Guar gum: Versatile natural polymer for drug delivery applications

Accepted Manuscript Guar gum: Versatile natural polymer for drug delivery applications Archana George, Priyanka A. Shah, Pranav S. Shrivastav PII: DOI: Reference:

S0014-3057(18)31399-5 https://doi.org/10.1016/j.eurpolymj.2018.10.042 EPJ 8675

To appear in:

European Polymer Journal

Received Date: Revised Date: Accepted Date:

29 July 2018 16 September 2018 28 October 2018

Please cite this article as: George, A., Shah, P.A., Shrivastav, P.S., Guar gum: Versatile natural polymer for drug delivery applications, European Polymer Journal (2018), doi: https://doi.org/10.1016/j.eurpolymj.2018.10.042

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Guar gum: Versatile natural polymer for drug delivery applications Archana Georgea, Priyanka A. Shaha, Pranav S. Shrivastava* a

Department of Chemistry, School of Sciences, Gujarat University, Ahmedabad-380009, India

Running Title: Micro- and nano-formulations of guar gum for drug delivery

Corresponding author: Department of Chemistry, School of Sciences, Gujarat University, Ahmedabad-380009, India E-mail address: [email protected] (P. Shrivastav)

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ABSTRACT Guar gum a non-ionic polysaccharide obtained from the seeds of Cyamopsis tetragonolobus of the Leguminosae family is found abundantly in nature. It finds extensive use in a variety of fields such as food industry, textile industry, paper industry, cosmetic industry, pharmaceutical industry among many others. Guar gum being a natural polymer with several interesting properties like biodegradability, biosafety, biocompatibility and sustainability presents a potential case for use in pharmaceutical formulations and drug release studies. Although guar gum in its native form finds limited use as delivery carriers owing to its high swelling characteristics in aqueous medium, this property can be significantly altered through derivatization of functional groups, cross-linking and grafting for application in a wide spectrum of biomedical fields. This review article provides a comprehensive overview of different modifications made on guar gum through derivatization in the quest to make them more versatile for drug delivery applications. The drug entrapment efficacy and in vitro drug release from different micro- and nano-formulations using guar gum for controlled release are also assessed. Keywords: Guar gum; chemical modifications on guar gum; drug delivery; micro- and nanoformulations; drug entrapment efficacy

1. Introduction Natural gums are polysaccharides with heterogeneous composition consisting of numerous sugar units such as glucose, galactose, rhamnose, arabinose, xylose, mannose and uronic acids. They are one of the most abundant industrial raw materials having good biodegradability and lower toxicity. Many of these natural gums are known to form three dimensional interconnected molecular networks called ‘gels’. The strength of these gels primarily depends on the structure and concentration of the gum concerned, along with factors such as ionic strength, pH and temperature. Natural gums have diverse properties and are preferred over comparable synthetic polymers due to 2

their availability, lower-toxicity and pocket-friendly traits. Majority of the gums are safe enough to be consumed and are hence, widely used in the field of drug delivery and as food additives. However these advantages come with their fair share of limitations. These include drop in viscosity on storage, possibility of microbial contamination apart from uncontrolled rates of hydration and pH dependent solubility. As a result, chemical modifications can help to improve their capability for drug delivery applications [1]. This article provides a critical review on the application of guar gum as a potential carrier for drug delivery. Guar gum is a seed gum obtained from the embryos of Cyamopsis tetragonolobus, family Leguminosae, where they are stored as food reserve. It contains about 80 % galactomannan, 12 % water, 5.0 % protein, 2.0 % acidic insoluble ash, 0.7 % ash, 0.7 % fat and consists of linear chains of (1→4)-β-d-mannopyranosyl units with α-d-galactopyranosyl units attached by (1→6) linkages (Figure 1) [2]. Guar gum hydrates readily in aqueous media to produce a viscous pseudo plastic solution that has greater low shear viscosity than most other hydrocolloids [3,4]. The gelling property and enzymatic degradation of this seed gum in the colon has been reported as essential determinants for its prospects as a drug carrier. Hence, it is now being extensively used in pharmaceuticals as a potent candidate in colon targeted delivery [5-8]. While guar gum has been used as a hydrophilic matrix for controlled release of oral dosage forms, it is also used as a binder and disintegrates in solid dosage forms [9]. Chemical modifications of this seed gum by pH responsive functional groups such as –COOH, -CH3, -CONH2 and SO3H makes it a more sought after polymer for drug delivery applications [10-12].

2. Guar gum- a potential candidate for drug delivery Guar gum is a galactomannan that shows absence of uronic acid making it different from a majority of plant gums and has one of the highest molecular weights among naturally occurring water soluble polysaccharides [13]. Galactomannans are insoluble in all organic solvents except 3

formamide. When they come in contact with the aqueous media, they not only get hydrated but also form colloidal solutions of extraordinarily elevated viscosity characteristics even at very low concentrations. This is because inter-molecular chain entanglement takes place at the galactose side chains attached to mannose backbone interact with the surrounding water molecules. This entanglement increases viscosity with the increasing concentration of guar gum further inducing gelling or thickening property. Another fascinating property of guar gum is that even though it is hydrophilic, it is not hygroscopic in nature as water vapor in air merely changes its moisture equilibrium. While most of the natural gums reach their full viscosity potential after prolonged cooking, in case of guar gum it is attained in cold water itself [14]. The viscosity of guar gum solution can be more appropriately termed as apparent viscosity and like most of the hydrocolloids is strongly dependent on shear rate. With increasing shear rate the viscosity decreases and the solution start exhibiting shear-thinning properties with non-Newtonian, pseudoplastic flow [15]. Similarly when temperature increases the viscosity decreases as the water molecules around the gum molecules start losing their ordering thus disturbing the conformation [16]. As guar gum is anionic in nature, it remains stable and gives consistent viscosity over a wide pH range. The maximum viscosity is obtained in the pH range of 6-9 while the lowest at pH 3.5 [17]. Guar gum forms hydrogen bonding in aqueous medium owing to the presence of many hydroxyl groups across the chain. The mannose structure along with the galactose branches further adds to the number of exposed hydroxyl groups. This causes the product to exhibit unusual effect on other hydrated colloidal systems through hydrogen bonding. Guar gum is capable of influencing most of the systems as it can interact with organic surfaces as well as hydrated minerals. As a result it can significantly influence the electro-kinetic properties of the attached system even when present in trace amounts. Hence, it can play multiple roles such as dispersant for organic systems especially

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with hydroxyl or carboxylic functional groups and as a coagulant for inorganic systems especially for those with clay characteristics [13].

