Gellan gum in drug delivery applications

CHAPTER 6

Gellan gum in drug delivery applications Milan Milivojevic1, Ivana Pajic-Lijakovic1, Branko Bugarski1, Amit Kumar Nayak2, Md Saquib Hasnain3 1

Faculty of Technology and Metallurgy, University of Belgrade, Belgrade, Serbia; 2Department of Pharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Mayurbhanj, Odisha, India; 3 Department of Pharmacy, Shri Venkateshwara University, Gajraula, India

Chapter Outline 1. Introduction 145 2. Sources and structure 3. Properties 148

146

3.1 Gelation 148 3.1.1 Influence of content of acyl groups on gelation 149 3.1.2 Influence of ion type and concentration on gelation 150 3.1.3 Influence of pH on gelation 151 3.1.4 Presence of hydrophilic ingredients and other polymers 151

4. GG in drug delivery

152

4.1 GG in peroral drug delivery 153 4.1.1 Tablets and capsules 154 4.1.2 Liquid oral in situ gelling systems 154 4.1.3 Multiparticulate drug delivery systems 155 4.2 Ophthalmic drug delivery 156 4.3 GG in nasal drug delivery 163 4.4 GG in topical (dermal, cutaneous, subcutaneous, transdermal) drug delivery 4.5 GG in other drug delivery routes 171

167

5. Conclusions 172 Acknowledgments 174 References 174

1. Introduction In the past, excipients were mostly used only as vehicles (pharmacologically inert component) that provide the needed weight and volume for the appropriate dosage formulation [1]. However, modern role of the excipients includes many different functions such as tablet binder, lubricant, viscosity enhancer, stabilizer in disperse systems, Natural Polysaccharides in Drug Delivery and Biomedical Applications. https://doi.org/10.1016/B978-0-12-817055-7.00006-6 Copyright © 2019 Elsevier Inc. All rights reserved.

145

146 Chapter 6 antiadhesive agent, agent that prevents too rapid decomposition, tablet disintegrant, filling agent, coating agent, solubilizing agent, hydrophilization agent, emulsifying agent, gelling agent, and swelling agent [2]. Those functions are needed to enhance the drug stability, solubility, absorption, and bioavailability; improve processing (powder flow and compactibility); optimize product performance (for sustained and targeted drug release); upgrade drug esthetics; and/or facilitate patient compliance [3,4]. In addition, excipients are nowadays required to fulfill plenty of regulatory restrictions about their safety, quality, and functionality, to follow rigid guidelines of current good manufacturing practices (cGMPs), to have low cost, etc. Although the excipients are generally synthetic, natural polymers are currently gaining more and more attention because they are abundant, have low cost, and possess inherent biocompatibility. In addition, the presence of susceptible reactive groups in natural polymers gives wide possibilities for different chemical modifications [5]. The natural polymers that may be used as excipients include animal, plant, and microbialderived. The microbial-derived polysaccharides, or exopolysaccharides (e.g., mannitol, dextran, gellan gum, xanthan gum, rhamsan gum, welan gum, etc.), are all soluble in water ionic or nonionic polymers, and among them, gellan gum (GG) is now drawing increased attention because of its favorable physicochemical, mechanical, and functional properties such as abundance in nature, nontoxicity, easy modification (because of the presence of carboxylic groups), easy gelation, adjustable gel elasticity, mucoadhesiveness, good thermal stability, acid reliability, and high transparency [6]. In addition, gellan, like other natural polysaccharides, is relatively inert material and does not release toxic monomers during degradation, which is of utmost importance for biomedical applications [7]. Thus, it is not surprising that GG is used in many different dosage forms (gels, as mucoadhesive or granulating agent, and tablet binder, in controlled release dosage forms, for production of beads, films, microspheres and microcapsules, nanohydrogels, nanoparticles, etc.) and for different routes of administration (ophthalmic, nasal, oral, topical, buccal, periodontal, gastrointestinal, vaginal, colon, etc.) [4]. However, although it has preferable properties, it may be noticed that GG as an excipient is still underused biopolymer.

2. Sources and structure GG is produced during aerobic fermentation of the nonpathogenic, Gram-negative bacterium Sphingomonas elodea (earlier Pseudomonas elodea), separated from water lily [8]. On industrial scale, gellan is at present produced by assorted varieties of Sphingomonas paucimobilis strains [9]. Separation of GG from the fermentation broth goes through the multistep process, which includes heating, centrifugation and several rounds of precipitation with alcohol, resuspension, and dialysis, after which purified gellan is

Gellan gum in drug delivery applications 147 dried and lyophilized [10]. Extraction procedure, as well as cell population, temperature (30
C), pH (6.5e7), carbon source, nitrogen source, the addition of precursors, agitation speed, etc., influences the physical characteristics of extracted GG, its quantity, and purity [11]. Gellan has few trade names (Phytagel, Kelcogel, Nanogel-TC, Gelrich, Grovgel, AppliedGel, Gelrite, Gelzan, Gel-Gro), and there are two types of commercially available GG. The natural form of GG is called acylated GG, or high acyl GG, whereas the second form is alkali-treated natural GG called deacylated GG, or low acyl GG [12]. The low acyl GG is more known and more applied in food, cosmetics, and pharmaceutical industry. Structurally, gellan is a linear, anionic, tetrasaccharide with average molecular weight of about 500 kDa [13], consisted of repeating carbohydrate units (1,3-b-D-glucose, 1,4-b-Dglucuronic acid, 1,4-b-D-glucose, 1,4-a-L-rhamnose). It is consisted of about 50,000 carbohydrate units, and in the native form (high acyl gellan), the 1/3-linked glucose unit contains two acyl substituents: L-glyceryl at O(2) and acetyl at O(6). On average, there is 1 glyceryl and 0.5 acetyl substituents per repeating tetrasaccharide unit. Both substituents can be simply removed by hot alkali treatment to produce low acyl gellan [7]. The low acyl gellan is the most common and commercially most available form [14]. At low temperatures, gellan molecules have the form of double helices, whereas at high temperatures, they exist in the form of random coils [15]. Structure of high and low acyl gellan units is given in Fig. 6.1.

Figure 6.1 High and low acyl gellan gum structure.

148 Chapter 6

3. Properties Properties of GG, such as rapid gelation in the presence of cations (even at very low gellan concentrations compared with other hydrocolloids), mucoadhesiveness, biodegradability, biocompatibility, nontoxicity, temperature resistance, high water holding capacity, dynamic networks (ability for significant recovery from mechanical disruption or expulsion of water by slow compression), resistance to acidic environment and enzymes in the gastrointestinal tract (GIT), and stability [16e18], made it become a useful component of various ophthalmic, nasal, oral, buccal, rectal, topical, and other formulations [19].

3.1 Gelation Gelation is one of the most important properties of native and deacylated GGs for their applications in drug delivery. Namely, hydrogels offer a wide range of possibilities for the regulation of drug loading efficiency and release kinetic because of their adjustable properties such as porosity, mechanical stability, swelling, and response to different physical stimuli. All hydrogels have a porous structure, which can be regulated by controlling the cross-linking density of the gel matrix, or in some cases, it can be changed as a response to external stimuli (i.e., temperature, pH, ionic strength change). GGs in addition to those common properties of hydrogels possess some specific ones that enable their gel to have finely tunable characteristics. This is caused by the fact that characteristics of gellan gels are influenced by many different factors such as the content of acyl groups, type and concentration of ions, pH, and presence of hydrophilic components, other hydrocolloids, or chelatants [20]. Both gellans (acetylated and deacetylated) are soluble in water, but high acyl gellans become completely soluble only in hot water (at 85e95
C), whereas low acyl ones are soluble even in cold water [9]. At appropriately high temperature (at which gellan is completely solved in water), GG molecules have coil form. When this solution is cooled, those random coil chains produce highly ordered double helices, which is a thermally reversible transition. These transitions happen regardless of the ions presence [18], but if the cations are present in the solution, the electrostatic interaction significantly affects the coilehelix transition [21]. The temperatures at which these coilehelix transitions occur also depend on the polymer concentration and presence of salt [20]. In this ordered state, the gellan solution viscosity is increased, and when gellan concentration is high enough, this solution can behave as “weak gel” (it can suspend particles under zero shear and flow when yield stress is exceeded). However, if “true hydrogel” is to be formed, the presence of metal ions in gelling solution is needed [22]. Namely, after the coilehelix transition, if so formed double helices are further cooled, they aggregate and create a three-dimensional network by complexation with present cations and by hydrogen bonds with water [9]. This is so-called solegel transition, and temperature of this transition may vary between

