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Beta-glucan and arabinogalactan-based xerogels for abuse-deterrent opioid formulations
European Journal of Pharmaceutical Sciences 129 (2019) 132–139
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European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps
Beta-glucan and arabinogalactan-based xerogels for abuse-deterrent opioid formulations
T
Miroslav Veverkaa, Tibor Dubajb, , Eva Veverkovác, Peter Šimonb, Štefan Husárd,e, Katarína Tomanováb, Vladimír Joríkb ⁎
a
EUROFINS BEL/NOVAMANN Ltd., 940 02 Nové Zámky, Slovakia Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37 Bratislava, Slovakia c Faculty of Natural Sciences, Comenius University, 842 15 Bratislava, Slovakia d Saneca Pharmaceuticals, 920 27 Hlohovec, Slovakia e Faculty of Pharmacy, Department of Pharmaceutical chemistry, Comenius University, 832 32 Bratislava, Slovakia b
ARTICLE INFO
ABSTRACT
Keywords: Opioids Xerogel Drug delivery Drug abuse Release kinetics
Novel polysaccharide hydrogels based on Methocel and beta-glucan or arabinogalactan and corresponding xerogels were prepared and described. Phase stability of hydrogels was confirmed over multiple freeze–thaw cycles. Binary beta-glucan:Methocel hydrogels showed the highest freeze–thaw stability in terms of their syneresis. The viscosity of binary hydrogels was further increased by adding water-soluble resin. Freeze drying of polysaccharide gels yields xerogels suitable as abuse-deterrent vehicles for opioid delivery. The xerogels were characterized by infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, scanning electron microscopy and by their swelling behavior. As a model opioid, tramadol hydrochloride formulations were prepared with various xerogel matrices and dissolution-release profiles were determined. The xerogel matrix acts as a functional excipient that forms a viscous gel barrier with decreased rate of tramadol release. Moreover, slower drug release with no dose dumping is observed in the presence of ethanol. The release kinetics demonstrated that hydrophilic gels with beta-glucan or arabinogalactan are effective for controlling and prolonging the drug release for 12 h which could reduce the required number of administrations.
1. Introduction Controlled-release tablets enable patients to gain considerable control over their pain; however opioid drugs are a significant source of drug abuse. Therefore, many pharmaceutical companies are developing various abuse-resistant technologies to mitigate the potential abuse of their opioid formulations (Webster, 2009; Schaeffer, 2012). Formulations incorporating both physical and chemical barriers represent a promising approach that resists abuse patterns via forming ingestible high-viscosity material (Mastropietro and Omidian, 2015; Webster, 2011). Hydrogels are hydrophilic three-dimensional polymeric networks that can absorb and retain large quantities of water within their structure. Interpenetrating polymer network (IPN) technology is a suitable route for preparing hydrogels via physical crosslinking, chemical gelation, or self-assembly (Matricardi et al., 2013; Kim et al., 2003; Gupta and Srivastava, 1994; Hu et al., 2014). IPN hydrogels are usually
prepared by diffusing linear polymer chains into a preformed polymer network. While being physically interlocked, polymers within IPN are chemically independent of each other (Burugapalli et al., 2001; Sikora et al., 2008; Dragan, 2014). In this way, the mechanical stability of the hydrogels is improved due to physical entanglement and network interactions. Cellulose derivatives such as Methocel (MT) or their combination with a second polymer are frequently used as gel-forming polymers for hindering extraction of opioids from pharmaceutical formulations (Wright et al., 2016; Mastropietro and Omidian, 2015; Joshi and Somma, 2007; Micka et al., 2016). Only a comparatively few beta-glucans (BGs) form gels and these vary widely in gel character and texture so that they are suitable for food and cosmetic applications. For example, heating an aqueous suspension of curdlan yields a thermo-reversible gel with high strength and syneresis. Further, in contrasts to other polysaccharides multiple freeze–thaw cycles (FTCs) do not affect its properties (Thomas et al., 2013). To date, despite the ability of BGs to form viscous aqueous suspensions
Abbreviations: AG, arabinogalactan; BG, beta-glucan; MT, Methocel; PO, Sentry Polyox; LU, Lutrol; TM, tramadol hydrochloride ⁎ Corresponding author. E-mail addresses: [email protected] (M. Veverka), [email protected] (T. Dubaj). https://doi.org/10.1016/j.ejps.2019.01.003 Received 8 November 2018; Received in revised form 18 December 2018; Accepted 4 January 2019 Available online 06 January 2019 0928-0987/ © 2019 Elsevier B.V. All rights reserved.