3. Extraction of guar gum The endosperm from the guar seed is separated from the hull and embryo following multistage grinding and sieving operations where they are also combined with other physical treatments to crack and separate the seed parts. The separated endosperm from the seed which is a galactomannan is commonly known as guar splits which is ground to powder for making marketable guar gum. Detailed protocols for separating the endosperms from the guar seeds are available in the literature [18]. Figure 2 gives a schematic pathway for the extraction and separation of guar gum. The usual commercial purification techniques do not offer completely pure endosperm as they contain traces of hull and germ. Guar splits when powdered contains 75-86 % water soluble galactomannan, 8.0-14.0 % moisture, 5.0-6.0 % protein, 2.0-3.0 % fiber and 0.5-1.0 % ash [19, 20]. Nevertheless slight variations are observed in the solubilization rates and viscosity from batch to batch due to its natural origin. Guar gum is widely used in food, paper, cosmetics, textiles, explosives and mining industries [21]. Based on some parameters such as viscosity of the gum, and additional impurities present, guar gum is graded as food grade and industrial grade [13].

4. Chemical modifications on guar gum Guar gum has received a great deal of attention in controlled oral drug delivery owing to its proclivity towards microbial degradation in the large intestine. More to the point, the likely use of guar gum as a colon-specific, antihypertensive and transdermal drug delivery system has also been investigated. Nonetheless, a major impediment in its usage lies in its high hydrophilic nature which leads to an invasive swelling and thereby causing rapid release of loaded drugs. To surmount this inherent shortcoming, guar gum is frequently engaged with other polymers to form interpenetrating polymer networks (IPN) which offers resilient mechanical and thermal properties to the otherwise 5

fragile hydrogel. Guar gum has also been developed in correlation with pH-sensitive polymers and explored for their competence in target specific drug delivery [2, 22]. However, native guar gum is not much of use as it has uncontrolled rates of hydration, high swelling, thickening effect, highly vulnerable to microbial attack and the complexity in controlling its viscosity due to relative fast biodegradation. Therefore, attempts have been made to overcome these issues by various derivatization processes such as methyl etherification [23], sulfation [24], hydroxyalkylation [25, 26] or carboxymethylation [27-29] (Scheme 1). Guar gum has also been partially methyl-etherified under heterogeneous reaction conditions to obtain products (methyl ether guar gum) with different degrees of substitution. The introduction of methoxyl groups in the polysaccharide chains reduces the hydrogen bonding sites on the guar backbone and thereby their tendency to aggregate [23]. Sulfated guar gum possessing antioxidant property has been prepared with low degree of substitution employing triphenylchloromethane as a protected precursor [24]. Hydroxyethyl and hydroxypropyl guar gums have been synthesized via irreversible alkylation of native guar gum with ethylene or propylene oxide in the presence of an alkaline catalyst. They show better solubility towards alcohols and are thermally and chemically stable in solution [25, 26]. Carboxymethylation has been a subject of several reports as it covers wide range of industrial applications [27-29]. Carboxymethyl guar gum is obtained by reacting guar gum with monochloroacetic acid or preferably its sodium salt following activation of the guar gum with aqueous NaOH in slurry of an aqueous organic solvent. During carboxymethylation reaction the hydroxyl groups of the guar gum molecules are first activated via alkalization to form more reactive alkoxide species which then reacts with the sodium salt of monochloroacetic acid. Other modifications on guar gum includes poly (dialdehyde) guar gum obtained by selective oxidation using sodium periodate [30] and guar gum-g-(N,N-dimethylamino) ethyl methacrylate [31] as illustrated in Scheme 2. Free radical polymerization is another promising approach to 6

synthesize guar gum-g-polyacrylamide [32] and guar gum-g-N-isopropylacrylamide [33] derivatives as depicted in Scheme 3.

5. Preparation of guar gum micro- and nano-formulations for drug delivery Various methods have been employed for the preparation of guar gum micro- and nanoformulations. This varies according to the ingredients used during the preparatory stage of the formulation. Apart from the many other singular methods, the most common approaches for the preparation of guar gum formulation specifically for drug delivery include emulsion cross linking method and ionic gelation method. Emulsion cross linking method is a widely preferred synthesis route as it creates IPN of microspheres using glutaraldehyde as a cross linking agent [31, 34], while ionic gelation is a very simple and efficient method for preparation of microspheres using milder reagents [35]. In cases when the formulation requires the polymer to be grafted, different kinds of polymerization techniques are also adopted of which the most common ones are the photo initiated free radical polymerization [36] and free radical grafting polymerization techniques [37]. In the former method the polymer is treated with a suitable photoinitiator and kept under high energy radiation while in the latter case the polymer is treated with a redox initiator to commence the polymerization process. Both the methods yield hydrogels that are capable of being used for drug delivery. Another well known method used in the early phase of drug delivery is the compression coated tablets wherein granules of polymer containing matrix, drug and suitable binders were compressed to give formulation in the form of tablets [38, 39]. However, the trend of compression tablets gave way to the era of nano-formulation. Apart from microspheres, nano-formulations have also created a mark in the field of targeted drug delivery owing to their size. The most widely approached method in case of nano-formulation is the single/double step emulsion method depending on the nature of the drug, which gives stable and uniform particle size [40, 41]. Ultrasonication [42] and simple magnetic stirring [43] are the other common methods employed for 7

the preparation of nanoparticles. However, these methods demand modification in the preparatory stage as per the nature of the drug and the reagents used. Figure 3 gives an overview of methods to prepare guar gum micro- and nano-formulations. 5.1. Guar gum microparticles At first, guar gum microparticles were developed for the oral release of the drug in the body. The first ever work reported on this was in 2002 and was based on three layer guar gum matrix tablet formulation for controlled oral delivery of metoprolol tartrate, primarily used in the treatment of angina and hypertension [38]. Multi-layer tablets have gained importance as they have layers of release retardant biodegradable polymers applied on both the sides of matrix tablets enabling the swollen hydrophilic polymer to channel the drug release after oral administration. This helps in controlled and predetermined release rate, thus sustaining the drug in systemic circulation for an extended period of time. Krishnaiah et al. [38] prepared three layer matrix tablet (TLMT) granules containing either 30 %, 40 % or 50 % of guar gum with matrix ingredients including talc, magnesium stearate (lubricant), hydroxypropylmethyl cellulose and starch, which were compressed on both the sides with granules prepared separately containing 150 mg of metoprolol tartrate with either 50 or 75 mg of guar gum. Both the matrix tablets as well as TLMT were evaluated for thickness, hardness, drug content uniformity and were subjected to drug release studies in vitro. The results showed that TLMT containing 75 mg metoprolol tartrate (with 50 % guar gum in matrix tablets) presented the required release rate in accordance with the theoretical release rate for metoprolol tartrate formulations meant for twice administration daily. The same research group worked with another drug, namely trimetazidine hydrochloride following a similar protocol and obtained comparable results [39]. The matrix granules in both the cases were prepared by wet granulation method. Both the formulations were subjected to stability studies by storing them at 40 ˚C/75% relative humidity for six months under climatic zone IV conditions to evaluate their long 8

