Xylan extracted from corn cobs was used to produce mesalamine-loaded xylan microparticles (XMP5-ASA) by cross-linking polymerization using a non-hazardous cross-linking agent. The microparticles were characterized by thermal analysis (DSC/TG), X-ray diffraction (XRD), Infrared spectroscopy (FTIR-ATR) and scanning electron microscopy (SEM).
Carbohydrate Polymers 250 (2020) 116929 Contents lists available at ScienceDirect Carbohydrate Polymers journal homepage: www.elsevier.com/locate/carbpol Xylan microparticles for controlled release of mesalamine: Production and physicochemical characterization ´ria Maria Oliveira Alves b, Camila de Oliveira Melo c, Silvana Cartaxo da Costa Urtiga a, Vito b Marini Nascimento de Lima , Ernane Souza d, Arcelina Pacheco Cunha e, ´gila Maria Pontes Silva Ricardo e, Elquio Eleamen Oliveira b, Eryvaldo So ´crates Tabosa Na Egito a, * a Graduate Program in Health Sciences, Federal University of Rio Grande Norte, Gen Gustavo Cordeiro de Faria, 59010-180, Natal, Rio Grande Norte, Brazil Department of Biology, State University of Paraíba, Hor´ acio Trajano, 58070-450, Jo˜ ao Pessoa, Paraíba, Brazil c Federal University of Paraíba, Conjunto Presidente Castelo Branco III, 58033-455, Jo˜ ao Pessoa, Paraíba, Brazil d University of Michigan, College of Pharmacy, 428 Church St., Ann Arbor, Michigan, 48109, USA e Laboratory of Polymers and Materials Innovation, Department of Organic and Inorganic Chemistry, Sciences Center, Federal University of Cear´ a, Campus of Pici, 60455-760, Fortaleza, Cear´ a, Brazil b A R T I C L E I N F O A B S T R A C T Keywords: Mesalazine Biopolymer Hemicellulose Drug delivery systems DDsolver Xylan extracted from corn cobs was used to produce mesalamine-loaded xylan microparticles (XMP5-ASA) by cross-linking polymerization using a non-hazardous cross-linking agent The microparticles were characterized by thermal analysis (DSC/TG), X-ray diffraction (XRD), Infrared spectroscopy (FTIR-ATR) and scanning electron microscopy (SEM) A comparative study of the in vitro drug release from XMP5-ASA and from gastro-resistant capsules filled with XMP5-ASA (XMPCAP5-ASA) or 5-ASA was also performed NMR, FTIR-ATR, XRD and DSC/TG studies indicated molecularly dispersed drug in the microparticles with increment on drug stability The release studies showed that XMPCAP5-ASA allowed more efficient drug retention in the simulated gastric fluid and a prolonged drug release lasting up to 24 h XMPCAP5-ASA retained approximately 48 % of its drug content after h on the drug release assay Thus, the encapsulation of 5-ASA into xylan microparticles together with gastro-resistant capsules allowed a better release control of the drug during different simulated gastrointestinal medium Chemical compounds studied in this article: Sodium trimetaphosphate (PubChem CID 24579) Mesalamine (PubChem CID 4075) Introduction Over the last years, biopolymers extracted from agricultural wastes have received a great attention in several research fields, of which xylan has substantial importance (Lucena, Costa, Eleamen, Mendonỗa, & Oliveira, 2017; Oliveira et al., 2010; Samanta et al., 2012, 2015) Xylan, the most common hemicellulose and the second most abundant biopolymer in the plant kingdom, can be extracted from many different agricultural products including wheat straw, corn stalks and cob, sor ghum and sugar cane, hulls and husks from starch production, as well as from forest and pulping waste products from hardwoods and softwoods ´ & Heinze, 2000; Kayseriliog ˘lu, Bakir, Yilmaz, & Akkas¸, (Ebringerova 2003) Several beneficial properties related to xylans have been reported in the literature, such as antiphlogistic effects, immune function, anti mutagenic activity, inhibitory action on the growth rate of tumors and ´ & Heinze, 2000; Ebringerov antimicrobial activity (Ebringerova a, , Alfo ădi, & Hr ́balova ´, 1998; Melo-Silveira et al., 2012, Hrom´ adkova 2019) Additionally, studies reported that xylan has the ability to remain intact in the physiological stomach environment and small intestine, once its complete degradation requires the activity of several enzymes specifically produced by human colonic microflora (Rubinstein, 1995) Such characteristic would allow the use of this polymer as a suitable raw material for the development of a colon-specific mesalamine (5-ASA) drug (Oliveira et al., 2010) 5-ASA is an anti-inflammatory drug commonly used on the treatment of Crohn’s disease and ulcerative colitis (Mladenovska et al., 2007) However, the conventional oral administration of 5-ASA is associated to * Corresponding author at: Department of Pharmacy, Federal University of Rio Grande Norte, Rua Gen Gustavo Cordeiro de Faria, SN, CEP 59010-180, Natal, Rio Grande Norte, Brazil E-mail address: socrates@ufrnet.br (E.S.T Egito) https://doi.org/10.1016/j.carbpol.2020.116929 Received March 2020; Received