Gellan gum in drug delivery applications 149 30 and 50
C. Thus, formed gel properties are dependent on many factors; among which, polymer type (content of acyl groups in it) and concentrations, type and concentration of the used cations, pH, presence of hydrophilic ingredients and/or other hydrocolloids, and conditions during cooling are the most important [11,20]. Gelling of GG may be also accomplished by enzymatic linkages, by adding salt, by treating with heat, and by applying pressure [15]. Numerous analytical techniques have been used to establish the gel formation mechanism and properties of gellan solutions such as rheological measurements, texture analysis, tensile testing, circular dichroism spectroscopy, differential scanning calorimetry, confocal laser scanning microscopy, nuclear magnetic resonance, polarization modulation spectroscopy, atomic force microscopy, and others [10,19]. The most important factors that influence the gel properties and strength are described below. 3.1.1 Influence of content of acyl groups on gelation Numerous investigations have proved that the concentration of acyl groups present in the polysaccharide chain of GG is the most important factor that influences the gel strength and other characteristics [11,18,20]. Native, high acyl GGs are rich in acetyl and L-glyceryl groups that cause the less effective (less compact) packing of the polymer chains, although they do not alter the overall helix structure [20]. Although L-glyceryl groups form additional hydrogen bonds between and within the two coil chains in formed double helices, and thus they stabilize the double helix and rise the gelation temperatures, they also change the orientation of the adjacent glucuronate residue and its carboxyl group, which disable those sites for the metal cations binding. As the consequence of this loss of the cation-mediated aggregation, gel brittleness and strength are reduced, and its thermal hysteresis eliminated. The helix aggregation is further hampered by acetyl groups located on the periphery of the double helix [20]. Thus, native GG forms soft (very weak), elastic, dull, thermoreversible gels [21,23] and have the gelation temperatures around 65
C [24]. Deacetylated GG, because of the absence of L-glyceryl and acetyl groups, can form bridges between polymer chains much easier, enabling the formation of a branched network of double helices during the solegel transition, and a higher degree of their aggregation [19]. Increased aggregation stabilizes the helices even at temperatures that are higher than those at which they were formed during cooling, which gives thermal hysteresis between gelation and melting [20]. Because of the closer association between the polymer chains during double helix formation and more compact packing of double helices during solegel transition, deacetylated GG forms strong, brittle, shiny, transparent, thermoreversible gels with higher thermal stability [23,25]. Those GGs have lower gelation temperatures that are around 40
C, depending on the degree of deacetylation [24].

150 Chapter 6 3.1.2 Influence of ion type and concentration on gelation The GG gels can be produced even by hydrogen ions by cooling their solution [18,22]. However, thus obtained gels are weak and to stabilize them and produce useful gels, addition of metal cations is needed. The GG because of its reactivity can form a gel at remarkably small concentrations of cations compared with other hydrocolloids [26]. The gel properties, rate of gel formation, gel strength, texture, clarity, and gelling temperature, are strongly influenced by the concentration and type of used cations [19]. Because gelation takes place because of the aggregation of double helices, which is promoted when the electrostatic repulsion between the negatively ionized carboxylate groups on the GG chains is decreased, it is obvious that addition of cations would enhance gelation and gel strength. The decrease of electrostatic repulsion between the helices depends on the binding strength, which increases with increasing ionic size (Hþ < Liþ < Naþ < Kþ < Rbþ < Csþ), so the level of aggregation and gel formation effectiveness increase in the same order [20]. To produce a gel with the same strength, larger concentration of sodium ion (0.16% m/v) will be needed compared with the potassium (0.12% m/v) [27]. Compared with the gels formed by monovalent cations, those with divalent are stronger and formed at much lower ion concentrations. The concentrations of Naþ and Kþ ions needed for gelling gellan are about 20 times higher than those of divalent cations such as Mg2þ and Ca2þ [18]. This is the consequence of the fact that divalent cations not only have the screening effects, like monovalent, but they induce gelation and aggregation via chemical bonding by direct bridges between pairs of double helices formed between divalent cations and two carboxylate groups belonging to glucuronic acid molecules in the gellan chains [20,23]. Gels formed by the addition of divalent cations may be produced at temperatures high above the transition temperatures and give structures with excellent heat resistance that can be “unzipped” only when heated at 120
C [9,14]. Although this suggests that GG gelling with divalent ions is practically irreversible [10], these physically cross-linked hydrogels tend to lose their stability in vivo because of the exchange of divalent cations with monovalent ions, which are present at higher concentrations in the physiological environment [28]. As concentrations of divalent and monovalent ions needed for gelling are within physiological boundaries [22], they are among perfect candidates for in situ gelling systems used for nasal and ocular drug delivery [17,21]. However, although higher ion concentrations give stronger gels, optimal values are around stoichiometric equivalence to the number of carboxylate groups in gellan because excessive aggregation reduces gel strength [20]. The strongest gellan gels are produced when the value of the cation/carboxylate ratio is 10e30 and 0.5, for monovalent and divalent cations, respectively [29]. Many physical properties of the resulting hydrogels may be modulated by modifying the concentrations of GG and cations present in the solution [10]. The electropositivity of cations plays an important role in gelation of gellan because drug loading increases as the

Gellan gum in drug delivery applications 151 atomic number of the used divalent ion increases. However, although the drug loading efficiency was much higher in the presence of transition elements (compared with alkaline earth metal ions), the beads prepared with Ca2þ have better quality and mechanical strength [21]. It also may be noted that for the same ion concentration, gels formed with Ca2þ cations are 1.1e1.4 times stronger than those with Mg2þ cations [9]. 3.1.3 Influence of pH on gelation Although GG is generally not a pH-sensitive material [30], it was determined that the pH value has a strong influence on gellan gel strength, texture, clarity, gelling temperature, and gel formation kinetics [31,32]. At pH values below 3.6, GG forms acid gels that have a lower hardness than those ionotropically gelled [29]. Namely, when pH is reduced, the aggregation and gelation are promoted because of the decrease of electrostatic repulsion between the helices; therefore, harder gels are produced in acidic solutions [32]. However, very low pH causes excessive aggregation, which consequently reduces the strength of formed gel [20]. Thus, the optimal gel strengths are obtained when pH values are between 3.5 and 8 [31]. Type of GG also influences the gel characteristics because deacetylated GG is acid sensitive and forms strong gels at low pH [33], whereas high acyl GG is much less sensitive [34]. The gellan gels swell at high pH [35], but in gastric fluid (pH ¼ 1), only hydrogels with high gellan concentration (2%) slightly swell. Swelling is also low if large amounts of sodium ions are present in the solutions (i.e., physiological saline solution (0.9% g/v) or solution that simulates intestinal fluiddphosphate buffer, pH ¼ 7.4) [9]. Because gellan gels are stable at low pH, they may be used to protect drugs from gastric fluid [18,36]. The pH value does not affect the temperature of gel formation, but when gels are produced with low concentrations of monovalent ions, melting temperature is slightly increased when pH was decreased from neutral to 3.5 [11]. Gels prepared with divalent ions do not show such trend [6]. It may be also noted that in comparison with other polysaccharides, gellan gels are less sensitive to pH [9]. 3.1.4 Presence of hydrophilic ingredients and other polymers In many cases, physically cross-linked gellan gels do not have desirable characteristics, and to overcome those drawbacks (e.g., poor mechanical strength, poor stability in physiological conditions, high gelling temperature, and small temperature window), or to improve existing and obtain new characteristics, gelling is performed in the presence of different hydrophilic ingredients and other natural or synthetic polymers [18]. Depending on the demands, either interpenetrating or cocross-linked polymer networks are developed, or previously formed physical gels are chemically cross-linked or photocross-linked [7]. Blends with various sugars, proteins, natural polysaccharides, organic acids, synthetic polymers have been tested for applications in different industries [18].

152 Chapter 6 Combination of GG with different sugars such as sucrose, fructose, and glucose was investigated to improve gelling properties [9,18,37]. Presence of these components has a complex influence on gel strength, clarity, texture, gelling temperature, and water holding capacities, whereas this influence depends on sugar type and concentrations of sugar, GG, and cations. High concentrations of sugar (70 wt%) inhibit aggregation and create gels with reduced cross-linking [20]. There are contradictory results about the efficiency of sugars (sucrose, glucose, fructose) in obtaining gellan gels with optimal strength [9], which may be explained by the difference in the type of used gellan [20]. In addition, cation concentrations have different effects on sugar influence [11]. GG was blended with many natural (e.g., chitosan, pectin, alginate, carrageenan, xanthan gum, gum cordia, tamarind seed polysaccharide, starch, proteins, etc.) and synthetic polymers (i.e., polyacrylic acid, polyethylene glycol, polyvinyl alcohol, ethyl cellulose, carboxymethyl cellulose, Pluronic 123, poloxamer 407, Carbopol, etc.). With those polymers, GG may form coupled networks, interpenetrating networks, or complex coacervates, which modify and/or improve the gelling characteristics and gel properties (such as mechanical, antiradical, barrier qualities, etc.) in the desired manner [18,20]. The presence of some other substances such as chelatants (e.g., sodium citrate, sodium metaphosphate, and EDTA) may decrease solegel transition temperature and gel strength [11]. In some cases, enhancement of their mechanical properties and achievement of specific drug release profiles may be obtained by chemical and/or photocross-linking of preformed physical networks with different cross-linkers (N-hydroxysuccinimide, 1-ethyl3-(3-dimethylaminopropyl)carbodiimide, etc.) [7,23].