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with shear-thinning flow behavior (Burkus and Temelli, 1998; Burkus and Temelli, 1999) its application to binary gels remains scarce, mainly because of lower viscosity in solution compared to gums and inferior gel-forming capacity. It was observed that solutions of BG and gums (iota carrageenan, xanthan gum, cellulose) exhibit enhanced rheological properties including increased shear tolerance (Vasanthan et al., 2006); however, the yeast-derived BG alone forms mechanically weak hydrogels. On the other hand, both BG and arabinogalactan (AG) exhibit very good complex-forming ability with various nutraceuticals (Veverka et al., 2014), conjugated linoleic acid (Veverka et al., 2017) and were proposed as carriers for recombinant human thrombin (Veverka et al., 2016). Moreover, BG-based gels form stable emulsions with various oils (Veverka et al., 2018). Tramadol hydrochloride (TM) is administered in the therapy of acute and chronic pain due to its specific mechanism of action which evokes a low incidence of adverse effects when compared to classical opioids such as morphine and fentanyl (Coluzzi and Mattia, 2007). Extended-release TM tablet formulated in a self-correcting hydrophilic controlled-release matrix is a secure-release once-daily formulation that cannot be crushed for abuse. For controlled TM delivery, double-phase hydrogels and hydrophilic natural gum-based tablets were described by Kamel et al. (2012) and Varshosaz et al. (2006). Gel applications for the above-mentioned goal via corresponding xerogels by swelling/rehydration are rare (Toworfe et al., 2016; Forsgren et al., 2011; Ahola et al., 2008). Xerogels are usually formed by removing liquid from a gel (Mehling et al., 2009; Gulrez et al., 2011). In general, the hydrophilic character of polysaccharide-based xerogels leads to moisture sensitivity and allows flexible renewability of gel (Xue et al., 2004; Khalid et al., 2002; Kuang et al., 2011). These xerogels swell to an equilibrium state that retains a significant amount of water; however, some formulations can only swell gradually due to slow water diffusion into a glassy polymer matrix. To achieve a highly viscous gel in liquid phase, a mixture of water-soluble/swellable cellulose derivatives, polysaccharides, poly(ethylene oxide), gums, clays and carbomers have been suggested (Wright et al., 2016; Micka et al., 2016; Bastin and Lithgow, 2001; Matthews et al., 2012). In addition to polysaccharide-based matrices, surface modified diatomaceous earth microparticles with silica xerogel were studied recently as a potential matrix for controlled drug release (Uthappa et al., 2018) The goal of this study was to prepare tablets with prolonged-release profile for opioids and evaluate their abuse-deterrent properties. Series of MT:AG and MT:BG hydrogels and xerogels were prepared in bulk form with a special focus to rapidly achieve a highly gelled state in a system reconstituted from xerogel. The effect of BG and AG mass ratio on viscosity of mother gel and the swelling behavior of xerogel was studied; the influence of the addition of another thickening excipient (Sentry Polyox WSR 303 or Lutrol F 127) was also studied.
2.1. Hydrogel preparation
2. Materials and methods
The powder X-ray diffraction pattern was collected within the 2θ range of 2–60° on a Brag-Brentano θ/θ focusing powder diffractometer Bruker AXS D8 Advance. The instrument was equipped with X-ray tube providing CuKα radiation (λ = 0.154062 nm). The experimental conditions were as follows: exciting voltage 40 kV; anode current 40 mA; step size 0.01°. Samples of xerogels were gently crushed using an agate mortar and pestle and pressed into a powder disk. The measurements were carried out at room temperature using a flat silicon zero-background sample holder.
