Gums’ based delivery systems: Review on cashew gum and its derivatives

Carbohydrate Polymers 147 (2016) 188–200

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Carbohydrate Polymers journal homepage: www.elsevier.com/locate/carbpol

Review

Gums’ based delivery systems: Review on cashew gum and its derivatives António J. Ribeiro d,e,∗ , Flávia R. Lucena de Souza a , Janira M.N.A. Bezerra a , Claudia Oliveira d,e , Daniela Nadvorny a , Monica F. de La Roca Soares a , Lívio C.C. Nunes b , Edson C. Silva-Filho b , Francisco Veiga c,d , José L. Soares Sobrinho a a Núcleo de Controle de Qualidade de Medicamentos e Correlatos—NCQMC, Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco—UFPE, Brazil b Laboratório Interdisciplinar de Materiais Avanc¸ados—LIMAV, Centro de Ciências da Natureza—CCN, Universidade Federal do Piauí—UFPI, Brazil c CNC.IBILI, Universidade de Coimbra, 3000-548 Coimbra, Portugal d Faculdade de Farmácia, Universidade de Coimbra, 3000-548 Coimbra, Portugal e I3S, Instituto de Investigac¸ão e Inovac¸ão em Saúde, IBMC—Instituto de Biologia Molecular e Celular, Genetics of Cognitive Dysfunction, Rua do Campo Alegre 823, 4150-180 Porto, Portugal

a r t i c l e

i n f o

Article history: Received 9 November 2015 Received in revised form 6 February 2016 Accepted 14 February 2016 Available online 18 February 2016 Keywords: Cashew gum Chemical derivatives Delivery system Physicochemical properties Purification Submicron particle

a b s t r a c t The development of delivery systems using natural polymers such as gums offers distinct advantages, such as, biocompatibility, biodegradability, and cost effectiveness. Cashew gum (CG) has rheological and mucoadhesive properties that can find many applications, among which the design of delivery systems for drugs and other actives such as larvicide compounds. In this review CG is characterized from its source through to the process of purification and chemical modification highlighting its physicochemical properties and discussing its potential either for micro and nanoparticulate delivery systems. Chemical modifications of CG increase its reactivity towards the design of delivery systems, which provide a sustained release effect for larvicide compounds. The purification and, the consequent characterization of CG either original or modified are of utmost importance and is still a continuing challenge when selecting the suitable CG derivative for the delivery of larvicide compounds. © 2016 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 Cashew gum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 2.1. Source and production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 2.2. Purification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 2.3. Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 2.4. Physicochemical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 CG blends and derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 3.1. Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 3.2. Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 3.3. Physicochemical properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .195 Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 4.1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 4.2. Pharmaceutical field . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

Abbreviations: Dox, doxorubicin; CG, cashew gum; AO, Anacardium occidentale; CMCG, carboxymethylated cashew gum; Con, concanavalin; ALG, alginate; CHI, chitosan; LsEO, Lippia sidoids essential oil; DDVP, dichlorvos [2,2-dichlorovinyldimethyl phosphate]; MOS, Moringa oleifera seeds. ∗ Corresponding author at: Faculdade de Farmácia, Universidade de Coimbra, 3000-548 Coimbra, Portugal. E-mail address: [email protected] (A.J. Ribeiro). http://dx.doi.org/10.1016/j.carbpol.2016.02.042 0144-8617/© 2016 Elsevier Ltd. All rights reserved.

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4.3. Delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

1. Introduction The pharmaceutical and food industries are constantly trying to develop delivery systems and to discover new agents that could be used in a selective form for specific applications, thus, obtaining the desired effect. Polymeric systems obtained by mixing and/or in combination with different polymers in the form of gels, particles, and networks have received attention from researchers in recent years, mainly, due to their extensive use in the pharmaceutical, medical, technological and agricultural fields (Paula, de Oliveira, Abreu, & de Paula, 2012; Yang, Han, Zheng, Dong, & Liu, 2015). Among natural polymers, carbohydrate polymers or polysaccharides have been proposed as delivery systems for compounds with activity against pathologies such as high blood pressure, cancer and diabetes. For instance, polysaccharide-doxorubicin nanoparticles prepared via conjugation of doxorubicin (Dox) to galactoxyloglucan (Joseph et al., 2014) and chitosan (Su et al., 2015) revealed superior therapeutic efficiency as compared to free Dox. Besides, they allow for postsynthetic modifications with the aim of tailoring their physicochemical properties towards an improvement of the active compound to achieve the desired action locally without suffering degradation (Liu, Jiao, Wang, Zhou & Zhang, 2008). Gums, like cellulose and alginate are polysaccharides. They differ from them in structure, more precisely in the chemical configuration and in the way the monomeric units are joined. Those monomeric units, monosaccharides or its derivatives are linked in a bewildering variety. The term gum refers to polysaccharide hydrocolloids, which do not form a part of the cell wall, but are exudates or slims (Prajapati, Jani, Moradiya & Randeria, 2013). They have a large variety of compositions and rheological properties that cannot be easily mimicked by synthetic polymers. These properties can be an advantage for several applications, for instance the preparation of solutions with a high content in solids and low viscosity, as well as its low cost, low risk of side effects, biocompatibility, environmentally friendly processing and local availability. Cashew gum (GG) is a polysaccharide extracted from Anacardium occidentale, and Brazil’s average production of CG/tree/year is 700 g, with a potential annual CG production around 50,000 tons (Cunha, Paula & Feitosa, 2009). This versatile, naturally occurring biopolymer has been used recently in the pharmaceutical (Hani, Krishna & Shivakumar, 2015; Pitombeira et al., 2015) and food industry (Porto & Cristianini, 2014). CG is a hydrophilic, branched polysaccharide with a high molecular mass whose properties have been investigated (Lima, Lima, de Salis & Moreira, 2002; Ofori-Kwakye, Asantewaa & Kipo, 2010; Owusu, Oldham, Oduro, Ellis & Barimah, 2005; Paula, Heatley & Budd, 1998), however, there is a lack of understanding of its physicochemical properties thus limiting its utilization in food and pharmaceutics. Chemical structure, solubility and molecular weight of CG closely affect its solution properties as well as its interactions with other polysaccharides. The modification of CG can improve its technological and functional properties (Porto, Augusto, Terekhov, Hamaker & Cristianini, 2015). The long-term strategy for promoting the use of CG in the industry is therefore to understand and exploit the physicochemical properties of the gum, in its original state or chemically modified, either isolated or blended with other polymers.