term stability which confirmed that the formulations could provide a minimum shelf life of two years. The FT-IR analysis and DSC thermograms indicated that there was no possible interaction between the drug and the guar gum/other excipients used in the matrix tablets. The former work showed good drug entrapment but failed in providing a controlled release; while in the latter work a desired hold over controlled delivery was obtained. In another report the physico-mechanical and free volume behavior of guar gum filled polyurethane/polyacrylonitrile was studied along with its biodegradation nature using fungi Aspergillus niger where the outcome confirmed good biodegradation character of guar gum [44]. During the same course of time a polyelectrolytic hydrogel was developed using cationic guar gum and acrylic acid monomer synthesized by photoinitiated free radical polymerization [36]. This work also studied the swelling property and the in vitro analysis of cationic guar gum hydrogels cross linked with poly acrylic acid (CGG/PAA) using ketoprofen as a model drug. The purpose of developing cationic guar gum was to improve its affinity for the negatively charged groups of the components of skin and mucosa leading to increased residence time of these substrates. Chemically modified cationic polysaccharides have specific characteristics compared to naturally occurring ionic polysaccharides such as chitosan. The ionization degree is almost independent of pH in cationic polysaccharides due to the presence of quaternary ammonium substituents. The presence of a significant number of hydroxyl groups along with these substituents create possibility of different types of interactions with ionic as well as the non-ionic drugs. FT-IR studies indicated two possible interactions taking place in the polyelectrolyte complex, which includes, (i) ionic cross-links between cationic groups of guar gum (-N+(CH3)3) and the carboxylate ion of poly acrylic acid (-COO-), (ii) hydrogen bonds within CGG/PAA. It was found that the ionic bond between -N(CH3)3+ and -COO- was the strongest inducing crosslinking and preventing dissolution and excessive swelling of the polymer matrix in presence of water. The swelling experiments rendered important information on drug diffusion 9

properties which signified that guar gum hydrogels were remarkably sensitive to pH environments which was confirmed during the successive in vitro analysis. The release mechanism was studied by fitting experimental data to model equations and then calculating the corresponding parameters. Ketoprofen release had a great influence on the composition of the hydrogel. An increase in n value from 0.53 to 0.83 indicated a non-Fickian release mechanism of ketoprofen. The n value is used to characterize different release for cylindrical shaped matrices. In case of cylindrical tablets, 0.45 ≤ n corresponds to a Fickian diffusion mechanism, 0.45 < n < 0.89 to non-Fickian transport, n = 0.89 to Case II (relaxational) transport, and n > 0.89 to super Case II transport [45]. On the other hand, for tablets, the n values were found to be between 0.90 and 0.95, as a result case II transport was observed at more basic pH values, indicating that the drug release mechanism was highly influenced by macromolecular chain relaxation. The results obtained from this work inferred that guar gum hydrogels can work out as a prospective candidate for colon-specific drug delivery. Subsequently, another piece of work was done on the design and in vitro evaluation of compression coated delivery systems for colon targeting of diclofenac sodium which is widely used against colon cancer [46]. This work aimed at developing compression coated delivery systems using different proportions of guar gum along with another natural gum of similar nature called the locust bean gum with hydroxyl propyl methyl cellulose as coating materials. The outcome showed that minute quantities of the drug was released in the physiological environment of stomach and small intestine while more than 90% of the drug got released in the physiological environment of the colon which was the target area. Another work was reported in which metronidazole gel using guar gum was prepared for the local treatment of periodontitis, which was capable of fulfilling many requirements of ‘once a week’ delivery system [47]. However, this work showed the need for an improved sterilization method to make this delivery system practically compatible. Modification of guar gum to carboxymethyl guar gum has also been adopted by researchers to improve water 10

solubility, higher viscosity and longer shelf life of the polymer [48]. In one such work carboxymethyl guar gum was blended with gelatin, another natural polymer to obtain a semiinterpenetrating polymer network (semi-IPN) in the form of microspheres [34]. This was geared up by water-in-oil emulsion method to explore the controlled release of theophylline, an anti-asthmatic drug. The calculated % entrapment efficiency of the microspheres varied from 56 to 74% and was not affected by % drug loading; however, the amount of carboxymethyl guar gum and the extent of cross linking had a great influence. The release profiles were fitted to several approaches such as Zero-order, First-order, Higuchi model, Hixon-Crowell model and Ritger-Peppas equations to compare the kinetics of drug release in a quantitative manner [49]. The initial release data obtained before 10 h fitted to these equations; however, the release kinetics did not follow the First-order equation but showed improved results for Higuchi equation implying that diffusion was the dominant mode of drug transport through the matrix. For spherical and non-swellable particles, the limiting values of n are n = 0.5 for Fickian diffusion or, n = 1 for zero order release where the driving force for drug transport is the polymer relaxation mechanism while for the values in the range of 0.43
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work showed a release of 97 % of the drug, a controlled release was not observed as the microspheres developed cracks and caused rapid release of the drug from the polymer. Functionalized guar gum has also been accepted as a promising effective system in tissue engineering applications.

Collagen-poly(dialdehyde)

guar

gum (PDAGG)

based

hybrid

functionalized scaffolds were prepared that covalently immobilized with platelet derived growth factor (PDGF) - BB for tissue engineering [30]. PDGF-BB is one of the pleiotropic growth factor that promotes cell proliferation, chemotaxis and angiogenic response in vivo [50]. PDAGG cross linked collagen demonstrated a sustained release of the drug over a long period of time and was found to be compatible in tissue engineering applications. Polymeric blend microspheres of soy protein isolate (SPI) with guar gum have been studied for the controlled release of tolterodine, used in the treatment of urinary incontinence [51]. Both the materials were blended in order to enhance the mechanical properties of the carrier and also to inherit the bioactivities of the added components [52, 53]. The controlled release of the drug could be varied to different time periods by varying the concentrations of the polymers used. The drug release kinetics of the developed formulation indicated non-Fickian diffusion and could be used as a potential drug delivery system especially to facilitate the prompt release of drugs for detrusor overactivity in the human body [51]. Cross linked guar gum-g-(acrylate) porous superabsorbent hydrogels are also prepared by employing free radical initiated open air grafting polymerization technique [37]. However, the potential of this work in the field of drug delivery is yet to be realized. Recently, a pH sensitive IPN microgels of guar gum-g-poly((2-dimethylamino)ethylmethacrylate) (GG-g-PDMAEMA) and chitosin were prepared by emulsion cross linking method using glutaraldehyde as a cross linker [31]. The grafting reaction was confirmed by 1H NMR, FT-IR and DSC analysis. These microgels were used a responsive drug carriers for an anticancer agent, 5-fluorouracil and showed an entrapment efficiency of 81 %. In vitro study results revealed that the controlled release 12

