenthal et al., 2011a,b). Traditional ophthalmic solutions or suspensions are easy to administer and thus well tolerated by the patients. Unfortunately, one has to consider that within a short time after instillation dilution takes place and the active substance is rapidly removed by a tear liquid from the corneal surface. Blinking eliminates the drug to the lachrymal duct and nasal cavity, therefore, only a small amount of the medication is delivered and maintained in the place of action (Gurtler et al., 1995). As a result of such limitations, higher concentrations of API are required to obtain the desired efficiency. Taking into account particular sensitivity of the ocular region toward high drug concentrations, it seems desirable to design novel in situ gelling systems with the prolonged drug release (Kumar et al., 2009; Thakur and Kashiv, 2011). Gellan may be successfully applied in such formulations as a thickening and gelling agent. It is well tolerated and can be used without the risk of any toxic effects (Singh et al., 2009). The most popular gellan-based formulation, already marketed and well recognized, is Timoptic XE1. In comparison with the standard timolol solution, Timoptic XE1 applied to the rabbits cornea enhances the bioavailability of the drug by three- to four-fold (Rozier et al., 1989). According to Shedden et al. (2001), the undesired systemic effects are less frequent in the case of Timoptic XE1. Similar effects were observed for gellan in situ gelling systems with indomethacin (Balasubramaniam et al., 2003). Gellan gum has been also investigated as a component of complex ocular formulations. Kesavan et al. (2010) evaluated the properties of mucoadhesive systems composed of gellan alone or in combination with sodium alginate and carboxymethylcellulose. Gatifloxacin in a concentration of 0.3% was used as a model drug. The formulated systems provided in vitro sustained release of the drug for over 12 h. Liu et al. (2010) studied different combinations of Gelrite1/alginate mixtures containing matrine. In vivo precorneal retention studies indicated that the applied polymers are appropriate to prolong the retention of the active substance. Rheological tests revealed that all of the formulations displayed shear-thinning behaviour in the presence of an artificial tear fluid. This feature is favorable for ophthalmic formulations in terms of application and distribution of the formulation on the eye surface. Tayel et al. (2013) designed a microemulsion-based system to deliver terbinafine hydrochloride. The viscosity tests for gels alone and combined with mucine revealed the possible interaction between gellan and mucine chains. This indicates the presence of adhesive forces between gellan and biosurfaces.

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2.3. Nasal formulations

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Nasal cavity is used mainly for the local treatment of nasal congestion, infections or allergic symptoms (Illum, 2012). However, intranasal route may be suitable to achieve the systemic action, especially for drugs that are quickly metabolized or not efficiently absorbed in the GI tract (Jansson et al., 2005). Targeting to the nasal cavity is easy and generally well tolerated. The abundance of blood vessels in the mucosa contributes to drug absorption rates almost equal to intravenous injections (Rathbone et al., 2003). Bioadhesive polymers play an important role in the intranasal drug delivery by controlling drug release and providing close adherence to the mucus layer (Nakamura et al., 1996a; Ugwoke et al., 2005). Jansson et al. (2005) studied the transmucosal uptake of high molecular weight fluorescein dextran. Gellan improved the epithelial transport more effectively than isotonic D-mannitol solution. Moreover, the residence time in the nasal cavity was up to 4 h and no harmful side effects were observed. Cao et al. (2007) evaluated the properties of in situ gels containing 0.2%, 0.5%, and 1.0% of gellan as carriers for scopolamine

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hydrochloride. The experiments showed that bioavailability from gellan gels was higher than after oral or subcutaneous administration of the drug. A different technique was proposed by Mahajan and Gattani (2009). The authors prepared gellan microparticles with metoclopramide hydrochloride. After application, a spontaneous gel formation was observed. Therefore, the drug release was sustained and followed anomalous, non-Fickian release mechanism. Similar experiments with microspheres containing sildenafil citrate were performed by Shah et al. (2010). However, contrary to the data presented by the previous authors, the drug release appeared to be Fickian. Another study presented by Mahajan et al. (2009) concerned the comparison between nasal formulations based on untreated gellan and thiolated gellan. Dimenhydrinate, an antihistaminic agent, was used as a model drug. The reason for such modification was to improve gelation strength and to increase mucoadhesive properties of the polymer.