In this review, production, focused on purification procedures, and physicochemical properties of CG and its derivatives are described. Its current and potential applications, mainly focused on the development of submicron delivery systems such as microand nanoparticles, are described and the reported applications are explored and discussed. 2. Cashew gum 2.1. Source and production Cashew gum is an exudate extracted from A. occidentale, a popular tree known as cashew. Cashew is a rustic tree that can grow up to 12 feet tall and can be easily found in tropical countries like Brazil, mostly in the northern and northeastern regions such as Piauí, Ceará, and Rio Grande do Norte. The exudate is produced naturally by the bark’s epithelial cells in response to mechanical stimuli or attacks by pathogens. Its production can occur in all parts of the tree and its qualitative and quantitative composition depends on tree maturity and environmental conditions (Kumar, Moin, Shruthi, Ahmed & Shivakumar, 2012). The extraction is performed physically by making incisions into the bark (similar to the extraction of latex in the manufacturing of rubber) or chemically by introducing substances such as ethylene oxide, benzoic acid derivatives and 2-chloroethylphosphonic acid into the bark (Araujo, 1991). The collected brown resinous mass (Fig. 1A) is refined through solubilization, centrifugation, filtration, and precipitation in ethanol. Then it undergoes a drying step resulting in a polysaccharide rich yellow powder as we can see in Fig. 1B (Rodrigues, de Paula & Costa, 1993). 2.2. Purification Natural polysaccharides, such as gums, are often contaminated with inorganic salts, proteins, lignins, and nucleic acids that need to be separated. That is why purification must be performed, including chromatographic separation, complexation of metallic ions or quaternary ammonium salts, precipitation with ethanol or acetone, and drying (Rodrigues et al., 1993). Purification of CG has been performed over several decades accompanied by the improvement of techniques enhanced to obtain increasingly purer CG in less time. Like all biopolymers, purification is an essential step in ensuring a credible alternative to the use of synthetic polymers, however many of the disclosed processes are not described well enough in order to be understood and reproduced. CG was separated from most of its impurities and their acid constituents neutralized (Costa, Rodrigues & de Paula, 1996) as it can be seen in the flowchart of Fig. 2. The first purification aimed to replace the cations present in the gum by sodium, through the addition of excess of NaCl, and remove the remaining impurities. Upon the addition of sodium chloride the system was submitted to filtration and precipitation of the gum. The precipitated CG was washed with ethanol and acetone, and the excess sodium chloride was eliminated in the second purification step. To accomplish this second purification, CG was dissolved again in water and submitted to the same steps discriminated for the first purification. To guarantee that all the gum was in the form of a sodium salt, an ionic exchange column with NaCl at 1 M was used, followed by freeze-

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Fig. 1. Resin extracted from the cashew tree trunks (A) and cashew gum after purification (B) (Furtado et al., 2013) Photos: Roselayne Ferro.

drying. Highly pure and soluble CG was obtained, predominantly as a sodium salt. The CG purification was also performed by its dissolution in distilled water at 20 ◦ C. After one hour, the supernatant was discarded and the precipitated gum recovered (a yield of around 90%) by vacuum filtration (Britto, Rizzo & Assis, 2012). The method seems simpler than the previous, although no important parameters such as CG solution concentration, pH adjustment and CG precipitation solvent, were disclosed. In a recent method developed by the same group (Forato, de Britto, de Rizzo, Gastaldi & Assis, 2015) more details were provided. Thus, the exudate, free of bark, was milled, followed by solubilization, centrifugation, precipitation with alcohol, and drying under low pressure. The dried powder sample was designated as purified CG. 2.3. Characterization CG structure has been elucidated by various techniques under different conditions, such as immunochemical reactions, hydrolysis, methylation, periodate oxidation studies and cross reactions with different antisera (Bose & Biswas, 1985). The polysaccharide chains of CG contain arabinogalactans with a variety of side chains, including glucuronic acid residues. There are studies about the composition of CG from countries such as India, New Guinea and Brazil. Studies by (Paula et al., 1998) about the composition, structure and molecular weight distribution of Brazilian CG using different characterization techniques such as nuclear magnetic resonance (NMR) spectroscopy, gel permeation chromatography (GPC), light scattering and dilute solution viscometry, showed that the CG consists of 72% ␤-d-galactopyranose, 14% ␣−d-glucopyranose, 4.6% ␣-l-arabinofuranose, 3.2% ␣-lrhamnopyranose and 4.5% ␤-d-glucuronic acid. Moreover, three kinds of branched units within the core galactan were found: linked at C-1 and C-3, at C-1 and C-6, at C-1 and C-3 and C-6 (Fig. 3) (Paula et al., 1998). CG is a mixture of acid polysaccharides containing various metal ions such as neutralized cations. The nature and content of these constituents depend on the composition of the soil upon which the trees grew. The major cations of A. occidentale are K+ , Na+ , Ca2+ and Mg2+ . Crude CG, containing these cations, tends to be naturally transformed into Na+ salt, after purification or dialysis against NaCl 0,15 M, as previously described (Paula et al., 1998). 2.4. Physicochemical properties CG dissolves partially in water at room temperature and the dissolved portion introduces considerable viscosity decrease at pH