characteristics of 5-fluorouracil depended on the blend ratio and crosslinking agent. Formulation containing 0.25 % (w/w) of graft polymer exhibited higher release rate for 5-fluorouracil (98 %) up to 48 h, whereas the sample with 0 % (w/w) of graft polymer showed 87 % release during the same time span. The probable reason could be due to increase in the composition of GG-g-PDMAEMA in the matrix, which is responsible for greater swelling, leading to the release of drug. Likewise, controlled release studies were also observed for formulations having plain graft polymer and pure guar gum, where it was observed that the rate of release was much slower, specifically only 79 % and 73 % up to 24 h respectively, while on the contrary blend microbeads of chitosin/GG exhibited burst release (87 %) within 9 h resulting from the respective network composition. Moreover, this IPN microgel also showed an excellent controlled release pattern going up to a desired range which was monitored by evaluating the data using different empirical equations such as Zero order, First order, Higuchi square root, Hixson-Crowell cube root and Koresmeyer-Peppas [49, 54]. The analysis report stated that the best results were fitted with Higuchi kinetic model equation suggesting diffusion controlled drug release process. The n values ranged from 0.509 to 0.908 which was in accordance with the Fickian diffusion process. Various approaches adopted to prepare guar gum based microparticles are summarized in Table 1 and the details of the micro-formulations are presented in Table 2. 5.2. Guar gum nanoparticles With the onset of nanotechnology researchers gradually shifted from microspheres to nanoparticles. The main reason for switching over to nanoparticles was to improve the targeted and controlled delivery of the drugs. The first such work was reported in 2009 wherein cross linked guar gum nanospheres were prepared by polymer cross linking method using tamoxifen citrate as model drug which is primarily used in breast cancer [40]. During the process, different solvents were tried to analyze a comparative drug loading capacity where dichloromethane was found to 13

give the best results. On cross linking guar gum with glutaraldehyde the initial burst release of the drug from the formulation got delayed and the release process took a longer time making this delivery system a sustained drug release system for the anticancer drug tamoxifen citrate [41]. The most favorable concentration of guar gum was found to be 0.5 % (w/v) while that of glutaraldehyde was 2.0 % (w/w) to obtain nanoparticles of the desired size and the drug release was found to be 87.36 %. Since glutaraldehyde is a bifunctional cross linker with two aldehyde groups at both ends, it crosslinks with the active primary hydroxyl groups of the galactose and mannose unit of guar gum by H-bonding, thus interfering with the access of water to the hydroxyl group of guar gum. This crosslinking effect notably reduces the swelling rates of guar gum by obstructing the invasion of the solvent into the nanoparticles and thereby retards the release of the drug from the formulation. It was found that in alkaline medium the cross linking of nanoparticles break and as result they start swelling as water penetrates into the polymer matrix [55]. Because of this phenomenon, the drug dispersed in the polymer matrix starts to diffuse out. Hence in this case it was found that the mechanism of drug release from the polymer matrix depended on two concurrent processes i.e. water diffusion into polymer and chain relaxation process where the overall drug release was controlled by the rate of polymer swelling caused by water diffusion. The kinetic studies of the drug release showed that the current formulation exhibited a coupling of diffusion and macromolecular relaxation which caused the drug to diffuse outward with a kinetic behavior. For efficient chemotherapy it is imperative that the drug concentration in the blood is maintained between the minimum effective therapeutic level and maximum tolerable level for long periods of time. The in vivo studies on the same also demonstrated the maximum uptake of the drug by the mammary tissue from the nano-formulation. Soon thereafter a novel carboxymethyl guar gum chemically modified multiwalled carbon nanotube (CMG-MCNT) hybrid hydrogels were prepared as a potential device for sustained trans14

dermal release of diclofenac sodium [42]. This work aimed at diminishing the toxicological profiles in the body attributable to nanofillers by functionalizing CNT to achieve trans-dermal delivery route. Strong CMG-MCNT interactions were observed with increase in MCNT concentration and the drug encapsulation efficiency was highest at 1.0 % (w/w) MCNT. Favorable drug release profile was observed showing non-Fickian type mechanism with the addition of CNTs. In order to avoid the toxic cross linkers, thermoresponsive magnetic hydrogel system was prepared for the sustained release of doxorubicin hydrochloride using aminated guar gums [56]. Inclusion of magnetic resonance imaging (MRI) agents in the injectable hydrogel helped in portraying the targeted agent and identification of the lesion sites. The in vitro studies suggested that the maximum de-gelation for all the nano-formulations prepared were around 90 % after 20 day incubation with no significant difference in their de-gelation rate. The results suggested that the prepared nano-formulation provided long term stability and could withstand up to 95 ˚C, sustained drug delivery and theranostic properties for the solid tumor treatment. A new simpler and a mild method to prepare carboxymethyl guar gum nanoparticles has been proposed by nano-precipitation and sonication [43]. Depending upon the sonication time, solvent and the stirring time, this method offers nanoparticles in the range of 12-30 nm, which may be useful in pharmaceuticals and drug delivery. Another major contribution of guar gum is in the successful development of biphasic pulsed drug release of losartan potassium by fabricating ‘Tabs in Cap’ system wherein drug loaded tablets sandwiched the erodible guar gum time spacer tablet [57]. The basic principle was encapsulating the system in non biodegradable body capped with water soluble cap. It was studied for in vitro release as well as ex-vivo continuous dissolution-absorption and stability. The evidences showed a controlled release of drug with excellent physical stability, potency and shelf life of 15 months. The in vitro release studies showed a bipulse drug release from the ‘Tabs in Cap’ system. At the beginning of the experiment the water soluble cap dissolved within 5 min, followed by 15