in revised form August 2020; Accepted August 2020 Available online 17 August 2020 0144-8617/© 2020 Elsevier Ltd This article is made available under the Elsevier license (http://www.elsevier.com/open-access/userlicense/1.0/) S.C.C Urtiga et al Carbohydrate Polymers 250 (2020) 116929 its absorption through the upper gastrointestinal mucosa, which is responsible for the low bioavailability that compromises its pharmaco logical effect in the colon region and causes several side-effects including nephrotic syndrome, hepatitis and pancreatitis (Palma et al., 2019; Sardo et al., 2019) Thus, 5-ASA delivery systems have been developed to overcome these limitations, thereby, delivering maximal amount of drug in the colon (Günter et al., 2018; Palma et al., 2019) In this context, limited studies aiming the 5-ASA encapsulation into xylan microparticles have been performed Nagashima-Jr and coworkers produced 5-ASA-loaded xylan microcapsules by interfacial cross-linking polymerization using terephthaloyl chloride as the crosslinking agent (Nagashima-Jr et al., 2008) Despite its development success, this system presented high toxicity, indicating that it does not exhibit biological safety (Marcelino et al., 2015), probably due to re sidual cross-linkers presence It has been know that cross-linkers such as epichlorohydrin, glutaraldehyde and terephthaloyl chloride are toxic and the presence of residues could lead to major side effects, like DNA-damage and cytotoxicity (Li, Wang, Li, Bhandari et al., 2009, Li, Wang, Li, Chiu et al., 2009; Marcelino et al., 2015) To overcome this drawback, 5-ASA-loaded xylan microcapsules were produced by spray-drying process, an alternative that avoids the use of cross-linking agents (Silva et al., 2013) However, the kinetic release of the drug from the microparticles showed that spray-dried formulations completely released the drug once in contact with the buffer medium due to the formation of pores on the microparticles surface related to intrinsic characteristic of the polymer (Nagashima-Jr et al., 2008; Silva et al., 2013) The aim of the present work was to prepare 5-ASA-loaded xylan microparticles (XMP5-ASA) intended to 5-ASA controlled release and colon specific delivery Therefore, a cross-linking polymerization method using a safe cross-linking agent was used in order to obtain the microparticles Physicochemical characterization, including micropar ticles size, morphology, drug content and drug–polymer interaction, was performed A comparative study of the in vitro drug release from XMP5ASA and from gastro-resistant capsules filled with XMP5-ASA (XMPCAP5-ASA) or 5-ASA alone was also performed In addition, the use of mathematical models of drug release was used to explain the drug release from such delivery systems First, the corn cobs were dried at 50 ◦ C for 72 h and grinded Subse quently, the corn cobs powder was washed with water for 24 h at 25 ◦ C The residue (Residue I) was recovered by filtration and dried at 50 ◦ C for 24 h To remove impurities, the Residue I was pre-purified with 1.3 % (v/v) sodium hypochlorite for h at 25 ◦ C The same procedure of filtration and drying was carried out and the Residue II was obtained The Residue II was treated with % (v/v) sodium hydroxide for h, at 25 ◦ C, to obtain the Extract I This extract was neutralized and xylan was separated by settling down after methanol addition The xylan (precip itate) was separated by filtration, washed several times with methanol and isopropyl alcohol and dried at 50 ◦ C for h 2.3 Characterization of xylan 2.3.1 Quantification of free reducing sugars, total phenolic compounds and protein Free reducing sugars quantification was performed by Gas Chroma tography (GC) (Model GC-2010 Plus, Shimadzu, Japan) coupled to a Flame Ionization Detector (FID) (FID-2010 Plus, Shimadzu, Japan) The hydrolysis of hemicellulose and derivatization of monosaccharides were obtained according to the literature with some modifications (Lakhera & ´ndez- Kumar, 2017; Pazur, Miskiel, & Liu, 1987; Ruiz-Matute, Herna ´ndez, Rodríguez-Sa ´nchez, Sanz, & Martínez-Castro, 2011; Sca Herna larone, Chiantore, & Riedo, 2008) Individual neutral sugars of the xylan preparations were analyzed, after hydrolysis, by GC, in the form of alditol For acid hydrolysis of 10 mg of sample, mol L− of trifluoro acetic acid was used for h at 100 ◦ C Residues of free monosaccharides were converted to alditols by reduction with 22 mg of sodium borohy dride (NaBH4) Then, samples and standards reduced to alditols were acetylated using acetic anhydride and pyridine (2:1 v/v) The alditol acetates were dissolved in chloroform and analyzed with a VF-5 ms inert % phenylmethyl polysiloxane column (60 m × 0.25 mm ×0.25 μm) A gun ACC-5000 model for self-injection of samples (1 μL) and standards were used The analyses were made with a split ratio of 1:20 for a better resolution