5.5. Heating may improve gum dissolution up to 21% (Zakaria & Rahman, 1996) and pH reduction produced only a slight reduction in the viscosity of CG without appreciable loss in viscosity, like Arabic gum (Owusu et al., 2005). Rheological studies performed on CG from Ghana in comparison to Arabic gum (Gyedu-Akoto, Oduro, Amoah, Oldham, Ellis, Opoku-Ameyaw, Asante et al., 2008; Gyedu-Akoto, Oduro, Amoah, Oldham, Ellis, Opoku-Ameyaw, Hakeem, 2008) showed that the higher the viscosity, the better the quality of the gum. CG viscosity, produced by mature trees in different locations, is higher than that produced by young trees and this may be attributed to the differences in the molecular structure and the pH (Kumar et al., 2012). Gum from mature trees generally has higher levels of protein, moisture, sugars and phenols than that from young trees (GyeduAkoto, Oduro, Amoah, Oldham, Ellis, Opoku-Ameyaw, Asante et al., 2008; Gyedu-Akoto, Oduro, Amoah, Oldham, Ellis, Opoku-Ameyaw, Hakeem, 2008). The intrinsic viscosity (limiting viscosity number) [␩] obtained for the Brazilian CG gum in aqueous NaCl was 8,8 ml/g (Paula et al., 1998) and the viscosity of an aqueous solution of CG at 2.5% (w/v) showed a Newtonian behavior with absolute viscosity of 1.4 MPa s (Silva, Paula & Feitosa, 2007). Gel permeation chromatography (GPC) of CG detected the presence of 6% polysaccharide–protein complex and, 42% polysaccharide (peak molar masses equal to 2.3 × 104 ) (Neto, Maciel, Cunha, de Paula & Feitosa, 2011). The whole gum is a low viscosity polysaccharide with an activation energy of flow characteristic of systems with little intra and intermolecular interactions (Paula & Rodrigues, 1995). The presence of glucuronic acid in CG provides anionic groups that allow the gum to interact with polycations (Furtado et al., 2013; Guilherme, Campese et al., 2005; Okoye, Onyekweli & Kunle, 2012). For instance, nanostructured layer-by-layer films were assembled using polyaniline as polycationic solutions in conjunction with CG as polyanionic solutions (Barros et al., 2012). The adsorption behavior of CG on silicon wafers and on an amino-terminated surface was investigated by means of atomic force microscopy, contact angle measurements and ellipsometry, a sensitive technique that allows protein adsorption on polymer brushes to be studied in an aqueous environment as external stimuli, such as temperature and pH, are varied (Kroning et al., 2015). Obtained results revealed a strong influence of pH on the adsorption behavior. At pH 6, CG adsorption onto bare silicon wafers is moderate due to repelling forces between negative charges on the substrate and CG glucuronic segments (Maciel, Kosaka, de Paula, Feitosa & Petri, 2007). On the other hand, hydrogen bonding may occur between substrate silanol groups and CG sugar hydroxyl groups and drive the adsorption of CG onto this substrate. In

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Fig. 2. Flowchart of purification of cashew gum. Boxes outlines and arrows represent operations and experimental conditions used: in all purification steps (black); 1st purification (blue); 2nd purification (red); 3rd purification. Adaptation of (Costa et al., 1996). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

contrast, at pH 4, the adsorption of CG onto amino-terminated substrates is favored and governed by electrostatic interactions. According to the authors, irrespective of the nature of the substrate, smooth and hydrophilic CG layers were observed. These layers become attractive surfaces toward the immobilization of lectin Concanavalin (Con). Below a pH of 4, the adsorption of lectin onto amino-terminated substrates increases proportionally with its concentration. Below a pH of 6, the adsorption behavior of Con onto CG-covered silicon wafers is similar to that found for the adsorption of lectin onto polysaccharide carboxymethylcellulose or mannose films. The strong affinity between Con and glucose is likely to depend on the amount of glucose or mannose units present in the polysaccharide, as well as the monomer units that are available for its specific sites (Maciel et al., 2007).

3. CG blends and derivatives CG reactive groups are restricted to hydroxyls, the majority, and to carboxyls. Thus, as the composition and properties of CG were disclosed, blending of CG with other polymers and/or its chemical modification were proposed to increase their reactivity as it happened with other polysaccharides such as alginate (Bui, Jeon, Um, Chung & Kim, 2015), pectin (Liang, Wang, Chen, Liu & Liu, 2015), chitosan (Benner, John & Hall, 2015), cellulose (Wang, Wang, Ma, Liu & Ning, 2015) or carrageenan (Li, Ni, Shao & Mao, 2014). Following the use of CG blended with other polymers such as polyvinyl alcohol (PVA) (Moreira, Batista, Castro, Lima & Fernandes, 2015), alginate (Oliveira, Paula & Paula, 2014), polyacrylates (Das, Nayak & Nanda, 2013) and chitosan (Abreu, Oliveira, Paula & de Paula, 2012) very interesting results have been obtained when pro-

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Fig. 3. Structural fragment from unmodified cashew gum. R represents d-mannose, l-rhamnose, l-arabinose or 1, 2-linked arabinose chains.

ducing sensing devices and delivery systems like microparticles, nanoparticles, films as we can see in Table 1. Several applications of blended CG were described, more precisely films prepared with polyaniline modified with phosphonic acid intercalated with CG were evaluated in determination of dopamine (Barros et al., 2012). A layer-by-layer film containing CG using a polyanionic solution with a potential application in theranostics’ devices (Araujo et al., 2012) and a biodegradable and bioactive CG/PVA film prepared by casting for fungal growth inhibition (Silva et al., 2012) and immobilization of papain (Silva et al., 2016) were developed successfully. Carboxymethyl CG (CMCG)/CHI microspheres (MIC) loaded with bovine serum albumin (BSA) have been prepared to modulate BSA

release (Magalhaes et al., 2009). Addition of CMCG to the CHI gel decreased the pilocarpine release rate in the medium (Maciel, Paula, Miranda, Sasaki & de Paula, 2006). Moreover, CMCG/CHI complexes were using different proportions of CHI and CMCG. The thermal stability of the polyelectrolytes (PEC) was found to be: CMCG > CHI > PECs samples (Maciel, Silva, Paula, & de Paula, 2005). These results had an impact towards the synthesis of polymers containing properties of the original polymers used in the blend. Chemical modification methods described for CG are oxidation, sulfation, copolymerization with acrylamide, crosslinking with epichlorohydrin, carboximethylation, among others, as we can see in Table 2. These modifications are very similar to the ones

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Table 1 Composition and applications of blends of cashew gum (CG) with other polymers. CG source

Polymer(s)