disintegration of drug containing tablet and the first pulse was generated with a cumulative drug release (CDR) of 93.53 % within 1 h. The second pulse with a lag time of 6 h generated a CDR of 95.12 %. More than 90 % release from both the pulses signifies the potential therapeutic efficacy of the developed system. When extrapolated to clinical environment the “Tabs in Cap” system would provide first pulse-burst release without delay to bring down rise in blood pressure in evening and second pulse after a lag time of 5 h to overcome the early morning blood pressure surge. The drug release kinetics indicated that the mechanism behind drug release was the swelling of erodible tablet succeeded by diffusion and erosion mechanism of guar gum erodible tablet. This system has immense potential for chronotherapeutics in hypertension. For the treatment of tuberculosis an effective vaccination route was developed in which the mannose moiety of guar gum was studied to bind with the mannose receptor in human body to provide a strong mucosal as well as systemic immune response [58]. Another noteworthy work involved development of guar gum based porous nano-aggregates for pulmonary delivery of antitubercular drugs, isoniazid and rifampicin. The nano-formulation used for administration through inhalation provided therapeutic drug concentrations of 30-50 % in the lungs [59]. Furthermore, a novel method to prepare nano-embedded microparticles of chitosan with guar gum showed a 5-fold reduction in number of bacilli growth in the lungs compared to free drug, thus giving a new dimension to this area of research [60]. A novel nanocomposite of biopolymeric gel beads containing silver nanoparticles (Ag-NPs), a powerful material in the treatment of microbial infections stabilized in guar gum alkyl amine (GGAA) and ciprofloxacin was studied for controlled release of both the antimicrobials [61]. Such co-encapsulated systems have developed more interest as cases of multi-resistant opportunist pathogens have increased. The release profiles and diffusional mechanism of both the antimicrobials were analyzed at different pH. The release profiles confirmed that ciprofloxacin was 16

released by pH independent diffusional mechanism while Ag-NPs release was controlled by matrix erosion. The TEM results confirmed the interaction of Ag-NPs with bacterial surfaces followed by their membrane damage. The proposed formulation was capable of providing protection against Ag-NPs degradation at acidic pH of human stomach which makes them potential carriers for oral drug delivery, preventing their degradation in gastric environment. The synergic effect of both the antimicrobials suggested the biopolymer nanocomposite as a prospective system in the treatment of chronic infections caused by multi-resistant pathogens, but optimization of the drug dosage and cytotoxicity studies still needs to be explored. In another work carboxymethyl guar gum was synthesized via ionic gelation method using Rhodamine B as model drug [62]. This nano-formulation also showed a significant drug loading capacity of around 83 % and a prolonged release of the drug controlled by pH demonstrating a sustained release profile. A burst release of 13 % was observed in simulated gastric (pH 2.2) and intestinal (pH 7.4) fluids immediately after the addition of drug loaded nanoparticles. This was probably due to a fraction of Rhodamine B present on the surface of the nanoparticles which got immediately released while coming in contact with the simulated fluids. The drug released in acidic medium over the entire length of the testing reached only 37.1 % while in alkaline environment the drug release was up to 92.7 %, indicating that the release from the nano-formulation can be controlled by pH. The drug release kinetics followed Ritger-Peppas equation which suggested an anomalous diffusion mechanism close to Fickian model (n = 0.5) for acidic conditions (pH 2.2) and a non-Fickian (n = 0.83) release profile in alkaline medium. Dose dependent cytotoxicity was also studied, which confirmed a completely non-toxic nature of the formulation. Development of biomaterials for transdermal drug delivery systems (TDDS), which have the advantages of sustained release, protection from enzymatic degradation and non-invasiveness has been the subject of study using guar gum. An ex situ approach to fabricate nanosilica reinforced 17

polyacryamide grafted guar gum nanocomposites has been reported for TDDS with significantly good cyto-compatibility and non-irritant behavior [32]. The nanocomposites containing 1.0 wt% nanosilica showed drug release of 8.58 and 24.76 % after 5 and 20 h, respectively during in vitro release study. Another promising work related to preparation of transdermal membrane using jutederived cellulose nanofibrils reinforced poly(N-isopropylacrylamide)-g-guar gum nanocomposite for drug release is also proposed [33]. The material exhibited controlled release of the drug, diltiazem up to 7.78 and 22.9 % at 5 and 20 h, respectively. The release data for both the methods were best fitted according to Korsmeyer Peppas kinetic model showing all values of n > 0.5, indicating that the drug release mechanism was controlled by swelling and diffusion. The need for advanced functional materials for biopolymers has given impetus to the development of an innovative class of versatile materials comprising of clay-biopolymer nanocomposites with promising applications in drug delivery systems and tissue engineering [6365]. Guar gum-montmorillonite bionanocomposites were prepared for the controlled release of ibuprofen [66]. These materials exhibited a reduced initial burst effect and provided sustained release for several hours in a simulated environment (pH 7.4). Release kinetics were best fitted for the Higuchi model which is generally applicable in cases where drug is released from semi-solid and solid matrices and the release is diffusion controlled. However the work requires advanced studies on the drug release as a function of pH and different ratios of clay mineral to the drug and the biopolymers. In a very recent work, mesoporous silica nanoparticle based enzyme responsive system for colon specific drug delivery was developed through guar gum capping [67]. 5Flurouracil was used as a model drug and the in vitro study demonstrated that the drug loaded formulation did not demonstrate any undesired drug release in different pH conditions of gastrointestinal (GI) tract in the absence of enzyme. In order to exhibit that the formulation was able to withstand different pH conditions of GI tract and deliver drug under the desired condition, 18

drug loaded nanoparticles (0.8 % (w/v) guar gum) was placed under simulated conditions of stomach (pH 1.2), intestine (pH 7.4) and colon (pH 6.8) in absence of any enzymes at 37˚C. No significant release of the drug was detected in the buffer mediums under the set conditions even up to 12 hours. These results established the fact that within the pH range of 1.2–7.4, the guar gum coating served as an effective capping layer and its structural integrity is least affected by strongly acidic condition. Hence, this formulation revealed a ‘zero release’ property in the simulated GI condition which can be unlocked only in the presence of any biodegrading enzyme. This system was specifically triggered by colonic enzyme mixture acting as a stimulus and subsequently the released drug caused cytostatic action in colon cancer cell lines cultured in vitro under the simulated colonic microenvironment. Details related to synthesis of guar gum based nanoparticles, their characterization and applications are described in Table 3. Further, the salient features of the prepared nano-formulations are shown in Table 4.

6.

Future prospects Guar gum being a natural polymer has shown tremendous promise as a carrier in drug

formulations. Other than acting as drug carrier, guar gum and its derivatives themselves possess certain therapeutic properties. Because of its gel forming nature, guar gum can play a significant role in lowering cholesterol and glucose level in the body [68, 69]. Guar gum and its derivatives were also found to be resistant against pathogens of cholera and diarrhea [70]. Being a water soluble substance it has shown encouraging results in relieving chronic functional bowel ailments [71]. Owing to its inherent medicinal properties, a vast area of research is opened up for using guar gum in combination with specific drugs for improved results. Modifications made on guar gum enable it to be used with a wider class of drugs which is yet to be traversed. Currently limited work has been done towards the use of guar gum in tissue engineering and biomedical fields, which still

19

remains largely untouched. This makes guar gum an ideal candidate as the next generation drug carrier.

7.