of the peaks under analysis by GC-FID The carrier gas was nitrogen (0.838 mL.min− 1) and the injector temperature was settled at 280 ◦ C and the detector (FID) at 300 ◦ C The injections were performed with a heating ramp programmed initially at 190 ◦ C for min, in the sequence, varying from 190 ◦ C to 230 ◦ C, with a rate of ◦ C/min, and at the end, remained at 280 ◦ C, for The protein content of the samples was determined based on the total Nitrogen (N × 6.25), measured by the Kjeldahl method according to the American Association of Cereal Chemists American Association of Cereal Chemists (AACC) (1995), and the total phenolic content, by the Folin-Ciocaulteau assay using gallic acid as calibration standard ´s, 1999) (Singleton, Orthofer, & Lamuela-Ravento Materials and methods 2.1 Materials Sodium hydroxide, liquid paraffin, and acetic acid were purchased from Vetec®, Chemical (Duque de Caxias, Rio de Janeiro, Brazil) Span® 80, 5-ASA, sodium trimetaphosphate (STMP), trifluoroacetic acid, acetic anhydride, pyridine, chloroform, gallic acid, N,N-dimethylformamide, N,N-dimethylacetamide, lithium chloride, dimethyl sulfoxide-d6 anhy drous (DMSO-d6) and sodium phosphate monobasic and dibasic (com ponents of sodium phosphate buffer) were purchased from Sigma˜o Paulo, Sa ˜o Paulo, Brazil) Tween® 80 and methanol Aldrich Co (Sa ˜o Paulo, Sa ˜o Paulo, Brazil) Acetone were purchased from Sol-Tech (Sa ˜o Paulo, Brazil) and ethanol were purchased from Cin´etica (Jandira, Sa Petroleum ether was purchased from Panreac (Barcelona, Spain) Iso propyl alcohol was purchased from Isofar (Duque de Caxias, Rio de Janeiro, Brazil) Water was obtained from deionization, followed by a reverse osmosis process using a Deionizer system, Model Osmose10 LX ˜o Paulo, S˜ GEHAKA (Sa ao Paulo, Brazil) The corn cobs were kindly ˜o” (Joa ˜o Pes provided by the commercial establishment “Casa Serta soa, Paraíba, Brazil) on March 2015 All chemicals were of analytical grade and used as received without any further purification 2.3.2 Gel permeation chromatography The identification of xylan molecular weight was performed by Gel Permeation Chromatography (GPC) The GPC analysis of xylan was performed on two Shodex SB-803 M HQ (8 mm × 300 mm) and SB806 M HQ (8 mm × 300 mm) columns protected by a Shodex SB-G (6 mm × 50 mm) pre-column using a chromatography system (SHI MADZU LC-10AD, Kioto, Japan) with refractive index detectors RID10A and UV–vis SPD-20A The columns, guard column and injection system were maintained at 80 ◦ C An adapted method was used for GPC analysis (Shatalov, Evtuguin, & Pascoal-Neto, 1999) The eluent (N, N-dimethylformamide 100 %) was pumped at a flow rate of 0.9 mL min− and injection volume of 20 μL Xylan was dissolved in N, N-dimethylacetamide (DMAc) containing 0.5 % lithium chloride (LiCl) (w/v) and filtered in a 0.45 μm Millipore Millex-FH (Polytetrafluoro ethylene (PTFE)) filter before analysis The average molecular weight of the xylan was obtained using polystyrene calibration standards, based on the studies of Fundador, Enomoto-Rogers, Takemura, & Iwata (2012) The standard polystyrenes were obtained from Allcrom’s PSS-PSKITL brand (Sao Paulo, Brazil) with molar masses in a magnitude 2.2 Extraction of xylan from corn cobs The extraction and purification of xylan from corn cobs were per formed following the methodology described by Oliveira et al (2010) S.C.C Urtiga et al Carbohydrate Polymers 250 (2020) 116929 range of 102 to 106 Da The experiments were performed in triplicate pH 7.4 and kept at 25 ◦ C ± under magnetic stirring for 24 h After wards, the suspension was sonicated (amplitude of 40 % and 20 KHz) for The suspension was filtered using nylon filter (0.45 μm) The amount of 5-ASA encapsulated was determined through UV/Vis Spec trophotometry (SP2000UV, Spectrum, Brazil) at λ =330 nm using a previously validated spectrophotometric method, and the following parameters: y = 0.0203x + 0.0406, R2 = The entrapment efficiency (EE%) was calculated by the following equation: 2.3.3 Nuclear magnetic resonance H and 13C Nuclear Magnetic Resonance (NMR) spectra of xylan were recorded on a spectrometer (Model Varian Unity Plus 400 MHz, Quebec, Canada) at 400 MHz for 1H and 100 MHz for 13C, in DMSO-d6 at 25 ± 0.1 ◦ C 2.4 Preparation of 5-ASA-loaded xylan microparticles EE% = (Quantified drug content ữ Initial drug content added) ì 100 The 5-ASA-loaded xylan microparticles (XMP5-ASA) were prepared according to the method described by Urtiga et al (2017) with modi fications using the cross-linking polymerization method, following four main steps: (i) the aqueous phase was prepared by dissolving xylan, 5-ASA and STMP, the cross-linking agent, in mL of NaOH 0.6 M so lution under magnetic stirring for 10 at 50 ◦ C; (ii) the oil phase was prepared by dissolving 0.75 g of a mixture of Span® 80 and Tween® 80 (9.7:1 w/w) in 15 mL of liquid