4. GG in drug delivery GG has been investigated for a wide range of different solid, liquid, and semisolid dosage forms to improve the properties of the existing dosage forms in the desired manner. Drug delivery utilizes many different routes and formulations to achieve the desired drug pharmacokinetics and distribution. In the conventional dosage forms, GG was investigated as tablet binder, disintegrant, or coating material, but those applications are less attractive. Nowadays, many new dosage forms are investigated to overcome problems with conventional forms. To alter drug pharmacokinetics and improve bioavailability, many modified release formulation systems have been developed such as delayed release, sustained release, sitespecific release, and receptor targeted [38]. Delayed drug release is mostly used in oral dosage forms to prevent drug-induced mucosal irritation and/or to protect drugs from low pH and enzymes in the stomach, as well as to target the drug delivery to a specific site (i.e., colon) [39]. The drug release mechanism is based on time, or environmental changes

Gellan gum in drug delivery applications 153 (pH, enzyme presence), and after its onset, further drug release, it may be sustained or immediate [38]. Sustained drug release systems are used to provide optimum drug concentrations for an extended time to maintain therapeutic drug levels at the desired site and/or to avoid side effects and toxic drug levels. Many different modified release systems have been developed to sustain drug release. In the case when drug delivery vehicle is polysaccharide based, drug release can be described as a complex function of the extent and rate of the vehicle swelling, rate of the drug diffusion through the hydrated vehicle, and vehicle dissolution/erosion. Generally, increase in the relative amount of polysaccharides in the formulation decreases the drug release by increasing swelling volume, reducing the drug diffusion, and delaying the vesicle erosion. Beside conventional tablets, relatively modern formulations include gel beads, micro- and nanoparticles, films, viscous liquid formulations for oral and topical delivery, etc. Among recently developed formulations, particularly interesting are those physiologically responsive. Namely, some polysaccharides may respond to the physiological environment either by interacting with the tissue surface (bioadhesion/mucoadhesion) or by changing mechanical behavior (because of solegel or gelesol transition) in contact with physiological fluids (e.g., lacrimal, nasal, saliva, or GIT fluids). Because of its relatively high mucoadhesiveness and exceptional ability for solegel transition in physiological fluids, GG is especially interesting for development of different physiologically responsive types of drug delivery formulations. Another, very interesting formulations are the socalled fluid gels or sheared gels that are produced by applying shear force during the gelation process. They are particularly suitable for oral formulations in case of patients with swallowing problems because created gel particles are microsized (size depends on the applied shear force). However, in designing the new dosage forms, not only the right choice of the dosage form but also the right choice of formulation materials is important [40]. The GG, because of its favorable properties, is nowadays attracting increased attention as the formulation material, and it is used for different routes of administration and in many different dosage forms.

4.1 GG in peroral drug delivery The oral drug administration is considered the safest and most convenient one. The optimal oral delivery formulation should provide effective drug concentrations in the systemic circulation for a long time period, easy administration, flexible formulation, and patient compliance. However, in some cases, conventional oral dosage forms may suffer from low gastric retention time, drug release in the wrong place, or rapid gastric release rate. This may result in either too low (inefficient) or too high drug concentrations (leading to local or systemic toxicity). Those limitations have led to the development of new oral gastroretentive dosage forms for upper GIT (i.e., floating, mucoadhesive,

154 Chapter 6 swellable, expandable, or unfoldable systems) and for lower GIT drug delivery (i.e., highdensity sinking systems, colon-specific biodegradable systems, systems with combined polysaccharides, pH-sensitive or biodegradable matrix-based systems, etc.) [41e43]. GG has been widely investigated for different oral delivery formulations, mainly for delivery and/or retaining the active pharmaceutical ingredients at specific sites of GIT. The main reasons for this are not only its biodegradability and nontoxicity, but most of all its stability over the wide pH range [2e10] and insensitivity to most GIT enzymes (i.e., pectinase, amylase, cellulase, papain, lipase, etc.) [44]. All these have made GG appropriate selection for GIT-specific drug delivery formulations. The GG-based oral formulations are known to sustain the drug levels at acidic pH because of cross-linking [45], which makes them appropriate for intestinal drug delivery. In addition, GG is subjected to degradation by galactomannanase present in the colon, thus making GG a good candidate for controlled colonic delivery formulations too [46]. 4.1.1 Tablets and capsules GG has been used in tablet formulations as swelling agent, disintegrant, and binding agent. Several investigations have shown that GG is a good swelling agent, particularly when combined with other polysaccharides, but swelling degree depends on the type of gelling cations [47,48]. Acrylamide-grafted GG was also investigated as a swelling agent for the development of sustained release dosage form [49]. When used as tablet disintegrant, GG was found to be as effective as standard disintegrants (sodium starch glycolate and maize starch) at low concentration (0.2% w/w), whereas increase in concentration increased disintegration times in acidic conditions [50,51]. When used in sublingual tablets, GG had the shortest disintegration time compared with other disintegrants in neutral pH [52]. Besides its use as a disintegrant, GG at higher concentrations may be also used as a binding agent for granules used in tablet formulating or capsule fillings. Investigations have proven that its binding capacities were as good, or better, than for acacia gum, gelatin, and maize starch [53e55]. Polymethacrylamide-grafted GG was tested for the production of sustained release tablets [56]. GG was also used for production of hard and soft capsules in combination with HPMC, sodium alginate, or using a combination of high and low acyl GG [57,58]. 4.1.2 Liquid oral in situ gelling systems One of the very interesting formulations is oral in situ gelling liquid system, and to be used for this formulation, polymer material must have needed solution viscosity, gelling ability, and fast solegel transition in the presence of released cations, or low stomach pH [59]. GG has all those prerequisites and is widely investigated for different in situ gelling oral liquid formulations. Liquid oral dosage forms are more compliant than solid forms. However, liquid forms often have lower bioavailability because of quick transition through the stomach/duodenum, which is a serious problem for drugs, which are either absorbed

Gellan gum in drug delivery applications 155 only in those sites of the GIT (have narrow absorption window) or need to be locally administrated there [60]. In those formulations, solegel transition is triggered by the presence of released, previously complexed, calcium cations, or because of a change in pH. Because, in that way, formed gels are lighter than gastric fluids, they float over the stomach contents and retain there for a long time, thus enhancing the local or systemic bioavailability of the administered drug. Different antibiotics were used in those systems for Helicobacter pylori eradication, and obtained results showed improvement in eradication and reduction of the required antibiotic amount [59,61e65]. Many other drugs were also investigated for administration by liquid oral in situ gelling systems, and obtained results proved that those systems give the same or up to fivefold increased relative bioavailability of the drugs compared with the conventional formulations [66e72]. An interesting application of GG is for production of fluid gels (sheared gels), which actually are suspensions of gel particles prepared by introducing a shear force during gelation. The properties of those microgel particles could be controlled by varying the concentration of polymer and shearing rate used during gel production, and GG is particularly suited for such applications [73]. 4.1.3 Multiparticulate drug delivery systems Multiparticulate drug delivery systems consist of many small (0.05e2.00 mm) discrete units, which may provide numerous advantages over single-unit systems because of their small size. Multiparticulates are less dependent on gastric emptying, cause less local irritation, increase bioavailability, and reduce the risk of systemic toxicity. They also have better disintegration in the stomach and better reproducible pharmacokinetic behavior than conventional formulations, but they also have some drawbacks [74]. They are based on subunits such as macro- or microbeads, particles, granules, spheres, pellets, and spheroids. The drug-loaded gellan beads are simply produced through the external ionotropic gelation method by the dropwise addition of aqueous solution of GG with dissolved or dispersed drug into the aqueous solution of cations [75]. Prepared beads are then washed and dried, whereas their characteristics can be regulated by concentration and molecular weight of the polymer, type and concentration of cations, aperture size, cross-linking medium pH, drying parameters, drug nature, and others [76,77]. GG beads are generally more preferable for drug release in the intestinal conditions because gellan beads are stable and swell rapidly in low pH stomach media, whereas in high pH media, they dissolve, leading to faster release of encapsulated drug [78]. Among all investigated GG-based drug delivery formulations, those with drug-loaded beads are the most numerous. GG has been used for formulation of many macrobeads loaded with different drugs for sustained release systems either alone [46,77e91] or mixed with clay [92], different filers [93], different polymers such as alginate [94], chitosan [44,61,75,76,95e100], pectin and low methoxy pectin [16,96,101], tamarind xyloglucan [102], carrageenan, guar gum, cellulose sulfate,