Conclusions With an innate quality of resistance to dissociation in low pH environment in stomach to gel

formation in reducing drug release and vulnerability to enzymatic and microbial degradation in the large intestine, guar gum has become a fitting candidate for controlled release of drugs. Moreover, the flexibility of this polymer to obtain a favorable drug release profile, cost-effectiveness and its adaptability to be converted into various forms such as oral drug delivery systems, tablets, matrix, coatings, nanoparticles and hydrogels adds to the growing stature of guar gum. Also, the film forming ability of this polymer makes it a candidate of choice for transdermal drug delivery devices. Although guar gum has the potential to be used a unique polymer for drug delivery applications, further research in the area of micro- and nano-formulations is imperative for targeted and sustained delivery with fewer side effects.

Funding None to declare

Declaration of interest None to declare

Acknowledgements The authors thank Department of Chemistry, Gujarat University for supporting this work. One of the authors, Priyanka A. Shah gratefully acknowledges Human Resource Development GroupCouncil of Scientific & Industrial Research (CSIR), New Delhi for Research Associate Fellowship (File No.: 09/070(0058)2K18 EMR-I).

Data availability 20

There is no experimental data to share.

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Table Captions Table 1. Synthesis of guar gum microparticles, their characterization and applications. Table 2. Characteristics of guar gum microparticles based formulations for drug delivery. Table 3. Synthesis of guar gum nanoparticles, their characterization and applications. Table 4. Characteristics of guar gum nanoparticles based formulations for drug delivery.

Figure Captions Figure 1. Typical structure of guar gum. Figure 2. Schematic flow chart for the separation and extraction of guar gum. Figure 3. Major routes for preparation of guar gum micro- and nano-formulations.

Scheme Captions Scheme 1. Reaction pathways for derivatization of native guar gum to its O-methyl, hydroxyalkylated, carboxymethyl and sulfated forms. Scheme 2. Synthesis of poly(dialdehyde) guar gum and guar gum-g-poly((2-dimethylamino) ethylmethacrylate). Scheme 3. Synthesis of polyacrylamide and polyN-isopropylacrylamide grafted guar gum via free radical mechanism. 29

Table 1. Synthesis of guar gum microparticles, their characterization and applications Sr. No. 1.

2.

3.

4.

5.

6.

Polymer used

Experimental procedure

Guar gum + drug + HPMC  granulated with 10 % w/w starch paste  granules obtained were dried at 50 ºC for 2 h  lubricated with a mixture of talc and magnesium stearate  compressed using single station tablet machine. Guar gum Guar gum + drug + HPMC  granulated with 10 % w/w starch paste  granules obtained were dried at 50 ºC for 2 h  lubricated with a mixture of talc and magnesium stearate  compressed using single station punching machine. Guar Guar gum dissolved in distilled water + 50 wt % NaOH  stirred gum/poly at room temperature for 2 h + 50 wt % CHPTAC  stirred for 12 (acrylic acid) h at 50 ºC and neutralized with 10 wt % HCl. The product obtained was precipitated and washed with ethanol. Guar gum and Drug + PVP + lactose + talc + magnesium stearate  thoroughly LBG mixed and passed through mesh  powder obtained was compressed on a single station tablet punching machine. The obtained tablets were compression coated with guar gum-LBG and HPMC in different ratios. Guar gum and Locust bean gum dissolved in hot water + guar gum under LBG constant stirring to form a gel. Guar gum

CMGG and gelatin

Characterization

Applications

Ref.

HPLC, UVSpectrophotometry, FTIR

In vitro release study in rat caecum

[38]

HPLC, UVSpectrophotometry, DSC

In vitro release study in rat caecum

[39]

FTIR, SEM, DSC

In vitro study at different pH

[36]

Micrometer screw gauge, UVSpectrophotometry, FTIR

In vitro study in rat caecum

[46]

pH-meter, viscometer, bioadhesion test

In vitro study and antimicrobial susceptibility test Empirical in vitro study

[47]

Step 1: Guar gum + 2-propanol (87 %) and stirred for 30 min at 25 Optical º C. Reacted with 5N NaOH for 1 h at 25 ºC. Monochloroacetic acid microscopy, FTIR, in 2-propanol was added and reacted at 70 ºC for 2 h. Resultant DSC, XRD, SEM mixture was cooled and washed with methanol to obtain (CMGG). Step 2: CMGG and gelatin dissolved in distilled water was mixed to form homogeneous polymer solution at 37 ˚C. Resultant solution was added to light liquid paraffin oil containing 1% span80 at 350 rpm for 10 min. Gluteraldehyde prepared in 1N HCl was

[34]

30

Sr.

7.

added to Method the formed emulsion and Model stirred drug for 2 h. TheSize hardened of preparation of the microspheres were separated and washed with n-hexane/water mixture and further with 0.1M glycine solution to obtain semi-IPN microspheres of CMGG. Guar gum and Guar gum and sodium alginate dissolved in distilled water  sodium stirred for 1 h at 1000 rpm + calcium chloride in distilled water  alginate allowed to harden in gelling bath for 30 min followed by filtration. Polymer

Entrapment

Drug release (%)

SEM, FTIR, DSC

Ref.

In vitro study in USP dissolution paddle apparatus In vitro release study using ELISA

[35]

FTIR, DSC, SEM [30] Guar gum in distilled water  stirred for 30 min + sodium º periodate in distilled water  stirred in dark at 35 C for 24 h + ethylene glycol  stirred for 1 h. Resultant solution was centrifuged to obtain PDAGG. 9. Guar gum and SPI + 10 wt% NaOH + guar gum dissolved in distilled water  FTIR, XRD, SEM, In vitro study in [51] SPI UVphosphate stirred for 2 h + 10 % wt calcium chloride with continued stirring Spectrophotometry, buffer solution for 30 min to obtain microsphere formation. 13 10. Guar gum and Guar gum dissolved in distilled water + potassium persulfate + FTIR, C NMR, [37] º acrylamide TEMED in inert atmosphere at 70–80 C for a specific time period. SEM, Elemental Resultant gel was washed, dehydrated and dried in hot air to analysis obtain guar gum-g-poly(acrylate). 11. Guar gum and Guar gum dissolved in distilled water and stirred  addition of FTIR, 1H NMR, In vitro studies [31] º chitosan DSC, SEM, TGA, at pH 1.2 and DMAEMA  moderate stirring at 60 C for 1 h  solution 7.4 purged with N2 gas for 30 min  addition of potassium persulfate, XRD º stirred at 60 C for 3 h for complete polymerization. The obtained mixture was cooled and excess acetone added for precipitation. The resultant graft copolymer washed with methanol/water (80:20) and dried. HPMC: Hydroxypropyl methyl cellulose; HPLC: High performance liquid chromatography; UV: Ultraviolet; FTIR: Fourier transform infrared spectroscopy; DSC: Differential scanning calorimetry; CHPTAC: 3-chloro-2-hydroxypropyltrimethylammonium chloride; SEM: Scanning electron microscopy; LBG: Locust bean gum; PVP: Polyvinyl pyrollidone; CMGG: Carboxymethyl guar gum; XRD: X-ray diffractometer; Semi-IPN: Semi-interpenetrating polymer network; PDAGG: Poly(dialdehyde) guar gum; SPI: Soy protein isolate; ELISA: Enzyme linked immunosorbent assay; TEMED N,N,N’,N’ tetramethylenediamine; 13C NMR: 13C Nuclear magnetic resonance spectrophotometry; DMAEMA: (N,N-dimethylamino) ethyl methacrylate; TGA: Thermogravimetric analysis 8.