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Various novel drug delivery systems based on chemically modified gellan are currently widely explored. Interesting experiments were presented by Matricardi et al. (2009). The chemical hydrogels were obtained by linking gellan chains with L-lysine ethyl ester moieties. Such modification kept the polymer network in a disordered state and contributed to the explicit increase of water uptake ability. The swelling parameter was comparable to that of super-absorbent materials. D‘Arrigo et al. (2012) showed that the chemical cross-linking of gellan chains may be used for enhancing the bioavailability of poorly water soluble drugs. The authors conjugated prednisolone with carboxylic moieties of the polymer. The material revealed a tendency to self aggregate in the aqueous media and to form biocompatible nanohydrogels with the average size of 300 nm. Mundargi et al. (2010) obtained thermo-responsive microparticles consisting of two semiinterpenetrating ionic-crosslinked polymer networks, i.e. gellan gum and poly(N-isopropylacrylamide), with incorporated atenolol. The matrices released the drug in a controlled, temperaturedependent manner. It was shown that at 25  C the atenolol release increased in comparison with 37  C, which was attributed to p (NIPAAm) swelling at lower temperatures and possible precipitation at higher. The observed property allowed to obtain a pulsatille “on-off” release profile with the use of temperature fluctuations. Alupei et al., 2006 used a simple solvent evaporation method to prepare composite membranes consisting of gellan and poly(Nvinylimidazole). In the acidic media, interpolymer complexation was observed. Regardless of the composition, the obtained matrices showed stability in the acidic medium and were soluble in the alkaline. Hamcerencu et al. (2008) obtained a series of unsaturated esters by functionalization of gellan with acrylic acid, acryloyl chloride or maleic anhydride. Such treatment led to formation of easily polymerizable derivatives. Hydrogels prepared by further co-polymerization of the esters with N-isopropylacrylamide revealed pH and thermosensitive properties. Yadav et al., 2014 investigated the possibility to increase gellan mucoadhesive properties. The polymer chains were esterified with thioglycolic acid. The obtained conjugate retained biocompatibility, however, the sensitivity toward ion gelation decreased.

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3.1. Tissue engineering Gellan gum has been recently investigated in the field of tissue engineering, mostly as a material for cartilage reconstruction. It is important to note that the ability of cartilage to self-repair after degeneration or mechanical damage is limited. Therefore, novel

biomaterials with the potential to replace the damaged tissue or to induce regeneration are of great importance. Gellan-based structures are currently explored as injectable carriers for various autologous cells i.e. chondrocytes, bone marrow cells, articular chondrocytes or chondrogenic and non-chondrogenic adipose stem cells (Smith et al., 2007; Oliveira et al., 2009, 2010a,b,c). The results are very promising. In most cases, cells showed good viability during storage in the polymer matrix. Moreover, the formation of cell clusters was observed and hypothetically atributed to cell proliferation (Smith et al., 2007; Oliveira et al., 2010a). In vivo experiments concerning histological and biochemical response after subcutaneous administration of gellan confirmed its great biocompatibility and a tendency to integrate with the surrounding tissues. The presence of extracellular matrix components within the implants suggested that gellan was well tolerated (Oliveira et al., 2009). The mechanical properties of the scaffolds before and after implantation were similar although their mass decreased. This phenomenon can be explained by a possible resorption of the polysaccharide and migration of the cells to the surrounding tissues. Experiments concerning gellan injectable systems for the delivery of rabbit autologous cells showed that 1, 4 and 8 weeks after injection all of the implants stayed at the site of application, although animals were not prevented from moving. After 8 weeks, all damaged zones were filled. Adipose stem cells displayed the best total outcome, including progression, integrity and quality of the tissue (Oliveira et al., 2010b,c). It is important to note that simple gellan gels have poor mechanical properties, e.g. hardness, brittleness and low mechanical strength. High gelling temperature is also unfavorable. These problems can be solved by introduction of another polymer, either as a blended or chemically-bonded component. Gong et al. (2009) successfully modified the gelation point by cleaveage of gellan chains into smaller fragments with an oxidative agent – sodium periodate. The gelation temperature was dependent on the concentration of NaIO4 and reaction time. The histological investigation of the modified material with encapsulated chondrocytes revealed that most of the cells stayed viable, had normal morphology and proliferated well during 150 days of the experiment. However, Tang et al. (2012) observed that oxidation damaged the crosslinking points in gellan network and contributed to increased water absorption and faster degradation. The authors proposed an additional crosslinking of gellan with carboxymethyl chitosan (Fig. 5) to stabilize the gel structure. Gellan is also considered as a material suitable for the treatment of intervertebral disc disorders related to the disfunction and deformation of nucleus pulposus, the central part of the intervertebral disc. This painful disorder strongly impairs patients’ quality of life. Moreover, standard therapies with anelgesic drugs or surgical treatment are often ineffective. However, it must be taken into account that simple gellan gum implants gradualy dissolve in physiological fluids. This problem is attributed to non-covalent bonds between the polymer chains. Nevertheless, a comparative study concerning the behavior of gellan gum and two other polymers of natural origin, i.e. pectin and alginate in cell culture environment revealed that gellan possessed the most pronounced tendency to retain its original rheological characteristics (Jahromi et al., 2011). Pereira et al. (2011) designed implants consisting of gellan microparticles immersed in gellan matrix. Unfortunately, storage and loss moduli were different from those of human intervertebral disc. However, it turned out that swelling and degradation behaviour of the implants can be regulated by adjusting the concentration of low- and high-acyl gellan. Several methods have been proposed to improve the mechanical parameters of gellan by introduction of covalent bonds (Coutinho et al., 2010, 2012). The studies of photo-crosslinked methacrylated 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 was oxidized to dialdehyde, the addition of Ca2+ introduced ionic bonds between the carboxyl groups of gellan via electrostatic interaction, subsequently aldehyde groups and amino groups of CM-chitosan formed the second network via the Schiff-base reaction. The crosslinking mechanism of complex hydrogel (B). Gellan gum chains formed double helix 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). 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456