paraffin under mechanical stirring (IKA, ˜o Paulo, Brazil) at 50 ◦ C for min; (iii) 1.5 mL Model RW 20 DIGITAL, Sa of aqueous phase was added into oil phase dropwise using a mL glass pipet with an internal ending tip diameter of 1.5 mm and kept under high stirring at 50 ◦ C for h, until microparticles formation; (iv) the microparticles were settled by centrifugation and the supernatant was discarded Then, they were washed with acetone, petroleum ether and ethanol Afterwards, the microparticles were dried at 25 ◦ C for 24 h and kept in sealed vials (1) 2.5.6 In vitro Drug release 5-ASA-loaded microparticles were placed into dialysis bags (MW cut˜o Paulo, Brazil), sealed and dropped off 12,000 Da, Sigma-Aldrich®, Sa into the release medium An experiment was also performed using mi croparticles placed into gastro-resistant Capsules (ReleaseCaps™, ˜o Paulo, Brazil) (XMPCAP5-ASA), added into dialysis FagronCaps™, Sa bags, sealed and dropped into the release medium, following sink con dition The system was kept at 37 ± ◦ C with continuous magnetic stirring at 100 rpm Considering the transit time and the pH values prevailing at different segments of the gastrointestinal tract, the in vitro drug release study was performed following a gradient of pH The dialysis bag containing the formulation was first immersed in 0.1 M HCl (pH 1.2) for h to simulate the gastric medium Thereafter, to simulate mid jejunum, the system was transferred to phosphate buffer (pH 6.0) and the drug release study was continued for h Finally, the dialysis bags containing the formulation were immersed in phosphate buffer (pH 7.4) to simulate the colon region until complete 24 h of experiment Aliquots were withdrawn at predetermined time points and immediately replaced with the same volume of dissolution medium The drug quantification was determined by UV spectrophotometry (SP2000UV, Spectrum, Brazil) at 302 and 330 nm for HCl 0.1 M and phosphate buffer media, respectively In order to determine the mechanism of drug release from the for mulations, the experimental data were fitted to different kinetic models using Excel® add-in DDSolver (Zhang et al., 2010) The main mathe matical models were, then, analyzed (Table 1) The model that best described the release data was evaluated based on the adjusted coeffi cient of determination (R2 adjusted), the standard deviation of the re siduals (RMSE) and the model selection criterion (MSC) The most appropriate method will be that with the biggest R2 adjusted, smaller RMSE and largest MSC (Zhang et al., 2010) 2.5 Characterization of the microparticles 2.5.1 Particle size distribution and morphology The microparticles size distribution was determined by laser diffraction method (CILAS, Model 1090, Orl´eans, France) at range of 0.10–500 μm The microparticles morphology was studied by scanning electron microscopy (SEM) at 15 kV (Model ZEISS LEO 1430, Jena, Germany) The samples for SEM studies were mounted on metal stubs with double-side adhesive carbon tapes and coated with gold/palladium under argon atmosphere 2.5.2 Fourier transform infrared-attenuated total reflectance (FTIR-ATR) spectroscopy analysis The interaction between the components during the cross-linking process was evaluated by FTIR-ATR spectroscopy (Spectrum 65, Wal tham, Massachusetts, USA) The FTIR-ATR spectroscopy measurements were performed using the samples on solid state The samples were placed on the crystal area and the pressure arm was positioned over the crystal / sample area Each sample was subjected to scans at cm− resolution at room temperature using acetone to clean the crystal be tween the samples The runs were carried out from 4000 to 700 cm− Results and discussion 3.1 Characterization of xylan from corn cobs Chemical analyses of xylan were summarized in Table The major sugar components were xylose, arabinose and glucose Minor amounts of galactose, mannose and rhamnose were also detected It has been know that the arabinose/xylose ratios reflect the degree of branching of xylan chains by arabinosyl residues, allowing to predict the polymer solubility In fact, higher arabinose contents can be related to the ´ & Hroma ´dkova ´, 2010; polymer hydrosolubility (Ebringerova ´, Kova ´ˇcikova ´, & Ebringerova ´, 1999) Thus, the arabino Hrom´ adkova se/xylose ratio of our xylan-type hemicellulose was 0.19, revealing that the xylan extracted in this work has poor water solubility In addition, the analyses of protein and phenolic compounds showed the presence of a small content of these components (Table 1) Ac cording to the literature, xylan-type hemicellulose isolated from annual plants is usually contaminated with phenolic acids, proteins, and pectin ´ et al., 1999) Therefore, its functional properties may be (Kaˇcur´ akova affected by the presence of minor amounts of phenolic compounds, which, by coupling with polysaccharide chains