Xanthan gum in drug delivery applications

CHAPTER 5

Xanthan gum in drug delivery applications Gautam Singhvi, Neha Hans, Niharika Shiva, Sunil Kumar Dubey Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan, India

Chapter Outline List of abbreviations 122 1. Introduction 122 2. Biochemistry of xanthan gum 123 3. Properties of xanthan gum 125 4. Factors affecting xanthan gum production 4.1 4.2 4.3 4.4 4.5 4.6

125

Effect of pH 125 Effect of temperature 125 Effect of high pressure 126 Effect of carbon sources 126 Influence of polymer concentration and the effect of salts 126 Effect of viscosity on xanthan gum in presence of galactomannan

5. Production of xanthan gum

126

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5.1 Media used during production 127

6. Production kinetics 128 7. Application of xanthan gum 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10 7.11 7.12 7.13

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Solid oral dosage form 129 Liquid oral dosage form 129 Ophthalmic drug delivery 130 Buccal drug delivery 131 Topical drug delivery 131 Advanced drug delivery 132 Brain drug delivery 132 Wound healing 133 Dermal patches 134 Nasal drug delivery 135 Tissue engineering 135 Cosmetic uses of xanthan gum 136 Food 137

8. Conclusion 139 References 140

Natural Polysaccharides in Drug Delivery and Biomedical Applications. https://doi.org/10.1016/B978-0-12-817055-7.00005-4 Copyright © 2019 Elsevier Inc. All rights reserved.

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List of abbreviations CaCO3 CoA FeCl2 FTIR GG-III HEMA-co-AA MgCl2 MMP-9 MPa NaCl NaOH PCR PF 127 SEM SPF SPH XG XG-CH XG-MNP ZnO

Calcium carbonate Coenzyme A Ferric chloride Fourier transform infrared spectroscopy Guar gum III Hydroxyethyl methacrylate-acrylic acid Magnesium chloride Matrix metalloproteinase-9 Megapascal Sodium chloride Sodium hydroxide Polymerase chain reaction Pluronic 127 Scanning electron microscope Sun protection factor Super porous hydrogel Xanthan gum Xanthan gum-chitosan Xanthan gum-magnetic nanoparticle Zinc oxide

1. Introduction Xanthan gum is a naturally obtained heteropolysaccharide and a commonly used biopolymer [1]. The xanthan gum, later additionally popularized as polysaccharide1459 that is widely obtained from the microorganism Xanthomonas campestris NRRL B-1459. the gum was immensely researched due to its excellent rheological properties, which would enhance other kinds of widely used natural and synthetic soluble gums and different polysaccharides. Extensive analysis was conducted in different industrial laboratories throughout the 1960s, which caused the manufacturing of semicommercial product referred to as Kelzan1 by Kelco1 [2]. Xanthan gum (XG) is a naturally obtained extracellular polysaccharide of bacteria X. campestris. XG can also be obtained from other species of Xanthomonas such as X. arboricola and X. axonopodis. The primary structure of XG consists of pentasaccharide subunits and D-glucosyl, D-mannosyl, and D-glucuronyl acid residues in the ratios of 2:2:1 with different proportions of O-acetyl and pyruvyl residues [3e6]. The structure of XG is unbranched and consists of D-glucose (1e4) link, which is similar to cellulose backbone and can also undergo conformational transition due to thermal induction [7e9]. XG exhibits excellent water solubility and good biocompatibility. The relative molecular mass of XG ranges from 2  106 to 20  106 Da. It is a high molecular weight heteropolysaccharide consisting of several polymeric chains which also get branched (Fig. 5.1). XG is soluble in

Xanthan gum in drug delivery applications 123

Figure 5.1 Chemical structure of xanthan gum.

cold and hot water; however, it needs intense agitation when it is in contact with aqueous medium to prevent any agglomeration. XG solutions have a property similar to that of nonNewtonian fluids and exhibit high pseudoplastic behavior which gets modified considerably with time and shear rate. Usually, XG has way far better thermal stability against degradation or hydrolysis than the other water-soluble polysaccharides which happen due to the uniform but complex structure of XG that stops the molecules from depolymerization. Hence, the viscosity exhibited by XG solutions is not affected by the application of heat method (like sterilization) and has stability along with a wide range of pH values [4]. XG is an aqueous soluble polymer, employed as a wetting agent, as a stabilizer in dispersions, gelling, viscosity enhancing agent, etc. [5]. It is widely utilized in different biomedical, pharmaceutical, and food industries (Fig. 5.2).

2. Biochemistry of xanthan gum XG is a high molecular weight polysaccharide and can be produced by inoculating Xanthomonas campestris into aerobic culture fermentation of carbohydrates. It consists of a large quantity of trisaccharide side chain with a rigid polysaccharide backbone structure. To each alternate glucose residues of main chain one glucuronic unit and two mannose units are attached as a side chain. Terminal D-mannose residues have pyruvate function whereas nonterminal D-mannose shows acetyl function. At pH above 4.5, XG acts as a polyanion because of the reduction of O-acetyl and pyruvyl residues [8,10,11]. The acetyl and pyruvyl residues differ with the various bacterial species used and fermentation conditions adopted for the production of XG [6,12]. Lower pyruvyl content results in lower viscosity whereas higher pyruvate content exhibits a high viscosity of gel through an increased association between large molecules and the higher acetyl content decreases

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Figure 5.2 Applications of xanthan gum in pharmaceutical, biomedical and cosmetics.

gelling nature of XG in aqueous solution [13e15]. Anionic property of this biodegradable polymer came from glucuronic acid and pyruvic acid present on the side chain [16]. XG has a very typical and complex biosynthetic pathway. The composition of XG is mostly dependent upon the series of factors considered during the production process. It usually consists of D-mannose, D-glucose, and D-glucuronic acid. Firstly it proceeds with Entnerdoudoroff and tricarboxylic acid pathway which involves the conversion of glucose into pyruvate. The sequential addition of monosaccharide from nucleotide-sugar-phosphate includes CoA acetylation in which O-acetyl groups are moved from acetyl CoA to the nonterminal D-mannose unit. Glycosyltransferase helps in donating sugar molecules to the sugar acceptor. Each of the above-mentioned steps require special CoA or substrate for the completion of any cycle [17].