156 Chapter 6 dextran sulfates [91], Eudragit S-100 [103], hydroxypropyl methylcellulose and Carbopol 934 [64], and chitosan and gelatin [95]. Combination of different polymers may help in obtaining beads with diverse functionalities. Thus, the combination with chitosan improves encapsulation efficiency and mucoadhesiveness and prolongs drug release, demonstrating that combination of ionotropic gelation and polyelectrolyte complexation is better than ionotropic gelation alone and that dual cross-linked beads are a promising carrier for oral controlled release [44,61,76,97]. Addition of hydroxypropyl methylcellulose, pectin, and carrageenan prolonged drug release [75,91,104], whereas addition of Carbopol did not increase sustained release [105]. Many drugs, mainly different antibiotics, have been encapsulated within floating GG beads to increase retention time in the stomach [61,64,75,77,94,96,98,106]. Different types of beads with increased mucoadhesiveness has been produced by blending GG with gum cordia [86], fenugreek seed mucilage [107], jackfruit seed starch [108], ispaghula husk mucilage [109], and tamarind seed polysaccharide [35]. Carboxymethylated GG alone also exhibited higher mucoadhesiveness than the gellan alone, combined with increased drug release retention [88]. Micelle-loaded acetyl GG beads displayed pH-dependent dissolution and potential for controlled drug release [110]. In many cases, GG-based microbeads (microparticles, microspheres) were produced to improve drug entrapment efficiency and enhance drug release using either gellan alone [45,111e116], or in combination with polyvinyl alcohol [117], poly(Nisopropylacrylamide) [118], egg albumin [119], alginate [120], ethyl cellulose [113], starch, and pectin [104]. Other, less convenient formulations based on GG were prepared for oral drug administration such as bionanofillers [121] and nanofibers [122]. In the recent years, there were some investigations about drug delivery systems based on polymeric hydrogels that have suitable rheological characteristics for ease of administration to patients with swallowing difficulties (i.e., pediatric, geriatric, and patients with dysphagia). The GGbased gels [7,105,123e127], superporous gels [128], xerogels [129], and nanohydrogels [130,131] showed effective temporal and/or spatial control of drug release rates as well as sufficient integrity in the acidic stomach environment to achieve a sustained drug release. Table 6.1 summarizes most of the currently available publications related to the application of GG in oral drug delivery.

4.2 Ophthalmic drug delivery The ophthalmic drug delivery is one of the most desirable routes of drug administration because of the easy preparation and application, accurate dosing, and high patient

Gellan gum in drug delivery applications 157 Table 6.1: Oral drug delivery formulations based on GG. Formulation type

Polymer(s)

Active ingredient

Application

Beads

GG

Sulfamethizole

Antibiotic

Coated capsules and beads

GG (coating agent)

Theophylline

Phosphodiesterase inhibitor

Beads

GG

Theophylline

Phosphodiesterase inhibitor

Tablets

GG (disintegrant)

Ibuprofen

Antiinflammatory

Gel

GG/scleroglucan

Theophylline

Beads

GG

Salbutamol sulfate

Phosphodiesterase inhibitor Bronchodilator

Beads

GG

Propranolol HCl

Beta-blocker

In situ gelling system

GG

Theophylline

Phosphodiesterase inhibitor

In situ gelling system

GG

Cimetidine

In situ gelling system Beads

GG

Paracetamol

GG

Azathioprine

Reduction of gastric acid secretion Analgesic, antipyretic Immunosuppressive

Microspheres

GG/polyvinyl alcohol

Carvedilol

Beta-blocker

Gel

GG/scleroglucan

Theophylline

Beads

GG

Azathioprine

Phosphodiesterase inhibitor Immunosuppressive

Beads

GG

Cephalexin

Antibiotic

Tablets

GG (binding agent)

metronidazole; paracetamol

Beads

GG

Diclofenac sodium

Antibacterial; Analgesic, antipyretic Antiinflammatory

Reference Quigley and Deasy, 1992 [79] Alhaique et al., 1996 [210] Santucci et al., 1996 [92] Antony and Sanghavi, 1997 [50] Coviello et al., 1998 [211] El-Fattah et al., 1998 [80] Kedzierewicz et al., 1999 [81] Miyazaki et al., 1999 [66] Miyazaki et al., 2001 [67] Kubo et al., 2003 [68] Singh et al., 2004 [46] Agnihotri and Aminabhavi, 2005 [117] Coviello et al., 2005 [123] Singh and Kim, 2005 [82] Agnihotri et al., 2006 [83] Ike-Nor et al., 2006 [53] Patil et al., 2006 [84] Continued

158 Chapter 6 Table 6.1: Oral drug delivery formulations based on GG.dcont’d Formulation type

Polymer(s)

Active ingredient

Application

Granules

GG (granulating agent)

Ephedrine HCl

Sympathomimetic

Gellan beads with filler inclusion

GG/fillers

Diltiazem HCl

Calcium channel blocker

Floating beads

GG

Antibiotic

Floating in situ gelling system

GG

Acetohydroxamic acid Amoxicillin

Antibiotic

Swelling tables

GG/guar gum (swelling agent)

Acyclovir

Antiviral

Coated floating beads

GG/chitosan

Acetohydroxamic acid

Antibiotic

Coated beads

GG/Eudragit S-100

Azathioprine

Immunosuppressive

Tablets

GG

Chloroquine phosphate

Antimalarial, antiinflammatory

Floating in situ gelling system

GG

Clarithromycin

Antibiotic

Floating in situ gelling system

GG

Acetohydroxamic acid

Antibiotic

Microparticles

GG

Rifampicin

Antibiotic

Floating beads

GG/alginate

Ciprofloxacin

Antibiotic

In situ gelling system Beads

GG/alginate

Ibuprofen

Antiinflammatory

GG

Hydrochlorothiazide

Diuretic

Microbeads

GG

Ketoprofen

Antiinflammatory

Physically and chemically crosslinked gels Sustained release gel formulations

GG/L-lysine ethyl ester

Vitamin B12

/

GG

Paracetamol

Analgesic, antipyretic

Reference Franklin-Ude et al., 2007 [54] Gal and Nussinovitch, 2007 [93] Rajinikanth, 2007 [61] Rajinikanth et al., 2007 [62] Gromova et al., 2007 [48] Rajinikanth and Mishra, 2007 [61] Singh and Kim, 2007 [103] Franklin-Ude et al., 2008 [212] Rajinikanth and Mishra, 2008 [59] Rajinikanth and Mishra, 2008 [63] Rastogi et al., 2008 [45] Srinatha and Pandit, 2008 [94] Wu et al., 2008 [69] Emeje et al., 2009 [85] Mangond et al., 2009 [111] Matricardi et al., 2009 [7] Miyazaki et al., 2009 [124]

Gellan gum in drug delivery applications 159 Table 6.1: Oral drug delivery formulations based on GG.dcont’d Formulation type

Polymer(s)

Active ingredient

Application

Floating beads

GG

Clarithromycin

Antibiotic

Immediate release tablets Beads

GG (disintegrant) GG/gum cordia

Metoclopramide HCl Metformin HCl

Antiemetic gastroprokinetic Antidiabetic

Macrobeads

GG

Amoxicillin

Antibiotic

Tablets

GG (disintegrant)

Metronidazole

Antibacterial

Thermoresponsive microspheres

GG/poly(Nisopropylacrylamide)

Atenolol

Antihypertensive

Coated beads

GG/chitosan

Amoxicillin

Antibiotic

Tablets

Microwave-modified GG (disintregant)