To the water solution of AG an appropriate amount of MT as a sieved powder was carefully added at about 90 °C with mixing (a lumpy suspension can be formed transiently); mixture was stirred until all the MT particles were wetted. The reaction mixture was further stirred for 30 min without heating to reach room temperature until the MT powder completely hydrated and a smooth and clear gel was obtained. In case of ternary hydrogels, the third ingredient (PO or LU) was added according to the product specification. If not stated otherwise, gels containing 6.0 wt% MT were prepared. In case of the water-insoluble BG, the gel was prepared by a primary gelation of micronized BG in water for 48 h at 40 °C. The BG suspension was then stirred at 95 °C for 2 h with occasional homogenization using homogenizer (Ultra Turrax T18, IKA, Germany) at 4000 rpm and MT was finally added. The gel containing 4.0 wt% of BG was slightly turbid. 2.2. Viscosity measurements Viscosity was measured using a rotational viscometer (Anton Paar DV-1P, Berlin, Germany) equipped with a tempering bath. The measurements were carried out in triplicates at 22.0 ± 0.5 °C; the apparent viscosity was expressed in mPa·s. The viscosity of samples (approx. 20 g) was measured using spindle No. 4 in up/down cycles (0.3–60 rpm spindle speed) with each speed kept constant for 10 s before the measurement was made. 2.3. Syneresis A gel sample of about 12 g was sealed in a graduated centrifugal 15ml tube and placed into a refrigerator. Five FTCs were done where each of the hydrogel was stored at −10 °C for 12 h, followed by thawing at 25 °C for 6 h. The thawed samples were collected and tested for syneresis. Syneresis of the hydrogel after each FTC was determined by centrifuging the samples at 2200 rpm for 20 min in a centrifuge (WWR Compactstar CS4). The volume of exuded water was then determined. 2.4. Fourier transform infrared spectroscopy (FTIR) Attenuated total reflectance FTIR spectra were measured in 4000–580 cm−1 range using FTIR spectrometer Nicolet Impact 410-IR (Thermo Scientific, WI, USA). The ATR technique (diamond ATR crystal) was used with Omnic 5.2 software. Fifty scans were collected for each sample. The FTIR spectra of the materials prepared were compared with those of the parent polysaccharides. 2.5. X-ray diffraction (XRD)
BG (from Pleorotus ostreatus, purity 93%, MW 450 kDa) was obtained from Natures Ltd. (Trnava, Slovakia) as micronized particles with a mean diameter of 4.5 μm. AG (purity 98.7%; isolated from Larix sibirica) was obtained from the Favorskii Irkutsk Institute of Chemistry, Siberian Branch (Irkutsk, Russia). The active pharmaceutical ingredient (tramadol hydrochloride) was obtained from Saneca Pharmaceuticals (Hlohovec, Slovakia). MT (Methocel K15 Premium CR grade) was obtained from the Dow Chemical Company (Bay City, USA). Commercial poly(ethylene oxide) Sentry POLYOX WSR 303 (PO, MW 7 · 106 g mol−1) was manufactured by Dow chemical (Philadelphia, USA). Lutrol F 127, that is, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), (LU, MW 9840–14,600 g mol−1), was provided by BASF (Ludwigshafen, Germany). Other chemicals of analytical or Ph. Eur. grade were purchased locally and used as received. In all experiments, double distilled water was used.
2.6. Differential scanning calorimetry Thermal behavior of hydrogels was studied using differential scanning calorimeter PerkinElmer DSC8500 equipped with an automatic cooling unit (IntraCooler II). Gel samples weighing 4–5 mg ( ± 0.01 mg) were placed in hermetically sealed aluminum pans; nitrogen was used as a purge gas. 133
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2.7. Gel drying
constant weight and potential matrix loss was evaluated gravimetrically.
A sample of approx. 100 g of hydrogel was transferred into a 300mL freeze-drying flask (ilShin Biobase, Korea) and frozen in an ultralow temperature freezer at −25 °C for 48 h. Subsequently, the flask was connected to a freeze-dryer (Coolsafe 55-4, Denmark) and freeze-dried at −55 °C under vacuum for 24 h to sublimate the solvent. The final desorption temperature was 20–22 °C after 24 h. Fluffy material was then pulverized using a coffee grinder for 30 s to obtain final powder. Moisture content in the xerogels was determined by Karl Fischer titration; the experiments were done in duplicate. Mass ratio of xerogel component is rounded to the nearest whole number.