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3. Properties of xanthan gum XG is white to cream in color, free-flowing powder, which gets easily solubilized in hot and cold water due to its ordered conformation. Moreover, XG remains stable in both acidic as well as in alkaline conditions due to its rigid structure and resistance to any pH change. The backbone structure of XG is quite similar to that of cellulose; therefore, it is biodegradable in nature. It is highly pseudoplastic in nature, that is, XG regains its viscosity even after applying high shear, which ensures good pourability in the finished product [5]. The viscosity of XG- based solutions depends mainly on parameters such as pH, concentration of XG in the solution, and concentration of buffer solutions [18,19]. RosseMurphy et al. proved that XG forms a weak network-structure in aqueous medium which undergoes a reversible transformation on the application of shear [20,21]. XG deacylates when it attains pH 9 or above and has the capability to form gel mostly at high pH, that is, greater than 10. Furthermore, XG is not digested by humans easily [5]. In the presence of salts such as sodium and potassium chloride, XG shows higher viscosity at high temperature and remains in stable form. Moreover, when 0.2% of NaCl solution is added to XG, it imparts higher viscosity due to its intermolecular association [22].

4. Factors affecting xanthan gum production 4.1 Effect of pH Many researchers believed that neutral pH is optimum for the growth of XG. Since acid groups are present in xanthan, during the production of XG pH decreases from neutral to 5. It was also investigated that pH value of the broth keeps on increasing at a fixed interval of time; that is, after 24 h of fermentation, pH value of broth ranged from 7e8 whereas, after 48 h of fermentation, it became 8e9.5, which purely depends upon the combination of agitation and temperature conditions. Hence, it is concluded that pH control had a greater impact on the growth of xanthan but negligible effect on xanthan production [23].

4.2 Effect of temperature The effect of temperature on XG has been broadly studied. A study done by Gumus et al. suggested that optimum temperature for the production of XG is between 25 C and 34 C but different in case of culture, that is, 28 C and 30 C [24]. In addition, Cadmus et al. studied that pyruvate content decreases when culture is produced at higher temperature. In contrast, Shu et al. suggested that the production medium is the main deciding factor for the optimal temperature of production of XG [25].

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4.3 Effect of high pressure Microfludization reduced the pseudoplastic behavior of XG as well as its intrinsic viscosity. Laneuville and coworkers studied the effect of dynamic high pressure on XG. In the investigation, they found that aggregates in gel disrupt with a first high shear force which converted gel into solution without any aggregates. On further application of severe high shear force, double helix structure of XG degraded into a single chain structure. However, XG regains its structure once the applied high pressure is removed [26].

4.4 Effect of carbon sources Carbon is an essential component of the culture medium. In order to grow, each and every cell needs nutrients and these growth factors and nutrients should be used in optimum concentration. Using a different concentration of nutrients or substrates does not affect the backbone of the structure but influences its side chain structure, yield, and molecular mass. The most common source of carbon in any type of media is glucose and sucrose. The most preferred concentration of carbon for the production of XG is 2%e4%, whereas growth is inhibited when a higher concentration of carbon is used [27]. Khouryieh et al. investigated the effect of deacylation on rheological properties of xanthan-guar interaction. The findings of their study revealed that native xanthan-guar mixture showed liquidlike behavior whereas deacylated xanthan and guar gum mixture showed gellike behavior. The reason being that its double-helical structure got destabilized and its side chain flexibility also increased. Moreover, the intrinsic viscosity of the deacylated XG was found to be higher compared to native XG [28].

4.5 Influence of polymer concentration and the effect of salts The viscosity of XG solutions mainly depends on the concentration of XG added to the solution. XG produces the viscosity due to its intermolecular bonding and network-like structure. It is observed that salt may change the viscosity of XG solution. However, the change in the XG solution’s viscosity depends upon the concentration of the XG solution. The viscosity of solution declines when a small quantity of salt is added into a low concentrated solution of XG. This occurs due to less availability in the molecular network which is due to reduced electrostatic forces responsible for increasing the viscosity [29]. But when salt is added to a solution containing high concentration of XG, it increases the viscosity of solution which occurs due to enhanced interactions between the molecules of XG and salts [11,30,31].

4.6 Effect of viscosity on xanthan gum in presence of galactomannan XG solution in presence of galactomannan shows an intense increase in the viscousness due to their interaction, but this interaction is majorly affected by temperature.

Xanthan gum in drug delivery applications 127 The temperature at which galactomannan is dissolved affects the viscousness along with the mesh size of the gel [30]. It depicts the maximum size of any molecule which can pass through it, and this affects the diffusibility. Once the rate of diffusion is measured, it can be utilized in estimating the release kinetics [32].