Diclofenac sodium

Antiinflammatory

Floating oil eentrapped beads

GG/hydroxypropyl methyl cellulose/ Carbopol 934 GG

Clarithromycin

Antibiotic

Ambroxol HCl

Beads

GG/chitosan/gelatin

Floating beads Microcapsules

GG/low methoxy pectin GG/egg albumin

Metronidazole and metronidazole benzoate Ofloxacin

Oral expectorant and mucolytic agent Antibiotic

Beads

Immediate release soft gel

Antibiotic

Diltiazemdresin complex

Antihypertensive

GG

Glipizide

Type 2 diabetes

Hydrogel beads

GG; GG/chitosan

Stavudine

Antiretroviral

Matrix tablets

GG/tamarind xyloglucan

Diltiazem

Antihypertensive

Floating beads

GG

Rifabutin

Antibiotic

Nanohydrogel

GG

Prednisolone

Antiinflammatory

Reference Rajinikanth and Mishra, 2009 [106] Shiyani et al., 2009 [213] Ahuja et al., 2010 [86] Babu et al., 2010 [78] Emeje et al., 2010 [51] Mundargi et al., 2010 [118] Narkar et al., 2010 [76] Shah and Jani, 2010 [214] Tripathi and Singh, 2010 [64] Dabhi et al., 2011 [125] Dixit et al., 2011 [95] Kabbur et al., 2011 [96] Kulkarni et al., 2011 [119] Maiti et al., 2011 [87] Patil et al., 2011 [97] Prashant et al., 2011 [102] Verma and Pandit, 2011 [77] D’Arrigo et al., 2012 [130] Continued

160 Chapter 6 Table 6.1: Oral drug delivery formulations based on GG.dcont’d Formulation type

Polymer(s)

Active ingredient

Application

Reference

Floating beads

GG/chitosan

Metronidazole

Antibacterial

Floating in situ gelling raft system

GG

Verapamil HCl

Antihypertensive

Gel

Partially hydrolyzed poly(acrylamide)grafted GG GG/hydroxypropyl methyl cellulose; GG/Carbopol 934 GG/chitosan

Salbutamol sulfate

Bronchodilator

Amoxicillin

Antibiotic

Tripathi et al., 2012 [75]

Metronidazole, metronidazole benzoate Metformin HCl

Antibiotic

Verma et al., 2012 [99]

Antidiabetic

Metformin

Antidiabetic

Tranexamic acid

Antifibrinolytic

Vijan et al., 2012 [49] Ahuja et al., 2013 [88] Bhattacharya et al., 2013 [112] D’Arrigo et al., 2014 [131] Dowling et al., 2013 [100]

Floating-coated pH-sensitive oil eentrapped beads Beads

Tablets

Microbeads

Acrylamide-grafted GG (swelling agent) Carboxymethylated GG GG

Nanohydrogel

GG

Paclitaxel, prednisolone

Anticancer, Antiinflammatory

Self-destructing macrobeads loaded with microbeads Microspheres for prolonged release Floating in situ gelling system

GG/chitosan

/

/

GG/alginate

Aceclofenac

Antiinflammatory

GG

Ornidazole

Antibiotic

Microbeads

5-Fluorouracil

Anticancer

Beads

GG; GG/ethyl cellulose GG/chitosan

/

Swelling tables

GG (swelling agent)

Bovine serum albumin Levofloxacin hemihydrate

Oral liquid gel

GG

Ibuprofen

Antiinflammatory

Mucoadhesive beads

GG/fenugreek seed mucilage

Metformin HCl

Antidiabetic

Beads

Antibiotic

Dixit et al., 2012 [98] Gulecha et al., 2012 [70] Maiti et al., 2012 [126]

Jana et al., 2013 [120] Parthiban et al., 2013 [65] Sahoo et al., 2013 [113] Yang et al., 2013 [44] El-Zahaby et al., 2014 [47] Mahdi et al., 2014 [73] Nayak and Pal, 2014 [107]

Gellan gum in drug delivery applications 161 Table 6.1: Oral drug delivery formulations based on GG.dcont’d Formulation type

Polymer(s)

Mucoadhesive beads Mucoadhesive beads Mucoadhesive beads Beads

GG/jackfruit seed starch GG/ispaghula husk mucilage GG/tamarind seed polysaccharide GG/pectin

Micelle-loaded beads

Active ingredient

Application

Metformin HCl

Antidiabetic

Metformin HCl

Antidiabetic

Metformin HCl

Antidiabetic

Ketoprofen

Antiinflammatory

Cetyl GG

Simvastatin

Lipid lowering

Microparticles

GG

Glipizide

Type 2 diabetes

Sustained release tablets

GG; polymethacrylamidegrafted GG GG

Diclofenac sodium

Antiinflammatory

Itopride HCl

Gastroprokinetic

GG

Metformin

Antidiabetic

GG

Ketoprofen

Antiinflammatory

GG

Baclofen

Polymethacrylamideg-GG/tamarind seed gum GG/retrograded starch

Metformin

CNS depressant and SM relaxant Type 2 diabetes

Ketoprofen

Antiinflammatory

Floating in situ gelling raft system Microbeads for sustained release Microspheres Superporous hydrogel Extended release tablet Gel

Xerogel

GG/polyethylene oxide

Sulpiride

Antipsychotic

Macrobeads

GG

Meloxicam

Antiinflammatory

Nanofibers

GG/polyvinyl alcohol

Ofloxacin

Antibiotic

Floating raft system

GG/LM-pectin 101

Gabapentin

Antiepileptic, Antineuropathic

Bionanofiller composite

GG/pectin

Metformin HCl

Antidiabetic

Reference Nayak et al., 2014 [108] Nayak et al., 2014 [109] Nayak et al., 2014 [35] Prezotti et al., 2014 [16] Kundu and Maiti, 2015 [110] Maiti et al., 2015 [114] Nandi et al., 2015 [56] Rao and Shelar, 2015 [71] Allam et al., 2016 [115] Boni et al., 2016 [116] El-Said et al., 2016 [128] Priyadarshini et al., 2016 [215] Cardoso et al., 2017 [127] Hoosain et al., 2017 [129] Osmałek et al., 2017 [89] Vashisth et al., 2017 [122] Abouelatta et al., 2018 [72] Bera et al., 2018 [121] Continued

162 Chapter 6 Table 6.1: Oral drug delivery formulations based on GG.dcont’d Formulation type

Polymer(s)

Active ingredient

Application

Coated microparticles

GG/starch/pectin

Insulin

Antidiabetic

Macrobeads

GG

Naproxen

Antiinflammatory

Macrobeads

Naproxen

Antiinflammatory

Beads

GG; GG/ carrageenan; GG/ guar gum; GG/ cellulose sulfate; GG/dextran sulfates GG/pectin

Resveratrol

Antiapoptotic

Pellets

GG (binder)

Theophylline

Phosphodiesterase inhibitor

Reference Meneguin et al., 2018 [104] Osmałek et al., 2018 [90] Osmałek et al., 2018 [91]

Prezotti et al., 2018 [101] Barbosa and Ferraz, 2019 [55]

convenience and compliance. However, it is at the same time the most challenging route because poor intraocular bioavailability is a big drawback of conventional eye drops and it is caused by high rates of drug dilution and elimination (within the 5 min) because of the lacrimal flow and blinking, as well as limited permeability of the cornea [4,19,30]. Thus, conventional delivery systems demand either the higher frequency of application or increased drug levels in the formulation, which may lead to problems with patient compliance or potential overdosing [132]. To overcome those problems, modern ocular drug delivery systems are usually formulated as liposomes, ocular implants, nanoparticles, or in situ gels. Among those formulations, in situ gels are particularly interesting because they offer some advantages such as no irritation or blurred vision, prolonged drug retention at the corneal site, and prolonged drug release, which minimizes the frequency of administration. Among many different natural and synthetic polymers that have been tested and used for in situ gelling systems in ophthalmic drug delivery, GG is particularly drawing attention, because of its thickening and gelling properties, good tolerance, transparency, and very low toxicity [19,133]. In addition, its ability to in situ produce strong hydrogels even at very low gellan concentrations and with concentrations of monovalent and divalent ions that are within physiological boundaries found in tear fluid [22] has made GG become one of the most explored polysaccharides for the ocular drug delivery [17,21]. However, appropriate gellan concentrations must be used in formulation because in vivo studies have shown that only if the gel strength is within specified limits, the maximum ocular bioavailability is obtained, whereas increased gellan concentrations lead to the increase of

Gellan gum in drug delivery applications 163 precorneal residence time [134]. Those systems are physically entangled, which makes them favorable for ocular delivery as they can easily disentangle with time by shear stress associated with blinking [135]. In many cases, GG has been used as a component of complex ocular formulations with other polymers. Among those polymers, alginate, carrageenan, chitosan, and carboxymethyl cellulose are the most used one. Combination of GG with alginate produces gels with improved gel strength and mucoadhesiveness and prolonged retention of the active substances, which in some cases could sustain the drug release for over 12 h [136e138]. In cases when chitosan is combined with GG, pH-sensitive ion-activated systems were obtained with prolonged drug retention at the corneal site and better transcorneal drug permeation [139e142]. The gelling solutions produced with a combination of carboxymethyl cellulose and GG give gels with improved gel mucoadhesiveness properties [136,143]. The mixing of GG with carrageenan creates formulations that have good mucoadhesiveness and prolonged drug retention without ocular irritation [144,145]. They are favorable for ocular systems because their viscosity, pseudoplasticity, and hardness are remarkably increased upon addition of cations, thus reducing nasolacrimal drainage [135]. When the synthetic polymers such as Carbopol were mixed with GG, they produced formulations with prolonged contact time and improved gelation characteristics of the in situ gel (synergistic effect), but they may cause drug precipitation upon storage [138,146,147]. GG-based ophthalmic drug delivery systems are mainly investigated for different types of antiglaucoma, antibiotic, antiinflammatory, and some other drugs that could be administrated by ocular route. Ophthalmic formulations represent the most frequent examples of current commercial GG applications in drug delivery [148]. Table 6.2 summarizes most of the currently available publications related to the application of GG in ophthalmic drug delivery.