Purpose

Output

Reference

Anacardium occidentale (AO)

Polyaniline

Formation of nanocomposites

Barros et al. (2012)

Metallic phthalocyanines Poly(allylamine hydrochloride) Polyvinyl alcohol (PVA)

Nanobiomedical devices

Great sensitivity of the nanocomposite film for dopamine CG has potential application as electrochemical sensors

Silva et al. (2012)

PVA

Development of a material for wound dressing applications Development of a stimuli-responsive, biodegradable and bioactive film

Immobilized enzymes on the biodegradable film leads to an effective inhibition of fungal growth CG/PVA-trypsin film reveals a high number of storage/use cycles without loss of activity Easy handling of malleable film made of CG/PVA Immobilized papain remained active after storage of film for 24 h in the presence of buffer or in a dry form Loaded floating systems shows floating ability, and adequate larvicide release pattern Encapsulation efficiency (EE) up to 55%, 45–95% of its release occurs within 30–50 h NPs shows slower and sustained release of oil and loaded NPs reveals high larvicide efficacy High skin permeation flux for lidocaine hydrochloride, gels are stable without occurrence of syneresis Crosslinked CG sustains release of TH

PVA

Immobilizing biodegradable film

Alginate (ALG)

Polymeric floating system for loading of LsEO

ALG

Nanoencapsulation of LsEO

Chitosan (CHI)

Nanoencapsulation of LsEO

Polyacrylate

Preparation of topical gels

AO

Natural and cross-linked, CG and CMCG

AO

Reacetylated CHI

AO

Carboxymethylcellulose (CMC)

Preparation of tablets for sustained release of theophylline (TH) Assess the potential of CG/CHI gels for controlled release Formulations as protective coatings on intact and cut red guavas

CMCG

CHI

Assess effect on the swelling and BSA release from CHI/CMCG MIC

CMCG

CHI

Preparation and characterization of polyelectrolyte complexes (PECs)

described for other polysaccharides, but, in some cases, they need to be adjusted due to CG hydrophylicity. 3.1. Preparation Oxidation of CG hydroxyl groups provides the introduction of carbonyl and carboxyl groups. The corresponding polyuronic acids can be obtained in high yields through a selective oxidation of C-6 primary hydroxyl to carboxylic groups (Kato, Matsuo & Isogai, 2003). The oxidized CG’s structure can be seen in Fig. 4A. The oxidation of CG has been introduced by using (2,2,6,6-tetramethylpiperidin-1-yl) oxidanyl reagent (Cunha, Maciel, Sierakowski, de Paula & Feitosa, 2007) following adaptations of a previously described method (Sierakowski, Freitas, Fujimoto & Petri, 2002). CG was dissolved in distilled water followed by addition upon stirring of oxidanyl and NaBr at pH 9.3. To stop the reaction, sodium borohydride was added and the reduction process was performed for 45 min. The product was isolated by centrifugation, washed with EtOH, filtered and dried.

Addition of CG to the CHI gels decreases pilocarpine release rate Coatings based on CG associated with plasticizers (Gly) and CMC extended the shelf life of guavas CHI/CMCG MIC size varies proportionally to both charge (DS of CMCG) and molar mass of CHI PECs formed by CH and CMCG start decomposition at lower temperature than the original polysaccharides

Araujo et al. (2012)

Moreira et al. (2015)

Silva et al. (2016)

Paula et al. (2012)

Oliveira et al. (2014)

Abreu et al. (2012)

Das et al. (2013)

Kumar et al. (2014)

Maciel et al. (2006)

Forato et al. (2015)

Magalhaes et al. (2009)

Maciel et al. (2005)

The carboxymethylation of CG has also been disclosed (Silva, Feitosa, Maciel, Paula & de Paula, 2006). The CG was dispersed in water until a homogeneous paste was formed. A NaOH solution was added and the mixture was kneaded for 10 min. Then, monochloroacetic acid was added to the paste. The system was neutralized with HCl and dialyzed against distilled water. The solid carboxymethylated products were recovered by freeze-drying. The introduction of sulfate groups to CG was performed by an adaptation by Neto et al. (2011) of a method previously proposed for other polysaccharides (O’Neill, 1955; Ono et al., 2003). For this modified route the precursor of the sulfate groups was always chlorosulfonic acid. After dissolving the polysaccharide in a mixture of pyridine: formamide, the system was cooled and the sulfating agent was slowly added. After neutralizing the medium, the system is dialyzed in water for 3 days, lyophilized, dissolved in water and reprecipitated with ethanol (Neto et al., 2011). Acetylation of CG was carried out recently towards the preparation of nanoparticles by self-assembly of amphiphilic CG (Pitombeira et al., 2015). Evaluation of acetylated CG physicochem-

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Table 2 Physicochemical properties of chemically-modified cashew gum (CG). CG source

Modification

Purpose

Physicochemical properties

Reference

AO

Oxidation

Increase the polyelectrolyte behavior and amplify CG applications

Cunha et al. (2007)

AO

Carboxymethylation

Preparation and characterization of CMCG with degrees of substitution (DS) varying from 0.10 to 2.21

AO

Sulphation

Increase the reactivity towards the preparation of polyelectrolyte complexes

AO

Acetylation

AO

Copolymerization with acrylamide (AAm)

Synthesis and characterization of self-assembled NPs from less hydrophilic CG Preparation of biodegradable superabsorbent hydrogel

CG glycidyl methacrylate (CGMA)

Copolymerization with acrylamide (AAm)

Manufacture of superabsorbent hydrogels using CGMA and AAm

AO

Crosslinking with epichlorohydrin (E)

Synthesis and characterization of gels

Increased the uronic acid content of CG An augment of 10% in its solution viscosity Lower thermal stability Intrinsic viscosity of CMCG is smaller than the value for starting gum CMCG chain degradation occurs, even under less drastic reaction condition An increase of at least 4% of the solution viscosity Higher chain degradation with an increasing degree of sulfation Lower thermal stability than original CG but higher when compared to CMCG FTIR spectra show decrease of hydroxyl groups and the insertion of acetyl groups in CG structure CG-g-PAM (polyacrylamide) solution viscosity is 33 and 3.3 times higher than CG and PAM values CGMA-co-AAm superabsorbent hydrogels swelling up 1500 times and depends on CGMA content. Improved mechanical strength of CGMA-co-AAm hydrogels due to a more rigid structure Swelling of CG gels decrease with E/CG ratio Stability against thermal degradation follows the order: CGgel > CMCG > CMCGgel > CGa

a

Silva et al. (2004)

Neto et al. (2011)

Pitombeira et al. (2015)

Silva et al. (2007)

Guilherme et al. (2005)

Silva et al. (2006)

CGgel—cashew gum crosslinked gel; CMCG—carboxymethylated cashew gum; CMCGgel—carboxymethylated cashew gum crosslinked gel.