5. Production of xanthan gum Various kinds of inexpensive substrates and nutrients are used in the production of XG. Sugarcane molasses, whey, as well as sucrose are being used as a source of carbohydrates in the production medium. In contrast, wide varieties of soy-meal peptone, yeast extract soybean, ammonium and nitrate salts have been used as a source of nitrogen in the medium. During the initial stage of production, pH starts decreasing because of the formation of organic acids whereas if pH of the medium goes below 5 then it affects xanthan production greatly. In spite of continuous production, usually batch production is preferred by the industries, which involves various steps including fermentation, thermal treatment, cells removal, recovery with alcohol drying, and milling of the gum. To get the efficient yield of XG, one must evaluate the setting of bioreactor carefully. Temperature, aeration, concentration of culture medium, pH, agitation speed, and most importantly fermentation time should be optimum [17]. Its production consists of glucose or invert sugars. Inoculums of X. campestris are introduced into fermented media using mechanically agitated bioreactors. Approximately 28e30 C temperature and aeration condition greater than 0.3(v/v) should be maintained. It is a continuous process of 100 h after which 50% of glucose gets converted into product. As the time passes, cells would grow which results in the rapid consumption of nitrogen source. For destroying the microorganism, pasteurization of broth is required after the fermentation process. For isolation, xanthan is further spray dried, precipitated in alcohol, or suspended in water [17]. To get the pure XG, dewatering and washing should be done, since it is obtained as wet solid mass [11].

5.1 Media used during production For XG production, microbe X. campestris requires special supplements of nutrients which includes macro and micronutrients, carbohydrate source, carbon source (glucose, sucrose, maltose in 2%e4%), nitrogen source (glutamate in 15 mg), amino acids, aeration, and trace quantities of organic (succinates, citrates) and inorganic nutrient supplements [2,33,34]. Carbon and nitrogen supplement concentration is usually kept at a lower level for optimum growth and production of XG. The most commonly used composition for large-scale production of XG includes sucrose (40 g), citric acid (2.1 g), ammonium nitrate (1.144 g), potassium dihydrogen phosphate (2.866 g), MgCl2 (0.507 g), sodium sulfate (0.089 g), hydrogen borate (0.006 g), ZnO (0.006 g), FeCl2 (0.020 g), CaCO3 (0.020 g), and concentrated hydrochloric acid (0.13 mL); with the pH maintained at 7 using alkali hydroxide NaOH [35].

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6. Production kinetics Various methods have been developed to optimize the production kinetics. Production kinetics is basically based on fermentation as microbe X. campestris is an aerobic microbe [36]. The models prepared are used to depict the production kinetic profiles and the oxygen content, and rate of mass transfer is usually monitored using arithmetic equations for estimating oxygen mass transfer coefficient and it is affected by variables like speed of the impeller, the rate of airflow, viscosity, and tank size [30,35]. Kinetic models prepared usually depict the time period required for the growth and development, the number of nutrients taken up, the amount of oxygen supply required, and the pattern of production of XG [36,37]. Some kinetic models show that nitrogen supply is considered to be a growth limiting factor whereas some kinetic models consider carbon source as a rate-limiting factor during the production of XG, which indirectly affects the performance of the method developed [34e36].

7. Application of xanthan gum XG has been explored for various applications including pharmaceutical product development, cosmetic products, biomedical, tissue engineering, and food items. The following section will give a detailed insight of XG application in different areas as shown in Fig. 5.3.

Figure 5.3 Potential role of xanthan gum in healthcare systems.

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7.1 Solid oral dosage form Natural polymers are nontoxic, inexpensive, highly stable, as well as compatible. When polymers, either synthetic or natural, are combined with a drug, it will release the drug in a systematic manner. These days consumers are always looking for natural ingredients in food and drugs because natural products are safe and have minimum side effects. XG has been used as controlled release matrix polymer for solid oral product development. It can provide sustained drug release alone and in combination with other polymers [37]. Ramasamy and coworkers formulated and evaluated XG- based aceclofenac tablets for colon targeted drug delivery. In this study, they prepared multilayer coated tablets which were resistant to drug release in gastric and small intestine medium but degraded easily in the colon. In vitro drug release studies showed that the release of the drug in acidic medium was negligible, that is, less than 10% but in phosphate media (6.8 pH) drug release was approximately 80% in 8 h which was considered as suitable for colon targeting [38]. Furthermore, Patel et al. formulated gastroretentive tablets using different hydrocolloids such as carbopol, hydroxypropylmethylcellulose, and XG using direct compression technique. Various physiochemical parameters were also evaluated, that is, hardness, weight variation, thickness, friability, drug content, buoyancy studies, swelling index, as well as in vitro drug release studies. In vitro release studies revealed that formulation containing XG demonstrated prolonged drug release up to 24 h and tablet remained buoyant for more than 24 h [39]. Kavitha and coworkers developed and evaluated rosiglitazone maleate floating tablets using xanthan and guar gum. The results of the in vitro drug release study showed sustained release (98%) for 12 h [40]. Butani et al. formulated venlafaxine multilayered matrix tablets using XG and hypromellose as rate controlling ingredients. Hybrid wet granulation barrier layer technology was employed for the preparation of controlled release tablets. XG was used in the barrier layers whereas hypromellose was used in the middle layer. The findings of in vitro release studies showed that it can provide sustained action for 24 h. Hence, it was concluded by the authors that bursting of the tablet at initial time points can be controlled by the addition of XG [41].