4.3 GG in nasal drug delivery Although nasal drug delivery is mostly used for local actions such as the treatment of nasal infections, congestion, or allergic symptoms [149], recently, nasal drug delivery attracted grooving interest for the systemic actions because of its advantages. Its rapid onset of action because of high vascularization and permeability, avoidance of hepatic first-pass metabolism, and harsh (pH and enzymatic) GIT environment, direct delivery to CNS, lower drug amounts, as well as improved compliance, has made it a promising route particularly for drugs that are not efficiently absorbed in the GIT, are quickly metabolized, or are used for treatment of nausea and vomiting [150]. However, some limitations, such as low bioavailability, mucociliary clearance, and irritation of nasal mucosa, have reduced application of this administration route. Among many different formulations and

164 Chapter 6 Table 6.2: Ophthalmic drug delivery formulations based on GG. Formulation type In situ gelling solution In situ gelling solution In situ gelling solution Sustained delivery films and drops Nanoparticles In situ gelling solution In situ gelling solution In situ gelling solution In situ gelling solution In situ gelling solution Film-type scleral implants In situ gelling solution In situ gelling solution In situ gelling solution Topical suspensions In situ gelling solution In situ gelling solution In situ gelling microemulsion Ocular insert In situ gelling solution In situ gelling solution

Polymer(s)

Active ingredient

Application

GG

Timolol maleate

Antiglaucoma

GG

Sezolamide, dorzolamide Timolol maleate

Antiglaucoma Antiglaucoma

GG; methylprednisolone ester of GG GG/albumin

Methylprednisolone

Antiinflammatory

Pilocarpine

Antiglaucoma

GG

Pilocarpine

Antiglaucoma

GG

Timolol maleate

Antiglaucoma

GG

Timolol maleate

Antiglaucoma

GG

Timolol maleate

Antiglaucoma

GG

Indomethacin

Antiinflammatory

GG

Indomethacin

Antiinflammatory

GG

Carteolol HCl

Antiglaucoma

GG

Pefloxacin mesylate

Antibiotic

GG

Piroxicam

Antiinflammatory

GG

2-methylsorbinil

Anticataract

GG

Ciprofloxacin HCl

Antibiotic

GG

Antibiotic

GG

Gatifloxacin sesquihydrate Cyclosporine A

Immunosuppressant

GG

Ciprofloxacin HCl

Antibiotic

GG

Timolol maleate

Antiglaucoma

GG/chitosan

Timolol maleate

Antiglaucoma

GG

Reference Rozier et al., 1989 [216] Gunning et al., 1993 [217] Laurence et al., 1993 [218] Sanzgiri et al., 1993 [132] Zimmer et al., 1995 [219] Meseguer et al., 1996 [220] Rozier et al., 1997 [221] Dickstein et al., 2001 [222] Shedden et al., 2001 [223] Balasubramaniam et al., 2003 [224] Balasubramaniam et al., 2004 [225] El-Kamel et al., 2006 [226] Sultana et al., 2006 [227] Hıˆncu et al., 2007 [228] Kador et al., 2007 [229] Ramaiah et al., 2007 [230] Kalam et al., 2008 [231] Gan et al., 2009 [232] Kumar et al., 2009 [233] Singh et al., 2009 [133] Gupta et al., 2010 [139]

Gellan gum in drug delivery applications 165 Table 6.2: Ophthalmic drug delivery formulations based on GG.dcont’d Formulation type In situ gelling solution In situ gelling solution In situ gelling nanoemulsion In situ gelling solution In situ gelling solution In situ gelling solution In situ gelling solution In situ gelling solution In situ gelling solution In situ gelling nanoemulsion In situ gelling solution for low watersoluble drugs In situ gelling nanomicellar solution In situ gelling solution In situ gelling solution In situ gelling nanoparticle solution In situ gelling liposome solution In situ gelling solution In situ gelling nanoparticle solution

Polymer(s)

Active ingredient

Application

Reference

GG/alginate; GG/ carboxymethyl cellulose GG; GG/alginate

Gatifloxacin

Antibiotic

Kesavan et al., 2010 [136]

Matrine

GG

Flurbiprofen axetil

Antibiotic/ antiinflammatory Antiinflammatory

GG

Moxifloxacin

Antibiotic

GG

Pilocarpine HCl

Antiglaucoma

GG

Cx43 antisense oligodeoxynucleotide Aesculin

Wound closure

Liu et al., 2010 [137] Shen et al., 2010 [234] El-Laithy et al., 2011 [235] Rupenthal et al., 2011 [135,236] Rupenthal et al., 2011 [237] Chen et al., 2012 [238]. Geethalakshmi et al., 2012 [239] Kumar et al., 2012 [138] Tayel et al., 2013 [240] Ferna´ndez-Ferreiro et al., 2014 [241]

GG GG GG/alginate GG/Carbopol 934 GG

Brimonidine tartrate Ketotifen fumarate

Antiinflammatory/ vasoprotective Antiglaucoma Antihistamine

Terbinafine HCl

Fungal keratitis

GG/cyclodextrin

Fluconazole

Antifungal

GG/pluronic 123/ TPGS

Curcumin

Antiinflammatory, antimicrobic

Duan et al., 2015 [13]

GG/chitosan

Levofloxacin

Antibiotic

GG/chitosan

Sparfloxacin

Antibiotic

GG

Doxycycline HCl

Antibiotic

Gupta et al., 2015 [140] Gupta et al., 2015 [141] Pokharkar et al., 2015 [242]

GG

Timolol

Antiglaucoma

Yu et al., 2015 [243]

GG

Ketotifen fumarate

GG

Moxifloxacin

Allergic conjunctivitis Antibiotic

Zhu et al., 2015 [30] Kesarla et al., 2016 [244] Continued

166 Chapter 6 Table 6.2: Ophthalmic drug delivery formulations based on GG.dcont’d Formulation type In situ gelling solution In situ gelling solution In situ gelling solution In situ gelling solution In situ gelling solution In situ gelling nanoemulsions

In situ gelling solution In situ gelling solution In situ gelling solution In situ gelling solution In situ gelling solution

Polymer(s) GG/carboxymethyl cellulose GG/calcium gluconate/ polyvinylpyrrolidone GG/poloxamer 407 GG

Active ingredient

Application

Gatifloxacin

Antibiotic

Timolol

Antiglaucoma

Pilocarpine HCl

Antiglaucoma

Estradiol

Anticataract

GG/carrageenan

Cysteamine

Cystinosis treatment

GG/xanthan gum; GG/hydroxypropyl methyl cellulose; GG/Carbopol GG/carrageenan

Acetazolamide

Antiglaucoma

Econazole

Antifungal

GG/chitosan/ polyvinylalcohol GG

Besifloxacin

Antimicrobic

Natamycin

Antifungal

GG/Carbopol 934P GG

Benzododecinium bromide Brinzolamide

Antimicrobic Antiglaucoma

Reference Kesavan et al., 2016 [143] Reed et al., 2016 [245] Dewan et al., 2017 [246] Kotreka et al., 2017 [247] Luaces-Rodrı´guez et al., 2017 [144] Morsi et al., 2017 [146]

Dı´az-Tome´ et al., 2018 [145] Imam et al., 2018 [142] Janga et al., 2018 [248] Ranch et al., 2018 [147] Sun and Zhou, 2018 [249]

approaches for overcoming those limitations, few are especially interesting. In situ gelling and micro-, nanosized systems are promising formulations to surpass those drawbacks. GG is almost an ideal polymer for in situ gelling systems because it produces solution that exhibits shear thinning behavior, with low enough viscosity to be sprayed, but is also viscous enough to adhere to the nasal tissue where, in contact with physiological concentrations of cations, it quickly forms gel that is strong enough to remain there for the required time interval (at least 4e5 h) [151]. In addition, it is a stable, biocompatible, and biodegradable polymer, without any irritant or toxic effect on the nasal epithelial mucosa tissue even for prolonged and persistent use [151e153]. Thus, it is not surprising that many investigations have proved high efficiency and beneficial properties of different GGbased systems for nasal drug delivery. Main formulations for nasal drug delivery based on GG are in situ nasal gels, dry intranasal micro- and nanoparticles, and hybrid system of micro- and nanosized particlesebased in situ gels. In situ nasal gels are promising formulation systems for the intranasal drug delivery as they provide increased nasal mucosal permeability and prolonged in vivo residence time,