Fig. 4. Structure of chemically-modified CG. A, B, C, and D represent oxidized, sulfated, carboxymethylated and acetylated CG, respectively.

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ical properties was not focused but infrared spectroscopy analysis of both original and modified CG revealed a decrease of hydrophilic groups in acetylated CG. The copolymerization of original (Silva et al., 2007) and chemically modified (Guilherme, Reis et al., 2005) CG with acrylamide (AAm) resulted in hydrogels with higher mechanical performance. The unmodified CG was copolymerized with acrylamide as previously disclosed (Singh, Tiwari, Tripathi & Sanghi, 2004) (Toti, Soppimath, Mallikarjuna & Aminabhavi, 2004) with some modifications (Silva et al., 2007). Briefly, grafts were obtained under a continuous flow of nitrogen gas using K2 S2 O8 as the initiator. Upon heating, the monomer was added and the system kept under stirring. Acrylamide was incorporated into the system which was allowed extra stirring time, followed by the addition of acetone to precipitate CG and washing with methanol to remove the unreacted monomers (Silva et al., 2007). GCMA-co-AAm hydrogels synthesis made use also of sodium persulfate (Guilherme, Reis et al., 2005) as previous reported (Reis, Cavalcanti, Rubira & Muniz, 2003). CG was cross-linked with epichlorohydrin by another method (Appukuttan, Surolia & Bachhawat, 1977). The gum was mixed with NaOH and distilled water until a homogeneous paste was formed. After adding epichlorohydrin to the mixture and kneading for homogenization, a heating-cycle was performed and the cross-linked gel was washed with distilled water, dialyzed against distilled water and freeze-dried. 3.2. Characterization Chemical modification of CG requires a strict monitoring taking into account the different behavior of CG components’ arabinogalactans and monosaccharide units. CG groups’ substitution is likely to occur in C-6, as we can see in Fig. 4 contrarily to monosaccharide units. CG derivatives from the point of view of their chemical structure were mainly analyzed by infrared spectral analysis, nuclear magnetic resonance (NMR), rheological studies, thermal analysis and average molecular weight. Different physicochemical properties such as density, intrinsic viscosity and surface tension were assessed. The characterization of these derivatives has a high importance taking into account the large potential uses of these modified CG-based compounds. CG has low solubility in water and it also lacks of reactive groups such as sulfate, phosphate and amines, and for this reason, most of the derivatives are synthesized to improve their reactivity towards the development of more versatile modified CG. There is room to improve characterization of modified CG, more precisely a more rigorous determination of degree of substitution, the impact of modification on molecular weight and its distribution on CG. 3.3. Physicochemical properties Carboxymethylation replaces few free-OH groups, which increase the aqueous solubility of gums (Rana et al., 2011). Following CG oxidation (Neto et al., 2011) and sulfation (Neto et al., 2011) an augment of 10% and 4% in its solution viscosity, respectively, was obtained due to the effect of high degree of chain degradation that overcomes almost all the chain expansion effect of the formation of a more negative polysaccharide. Copolymerized CG with acrylamide solution viscosity is 33 times higher than CG (Silva et al., 2007). However, most chemicallymodified polysaccharides have tendency to reveal less thermal stability when compared to unmodified ones and that is of major concern. A less thermally stable CG was obtained after oxidation (Cunha et al., 2007), carboxymethylation (Silva, de Paula, Feitosa, de Brito, Maciel & Paula, 2004) crosslinking with epichlorohydrin (Silva et al., 2006) and sulphation (Neto et al., 2011).

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4. Applications Several applications have been described for CG, some of them resulting from traditional use, such as thickener or emulsifier, often attributed to the properties of gums in general. More recently, other applications of CG in completely different areas, some examples displayed in Table 1, have been suggested, thus protruding applications even within the food industry and the pharmaceutical industry, as can be seen in the following subsections. In the latter the use of CG and its derivatives is emphasized in the preparation of micro- and nano delivery systems.

4.1. General Gums are frequently used as thickening, binding, emulsifying, suspending and stabilizing agents in food and pharmaceutical industries (Prajapati et al., 2013). Some of them have also been used for the preparation of pharmaceutical formulations, due to their high swellability, non-toxicity, low cost and high availability. Arabic gum is the most common emulsifier used for beverage emulsions. When compared to Arabic gum, the CG showed a 50% higher swelling, a 36% lower oil absorption capacity, a slightly lower (4–8%) solubility and a lower viscosity (Porto, Duarte Augusto & Cristianini, 2015). Thus, CG is a feasible polysaccharide, promotes lower viscosity solutions, and reveals good swelling property. Recent evaluation of the effects of high-pressure homogenization (HPH) on the functional characteristics of CG, revealed influence in rheological properties, molecular weight, glycosyl-linkage analysis, solubility, swelling and oil absorption capacity (Porto, Augusto et al., 2015). Since CG and gum Arabic properties were found to be similar (Paula & Rodrigues, 1995) and due to the limited supply and high cost of the latter, CG has been suggested for its replacement (Andrade, Carvalho, & Takeiti, 2013). As a matter of fact, it has been assessed as a coating agent in the production of chocolate pebbles (Gyedu-Akoto, Oduro, Amoah, Oldham, Ellis, Opoku-Ameyaw, Asante et al., 2008; Gyedu-Akoto, Oduro, Amoah, Oldham, Ellis, Opoku-Ameyaw, Hakeem, 2008) among other applications.