7.2 Liquid oral dosage form XG is widely used as a suspending agent and stabilizer in suspension due to its safety properties in food and drug applications. Moreover, it is soluble in water and can provide sufficient viscosity in low concentration. Devrim et al. developed and evaluated the reconstitutable suspension of ibuprofen-loaded microsphere using acrylic polymer wherein quasiemulsion solvent diffusion technique was employed for microsphere. XG was used as a suspending agent in formulating suspension. They further investigated specific properties including repose angle, redispersibility, rheological properties, pH value, drug release

130 Chapter 5 studies, and sedimentation volume. Repose angle studies revealed that all the prepared suspension powder had angle below 30 degrees which indicated powder had good flow properties. XG at a concentration of more than 0.6% showed stability in the suspension even after standing for 10 long days. Moreover, no changes were found in viscosity of xanthan solution between pH 1e13. Thus it was concluded by the author that stable suspension of ibuprofen-loaded microsphere was successfully prepared using 0.6% w/v of XG at pH 3.6 [42]. Roopa et al. developed and evaluated an antacid and antiulcer suspension containing herbal drugs. Herbal extracts of Glycyrrhiza glabra, Terminalia chebula, Terminalia belerica, Emblica Officinalis, and Turbinella rapa were used together as active ingredients in the suspension. Cold maceration process was employed to obtain the extract of herbal drugs. Different concentrations of XG were used and several parameters, that is, redispersibility, sedimentation volume, pH, and viscosity were evaluated. All the batches showed good redispersibility and high sedimentation volume, and pH of the suspension was basic, that is, 8.2. It was concluded by the authors that suspension containing 0.3% of XG along with herbal powders showed better consistency and redispersibility [43].

7.3 Ophthalmic drug delivery As the application of in situ gel or viscous dispersion helps in improving the residence time, so also the use of mucoadhesive polymers in the composition also provides similar advantages. Ceulemans and team investigated the role of XG in an ophthalmic liquid dosage form and also determined its interaction with mucin. They also examined the effect of polymer concentration, mucin concentration, sonification/boiling on the interaction between mucin and XG. Effect of sonification studies revealed that 0.2% dispersion of XG does not show any interaction whereas 1% dispersion of XG showed clear interaction [44]. In another research paper, Millazzo et al. demonstrated the effect of XG and sodium hyaluronate on corneal wound healing after photorefractive keratectomy. They formulated ophthalmic gel consisting of 1% XG and 0.15% sodium hyaluronate. The results of the study revealed that XG and sodium hyaluronate both were highly effective in healing corneal wound in 3 days and complete healing of eye was done in 9 days [45]. Faraldi and coworkers investigated the effect of an eye gel containing sodium hyaluronate and XG with the addition of antibiotic netilmicin for the treatment of posttraumatic corneal abrasions. Patients were assigned in two groups in which group A patients treated with an occlusive patch for 12 h with additional one drop of an eye drop containing 1% of XG and 0.3% of netilmicin whereas group B was treated with an occlusive patch with one drop of an ophthalmic ointment containing 0.3% of netilmicin. The results of the study revealed that administration of eye gel containing XG was able to decrease the length of occlusive patching [46].

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7.4 Buccal drug delivery Buccal drug delivery is becoming more important as it is an alternative approach for oral and parenteral route. Furthermore, the buccal cavity is easily accessible to the patients for self-administering the dosage. XG has been found suitable for buccal delivery of drugs. XG can be used as a potential drug release modifier as well as a mucoadhesive polymer for making successful buccal patches and tablets. Shiledar et al. formulated XG-based bilayer mucoadhesive buccal patches of zolmitriptan. They performed various studies like swelling index, ex vivo mucoadhesive strength, and in vitro drug release. In vitro drug release studies revealed that 43.15% of the drug was released within 15 min and then it showed a sustained release for 5 h [47]. Laffleur and coworkers studied the application of XG for treating sialorrhea. Sialorrhea is a buccal disease in which salivary flow increases due to excessive salivary reflex. XG was modified by a chemical method and mucoadhesiveness on the buccal mucosa and vapor uptake, erosion, and water uptake studies were performed. The experiment results demonstrated that modified XG showed 1.5 times more water uptake capacity compared to simple XG. In addition, there was a reduction of 2.61% of saliva when modified XG was used in contrast to unmodified XG which showed only 1.54% reduction [48].

7.5 Topical drug delivery Conventional topical drug delivery systems mainly provide local rather than systemic effect. A major limitation associated with topical formulation is its permeability through stratum corneum. Recently, nanocarrier-based topical delivery has been prepared with increased permeability compared to the conventional topical formulation. Moreover, these formulations attain therapeutic concentration within a reasonable time period along with therapeutic pharmacological action [49]. XG has been utilized as a gelling base for various conventional and nanocarrier-based topical preparations. XG provides a uniform gel with good spreadability. Bhaskar et al. formulated two different lipid nanoparticles of flurbiprofen for transdermal drug delivery using hot emulsification technique. These lipidic nanocarriers were embedded into XG gel. In vivo studies of designed gel demonstrated improved permeation and bioavailability. Moreover, gel formulations showed sustained released for 24 h [50]. In another research paper, Mishra and coworkers developed microemulsion-based XG hydrogel of liranaftate. The main aim of formulating this hydrogel was to enhance the permeation of antifungal drug. About 1.5% w/w of XG was used in the formation of a hydrogel. The findings of skin retention study of designed formulation showed six times higher drug retention capacity than the saturated liranaftate solution. The skin sensitivity studies indicated no signs of irritation or erythema [51]. Shinde et al. formulated niosomal gel of serratiopeptidase using XG. The results of the study showed good physical stability and spreadability in formulation containing XG as

132 Chapter 5 compared to the formulation without XG. This indicated that XG can be successfully used as a gelling agent with the help of dimethyl sulfoxide, that is, permeation enhancer in the formation of serratiopeptidase niosomal gel [52]. Chen et al. formulated and evaluated cream and gel consisting of zinc and copper alone or in combination. XG was used in the preparation of both cream and gel. The physical characteristics of cream and gel including viscosity, spreading, and stability showed the suitability of XG in topical preparation [53].