through ferulic acid di mers, are responsible, at least partially, for the insolubility of annual ´kov´ plant heteroxylans (Kaˇcura a et al., 1999) 2.5.3 X-Ray diffraction (XRD) XRD analyses were performed for all formulations and components Measurements of X-ray scattering angle were conducted with a copper anode (CuKα radiation, λ = 0, 15418 nm, 40 kV, 20 mA) fixed to the diffractometer (Bruker, Model D8Advance, Karlsruhe, Germany) A scanning rate of 2◦ /min throughout the range of - 60◦ 2θ was used to determine each spectrum 2.5.4 Thermogravimetry (TG) and differential scanning calorimetry (DSC) TG and DSC analyses were performed with a NETZSCH STA, Model 449 F3- JUPITER, Selb, Germany) Approximately 10 mg of the samples (microparticles, xylan and 5-ASA) were placed in alumina pan and heated from 25 to 450 ◦ C at a rate of 10 ◦ C.min− under a Nitrogen flow of 100 mL.min− 2.5.5 Entrapment efficiency (EE) A total of 50 mg of microparticles was suspended in phosphate buffer S.C.C Urtiga et al Carbohydrate Polymers 250 (2020) 116929 Table Chemical composition of xylan-type hemicellulose isolated from corn cobs Compound Phenolic compounds (%)a Proteins (%) a Xylan 1.26 1.38 Molar ratio % Xyl Rha Ara Gal Glc Man 64.65 5.17 12.64 2.81 11.04 3.69 Xyl = Xylose; Rha = Rhamnose; Ara = Arabinose; Gal = Galactose; Glc = Glucose; Man = Mannose a Expressed as % of dry matter Concerning the xylan molecular weight, the GPC results revealed a value of 31,300 g mol− with a polydispersity index of 1.06 Similar value was found by Ren and co-workers who isolated xylan-type hemi cellulose from wheat straw with a molecular weight of 26,800 g.mol− and polydispersity of 2.93 (Ren, Sun, Liu, Cao, & Luo, 2007) The same results were also detected in xylan-type hemicellulose isolated from woods and pups of Eucalyptus spp and Betula pendula (molecular weight between 24,000–31,000 g.mol− 1) and in wood pulp and brewer’s spent grain (17,000–19,000 g.mol− 1) (Laine et al., 2015; Pinto, Evtuguin, & Pascoal-Neto, 2005) On the other hand, xylan-type hemicelluloses extracted from corn cobs with molecular weight between 130,000–880, 000 g.mol− were also found in the literature (Dhami, Harding, Eliz ´ et al., 1998; Hrom´ ´ abeth, & Ebringerov´ a, 1995; Ebringerova adkova et al., 1999; Melo-Silveira et al., 2012; Van Dongen, Van Eylen, & Kabel, 2011) The differences in molecular weight, even within the same raw material, can be explained by the seasonality and by the different ´ & Heinze, 2000) extraction methods (Ebringerova The 1H and 13C NMR spectra of xylan from NMR analyses (Fig 1) confirm that the powder obtained from corn cobs was mainly consti tuted by xylan-type hemicellulose Proton and carbon signals were assigned by comparing the spectrum of xylan taken as a reference and the chemical shifts detected in previous studies (Cordeiro, Almeida, & Iacomini, 2015) The 1H NMR spectrum depicted in Fig 1A revealed that the β-(1→ 4)linked D-Xylpiranose units were characterized by the signals at δ 3.04, 3.21, 3.25, 3.49, 3.95 and 4.25 ppm, which correspond to H-2, H-5a, H3, H-4, H-5e and H-1, respectively Furthermore, it is noted that the two signals found downfield at δ 5.02 and 5.14 ppm were related to the protons of the hydroxyl groups attached to the C-3 (–C–OH, δ 5.1 ppm) and the C-2 (–C–OH, δ 5.2 ppm) positions of the D-xylpiranose units in xylan (Fundador et al., 2012; Habibi, Mahrouz, & Vignon, 2005) Additionally, a slight peak at δ 5.3 ppm was also observed, indicating the presence of 4-O-methylglucuronic acid (Fundador et al., 2012) The 13C NMR spectrum of xylan–type hemicellulose (Fig 1B) pre sented five signals at δ 102.21 (C-1), 75.88 (C-4), 74.39 (C-3), 73.08 (C2) and 63.69 (C-5) ppm, which were characteristic of D-xylopiranose units presented in Xylan Similar findings were observed with other xylan sources (Cordeiro et al., 2015; Habibi & Vignon, 2005; Habibi et al., 2005; Viana et al., 2011) No other additional signals were observed related to neutral sugars and acetyl groups It could be inferred Fig Nuclear Magnetic Resonance spectra of corn cob xylan powder 1H NMR spectrum (A) and 13 C NMR spectrum (B) S.C.C Urtiga et al Carbohydrate Polymers 250 (2020) 116929 that certain signals of the structural rally related to the monosaccharides overlap with the signals observed for the xylose residues Furthermore, it can be inferred that, because the xylan–type hemicellulose analyzed here was predominantly composed of xylose residues, and only minor amounts of other monosaccharides, the signals of greater amplitude depicted in the spectra correspond to xylose In order to confirm the spectroscopic results reported here, further characterization of the chemical composition of the xylan was efficiently carried out by using GC-FID (Table 1) microparticles 3.3 Fourier transform infrared-attenuated total reflectance (FTIR-ATR) spectroscopy