4.2. Pharmaceutical field CG itself has revealed therapeutic applications such as gastro protectant (Carvalho et al., 2015), anti-inflammatory (Yamassaki et al., 2015) and wound dressing (Moreira et al., 2015), among others. The use of this gum as a pharmaceutical excipient has also been proposed. CG was incorporated into tablet formulations, showing that its addition increased the mechanical strength of tablets, which led to a delayed disintegration of tablets in release medium (OforiKwakye et al., 2010). The use of CG and cross-linked CG in oral and vaginal tablets potentially provides binding properties (OforiKwakye et al., 2010) and higher solubility of clotrimazol (Hani et al., 2015), respectively. The suitability of CG as a gelling agent for skin delivery of the drug aceclofenac (Kumar, Patil, Patil & Paschapur, 2009) has also been demonstrated. The prepared gels did not produce any dermatological reactions in guinea pigs and the in vitro permeation study was found to be comparable with a commercial preparation. Some studies emphasize the use of CG as a component of the matrices for the delivery of drugs, at the site of action. Acetylated chitosan (CHI)/cashew gum (CG) gel release matrix was characterized and its potential for the controlled release of pilocarpine hydrochloride was assessed. The profile release of pilocarpine from CG/CHI gels in the first 100 min is similar, where about 60% of the pilocarpine was released (Maciel et al., 2006). Then, a slowdown effect on pilocarpine release from CG-containing gels was observed.

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The release of pilocarpine from CG/CHI matrix was found to be pH independent according to a Fickian mechanism (Maciel et al., 2006). Furthermore, CG-coated particles for controlled delivery of diltiazem hydrochloride have also been developed (Gandhi, Badgujar & Kasliwal, 2011). Sugar core particles were loaded with diltiazem hydrochloride, using microcrystalline cellulose and polivinylpyrrolidone as spheronizing agent and binder, respectively. Particles were further coated with CG by varying the amount of CG in a fluidized bed processor. In vitro release studies of diltiazem hydrochloride, a highly soluble drug, from particles, shows that the drug release from the coated pellets depends on the weight of the coats applied (Gandhi et al., 2011). Another example is the use of CG for the production of buccal tablets for delivery of curcumin (Gowthamarajan, Jawahar, Wake, Jain & Sood, 2012). Following their physicochemical characterization and in vitro curcumin release behavior, results revealed a 60-day stability under different temperatures and relative humidities. Curcumin release kinetics from tablets suggested that CG could be used as a polymer to produce buccoadhesive tablets of curcumin with the potential to bypass the first pass metabolism and improve the bioavailability of curcumin. Lidocaine is an anesthetic, which offers advantages of rapid onset, intermediate action, and low systemic toxicity. This makes local topical delivery of lidocaine a favorable approach. Thus, topical gels of lidocaine HCl using CG and Carbopol® 940 as gelling agents were prepared and evaluated for pH, viscosity, and in vitro skin permeation through excised porcine skin (Das et al., 2013). The in vitro lidocaine skin permeation from these gels showed a higher flux (1568.15 ± 14.03 ␮g/cm2 /h) upon addition of menthol at 0.01% and this flux was higher than that of the marketed 4% lidocaine HCl topical gel (1355.41 ± 10.92 ␮g/cm2 /h).

4.3. Delivery systems Gums are biodegradable materials that have been used as delivery systems. However, these materials have some drawbacks, like poor control rate of hydration, thickening, decrease of viscosity upon storage, microbial contamination susceptibility and some modifications of gums are required to overcome these problems (Singh & Sharma, 2008). As already described these modifications can be performed by carboxymethylation, grafting or crosslinking of vinyl monomers onto polysaccharides so a tailor-made material for delivery systems is produced. Among several alternatives to improve the potential of gums as delivery systems, micro- and nanoencapsulation stands out. A summary of those alternatives is displayed in Table 3, even though some of them were already presented in earlier sections. As a nanoencapsulation template, NPs made of CG and acrylic acids (AA) were prepared by free radical polymerization and characterized for their physicochemical properties (Silva, Feitosa, Paula & Paula, 2009). On increasing the CG/AA ratio from 0.5 to 2.0, the yields of NPs were between 40 and 65% and an increase in particle size, from 71 to 603 nm, was observed. The behavior of CG/AA NPs was also found to be pH sensitive. In the same context, NPs made of chitosan (CHI) and carboxymethylated cashew gum (CMCG) were obtained by complexation between the two polysaccharides (Silva, Maciel, Feitosa, Paula & de Paula, 2010). NPs were prepared with CMCG with two different degrees of substitution (DS = 0.16 and 0.36). Besides, the effect of polysaccharides’ concentration, molar mixing ratio and the mixing order of reactants on particle size distribution and zeta potential were investigated. A particle size under 200 nm was obtained for particles prepared with CMCG DS-0.16 but a lower polydispersity index was obtained when particles were prepared with CMCG DS-0.36. A directly proportional increase of the concentration of CMCG on particle size was observed, while zeta

Fig. 5. Relationship between larvicide in vitro release and larval mortality from delivery systems after 24 and 48 h. In vitro release assays were performed using a delivery system/water (m/v) ratio of 1/8 for CG/ALG MIC at 25 ◦ C; 1/2 for CG/CHI NPs and CG/CHI MIC at 25 ◦ C, all of three loaded with LsEO; 4/10 for CG/CHI MIC loaded with DDVP at 30 ◦ C, and 1/4 for CG NPs loaded with MOS. Larval mortality assays were performed using a delivery system/water (m/v) ratio of 2/5 for CG/ALG MIC; 2.4/5 for CG/CHI NPs; 1.8/5 for CG/CHI MIC; 6/10 for DDVP-loaded CG/CHI MIC, 7.5/5 for MOS-loaded NP. *Missing data were not available.