Gellan gum in drug delivery applications 167 which overall improves drug bioavailability. Thus, it is not surprising that there are numerous investigations about GG application for those systems [5,8,12,150,152,154e164]. Dry intranasal micro- and nanoparticle systems represent a relatively new approach to nasal drug delivery. They are based on in situ transition from a dry powder to a swollen gel as the microparticles delivered in the dry solid state come in contact with nasal mucosa [153]. Dried gellan particles withdraw water in contact with nasal mucosa and interact with physiologically present cations forming a highly viscous gel. Thus, formed gel reduces the ciliary clearance rate and consequently prolongs the drug residence time and thereby nasal absorption [151]. These formulations may be in the form of microspheres [151,153,165e167] and nanomicelles [168]. The latest approach is a hybrid system of two previous, nanotechnology delivery systems combined with in situ gelling technology, which gives in situ gels loaded with micro- and nanosized particles. Those systems generally significantly increase drug bioavailability by improving their pharmacodynamic activity and enhancing mucoadhesiveness. The in situ nasal gels are currently loaded with microemulsion [169,170], nanosized microemulsion [171], nanosuspension [172e174], and cubosomes [175]. An interesting approach is the application of lyophilized nasal inserts, produced from gellan gel, with a porous spongelike structure [17]. To increase the mucoadhesiveness of in situ formed nasal gel, and thus obtain sustained drug release and improved intranasal drug absorption, GG was blended with different polymers such as Carbopol [158,159,170], poloxamer [164], Lutrol F 127 [173], hydroxypropyl methylcellulose [8], chitosan [17], xanthan gum [5], and konjac gum [175]. In some cases, a mixture of high- and low-acyl GG [12] or thiolated GG [159] was used to increase the gel mucoadhesive potential. To increase the intranasal delivery of low watersoluble drugs, amphiphilic C18 grafted GG was applied [168]. Table 6.3 summarizes most of the currently available publications related to the application of GG in nasal drug delivery.

4.4 GG in topical (dermal, cutaneous, subcutaneous, transdermal) drug delivery Topical delivery includes local (dermal) and systematic (transdermal) drug administration. The locally delivered drugs are administrated either to treat skin diseases (of stratum corneum, epidermis and/or the dermis) or for improving the wound healing. In systematic topical delivery, skin is not the targeted organ but only the site for drug administration. Transdermal delivery has benefit of simple application and may be a good alternative to oral delivery in cases when orally administrated drug causes serious side effects, drug has low bioavailability (due to first-pass metabolism, low drug solubility, and/or a narrow

168 Chapter 6 Table 6.3: Nasal drug delivery formulations based on GG. Formulation type

Polymer(s)

Active ingredient

Application

In situ nasal gel

GG

Influenza vaccine

In situ nasal gel

GG

In situ nasal gel

GG

In situ nasal gel

GG

In situ nasal gel

GG

Fluorescein dextran Radix Bupleuri essential oil Scopolamine HBr Huperzine A

In situ nasal gel

GG/Carbopol 934P

Dimenhydrinate

In situ nasal gel

GG

Antiinflammatory

Dry intranasal microspheres

GG

Mometasone furoate Metoclopramide HCl

Dry intranasal microspheres

GG

Ondansetron

Antiemetic

In situ nasal gel

Thiolated GG

Dimenhydrinate

Antiemetic

In situ nasal gel

GG/Carbopol

Metoclopramide HCl

Antiemetic

Dry intranasal microspheres

GG

Ondansetron

Antiemetic

Dry intranasal microspheres In situ nasal gel

GG

Sildenafil citrate

GG

Gastrodin

Erectile dysfunction CNS sedation

In situ nasal microemulsion gel In situ nasal nanosuspension gel Dry intranasal microspheres

GG

Curcumin

Antidepressant

GG

Carvedilol

Beta-blocker

GG

Almotriptan malate

Antimigraine

In situ nasal gel

GG

Antimigraine

In situ nasal nanosized microemulsion gel Dry intranasal nanomicelles

GG

Sumatriptan succinate Saquinavir mesylate Budesonide

Antiallergic

C18-grafted GG

Antibody response Epithelial uptake testing Antipyretic Antiemetic Cognitive enhancer Antiemetic

Antiemetic

Protease inhibitor

Reference Bacon et al., 2000 [154] Jansson et al., 2005 [150] Cao et al., 2007a [155] Cao et al., 2007b [156] Tao et al., 2006 [157] Belgamwar et al., 2009 [158] Cao et al., 2009 [152] Mahajan and Gattani, 2009 [153] Mahajan and Gattani, 2009 [165] Mahajan et al., 2009 [159] Mahajan and Gattani, 2010 [160] Mahajan and Gattani, 2010 [166] Shah et al., 2010 [151] Cai et al., 2011 [161] Wang et al., 2012 [169] Saindane et al., 2013 [172] Abbas and Marihal, 2014 [167] Galgatte et al., 2014 [162] Hosny and Hassan, 2014 [171] Maiti et al., 2014 [168]

Gellan gum in drug delivery applications 169 Table 6.3: Nasal drug delivery formulations based on GG.dcont’d Formulation type In situ nasal droppable gel Thermo- and ionsensitive in situ nasal gel In situ nasal sprayable gels In situ nasal nanosuspension gel In situ nasal nanosuspension gel In situ nasal gel

Polymer(s)

Active ingredient

Application

GG

Granisetron HCl

Antiemetic

GG/poloxamer 407

Ketorolac tromethamine

Analgesic

HA GG/LA GG

/

/

GG/Lutrol F 127

Rivastigmine

GG

Resveratrol

Cholinesterase inhibitor Antiapoptotic

GG/hydroxypropyl methyl cellulose GG/chitosan

Salbutamol sulfate Ondansetron HCl

Bronchodilator

In situ nasal gel

GG/xanthan gum

Lamotrigine

Antiepileptic

In situ nasal microemulsion gel In situ nasal cubosome gel

GG/Carbopol 934

Lorazepam

Anxiolytic

GG/konjac gum

Donepezil HCl

Cholinesterase inhibitor

Lyophilized nasal inserts

Antiemetic

Reference Ibrahim et al., 2015 [163] Li et al., 2015 [164] Mahdi et al., 2015 [12] Wavikar and Vavia, 2015 [173] Hao et al., 2016 [174] Salunke and Patil, 2016 [8] Sonje and Mahajan, 2016 [17] Paul et al., 2017 [5] Shah et al., 2017 [170] Patil et al., 2018 [175]

therapeutic window), as well as, for sustained drug delivery [176]. Compared with hypodermic delivery, the topical has much greater patient compliance. Recently, to surpass some drawbacks of conventional topical dosage forms, innovative dosage forms are being developed for better and prolonged contact with the skin, which enables less frequent dosing [177]. Novel dosage forms are usually polymeric patches or (gel-)film-forming systems, and in those formulations, GG, although relatively not so widely investigated, may have the promising role. GG was studied for development of different formulations for drug delivery in wound healing applications mainly in the form of gels [178e182], coreeshell transfersomes [183], and nonwoven dressing [25]. Experiments have confirmed that GG may be highly suitable for wound healing applications because of its biocompatibility, biodegradability, sustained drug release, transparency, moist nature, and nontoxicity to important wound healing cells [179,182]. Yet more, GG hydrogels demonstrated a great ability to counteract the toxic effect induced by hydrogen peroxide in cells [181] and supported the growth of fibroblast (L929) cells [178]. GG was also used for local topical delivery of different antibiotics for the treatment of skin infections [184,185] and for delivery or antiinflammatory agents in the treatment of

170 Chapter 6 UVB skin inflammations [186,187]. It has been also used for local treatment of oral candidiasis [105] and oral cancer [188]. Systemic topical delivery of drugs that could affect GIT, or are sensitive to harsh conditions in GIT, is preferred, but because of the natural protective function of the stratum corneum, it may be a challenging task. Because of its advantage of increasing drug permeation, GG is a promising polymer for such formulations, especially as its permeation properties depend on concentrations of GG and/or cations in the formulation [189]. Thus, it is not surprising that was investigated for delivery of various antiinflammatory drugs [189e192], antibiotics [193], and proteins [194,195]. Table 6.4 summarizes most of the currently available publications related to the application of GG in topical drug delivery. Table 6.4: Topical drug delivery formulations based on GG. Formulation type

Polymer(s)