7.6 Advanced drug delivery The size of nanoparticles ranged from 1 to 100 nm which helps these small particles to easily get absorbed. These nanoparticles entrap or encapsulate the drug molecules to avoid its degradation. Novel drug delivery is based on two mechanisms, one is physical another is biochemical. The physical mechanism consists of erosion, osmosis, dissolution, and diffusion whereas biochemical mechanism includes monoclonal antibodies, liposomes, and vector systems. In addition, microparticles are made up of insoluble or soluble biodegradable polymers [54]. Harika et al. formulated and evaluated microsphere of lamivudine using natural polymers, that is, XG and guar gum. Solvent evaporation technique was used for the preparation of the microspheres. Particle size determination, stability studies, compatibility studies, and in vitro drug release studies were performed. Drug release studies revealed that formulation containing a higher concentration of polymer showed decreased release rate and sustained release up to 24 h. The findings of SEM studies depicted that XG-containing microspheres were rough, discrete spherical, glossy, and porous. The surface characteristics of these nanocarriers showed that xanthan can be explored in future for various drugs [55]. Mucoadhesive microsphere of metformin hydrochloride was prepared with different concentration of XG and guar gum using ionic gelation method. Designed microsphere showed drug release up to 94.96% and 92.98% at the end of 10 h which indicated controlled and prolonged release potential of XG. The results of stability studies revealed that formulation containing 93.72%e95.94% was stable up to 3 months during storage without any physical changes [56].

7.7 Brain drug delivery Intranasal route is considered as an alternative route for delivering the drug into the brain. It is a noninvasive route of administration. It can also bypass the blood-brain barrier which is the most difficult hurdle to cross for delivering the drug into the brain. Mucociliary clearance can be prevented with the help of mucoadhesive properties of XG which can prolong the contact time between mucosal layer and formulation. Samia et al. formulated carbamazepine mucoadhesive nanoemulgel for targeting the brain via the olfactory mucosa. In this formulation, 0.1% of XG was used as an anionic mucoadhesive polymer.

Xanthan gum in drug delivery applications 133 In vitro drug release, mucoadhesion, and oil droplet size studies were carried out. The findings of in vitro release study depicted that XG can be a better choice as natural mucoadhesive and rate controlling polymer for brain targeting delivery systems via olfactory mucosa [57]. Curcumin-loaded mucoadhesive liposomes coated with XG were investigated for efficient delivery to the brain via the nose. Solvent dispersion method was employed for the preparation of liposomes using XG as a mucoadhesive polymer and soya lecithin and cholesterol as solid lipid. Various studies were carried out like particle size determination, mucoadhesion, in vitro drug release, histopathological study, and ex vivo permeation. Higher drug distribution from liposomes was seen in brain, that is, approximately 1240 ng in contrast to drug solution which showed 65 ng. Thus, it can be postulated that XG-coated liposomes or other nanocarriers have the potential to deliver drug efficiently into the brain via nasal route [58].

7.8 Wound healing Disruption of the normal structure of a skin cell is defined as a wound. One of the typical responses which everyone experience after an injury occurs is a normal repair response. Basically, wounds are of two types, that is, acute wound and chronic wound. An acute wound is one which completely heals within 8e12 weeks with minimal scarring whereas chronic wound cannot completely heal within 12 weeks and can occur again. The main reason for chronic wound reoccurrence is diabetes, persistent infection, poor primary treatment, etc. Different stages of wound healing are hemostasis, inflammation, migration, and maturation. This entire process of wound healing lasts for 1 month and quite often these stages overlap. Reiss et al. studied whether wound healing was delayed by matrix metalloproteinase-9. Whenever wound occurs, there is an increased level of type IV collagenase named as metalloproteinase- 9. Their level diminishes as the wound starts healing. Recombinant prometalloproteinase-9 was developed in this study. XG and 4 aminophenylmercuric acetate were used to suspend active MMP-9. In a study of Reiss and coresearchers, wounds of 6 mm size were produced on the back of C57BL mice. These created wounds were treated with MMP-9 and measured daily. Further tissues were examined by immune histochemistry, real-time PCR, and densitometry. The findings of the study revealed that till 7 days 12% larger wounds were found in the MMP-9 injected group as compared to control. Overall, it was concluded by the authors that when the MMP-9 level is elevated in the wound it would lead to delayed healing [59]. Huang et al. incorporated silver nanoparticle into XG-based film to enhance the antimicrobial property of biomaterial. They developed transparent film using cross-linked XG and citric acid for treating and protecting the wound. Various bacterial inhibition tests and application of dressing on wound infected with methicillin resistant Staphylococcus aureus were carried out to determine the in vitro and in vivo antibacterial effect. From the in vitro antibacterial studies, it was found that when nanoparticles of silver were incorporated into