2.12. Dissolution tests Drug release from the dosage formulations prepared was monitored according to Ph. Eur. (general chapters Section 2.9.3) using a paddle apparatus. The active pharmaceutical ingredient (TM) was mixed with powdered excipients and corresponding xerogels (see composition of TM dosage formulations in Table 5); the dry mixtures were compressed into round flat 0.2-ml tablets with a diameter of 6 mm using a manual tablet compression machine (UD Tablet Maker). All samples were compressed at the main compression force 124 bar which corresponds to force of 5.68 kN at the punch tip. For the dissolution test, 500 ml of medium was used in each dissolution vessel with a paddle rotation speed of 50 rpm. One tablet of experimental dosage formulations was put into each dissolution vessel and the collected samples were analyzed by HPLC. The dissolution media consisted of either 0.1-M HCl (pH = 1.2) or 40% ethanol in 0.1M HCl. Dissolution tests were carried out using 6 tablets (n = 6) for each of the four formulations over a 12-h period with samplings at 0.5, 1, 2, 4, 8, and 12 h.
2.8. pH measurement A digital pH meter (Mettler Toledo, Columbus, OH, USA) was used to measure the pH values at 20.0 ± 0.5 °C of samples immediately after preparation. 2.9. Conductivity measurement As the gel was prepared, it was tempered to 20 ± 0.5 °C and the conductivity was measured immediately (conductometer Mettler Toledo S230, Switzerland) using the 731 ISM electrode directly in a reaction glass beaker.
3. Results and discussion Using water as a solvent, two series of MT:AG and MT:BG gels were prepared by varying the AG or BG content from 2.5 to 10% and from 0.5 to 4%, respectively. The concentration of MT in the mixtures was fixed at 6.0 wt%. Apparent viscosity was measured for all hydrogels under study. For further evaluation by XRPD, FTIR, DSC, and swelling kinetics, representative formulations were selected from those with higher viscosity.
2.10. Scanning electron microscopy (SEM) Electron micrographs were obtained using JEOL 7500F (JEOL, Japan) at 15-kV accelerating voltage; all samples were covered by a thin gold/palladium layer to avoid charging effect. The measurements were performed in SEM at laboratory temperature and pressure of 4.5 · 10−4 Pa. The micrographs were acquired and analyzed using the PC SEM 3.0.1.8 package. For the cryo-EM, the technique described by Veverka et al. (2018) was employed.
3.1. Viscosity and syneresis Despite of no quantification of synergistic effects, it was evident that the viscosities of the mixed systems MT:AB and MT:BG are much higher than the viscosities of sole components, i.e., synergism can be expected (Pellicer et al., 2000). The hydrogel formed by BG and subsequent PO addition showed the strongest increase in viscosity among all the systems studied, ranging from 37.8 Pa·s before the treatment to 1160 Pa·s after polysaccharide addition (Table 1a). The viscosity continued to increase to 1524 Pa·s after LU addition. Similarly, the MT:AG combination also showed increased viscosity, however to a lesser extent (Table 1a). Generally, the effect of adding a third polymer (PO, LU) on the synergism observed in the two above-mentioned systems was clear. These ternary systems produce highly stable gels with improved water retention as confirmed freezing–thawing treatments. Prior to FT treatments, no syneresis was detected indicating good water-holding capacity of the hydrogels upon formation. After the fourth and fifth FTC, only low syneresis averaging 3.5% and 5.2% or 3.9% and 5.9% was detected in the MT:AG 5% and MT:BG 0.5% complexes, respectively. No syneresis was detected in other MT-containing hydrogels for up to five FTCs, indicating strong gels with stable water-holding ability.
2.11. Swelling experiments The xerogels prepared as powders are difficult to handle repeatedly; therefore, during the swelling experiments they were manipulated in tea bags. The kinetics of swelling of the xerogels was followed gravimetrically on an electronic balance (Mettler, Model ML 104, Switzerland). An empty wetted bag was used as a blank. Three xerogel samples of 0.3–0.5 g were used; the average values of these three measurements are reported. A xerogel sample of weight m0 was immersed in a tea bag in deionized water at 22 °C (pH = 7.1); after a certain time, the hydrogel was slightly dried using filter paper and weighed at regular time intervals to obtain m(t). The water uptake capacity is then defined as
m (t ) m 0 100%, meq
WUC(t ) =
(1)
where meq is the hydrogel weight at swelling equilibrium (24 h) at 22 °C. The equilibrium water content, EWC, was calculated as
EWC =
meq
m0
meq
100%.