Guar gum

31

No. 1.

Guar gum

2.

Guar gum

3. 4.

Guar gum/poly (acrylic acid) Guar gum and LBG

5.

Guar gum and LBG

6.

CMGG and gelatin

7. 8.

Guar gum and sodium alginate Collagen-PDAGG

9.

Guar gum & SPI

10.

Guar gum-gpoly(acrylate)

Wet granulation method Wet granulation method Photoinitiated freeradical polymerization Direct compression technique Physical method (mechanical stirring) Emulsion crosslinking method Ionic gelation technique Sodium periodate based oxidation method Solution blending & cross linking Free radical grafting polymerization technique Emulsion cross linking method

used Metoprolol tartrate Trimetazidine dihydrochloride

microspheres Tablets

efficiency _

Tablets

98.6-102.3 %

Ketoprofen

7 µm

_

Diclofenac sodium Metronidazole

Tablets

_

_

99.25 %

Theophylline

136 - 234 µm

Nateglinide

_

[38]

68.5 % in simulated gastric environment 99.8 % within 2-4 h 98.03 %

[39]

[47]

54 – 74 %

78.23 % for 7 days 60 % by 26 h

781 – 842 µm

53 – 73 %

97 % in 10 h

[35]

_

15 ± 7 µm

_

_

[30]

Tolterodine

_

_

[51]

_

5.87 µm

_

100 % release in 12 h _

Guar gum-g- poly((25-Fluorouracil 130 ± 20 µm 26 – 78 % 98% in 48 h dimethylamino) ethylmethacrylate) Table 2. Characteristics of guar gum microparticles based formulations for drug delivery. LBG: Locust bean gum; CMGG: Carboxymethyl guar gum; PDAGG: Poly(dialdehyde) guar gum; SPI: Soy protein isolate 11.

[36] [46]

[34]

[37]

[31]

Table 3. Synthesis of guar gum nanoparticles, their characterization and applications 32

Sr. No. 1.

Polymer used

Experimental procedure

Characterization

Applications

Ref.

Guar gum

DLS, HPLC, SEM, FTIR

--

[40]

2.

Guar gum

SEM, TEM, HPLC

CMGG and MWCNT

In vitro release study in USP dissolution apparatus. In vivo studies in female albino mice. In vitro studies in Franz diffusion cell.

[41]

3.

4.

Aminated guar gum

UV-Vis spectrophotometry, FTIR, XRD, EDX, VSM, HR-SEM, HR-TEM

In vitro release study was done by incubating in phosphate buffered saline solution.

[56]

5.

CMGG

FTIR, SEM, TEM, HR-TEM

--

[43]

6.

Guar gum

Addition of Span 80 and dichloromethane to an aqueous solution of guar gum under constant stirring  after mutual saturation glycerol was added, followed by glutaraldehyde. Resultant nanosuspension was centrifuged at 20,000 rpm at 0 º C for 30 min. Addition of Span 80 and dichloromethane to an aqueous solution of guar gum under constant stirring  after mutual saturation glycerol was added, followed by glutaraldehyde. Resultant nanosuspension was centrifuged at 20,000 rpm at 0 º C for 30 min. MWCNT in acid mixture ultrasonicated for 1 h at room temperature and then at 70 ºC for 4 h  filtered and washed till neutral pH. The obtained MWCNT was ultrasonically dispersed in CMGG. Step 1: Ethylene diamine + guar gum + sodium borohydride + distilled water  homogenized for 30 min. Resultant solution was precipitated and washed with acetone to obtain aminated guar gum particles. Step 2: Ferric chloride + Ferrous sulphate  stirred at room temperature for 30 min. ammonium hydroxide added to attain pH 10  the black colored precipitates of iron oxide obtained were sonicated for 30 min  addition of sodium sulfide and stirred for 30 min; followed by addition of zinc acetate and stirring for 3 h. Obtained precipitates of CSNP washed with acetone and dried at 55 ˚C. Step 3: CSNP and AGG solutions were sonicated at 37 ˚C for 15 min to obtain injectable hydrogels. CMGG dissolved in deionized water kept at stirring overnight  resultant solution sonicated for 1h  addition of acetone under constant stirring to obtain whitish precipitates of CMGG nanoparticles. Guar gum + spray dried lactose sifted through mesh number

Vernier caliper,

In vitro study in USP

[57]

FTIR, TGA, 13 C NMR, PLM, SEM

[42]

33

80 + magnesium stearate and talc  blended to obtain homogeneous mixture  tablet on single punch tablet machine.

hardness test, tablet disintegration test machine, UV-Vis spectrophotometry

7.

Guar gum with antigens

Ethanol + water added to solution of guar gum containing Ag85A antigen  obtained particles spray dried using mannitol and L-leucine.

SEM, Zeta sizer, UV-Vis spectrophotometry, confocal microscopy

8.

Guar gum

Guar gum + cold distilled water, stirred + Tween 80 + fixed ratio of ethanol and water  spray dried by mannitol and leucine to obtain powder.

Particle size analyzer, SEM, UVspectrophotometry

9.

Guar gum, chitosan and mannan

Guar gum + cold distilled water + Tween 80  stirred at room temperature for 1 h. Milky solution obtained was filtered through membrane filter to obtain nanoparticles.

Zeta sizer, SEM

10.

Alkyl amine Guar gum & Agnanoparticles CMGG

Alkyl amine guar gum and silver nitrate stirred vigorously  added to pre heated water bath at 60 ºC  resultant conjugates separated by ethanol, washed with water and precipitated by ethanol in water. Guar gum dissolved in distilled water  stirred for 2h under N2 + NaOH + chloroacetic acid  stirred overnight  adjusted pH 7  nanoparticles extracted by acetone and separated by centrifugation. Guar gum dissolved in distilled water  stirred in N2 atmosphere for 30 min at 50 ºC + potassium persulfate at 75 ºC for 6h + hydroquinone. The obtained precipitates are washed with aqueous methanol and dried under vacuum.