134 Chapter 5 xanthan-based film, it showed larger inhibition zone as compared to film without silver nanoparticles. Hence, it was concluded by the authors that xanthan-based biofilm containing silver nanoparticles have a potential to treat wound infection [60]. Merlusca et al. formulated an oral controlled release drug delivery system using hydrophilic xanthan-chitosan complex which acts as a protector against wound caused by neomycin. Various studies were performed, that is, SEM analysis, FT-IR spectroscopy, and in vivo study on Wistar rats. Complexation between the amino groups of chitosan and an anionic group of xanthan results in the formation of a hydrogel. The findings of in vivo studies revealed that no significant weight gain was found in rats treated with neomycin-xanthanchitosan complex whereas when rats were treated with neomycin alone decrease in weight was seen. Moreover, no significant change in biochemical parameters was observed when the complex was administered [61]. Juris et al. developed hydrogel skin scaffold from mixtures of plant extracted polysaccharides. This prepared hydrogel has the potential to fulfill the desired function of artificial skin, biocompatibility with skin cell which helps in the healing of burns. XG and konjac gum had been used in the preparation of the hydrogel. The findings of the study revealed that 83.4% of hydrogel got degraded in 28 days [62].

7.9 Dermal patches Transdermal drug delivery is convenient, safe, and can also eliminate multiple dosing profiles. Transdermal patches are adhesive in nature and can be easily adhered to the skin. The major advantage of transdermal patches over intravenous injection is patient complaint and relatively painless. It can deliver the drug into systemic circulation through the skin at a predetermined rate. XG has been explored as controlled release polymer in dermal patches. Gorle et al. formulated matrix patch of paracetamol using blends of polymers and plasticizer. XG was used as a release retarding polymer. The prepared formulation was characterized for drug content, absorption, thickness, adhesion, weight variation, in vitro permeation study, and folding endurance. The findings of the in vitro release study suggested that with an increase in the concentration of XG release rate decreases. XG-based patches showed the extended drug release (98.65%) at the end of 12 h [63]. Abu- Huwaij and coworkers formulated nicotine loaded mucoadhesive patches using XG, and carbopol-934 and ethyl cellulose was used as a backing layer. The fabricated patches showed acceptable swelling behavior, adhesive properties, drug-polymer interaction, thickness, weight variation, and drug release. XG-based patches demonstrated initial fast release followed by extended release up to 10 h. In addition, no significant effect of drug loading on mucoadhesion strength was seen in patches containing XG. Above studies and many more indicated the suitability of XG in transdermal patches. Further, it can be explored with combination of other polymers [64].

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7.10 Nasal drug delivery Nasal route is considered as an alternative route for the delivery of poor bioavailability of drugs. It is considered as the most suitable passage since it has a large surface area and an epithelium which is highly vascularized. Therefore researchers prepared mucoadhesives or in situ gel drug delivery systems for prolonging the residence time of the drugs. In situ gel usually remains in sol form at room temperature, but as soon as formulation is administered into the nasal cavity it comes in contact with nasal fluid or due to pH change it will form a gel. Thus for preparing pH-dependent in situ gel various pH-sensitive polymers are being used. XG and its combination of various other hydrophilic polymers have been studied in various nasal drug delivery systems. Saudagar et al. formulated pHdependent in situ nasal gel of loratadine. They prepared nine different formulations using different pH-sensitive polymer ratio of XG and carbopol 934. Different parameters were evaluated like pH, clarity, rheological study, stability studies, and in vitro drug release. Formulation containing 0.2% XG showed sustained drug release for 8 h [65]. Paul and his colleagues studied lamotrigine-loaded mucoadhesive in situ gel for the treatment of epilepsy using a different polymeric solution of XG and gellan gum. Various studies like in vitro drug release, histopathological, and ex vivo permeation showed suitability of XG as mucoadhesive for nasal delivery with excellent acceptability, nonirritation, and safety. Hence, it was concluded that the use of XG in formulation increases the mucoadhesion and residence time, and also enhances the gelling property of the formulation [66]. Srivastava and his team formulated thermoreversible in situ nasal gel for the treatment of allergic rhinitis. Herbal extracts of Moringa olifera and Embelia ribes were used as active ingredients in the formulation. The in situ nasal gel was prepared using a different concentration of XG with PF127 (10% w/w). The prepared formulation was characterized for mucoadhesive studies, viscosity, drug content, gelling temperature, and irritancy studies. Gel strength studies showed that addition of XG into PF 127 imparts greater gelling strength. Hence, it was concluded by the authors that viscosity of the formulation increases with increased concentration of XG or carbopol, as well as these polymers markedly prolong the residence time of drug in the nasal cavity [67].

7.11 Tissue engineering Kumar et al. revealed that XG in combination with gellan acts as an excellent vehicle for various utilities in the tissue engineering field. The XG-gellan combination can be modified to an extent where their combined properties show similar activity as that of normal tissues; these were also added with alkaline phosphatase to enhance enzymatic mineralization of scaffolds in bone-tissue engineering. XG-gellan gels, when added with chitosan-nanoparticles, proved to enhance the basic fibroblast growth factor, and bone morphogenetic protein-7 differentiation in fetal osteoblasts. It is also seen to have