potential values were positive for almost all molar mixing ratios (Silva et al., 2010). Nanoparticles made of CG/ALG were prepared by spray-drying to encapsulate LsEO (Oliveira et al., 2014). CG was used as a stabilizing and reducing agent for the “green” synthesis of Ag NP which revealed antibacterial properties (Quelemes et al., 2013). Delivery systems of drugs and others substances using CG have been gaining increased attention in the scientific community, mainly, due to their physicochemical properties, biodegradability and biocompatibility. Thus, CG relevance as matrix for delivery systems such as micro- and nanoparticles has increased over the last years as we can see in Table 3. The use of CG as a polymer in the development of delivery systems for drugs, has mainly been focused on fighting dengue disease, an arbovirus that is transmitted to humans by infected Aedes aegypti (Linnaeus) mosquitoes—the primary vector, is the most prevalent arthropod-borne viral disease in humans and is a global and national public health concern in Brazil (Teixeira, Siqueira, Ferreira, Bricks & Joint, 2013). Lippia sidoides (Ls) is a native crop of the Brazilian northeastern region, whose leaves contain an essential oil rich in thymol (54–75%), which has been shown to exhibit antimicrobial action against fungi and bacteria as well as A. aegypti larvae (the dengue vector) (Camurca-Vasconcelos et al., 2007). Ls essential oil (LsEO) has been encapsulated in several microand nanoparticles through the use of different techniques. Obtained results for every delivery system described in regard to in vitro larvicide release and biological activity, provided experimental conditions and evaluation of results allowed a minimal rigorous comparison, are displayed in Fig. 5. LsEO was incorporated in CG/ALG floating MIC prepared by ionotropic-gelation, characterized according to its physicochemical properties and evaluated for its potential as a controlled release carrier (Paula, de Oliveira et al., 2012). Floating MIC with encapsulation efficiency around 70% were obtained and release studies results showed a 5-h extended release of 70% of LsEO from particles made of low CG and high carbonate content, the latter having contributed to increase the porosity of particles. Larvicide tests against A. aegypti larvae revealed that larval mortality was enhanced by this formulation, with 45% and 85%

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Table 3 Physicochemical properties and applications of cashew gum-based delivery systems. Encapsulant composition

Size and E.E.a

Performance

Application

References

Larvicide

Paula et al. (2011)

CG

Slower and sustained release profile CHI and CHI–CG presented a prolonged release effect Controlled release system

Paula et al. (2006)

MOS

Larvicide

Paula et al. (2012)

LsEO

ALG/CG NPs

Oliveira et al. (2014)

ALG/CG MIC

Larvicide

Paula et al. (2012)

Silver (Ag)

CG silver NPs (AgNPs)

Antibacterial

Quelemes et al. (2013)

LsEO

CHI/CG nanogels

45–95% of oil is released within 30–50 h Floating microspheres with 70% of LsEO release after 5 h CG stabilizes the “green” synthesis of Ag NP which possess antibacterial properties Slower and sustained release profile >90% is released over 10 min

Larvicide

LsEO

789 ␮m 83% 1270–1530 ␮m −c 288–357 nm 39–61% 223–399 nm 55% 1700 ␮m 70% ∼ =4 nm −c

Larvicide

LsEO

Chitosan (CHI) and cashew gum (CG) CHI and CG

Larvicide

Abreu et al. (2012)

Encapsulated b

DDVP

Vitamin B12 Indomethacin a b c

Cashew nut gum microspheres (MIC) Acetylated CG

335–558 nm 70% 3–20 ␮m −c 108–314 nm 47%

Controlled drug release up to 72 h

c

N.A.

Oliveira et al. (2013)

Controlled delivery

Pitombeira et al. (2015)

Encapsulation efficiency. Dichlorvos [2,2dichlorovinyldimethyl phosphate]. Not available or not relevant.

of mortality values after 24 and 48 h, respectively (Paula, de Oliveira et al., 2012). Due to the presence of a low percentage of uronic acid units, CG is a weak polyelectrolyte with a negatively charged backbone, and a PEC made from CHI and CG was reported in 2002 (Paula, Gomes & de Paula, 2002). Later on, PEC-based microspheres (MIC) made of CG/CHI with mean diameter around 1.8 mm were prepared as a delivery system for delivering dichlorvos 2,2-dichlorovinyldimethyl phosphate (DDVP) as a larvicide for A. aegypti control using a water-in-oil emulsion method. Analysis of the in vitro release profile of DDVP from MIC made of CHI and CG/CHI revealed a similar behavior between both formulations (Paula, de Paula & Bezerral, 2006). After 30 h, DDVP release reached 66% from CG/CHI MIC. When the larvicide release reached the maximum value, approximately 60% of larvae mortality was observed, whereas, at the same time, the efficacy of the larvicide released from CHI microparticles was only 42% although the latter seemed not to have completely released DDVP even after 72 h. Overall, DDVP-loaded CG/CHI MIC could provide 45% and 85% of mortality values after 24 and 48 h, respectively (Paula et al., 2006). Fig. 5. Particulate delivery systems also made of CG and CHI, were prepared and loaded with LsEO. In vivo release and biological studies showed that both CH and CG-CHI particles (sizing over 1 mm) presented a prolonged larvicide release and LsEO-loaded particles revealed efficiency for A. aegypti larval control, respectively (Paula, Sombra, Cavalcante, Abreu & de Paula, 2011). Another larvicide agent, an extract from Moringa oleifera seeds (MOS) was encapsulated by spray-drying in a CG matrix-based nanoparticle (CG-MOS NPs) followed by nanoparticle characterization for size, morphology, extract release kinetics and larvicide activity against A. aegypti (Paula, Rodrigues, Ribeiro, Stadler, Paula & Abreu, 2012). CG–MOS NPs showed a unimodal distribution with a mean size between 288 and 357 nm. The highest encapsulation efficiency of the larvicide was around 61% and its in vitro release profiles for the CG–MOS 1:1 (w/w) and CG–MOS 2:1 (w/w) NPs showed a prolonged release effect. The CG–MOS NPs presented an effective larvicide effect on A. aegypti, where the mortality rate increased according to the MO loading. In particular, NPs prepared with a CG/MOS ratio of 1 (w/w) showed 50 and 78% of larvicide-induced mortality after 24 and 48 h, respectively. Bioassays also revealed the preservation of the active principle entrapped in the CG–MOS