UVspectrophotometry, SEM, TEM

11.

12.

Guar gum and acrylamide

1

H and 13C NMR, FTIR-ATR, GPC, TG-DTG, SEM, DLS, NTA FTIR, 13C NMR, TEM, FESEM, rheological measurement

apparatus. Ex vivo study on everted chicken stomach and intestine. In vitro study carried out in simulated gastric and intestinal fluid. In vivo studies were done in female balb mice. In vitro study was done with the help of dialysis tubing technique. In vivo studies were carried out on Wistar rats of both sexes. In vitro study was carried out in Anderson cascade impactor. In vitro study carried out in simulated gastrointestinal conditions. In vitro study was carried out using cell cultures and cytotoxicity assay. In vitro toxicity assay. Skin irritation test on albino rats

[58]

[59]

[60]

[61]

[62]

[32]

34

13.

Guar gum, jute cellulose and NIPAA

14.

Guar gumMontmorillo nite

Guar gum dissolved in distilled water  stirred for 30 minutes at 50 ºC  cooled to ambient temperature. Add NIPAA solution (under N2 atmosphere) + potassium persulfate + TEMED. Hydroquinone was added to terminate the reaction. Precipitates were obtained on addition of excess acetone  washed with ethanol and dried. Clay dispersed in distilled water + guar gum  constant magnetic stirring for 2 weeks  a part dried at 50 ºC and ground with an agate mortar. Remaining part recovered by centrifugation at 5000 rpm. CTAB + NaOH at 80 ºC + TEOS under vigorous stirring  white precipitates  crude product obtained was centrifuged and washed with deionized water and ethanol and subsequently dried.

Viscometer, FTIR, 13 C NMR, DLS, XRD, FESEM, TGA, DSC, WVP

In vitro study in a Franz diffusion cell. Skin irritation test on albino rats.

[33]

XRF, XRD, SEM, EDS, CEC, TGDTG

In vitro study was [66] performed using a modified membrane dissolution method. 15. Mesoporous TEM, FESEM, In vitro release study [67] silica DLS, UVwas carried out on nanoparticles spectrophotometry, enzymatic activity as with guar FTIR, TGA, BET, well as cell gum capping BJH, XRD proliferation assay. DLS: Dynamic light scattering; HPLC: High performance liquid chromatography; SEM: Scanning electron microscopy; FTIR: Fourier transform infrared spectroscopy; TEM: Transmission electron microscopy; MWCNT: Multi-walled carbon nanotube; TGA: Thermo gravimetric analysis; 13C NMR: 13C Nuclear magnetic resonance spectrophotometry; PLM: Polarized light microscopy; AGG: Aminated guar gum; CSNP: core-shell nanoparticles; UV: Ultraviolet; EDX: Energy dispersive X-ray analysis; VSM: Vibrating sample magnetometer; HR-SEM: High resolution-scanning electron microscopy; HR-TEM: High resolution-transmission electron microscopy; FTIR-ATR: Fourier transform infrared spectroscopy-Attenuated total reflectance; GPC: Gel permeation chromatography; TG-DTG: Thermogravimetry-Differential thermogravimetry; NTA: Nanoparticle tracking analysis; NIPAA: Poly(N-isopropylacryl amide); DSC: Differential scanning calorimetry; WVP: Water vapor permeability; XRF: X-ray fluorescence spectroscopy; EDS: Energy dispersive spectrometer; CEC: Cation exchange capacity; CTAB: N-cetyltrimethylammonium bromide; TEOS: Tetraethylorthosilicate; BET: Brunauer-Emmett-Teller model; BJH: Barrett-Joyner-Halenda method

35

Table 4. Characteristics of guar gum nanoparticles based formulations for drug delivery. Sr. Polymer Method of Model drug Size of the Entrapment No. preparation nanoparticles efficiency 1. Guar gum Single step Tamoxifen 200-300 nm _ emulsion citrate 2. Guar gum Single step Tamoxifen 200-300 nm _ emulsion citrate 3. CMGG & Ultrasonication Diclofenac _ _ MWCNT sodium 4. AGG Amination Doxorubicin 16 ± 1.5 _ followed by hydrochloride synthesis of Fe-nanoparticles 5. CMGG Stirring _ 12 – 30 nm _ 6. Guar gum Direct Losartan _ 93.5 - 97.1 % compression potassium 7. Guar gum with Precipitation Ag85A antigen  895.5 nm 82.87 % antigens

Drug release

Ref.

_

[40]

87.36 % over a period of 12 h _

[41]

90 % after 20 days of incubation

[56]

_ >90 % release in 12 h

[43] [57]

12 % of antigen released in simulated gastric fluid after 4 h Initial burst release of 20 % in isoniazid and 5 % in rifampicin Cumulative release: 30 min for isonaizid and 2 h for rifampicin

[58]

[42]

8.

Guar gum

Precipitation

Isoniazid and Rifampicin

 1186.6 nm

50-60 %

9.

Guar gum

Precipitation

Isonaizid and Rifampicin

Guar gum with Ag- nanoparticles CMGG

Ciprofloxacin

63.44 % (Isonaizid) 52.43 % (Rifampicin) 65.6 – 85.4 % _

[60]

10.

1300 nm (Isonaizid)  1425 nm (Rifampicin) _

Rhodamine B

208 nm

33.5 – 83.2 % 92.7 %

[62]

Diltiazem hydrochloride

13-90 nm

_

[32]

Diltiazem

328.77 nm

_

12.

Guar gum and acrylamide

Modified process Modified process Free radical polymerization

13.

Guar gum, jute

Free radical

11.

8.58 % and 24.76 % drug release after 5 and 20 h, respectively 7.78 and 22.9 % drug

[59]

[61]

[33] 36

cellulose and polymerization hydrochloride release after 5 and 20 NIPAA h, respectively 14. Guar gumSolvent Ibuprofen _ 16.3 – 68.7 % _ [66] Montmorillonite intercalation 15. Mesoporous silica Sol-gel process 5-Fluorouracil _ _ 76.8 % in 72 h [67] nanoparticles with followed by guar gum capping capping CMGG: Carboxymethyl guar gum; MWCNT: Multi-walled carbon nanotube; AGG: Aminated guar gum; NIPAA: Poly(Nisopropylacrylamide)

37

38

39

40

41

42

43

Graphical abstract

44

Highlights



Functionalized guar gum with tuned physicochemical properties for controlled drug delivery applications



Guar gum based micro-formulations includes emulsion cross linking and ionic gelation method



Cross-linking of guar gum creates an interpenetrating polymer networks with mechanical and thermal properties



Most widely used approach for nano-formulation is the single/double step emulsion method

45