increased after the modification (Silva-Correia et al., 2011). The value of Young’s modulus was similar to the value reported for human nucleus pulposus (Leahy and Hukins, 2001). It was also shown that methacrylated gellan prevented nucleus pulposus by acting as a barrier for angiogenesis (Silva-Correia et al., 2012). Shin et al. (2012) designed hydrogels for the encapsulation of human fibroblasts consisting of two interpenetrating networks of methacrylated gellan gum and methacrylated gelatin. The obtained hydrogels were subjected to photocrosslinking (Fig. 6). Unfortunately, cell viability was worse than in the single network hydrogels, mostly because of the aggressive conditions during photocrosslinking. Nevertheless, more than 70% of encapsulated cells survived three days of incubation. Gellan gum constructs can also be applied in the guided bone regeneration (GBR). In this kind of treatment, a bone fracture is isolated from the surrounding tissues in order to avoid the development of an unwanted connective tissue in the damaged area. Materials used for isolation are usualy films made of various polymers, both degradable and non-degradable. The latter need to be removed after bone recovery. Wang et al. (2008) prepared gellan gum microspheres grafted with gelatin and designed to deliver living cells to the damaged tissue (Fig. 7). Gelatin displays high

similarity to collagen and contains receptor sites for proteins like fibronectin. Therefore, it was applied to improve the affinity of the microspheres to the cells implemented on their surface. Both human dermal fibroblasts and human fetal osteoblasts used in this study attached well to the surface of the spheres. Moreover, good cell viability, morphology and proliferation were observed in both cases. Alkaline phosphatase assay and von Kossa staining performed for microcarriers with osteoblasts revealed the signs of osteogenesis (Fig. 8). Shin et al. (2014) used the photocrosslinking reaction to obtain stiff microgels consisting of gellan. The product was immersed in a modified gelatin solution which was also photocrosslinked. The material displayed significantly higher mechanical strength than simple physical double-network gel. Mouse proteoblasts viability was better whenever the cells were placed in gelatin instead of gellan solution. It is noteworthy that the material can be applied as an injectable system and photocrosslinked in situ. Chang et al. (2010) proposed gellan bio-absorbable film for GBR. Artificially induced bone defects in rats were covered with the film for two months. The presence of the polymer film prevented an unwanted connective tissue penetration into the damaged areas. It is noteworthy 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 in gellan gum) and (B) gelatin methacrylamide (GelMA) (pictured as above for simplicity, although minor reactions occurred with other reactive groups than amine groups of gelatin). (C) Fabrication of DN hydrogels through a two-step photocrosslinking process (Shin et al., 2012).

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and the surrounding tissues displayed no signs of inflammation. Gellan can also be applied to improve poor mechanical properties of other materials applied in bone reconstruction. Barbani et al. (2012) used gellan to increase the mechanical strength of complex nanocomposite scaffolds containing hydroxyapatite and gelatin. Specific interaction between gellan carboxylate groups and amide residues of gelatin resulted in more dense microstructure and increased Young’s modulus of the obtained sponges. Spectral

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

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Fig. 7. Morphological observation and size analysis of gellan gel-based microspheres. (a) Microspheres prepared by emulsion method with good integrity under optical microscopy (scale bar = 500 mm). (b) Main distribution (frequency of each 50 mm segment >10%) of diameters of microspheres: 14%, 450–500 mm; 18%, 500–550 mm; and 32%, 550–600 mm (Wang et al., 2008).