NPs, which resulted in satisfactory mortality kinetics, even after 55 days of sample preparation (Paula, Rodrigues et al., 2012). Nanoparticles made of cashew gum/alginate (CG/ALG) were prepared by spray-drying to encapsulate LsEO (Oliveira et al., 2014). Nanoparticles were characterized for encapsulation efficiency and essential oil release profile, among others properties. The encapsulation efficiency was around 55% and in vitro release of oil from nanoparticles was between 45 and 95% within 30–50 h. Following kinetic studies, an oil release pattern fitting the Korsmeyer–Peppas mechanism was found. Upon addition of CG to alginate, the highest hydrophilic character of the polymer matrices was obtained, which allowed a quicker release of loaded oil. The profile of oil release from nanoparticles reveals that the concomitant use of alginate and CG for LsEO encapsulation is a delivery system with potentially tailored release rate. The nano spray-drying was used for drug delivery applications by nebulizing solutions containing different polymers to structure the respective matrices (gum arabic, cashew-nut gum, sodium alginate, sodium carboxymethyl cellulose and Eudragit® RS100) and to encapsulate a specific model drug (vitamin B12 ) (Oliveira, Guimarães, Cerize, Tunussi & Poc¸o, 2013). The added value of the use of CG for the production of solid particles using spray-drying is mainly due to its low viscosity at high concentrations, when compared to other polymers used under the same conditions. Considering the several factors affecting micro- or nanocapsulation of essential oils or other extracts by spray-drying method, more precisely chemical interactions, oxidation or volatilization of encapsulated or core material, the refinement of the spray-drying process parameters is critical (Botrel et al., 2012) and is of utmost importance to retain the essential oil followed the drying process. The description and specificity of each micro- or nanoencapsulation technique is out of the scope of this review but excellent reviews about it can be found elsewhere (Yang et al., 2015). Arabic gum has been broadly used as a protective wall material in micro- and nanoencapsulation by spray-drying. Biochemical, sensory and structural data suggest that low cost CG is a well suited alternative for essential oils microencapsulation to the more costly Arabic gum currently used in Brazil (Rodrigues & Grosso, 2008). Isoxsuprine HCl loaded particles using alginate (ALG)-CMCG polymer blends were developed through an ionotropic-gelation technique using ZnSO4 as a cross-linker (Das, Dutta, Nayak & Nanda, 2014). The effects of the polymer-blend ratio and crosslinking

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concentration on drug encapsulation efficiency (EE) and cumulative drug release at 7 h (R7h ) were optimized by a 32 factorial design. Optimized microparticles (MIC) revealed an excellent combination of high EE (79.92 ± 2.51%) and a suitable sustained drug release pattern over a prolonged period of 7 h (58.67 ± 2.26%). The microparticles’ surface morphology analyzed by SEM showed that these MIC were spherical in shape without agglomeration and at higher magnifications revealed cracks and wrinkles, which could be due to the method of preparation. The physical state of isoxsuprineloaded MIC analyzed by FT-IR and DSC indicated the formation of interpenetrating polymer network (IPN) structure between both anionic polymers and an amorphous form of the drug within ALGCMCG MIC matrix, respectively. In vitro isoxsuprine HCl released from ALG-CMCG MIC in phosphate buffer (pH, 6.8) showed prolonged sustained drug release and a Korsmeyer–Peppas model lasting over 7 h (Das et al., 2014). An increasing interest on the preparation of nanoparticles by self-assembly has been noticed. Hydrophilic polysaccharides such as CG can be hydrophobically modified resulting in amphiphilic biopolymers, which can self-assemble forming nanoparticles, and may be useful for delivery purposes. Self-assembled nanoparticles from hydrophobically modified CG were prepared towards the delivery of insoluble drugs such as indomethacin (Pitombeira et al., 2015). Followed CG acetylation self-assembled nanoparticles were produced by dialysis and characterization results revealed spherical nanoparticles, which presented a unimodal distribution with a mean size of 179 nm, which decreased upon drug entrapment (Pitombeira et al., 2015). The acetylated CG showed good colloidal stability, upon a one-year evaluation of their particle size and size distribution. In vitro release assays revealed an initial burst in the first two hours followed by an indomethacin controlled release up to 72 h (Pitombeira et al., 2015).

5. Overview The use of cashew gum (CG) is gaining prominence in the pharmaceutical field, more precisely in development of delivery systems. Advantages in the use of CG are related to their low cost and sustainability since delivery systems that make use of raw materials from natural origin are likely to cause less environmental impact. Moreover, CG physicochemical properties have been found to be similar to those of Arabic gum although their technological properties comparison still needs to be improved and, consequently, is considered as a cost-effective alternative to provide clean viscosity control and rheology in industry. Thus, CG, an exudate obtained from A. occidentale, has been used as a thickener, emulsifier, and sweetener in the food industry and as an agglutinant and compound release modifier in the agriculture and pharmaceutical fields. CG can also be utilized as a functional polymer in the development of delivery systems. The presence of glucuronic acid blocks in CG provides an anionic character to CG that allows for interactions with polycations and, consequently, the formation of polyelectrolyte complexes (PEC). A continuing challenge is matching the physicochemical properties of CG complexes to the need in a particular application. Thus, purification and, the consequent characterization of CG are of utmost importance. Consideration of different available modification strategies, using molecules with various chemical structures, molecular weights, and modified CG functionality, will often yield complexes suitable for each application. Modifications of CG such as sulfation, carboxylmethylation and acetylation aiming at the improvement of its reactivity can be effectively utilized to easier formulate micro and nanoparticles as delivery systems but, in some cases, adjustments are still neces-

sary due to the hydrophilicity of CG. Different chemically modified CGs have been used as carriers to promote and provide protection and/or sustained release of drugs, particularly larvicide compounds, through the development of micro- and especially nanoparticles. Unlike the limited repertoire available from natural sources, chemically modified CG allows for the obtainment of polymers, with controlled chemical and physical characteristics, which could revolutionize the use of this natural polymer as a substance carrier.

Acknowledgement The Brazilian authors are highly thankful to CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico e Coordenac¸ão de Aperfeic¸oamento de Pessoal de Nível Superior (CAPES) refa PVE 407317/2013-9, Brazil.

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