Active ingredient

Application

Reference

Implant film

Gellan

Insulin

Antidiabetic

Vesicular dispersion in GG solution Dry films

GG

Ampicillin

Antibiotic

GG/konjac glucomannan GG/Carbopol 934P hydroxyl propylmethyl cellulose E50LV GG/ polyethylenimine GG/hyaluronic acid ester/polyvinyl alcohol GG/chitosan

Nisin

Antibiotic

Clotrimazole

Oral candidiasis treatment

Plasmid DNA

Nonviral gene vector Wound healing

Goyal et al., 2011 [195] Cencetti et al., 2012 [25]

Wound healing

MatAmin et al., 2012 [178] Salim et al., 2012 [190] Novac et al., 2014 [185] Abioye et al., 2015 [191] Carmona-Moran et al., 2016 [192]

In situ oral topical gel

Nanocomposites Nonwoven dressings Bilayer film Modified nanoemulsion Particles Nanogel Thermoresponsive nanogels: semisolid gel and Solid hydrogel film Fluid gels

Silver

Levofloxacin and TiO2 Ibuprofen

Antiinflammatory

Ciprofloxacin

Antibiotic

Ibuprofen

Antiinflammatory

GG

Diclofenac sodium

Antiinflammatory

GG

Diclofenac

Antiinflammatory

GG/palm kernel oil esters Quaternized GG/ chitosan GG/chitosan

Li et al., 2001 [194] Carafa et al., 2004 [193] Xu et al., 2007 [184] Harish et al., 2009 [105]

Mahdi et al., 2016 [189]

Gellan gum in drug delivery applications 171 Table 6.4: Topical drug delivery formulations based on GG.dcont’d Formulation type

Polymer(s)

Active ingredient

Application

Reference

Gel

GG/chitosan/PEG

Apigenin

Wound healing

Semisolid gel with nanocapsules Nanocapsule suspensions

GG/pomegranate oil GG

Silibinin

Antiinflammatory Antiinflammatory

Hydrogel Subcutaneous application Nanohydrogels

GG

Coenzyme Q10 and vitamin E acetate Eumelanin

Wound healing

da Silva et al., 2017 [180] Manconi et al., 2018 [181] Manconi et al., 2018 [183] Musazzi et al., 2018 [250]

Coreeshell transfersomes Nanohydrogels for cutaneous administration Hydrogel; hydrogel with nanoparticles Patch

Cholesterolderivatized GG GG

Baicalin

Wound healing

Baicalin

Wound healing

GG

Piroxicam

Antiinflammatory

GG

Vancomycin

Wound healing

GG/glucosamine

Clioquinol

Oral cancer treatment

Shukla et al., 2016 [179] Marchiori et al., 2017 [186] Pegoraro et al., 2017 [187]

Shukla and Shukla, 2018 [182] Tsai et al., 2018 [188]

4.5 GG in other drug delivery routes Although not so extensively, GG was applied in drug formulations for other, less common delivery routes such as buccal, sublingual, periodontal, intracanal, vaginal, rectal, urothelial, and injectable. To be used for buccal delivery, GG was mixed with different polymers to improve its swelling, mucoadhesiveness, mechanical properties, and controlled drug release. The doublelayered films based on chitosan cross-linked with GG were designed to provide adequate adhesivity and unidirectional to the mucosa drug delivery (thus avoiding drug loss because of washout with saliva), as well as to control swelling and drug release [196]. Similar results were obtained for films produced in combination with pectin [197], whereas the addition of glycerol as a plasticizer was tried to overcome the brittleness of GG film [198]. The GG was used in sublingual drug delivery as a disintegrant, and it showed better results than ispaghula husk powder and sodium alginate [52]. Periodontal drug delivery system containing GG and Lutrol F127 was designed to evaluate the ability of formulation for sustained drug release and its mucoadhesiveness and syringeability [199].

172 Chapter 6 An intracanal pH-sensitive solegel system based on GG was developed to reduce drug toxicity and side effects. This system successfully demonstrated its simple and easy application combined with pH change triggered drug release caused by solegel conversion [200]. In situ vaginal gel formulations produced with GG as ion-activated gelling polymer and sodium carboxy methylcellulose [201], or hydroxypropyl methylcellulose [202], as mucoadhesiveness were used for local delivery of antibiotics. Those systems help in solving a number of problems involved with conventional vaginal formulations connected with poor patient compliance and inefficient drug dosage and delivery. Because they combine advantages of both gels and solution, they allow accurate dosing, easy administration, and reside at the site of infection for a prolonged period of time. Mucoadhesive in situ gelling liquid suppository for rectal administration of a drug that undergoes extensive hepatic first-pass elimination after oral administration was also developed using GG [203]. A biodegradable, in situegelling urothelial liposome-in-gel system was developed for installation into the bladder. Liposomes were incorporated into urine-triggered hydrogel, and results proved that this system has the potential for use in intravesical applications as it facilitates prolonged drug residence in the bladder [204]. Injectable delivery systems based on GG mainly were used for local administration of drugs for the treatment of different bone diseases [205e208] or delivery of radiosensitizing drugs to enhance the efficacy of chemoradiotherapy [209]. Table 6.5 summarizes most of the currently available publications related to the abovementioned application of GG in ophthalmic drug delivery.

5. Conclusions As it can be seen, gellan gum is one of the most widely investigated natural polysaccharides and it has been used as a versatile excipient in numerous oral, ophthalmic, nasal, and other drug delivery formulations. Main reasons for this are its advantageous characteristics, most of all gel forming in contact with cations present in physiological fluids and its mucoadhesiveness, but also its biodegradability, nontoxicity, resistance to temperature, acidic environment and enzymes in the GIT, high water holding capacity, stability, etc. It could be easily formulated in particles, hydrogels, films, fibers, in situ gelling systems, and many other dosage forms with the considerable ability for sustained and controlled drug release. Compared with the different types of marketed commercial formulations, the gellan gumebased formulations demonstrated much better or similar drug delivery characteristics in many cases. Gellan gum was also combined with different

Gellan gum in drug delivery applications 173 Table 6.5: Different drug delivery formulations based on GG. Formulation type

Polymer(s)

Active ingredient

Application

GG (cross-linking polymer)/ chitosan þ ethylcellulose GG

Nifedipine; oropranolol HCl

Antihypertensive

Carbamazepine

Antiepileptic

GG/sodium carboxymethyl cellulose GG/lutrol F127

Secnidazole

Antibiotic

Ornidazole

Antibiotic

GG (disintegrant)

Zolmitriptan

Antimigraine

GG/hydroxypropyl methylcellulose GG

Clindamycin HCL

Antibiotic

Vancomycin

Antibiotic

Injectable nanoparticle gel

GG

Sodium alendronate

Treatment of bone diseases

Injectable liposome-in-gel system Injectable liposomal in situ gel graft

GG

Paclitaxel

Chemotherapy

GG

Repair of alveolar bone clefts

Bilaminated buccal films Mucoadhesive rectal in situ gelling liquid suppository In situ vaginal gel Smart periodontal gel Sublingual tablets In situ vaginal gel Injectable nanoparticle gel

Injectable nanoparticles

GG

Recombinant human bone morphogenetic protein-2 (rhBMP-2) Gentamicin

Intracanal pHsensitive solegel Urothelial liposome-in-gel system Mucoadhesive buccal films Thin buccal film

GG

Chlorhexidine

Antibiotic

GG

Paclitaxel

Chemotherapy

GG/pectin

Triamcinolone acetonide Fluconazole

Treatment of canker sores Antifungal

GG/glycerol

Antibiotic

Reference ´n-Lo ´pez ˜a Remun et al., 1998 [196] El-Kamel and ElKhatib, 2006 [203] Narayana et al., 2009 [201] Dabhi et al., 2010 [199] Prajapati et al., 2014 [52] Patel and Patel, 2015 [202] Posadowska et al., 2015 [205] Posadowska et al., 2015 [206] GuhaSarkar et al., 2016 [209] Hassan et al., 2016 [207]

Posadowska et al., 2016 [208] Gandhi et al., 2017 [200] GuhaSarkar et al., 2017 [204] Fernandes et al., 2018 [197] Paolicelli et al., 2018 [198]

polymers to prepare formulations with desirable release mechanisms. All those formulations exhibited promising potential for different modified release oral formulation, in situ ophthalmic and nasal mucoadhesive gel sprays, and a rapid permeation topical gel formulations. However, because of its relatively short history in pharmaceutical

174 Chapter 6 formulations compared with other gelling agents, gellan gum has not yet realized its full potential despite those advantages. This work revealed how wide is applicability of gellan gum for improvements of conventional and designing novel drug delivery systems and to encourage further research.

Acknowledgments This research was funded by grant III46010 from the Ministry of Science and Environmental Protection, Republic of Serbia.

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