analysis FTIR-ATR analyses were performed in order to investigate the interaction between the components of the formulation Therefore, the analyses were carried out for the raw materials and microparticles As expected, the spectra of the xylan and STMP materials (Fig 3) were similar to those found in previous work published by our group (Oliveira et al., 2010; Urtiga et al., 2017) However, the spectra of XMP and XMP5-ASA were slightly different Indeed, the presence of an intense peak at 1110 cm− 1, related to the symmetrical stretching (P–O–P) in pyrophosphates and other peaks from 750 cm− to 775 cm− 1, attributed to the vibrational stretching of the phosphorus bridges (O–P–O and/ or P = O) and the symmetrical stretching (POP), respectively, were observed These peaks can be related to remaining STMP residues from the cross-linking process (Parize, Stulzer, Laranjeira, Brighente, & Souza, 2012; Suflet, Chitanu, & Popa, 2006; Urtiga et al., 2017) In addition, the cross-linking process was confirmed by the presence of a peak between 1200 and 1250 cm− 1, at 1217 cm-1 (Fig 3), which is attributed to the phosphate ester bond formation between the xylan and the STMP during the cross-linking process (Urtiga et al., 2017) Concerning 5-ASA, the spectrum of this drug presented absorption bands at 2552, 1650, and 1580 cm− 1, which correspond to the vibra tions of –NH2, –C = O and –C = C–, respectively (Tang et al., 2018) The loss of intensity for all characteristic absorption bands of 5-ASA in the microparticles spectrum was also observed, which can be attributed to the encapsulation process, since it is characterized by the restriction in the vibration 3.2 Characterization of xylan-based microparticles In order to obtain visual and morphological characterization of xylan-based microparticles, the SEM (Fig 2A-D) analysis was per formed, wherein it was possible to observe the microparticles spherical shape with the presence of residuals on their surface, which can be related to the cross-linking agent that remained after washing process (Fig 2A-D) The particle size analysis revealed a mean diameter size of 12.66 ± 1.01 and 14.64 ± 0.5 μm for XMP and XMP5-ASA, respectively, which confirmed the data from the SEM (Fig 2) Thus, the addition of 5ASA to the aqueous phase containing the polysaccharide induced a slight variation in the particle size after the cross-linking process The entrapment efficiency for XMP5-ASA was 65.41 ± 3.9 % Similar result was found by Palma et al (2019) who produced 5-ASA- loaded chitosan microcapsules by a spray-drying process with an entrapment efficiency of 65–70% On the other hand, a previous work from our group showed a 5-ASA entrapment efficiency of 23.61 ± 0.15 and 24.98 ± 0.12 % for xylan-based microcapsules produced by spray-drying and by interfacial cross-linking polymerization, respec tively (Silva et al., 2013) Concerning the interfacial cross-linking pro cess, in this work the authors attributed the low entrapment efficiency to the several washing steps used to avoid any residual of organic solvent and crosslinking agent (terephthaloyl chloride), which was also responsible for the high microparticles toxicity (Marcelino et al., 2015; Silva et al., 2013; Urtiga et al., 2017) In this work, similar washing steps were used; however, it could be possible that the crosslinking process using STMP as a cross-linking agent enhanced drug retention in the 3.4 X-Ray diffraction Drug release kinetics from the microparticles can be affected by the physical state of the drug in the polymeric matrix, which can vary from ˜ os, Peniche, amorphous to well-defined crystalline state (Aranaz, Pan Heras, & Acosta, 2017) Fig compares the XRD patterns of raw Fig SEM images of xylan microparticles: XMP (A and B) and XMP5-ASA (C and D) S.C.C Urtiga et al Carbohydrate Polymers 250 (2020) 116929 between 10◦ and 50◦ (2θ) due to their crystalline nature (Cesar et al., 2018; Li, Wang, Li, Bhandari et al., 2009, Li, Wang, Li, Chiu et al., 2009) Concerning the microparticles XRD patterns (XMP and XMP5-ASA), the results were similar to xylan alone Indeed, they showed a broad peak at the same angle as the xylan with the presence of some slight crystallinity peaks between 15◦ and 35◦ (2θ), which could be related to residuals of STMP from the cross-linking process, as confirmed by FTIRATR and SEM results In addition, the characteristic diffraction peaks of 5-ASA did not appear on the XRD pattern of the XMP5-ASA, which could be due to the perfected molecular dispersion of 5-ASA in the polymeric matrix, corroborating to the SEM observation in which no 5-ASA crystals were seen on the microparticles surface (Aranaz et al., 2017; Liu et al., 2019) 3.5 Thermogravimetry (TG) and differential scanning calorimetry (DSC) Thermal analyses have been used to investigate interactions between drug and polymers in several micro and nanoparticle