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Fig. 8. Proliferation and osteogenesis of human fetal osteoblasts (hFOB 1.19) on TriG microspheres. Under proliferative conditions: (a) optical microscopic observation highlighting the cell population and the cell growth-induced inter-microspherical conglutination, and (b) cell viability indication with the fluorescent “Live/Dead” assay (scale bar = 500 mm). Under differentiation conditions: (c) alkaline phosphatase (ALP) production varies from day 3 to 14, and (d) von Kossa indication of osteogenic mineralization Q4 at 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 and prevent scar formation. Lee et al. (2010) prepared a series of 26 mm thick, water insoluble films of low-acyl gellan, cross-linked with 1ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). No toxicity toward blood and fibroblast cells was observed. The films possessed antiplatelet (antiadhesive) properties. In vivo assays on rats showed a slight inflammation after surgical skin excision but long term effects turned out to be satisfactory. A different type of antiadhesive material was designed by Lee et al. (2012). Cinnamate moieties were grafted on gellan chains to achieve photosensitivity and perform the crosslinking process, but also to obtain the anti-inflammatory effect. Cencetti et al., 2011 studied the properties of biocompatible hydrogels composed of low-acyl gellan (2%) and sulphated hyaluronic acid (3%). The aim of the work was to evaluate the suitability of the gels in postsurgical epidural scar prevention. The materials showed remarkable elastic properties and maintained stable up to 12 months of storage time. No haemolytic effect was observed. Cencetti et al., 2012 examined antimicrobial wound dressings designed for slow silver release. Nonwoven gellan-Hyaff1 (benzyl derivative of hyaluronic acid) patches were used as a matrix. In order to enhance silver entrapment and prolong its release, a PVA/ borax system was applied. The prepared patches revealed strong antimicrobial activity toward Staphyloccocus aureus and Pseudomonas aeruginosa.

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The number of reports concerning the application of gellan gum in the different areas of medicine is still emerging. Some of them are particularly worth noting. Gellan has been considered as a material for preparation of dental cavitiy fillings after tooth extraction (Chang et al., 2012). Various concentrations of gellan in the range of 0.75–1.75% were tested. The obtained solutions were

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lyophilized to form sponges (Fig. 9) which were additionally crosslinked by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide for 24 h. It was observed that the pore diameter increased with the content of gellan. The material revealed high in vitro stability with superior blood absorption rate, higher than fillings already present on the market (Fig. 10). Gellan sulfate materials turned out to be promising candidates for rheumatoid arthritis treatment, as they have a tendency for selective binding of fibronectin molecules (Miyamoto et al., 2001). Another potential application of an immobilized gellan sulfate system is the development of cell-hybrid materials for artificial veins design (Miyamoto et al., 2002). Due to an anticoagulant activity of such derivatives, the thrombous reaction can be avoided (Miyamoto et al., 2010). Goyal et al. (2011) demonstrated that gellan can be used as a component of gene delivery devices. Branched polyethylenimine (PEI) molecules were applied as nonviral transfection agents. Gellan was added to reduce the positive charge, and the new material was used to prepare nanocomposites. Blending with the polymer contributed to more efficient transfection and provided better protection of DNA against enzymal cleavage.

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

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Fig. 10. Hemoglobin leak from the Teruplug1 (a) and 1.5% GG-DF (b). 546

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Gellan gum is one of the most extensively studied polysaccharide of natural origin, employed as multifunctional excipient in many various dosage forms. Its advantageous properties, e.g. biodegradability, non-toxicity, rapid gelation in the presence of cations, high water holding capacity or mucoadhesive potential, make it a useful component of multiple oral, ophthalmic, nasal and other formulations. Moreover, it has been successfully employed in biomedical areas as an absorbing material in wound healing and stomatology and also as a cell carrier in tissue engineering. Due to a large variety of potential applications of gellan gum, several reviews have been prepared (Giavasis et al., 2000; Bajaj et al., 2006; Morris et al., 2012; Prajapati et al., 2013). So far, none of them have focused on the particular role of gellan in the field of pharmacy and medicine. It is noteworthy that almost all of the described gellanbased formulations are still under laboratory investigation.

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Application of gellan gum in pharmacy and medicine.

Over the past few decades, microbial polysaccharides have been under intense investigation due to their advantageous physicochemical properties. A gre...
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