136 Chapter 5 antibacterial activity against various microbes [6]. Gills et al. found that a rapidly swelling hydrogel was produced by free radical graft copolymerization process using XG-hydroxyethyl methacrylate-acrylic acid (HEMA-co-AA) super porous hydrogel (SPH). Temperature stability of SPH was found at 600 C when checked in the theorem. Due to high swelling and deswelling properties, biodegradability of the prepared SPH can be used in various tissues and biomedical field [68]. Glaser et al. investigated that when xanthan membranes (XM) were immersed into a suspension of magnetic nanoparticles (MNPs) at varied time intervals, they formed hybrid scaffolds. These hybrid scaffolds were observed to exhibit magnetization values between 0.25 emu g 1 to 1.80 emu g 1 at 70 kOe and iron particles between 0.25% and 2.3%. These hybrid scaffolds were applied as matrix during in vitro analysis of bioadhesion and neuronal differentiation of embryonic stem cells. The bioadhesion rates were found to be enhanced vigorously after the cells were seeded on XM-MNP, but hybrid scaffolds did not show any impact on the proliferation levels. Embryonic stem cells were observed to have similar differentiation rates on XM-MNP hybrid scaffolds with a magnetization value of 0.25 and 0.60 emu g 1, however, it did not show any differentiation at 1.80 emu g 1. Magnetite particles possessing magnetic field present on XG-MNP were found to increase synapse formation and electrical transmission in comparison to another hybrid scaffold on embryonic stem cells [69]. Porous lamellar membranes were prepared and studied by Bellini and coworkers using XG-chitosan combination (XG-CH) in the fixed proportions of 1:1 and 1.2:0.8 ratios for dressing of wounds and treating skin lesions. The method used for preparing XG-CH membrane was by complexation method between the two polymeric solutions and immediate casting. The porosity of the membrane was adjusted using Tween 80 or Pluronic F68, which were added prior to casting. Uses of surfactants were avoided when the membrane was meant for the dressing of the wound, which had a thickness of about 0.10 mm, with a tensile strength of 25 MPa. Whereas, when in presence of surfactants the membrane was mostly utilized as hybrid scaffolds in tissuebone engineering, the porosity of membrane was maintained uniformly throughout the matrix of XG-CH membrane, but due to the presence of Tween 80 it was found to exhibit cytotoxicity toward L929 cells; hence this combination is avoided in tissue engineering [70]. The studies revealed that XG can be further instigated in tissue engineering as one of the natural and biocompatible materials.

7.12 Cosmetic uses of xanthan gum XG is used as a thickening agent, emulsion stabilizer, and texture enhancer in cosmetic and personal care. XG forms a gel structure in water and can also be used with another viscosity modifier like guar gum which gives enhanced results. Cao et al. patented XG as a fixative in hair cosmetic composition. XG was dispersed in water and then remaining components like conditioning polymer, fixative component, and other additives were

Xanthan gum in drug delivery applications 137 mixed. The results of the study revealed that composition containing heat-treated XG showed better performance as compared to the polyvinyl pyrrolidone/carbomer hair gel in the wet comb, dry comb, stiffness, etc. [71]. Collin and his team patented eyeshadow comprising a XG, mixed silicate aqueous medium, and dyestuff. Due to the gelling agent present in the composition, it remains homogeneous on storage at 45 C for 2 months. Moreover, due to its fluidlike texture, it spreads easily on the eyelids as well as it has excellent staying power. The prepared eyeshadow can be removed easily [72]. Further, Parente and coworkers formulated bioadhesive hydrogel for skin application wherein caffeine and XG were used as a model drug and secondary polymer. Characterization was done by rheological, spreadability, adhesion, as well as in vitro release studies. In vitro studies revealed approximately 80% of drug released in less than 5 h whereas other physiochemical studies helped in selecting optimum formulation [73]. In another research paper, Saharudin and his colleagues determined the effect of XG on physiochemical and rheological properties of rice bran oil. They prepared six formulations using the emulsification process. Droplet size and zeta potential studies revealed that with an increase in XG concentration, size of the droplet, as well as its zeta potential, also increases whereas formulations which do not contain XG showed lowest droplet size. It was concluded by the author that physiochemical properties of a formulation can be improved with the use of XG [74]. A sunscreen lotion was prepared with XG by Amnuaikit and coworkers. The designed sunscreen cream showed high sun protection factor (SPF) along with organic and inorganic UV filters. XG was used in the aqueous phase of formulation whereas titanium dioxide and anisotriazine were used as UV filters in the formulation. The prepared creams were evaluated for viscosity, stability, pH, physical appearance, and in vitro SPF. The results of in vitro SPF study showed that a combination of UV filters had a synergistic effect and provided more SPF value [75].

7.13 Food XG is a biosynthetic edible gum which is widely used in the food industry. Nowadays, additives have been widely used in the baking industry. It was found that consumption of edible gums like guar gum and XG lowers the serum cholesterol. Osilesi et al. performed the study in which diabetic and nondiabetic subjects were chosen to examine the acceptability of XG (present in muffins) in their diet with a daily dose of 12 g. The results of the study revealed that consumption of XG in their diet lowered postload as well as fasting serum glucose. This investigation suggested that the use of XG in the diet may prove useful in the initial treatment of diabetes mellitus [76]. In another study, Preichardt et al. investigated the role of XG in the quality of gluten-free cakes for celiac patients. Three formulations were prepared with different XG concentrations. The physical, chemical, and sensory analyses were done by the authors. The results revealed that cakes formed with XG showed improved quality characteristics like delaying staling, enhanced