formulations (Oliveira et al., 2013) Fig 5A illustrates the thermal behavior of xylan expressed by the TG curve The first degradation event was observed up to 110 ◦ C with a mass loss of %, which is suggestive of the water loss presented in the xylan powder (Marcelino et al., 2015; Silva et al., 2013) The second event occurred in the range of 193–410 ◦ C with a mass loss of 62 %, which was related to the onset of the polymer degradation processes The thermal behavior of 5-ASA (Fig 5A) showed a single weight loss (97.8 %) between 269–394 ◦ C, attributed to decomposition of the drug Regarding the thermal behavior of the microparticles (Fig 5A), two weight losses, similar to xylan events, were observed The first degra dation event (up to 116.4 ◦ C) showed a mass loss of 8–10 % and can be attributed to the water loss present in the systems The second thermal event occurred between 165 and 320 ◦ C, with a mass loss of 36.5 % and 35.6 % for XMP and XMP5-ASA, respectively As it can be seen, the system showed smaller weight loss when compared to the xylan itself, which may be attributed to the thermal stability of the phosphate ester linkages formation between xylan and STMP during the crosslinking process, highlighting that the cross-linking process was able to improve ˜ os, Pastrana, the thermal stability of the microparticles (Brassesco, Fucin ´, 2019) & Pico The DSC curves of the samples were in agreement with the TGA curves The DSC curve for xylan and for microparticles (Fig 5B) revealed an endothermic event in the temperature range of 55–116 ◦ C, indicating the water loss from xylan An exothermic peak was also observed at 292 ◦ C, 287 ◦ C and 290 ◦ C for xylan, XMP and XMP5-ASA, respectively Concerning the 5-ASA, an endothermic peak was observed around 290 ◦ C, which matches the melting point of the drug (Cesar et al., 2018) In addition, no thermal events related to 5-ASA were found in the thermal curves of XMP5-ASA Fig FTIR-ATR spectrum of raw materials and xylan microparticles (XMP and XMP5-ASA) materials and the microparticles The XRD pattern of xylan clearly exhibited a typical feature of predominantly amorphous materials with presence of slight crystallinity in the region of 10◦ to 30◦ (2θ) The broader peaks at 19.6◦ and 29◦ (2θ) are characteristic of crystalline re gions of semi crystalline xylan (Grodahl, Gatenholm, & Dekker, 2004) On the other hand, STMP and 5-ASA themselves showed intense peaks 3.6 In vitro drug release The in vitro release of 5-ASA from microparticles was studied in simulated physiological dissolution media to mimic the passage of the microparticles through the gastrointestinal tract The results revealed that approximately 52 % of the initial dose was released in less than h from XMP5-ASA into simulated gastric medium (pH = 1.2) (Fig 6A) This fast release of the drug can be explained by the formation of pores on the surface of the microparticles, related to the intrinsic character istics of the polymer (Nagashima-Jr et al., 2008; Silva et al., 2013) However, in simulated gut medium (pH 6.0), 80 % of the drug was released up to h, which indicates that the formulation XMP5-ASA might be able to reach the large intestine with approximately 20 % of its initial loading of 5-ASA Aiming to avoid the burst release effect found on the gastric medium, gastro-resistant capsules were filled with XMP5-ASA (XMPCAP5-ASA) The release profile of 5-ASA from the XMPCAP5-ASA showed a Lag time up to h Additionally, in the Fig X-ray powder diffraction patterns of raw materials and xylan micro particles (XMP and XMP5-ASA) S.C.C Urtiga et al Carbohydrate Polymers 250 (2020) 116929 Fig TG (A) and DSC (B) curves of raw materials and xylan microparticles (XMP and XMP5-ASA) predominant factor on the drug release of 5-ASA from the microparticles (Table 2) (Peppas & Sahlin, 1989) Conversely, the release kinetics of 5-ASA from XMPCAP5-ASA were better fitted on the Korsmeyer-Peppas model (Table 2) leading to release exponent (n) values of 0.26, indi cating the presence of a Fickian diffusion transport (Jha, Chakraborty, Chaudhuri, & Dey, 2016) Conclusion In this work, XMPCAP5-ASA was successfully produced as a new formulation for the colonic release of 5-ASA Additionally, no relevant interactions among the components of the formulation, which could interfere on the drug characteristics, were found, as demonstrated by the FTIR-ATR spectroscopy results The XRD and the thermal analyses revealed that the 5-ASA was able to be molecularly dispersed in the polymer matrix, inducing an increment on its thermal stability In addition, in vitro release studies of XMPCAP5-ASA showed the usefulness of this new formulation for colonic delivery of 5-ASA from xylan mi croparticles In fact, approximately 50 % of the drug content was able to be released at colonic pH (pH = 7.4), and the major mechanism of drug release was the