3.2. FTIR spectra
(2)
The FTIR spectra of xerogels (Fig. 1) consisted of broad absorption bands of the hydroxyl group of both pristine polysaccharides (about 3330 cm−1, strong and wide OeH stretch), 2900 cm−1 corresponding to CeH stretch, and broad bands at about 1370 and 1035 cm−1 of glucopyranose ring. Tables S1 and S2 in the Supplementary Material list several characteristic absorption bands for AG, MT, BG and representative xerogels. Apparent differences in the spectrum of starting polysaccharides and xerogels should arise from any intermolecular interactions between MT and polysaccharide in the matrices. In the series
Similarly, swelling ratio, SR, and equilibrium swelling ratio, SReq, were calculated as
SR(t ) =
SR eq =
m (t ) m 0 m0
meq m0
(3a)
m0 (3b)
Afterwards, the swelled material was dried (55 °C, 2 kPa) to 134
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of the xerogel samples there was observable fact that FTIR spectrum does not change from one to the other and is quite reproducible except for the difference in band intensities due to increasing amount of AB or BG in the xerogel. For structural characterization of polysaccharides two spectral regions are important. These are “sugar region” (1200–950 cm−1) and “anomeric region” (950–750 cm−1). The highly overlapping intense bands of CeO and CeC stretching vibrations in glycosidic bonds and pyranoid ring predominate in the former region (Synytsya and Novak, 2014). In xerogels, CeO vibrations were slightly shifted to 1350 cm−1 and 1100 cm−1. An increase in peak intensity appeared at 1100 cm−1 due to an increase in the extent of hydrogen bonding. Compared to pristine polysaccharide, the xerogel showed a weak broadened absorption band for ν(OH). The observed broadening and asymmetry of the ν(OH) band in the spectra of MT:AG and MT:BG samples suggests formation of a new type of hydrogen bonds by interactions between MT and polysaccharides. The shifts in spectra imply that new hydrogen-bonding interaction is formed between polysaccharide and MT in the MT:AG or MT:BG series. The FTIR spectra of the corresponding physical mixtures did not show such changes (data not shown).
Table 1 Composition and physico-chemical properties of AG (a) and BG (b) gels determined 2 h after preparation. (a) MT in base gel (wt%)
AG (wt %)
PO (wt %)
Viscositya (mPa·s)
Conductivity (μS/ cm)
pH
6.0 6.0 6.0 6.0 6.0
– 5.0 5.0 10.0 10.0
– – 4.0 – 4.0
37,750 141,250 358,940 288,649 470,120
nc 0.30 nc 0.21 0.35
nc 3.3 nc 3.4 3.4
(b) MT in base gel (wt%)
BG (wt%)
PO (wt%)
LU (wt%)
6.0 6.0 6.0 6.0 6.0 –
– 0.5 2.0 2.0 2.0 4.0
– – – 6.0 – 1.5
– – – – 6.0 –
Viscosity (mPa·s) 37,750 720,410 874,945 1,158,924 1524 195 1,020,450
Conductivity (μS/ cm)
pH
nc 0.88 0.90 1.00 0.95 1.10
nc 5.4 6.0 5.7 5.2 5.5
3.3. Swelling studies
nc test not conducted. a Apparent value.