138 Chapter 5 and uniform texture, as well as increased specific volume. Moreover, the physical appearance of the prepared cake was found to be the same as that of control cake [77]. Kohajdova´ et al. examined the effect of selected hydrocolloids on the quality of baked foods. Four formulations were prepared to contain different hydrocolloids like guar gum, Arabic gum, XG, methyl 2-hydroxyl ethyl cellulose, and certain parameters were evaluated like dough development time, mixing tolerance index, degree of softening, water absorption capacity. Furthermore, crumb hardness, sensory evaluation, and quality of baked food were evaluated. Water absorption capacity studies showed that dough which contains XG absorbed more water, that is, 68.3  1 due to the hydroxyl group present in the structure. In addition, loaves containing guar gum were comparatively softer than XG during 72 h of storage. Thus it was concluded by the authors that guar gum was the better additive compared to XG due to its capability of softening and reducing firmness of the baked products [78]. Easy and high availability, excellent biocompatibility, and having the ability to mimic biologically the natural extracellular matrix make XG a versatile natural polymer for pharmaceutical, biomedical, tissue engineering, and cosmetic applications (Table 5.1). The above section of XG showed its wider applications in pharmaceutical drug delivery; cosmetic, biomedical, and food industries. Thus, XG is a promising material for further development, modification, and broader applications in advanced drug delivery and clinical practice. Table 5.1: Summarizing different applications of xanthan gum. Application

Name and year of researchers

Solid oral dosage form

Ramasamy et al. (2011)

Aceclofenac

Patel et al. (2009)

Verapamil hydrochloride

Liquid oral dosage form

Devrim et al.(2011)

Ibuprofen

Ophthalmic drug delivery

Ceulemans et al. (2002)

-

Drug

Experiment Xanthan gum is used in the preparation of aceclofenac tablets for colon targeted drug delivery. They formulated gastroretentive tablets using different hydrocolloids like hydoxypropyl methylcellulose, carbopol, and XG using direct compression technique. They developed and evaluated the reconstitutable suspension of ibuprofen-loaded microsphere using acrylic polymer. XG acts as a suspending agent. They investigated the role of XG in an ophthalmic liquid dosage form and also determined its interaction with mucin.

Ref [38]

[39]

[42]

[44]

Xanthan gum in drug delivery applications 139 Table 5.1: Summarizing different applications of xanthan gum.dcont’d Application

Name and year of researchers

Drug

Faraldi et al. (2012)

Netilmicin

Buccal drug delivery

Shiledar et al. (2014)

Zolmitriptan

-

Advance drug delivery

Laffleur et al. (2017) Harika et al. (2015)

Brain drug delivery

Samia et al. (2012)

Carbamazepine

Wound healing

Reiss et al. (2010)

Metalloproteinase-9

Dermal patches

Gorle et al. (2017)

Paracetamol

Nasal drug delivery

Saudagar et al. (2016)

Loratadine

Cosmetic

Parente et al. (2015)

Caffeine

Food

Preichardt et al. (2008)

Gluten-free cakes

Lamivudine

Experiment They investigated the effect of an eye gel containing sodium hyaluronate and XG with the addition of antibiotic netilmicin for the treatment of posttraumatic corneal abrasions. They formulated xanthan gum based bilayer mucoadhesive buccal patches of zolmitriptan. They modified xanthan gum for treating sialorrhea. They formulated and evaluated microsphere of lamivudine using natural polymer, i.e., XG and guar gum. They formulated carbamazepine mucoadhesive nanoemulgel for targeting the brain via the olfactory mucosa. They studied whether wound healing delayed by matrix metalloproteinase-9. They formulated matrix patch of paracetamol using blends of polymers and plasticizer. XG was used as a release retarding polymer. They formulated pH-dependent in situ nasal gel of loratadine using XG as a polymer. They formulated bioadhesive hydrogel for skin application wherein caffeine and XG were used as a model drug and secondary polymer. They investigated the role of XG in the quality of gluten-free cakes for celiac patients.

Ref [46]

[47]

[48] [55]

[57]

[59]

[63]

[65]

[73]

[77]

8. Conclusion XG is a well-known heteropolysaccharide obtained from microorganism X. campestris; it is obtained through a fermentation process in presence of sucrose, lactose, and other sugars. XG possesses properties like shear thinning in aqueous systems, and its viscosity

140 Chapter 5 decreases on the application of shear. The viscosity also depends on various factors like temperature, the concentration of biopolymer, concentration of salts, and pH. As XG is a biopolymer, it is nontoxic, nonirritant, noninflammatory, inert, readily available, and has excellent rheological properties. It is widely used in pharmaceutical industries for the preparation of various solid, semisolid, and liquid dosage forms. In solid dosage form, XG has been explored and commercially used in controlled release tablets and capsule formulations. In liquid oral dosage form, XG is used in order to stabilize as well as enhance the viscosity of the dosage form. Recently, XG has been investigated in advanced drug delivery systems including microparticles, nanoparticles, liposomes, ion exchange resin, buccal mucosal patches, etc., as a matrix former or coating material for either retarding the release of drug or to have targeted drug release over a prolonged duration of time. It also acts as inert diluent in nasal insert gels with strong adhesive and release retardant property. Additionally, it also enhances bioavailability in many drug formulations as shown by many investigators. The application of XG is also studied in biomedical and tissue engineering field. XG when combined with lysozyme and bovine serum albumin is used in surgical wound dressing. XG has also been utilized in preparation of cosmetic and food items. Use of XG does not cause side effects; hence, it can replace the toxic excipients. In food industries, XG is commonly used in bakery, beverages, dairy, sauces, gravies, and dressings as a thickening agent or as a stabilizer.

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