Fickian diffusion Fig (A) In vitro release profile of 5- ASA along the time as a function of the pH, and (B) mathematical modeling of 5-ASA release profile according to distinctive models (5-ASA = free 5-ASA, CAP5-ASA = 5-ASA inside of gastroresistant capsules; XMP5-ASA = 5-ASA-loaded xylan microparticles; XMPCAP5-ASA = 5-ASA-loaded xylan microparticles inside of gastroresistant capsules) simulated gut medium (pH 6.0), only 49 % of 5-ASA was released, up to h Therefore, approximately 50 % of the initial loading of 5-ASA can reach the large intestine by using such approach In order to evaluate if the gastro-resistant capsule was not the only factor able to promote the drug release delay, samples containing free 5-ASA into the gastro-resistant capsules (Fig 6A) were also assayed For this sample, it was possible to evidence that the drug was totally released in h of experiment The overall results concerning the release profile allow us to infer the xylan microparticles importance on the 5-ASA release control, providing an improvement on the drug availability in the colon The in vitro release data from the entire set of dissolution media (the gradient of pH) were fitted together into mathematical kinetic equations in order to describe the kinetic profile of 5-ASA from the systems The results obtained from the modeling (R2 adjusted, RMSE and MSC) of each system, as well as their respective constant rates, were shown in Table The release kinetic profile presented by XMP5-ASA was better fitted on the Peppas-Sahlin model (Fig 6B), which explains that the drug release occurred through two processes, the Fickian diffusion phenom ena and the relaxation of the polymer chain The application of this model and the calculation of the k1 and k2 constants allows to evaluate the impact of each mechanism in the drug release process Indeed, once k1 (44.83) > k2 (-5.61) it can be inferred that Fickian diffusion was the CRediT authorship contribution statement Silvana Cartaxo da Costa Urtiga: Conceptualization, Formal anal ´ ria Maria ysis, Investigation, Methodology, Writing - original draft Vito Oliveira Alves: Conceptualization, Investigation Camila de Oliveira Melo: Conceptualization, Writing - review & editing Marini Nasci mento de Lima: Conceptualization, Investigation Ernane Souza: Re sources, Writing - review & editing Arcelina Pacheco Cunha: ´gila Maria Pontes Silva Ricardo: Re Methodology, Investigation Na sources, Writing - review & editing Elquio Eleamen Oliveira: Conceptualization, Supervision, Methodology, Writing - review & edit ´ crates Tabosa Egito: Conceptualization, Method ing Eryvaldo So ology, Supervision, Writing - review & editing, Project administration, Funding acquisition S.C.C Urtiga et al Carbohydrate Polymers 250 (2020) 116929 Table Evaluation of different mathematical models for the in vitro release profile of the drug and the rate release constants of the data Formulation Mathematical Model Equation F = 100 x (1- e F = kH x t0.5 F = kKP x tn –k1 x t XMP5-ASAd First-order Higuchi Korsmeyer-Peppas ) Peppas-Sahlin F = k1 x tm + k2 x t(2 x m) F = 100 x [1 x e− k1 x F = kH x (t-Tlag)0.5 F = kKP x (t-Tlag)n (t – Tlag) XMPCAP5-ASAe First-order Higuchi Korsmeyer-Peppas Peppas-Sahlin F = k1 x (t-Tlag)m+k2 x (t-Tlag)(2 ] x m) R2 Adjusteda RMSEb MSCc Constants 0.94 0.69 0.92 7.22 17.76 8.97 2.88 1.02 2.33 kf1 = 0.39 kH g = 27.46; kKP h = 45.68; n i = 0.28 kj1 = 44.83; k2 k = -5.61; m l = 0.51 – kH = 26.30 kKP = 48.48; n = 0.26 k1 = -132.24; k2 = 121.78; m = 0.16 0.99 2.93 4.57 – 0.94 0.98 – 9.36 5.68 – 2.14 3.08 0.87 13.72 1.98 a Adjusted coefficient of determination standard deviation of the residuals c Model Selection Criterion d 5-ASA-loaded xylan microparticles e 5-ASA-loaded xylan microparticles inside of gastro-resistant capsules f first order release constant g Higuchi release constant h release constant incorporating structural and geometric characteristics of the drug-dosage form i diffusional exponent indicating the drug-release mechanism j constant related to the Fickian kinetics k the constant related to Case II relaxation kinetics l diffusional exponent b Declaration of Competing Interest Grodahl, M., Gatenholm, P., & Dekker, M (2004) Role of acetyl substitution in hardwood xylan Polysaccharides: Structural diversity and functional versatility (2nd ed.) 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characterization of xylan- based microparticles, the SEM (Fig 2A-D) analysis was per formed,... 7.4), and the major mechanism of drug release was the Fickian diffusion Fig (A) In vitro release profile of 5- ASA along the time as a function of the pH, and (B) mathematical modeling of 5-ASA release. .. 250 (2020) 116929 Fig TG (A) and DSC (B) curves of raw materials and xylan microparticles (XMP and XMP5-ASA) predominant factor on the drug release of 5-ASA from the microparticles (Table 2) (Peppas