For practical xerogel applications the kinetics of water absorption is indicative to determine how quickly a hydrogel is restored. From a practical point of view, fast swelling of the xerogel prevents intravenous route of administration: a thick hydrogel is restored within a short time and the mixture cannot be drawn into a syringe. As the indicative criteria, swelling ratio and water uptake after 10 min (SR10 and WU10, respectively) were chosen; the time interval of 10 min might correspond to initial stage of swelling. The swelling rate depends mostly on xerogel composition and structure and on the nature of mutual interaction of polysaccharides. All xerogels showed similar hydration profiles, swelling data for representative xerogels are shown in Table 2. Clearly the AG-containing xerogels are quickly hydrated (see WU10 and SR10 values). When the weight ratio of AG in the xerogel is increased over the range 1 to 5 to the MT, the equilibrium swelling ratio SR10 was increased substantially. The observed results may be explained by the fact that an increased AG content in xerogel renders the network more hydrophilic and henceforth, the degree of water sorption and swelling ratio increases. In addition, the water-soluble AG particles may form a porous microstructure of MT:AG xerogel which is able to transport water into the matrix bulk. On the other hand, AG is more soluble than MT itself, however, its gel forming ability is negligible. It should be noted that swelling of AG-containing xerogels is probably accompanied by a partial loss of water-soluble AG which leads to a decreased final water content (comparing SReq data). Results in BG series may be attributed to the fact that BG is a hydrophilic gel-forming polymer and increasing its amount in the xerogel Table 2 Properties of representative MT:AG and MT:BG xerogels. Measurements were done in duplicates, mean values are listed. Xerogel (wt. ratio) MT:AG 3:5 MT:AG 6:5 MT:AG:PO 1.5:2.5:1 MT:BG 3:1 BG:PO 4:1.5 MT:BG:LU 3:1:3
Fig. 1. FTIR spectra (from top to bottom): AG, BG, MT, AG:PO:MT 2.5:1:1.5, BG:MT:LU 1:3:3, AG:MT 5:3, BG:PO 4:1.5.
135
Particle size, mean ± SD (μm)
Residual water (wt %)
Swelling parameters WU10 (%)
SR10
SReq
EWC (%)
128 ± 33 103 ± 29 105 ± 20
2.9 3.3 3.0
82.8 78.8 77.5
65.5 64.4 61.4
67.21 70.80 66.50
98.6 98.8 98.8
130 ± 22 99 ± 28 131 ± 38
3.8 3.5 4.8
65.9 70.5 73.6
61.5 59.8 60.1
86.61 79.26 79.14
99.5 99.5 99.7
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Fig. 2. Scanning electron micrographs of xerogel surfaces: MT:AG:PO 1.5:2.5:1, BG:MT:LU 1:3:3, MT:AG 3:5, BG:PO 4:1.5, BG, and pure BG (2 wt%) hydrogel.
matrices will obviously increase the gelling; thus, an increase in the swelling ratio is expected. On the other hand, higher volume of waterinsoluble BG in the MT:BG xerogel hinders water diffusion so that swelling is slower and the corresponding WU10 and SR10 parameters are lower. The EWC values for BG-containing formulations are slightly higher (≥99.5%) compared to AG series. However, some variation in the EWC and SReq values is expected due to inevitable manipulation losses of the xerogel mass in swelling experiments which is true mainly for soluble AG, especially after long swelling periods. Thus, for all AGbased xerogels the SR10 and WU10 swelling parameters are higher than those for BG xerogels; for equilibrium parameters SReq and EWC the opposite is true. However, as the LU was added to the BG:MT matrices, WU10 increased from 65.9% to 73.6%; the difference can be explained by increased hydrophilic nature of the xerogel matrix (Table 2). It is hypothesized that the intermolecular interactions between the BG and LU chains keep the components of the matrix in the largely amorphous form and so accelerate the swelling kinetics (Khalid et al., 2002).
3.4. Xerogel morphology Morphology of the xerogels prepared can be described as a structure consisting of high-density material. The interior morphologies of the xerogels and the BG hydrogel are shown in Fig. 2 (a–f). As depicted on representative micrograph for BG-based formulation (Fig. 2f), hydrogels exhibit a highly interconnected porous structure with uniform pore distribution. Moreover, the pure BG xerogel exhibited inter-connected a highly porous and fibrous structure with uniform and deep pore distribution. (Fig. 2e). Thus, for MT:AG and MT:BG xerogels a similar surface pattern and the pore sizes can be expected as identical preparation technique and conditions were used. However, in these xerogels the cracks in the particles happened probably due to various rates of water removal by evaporation from different matrices. Variable extents of the pores and channels were observed; xerogels have many pores with interconnecting capillary channels in their inner surface (Fig. 2 a–c). Probably the MT:AG system combining both swellable and
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Table 3 Quantification of water forms present in rehydrated xerogels. Formulation
Total water (wt%)
Free water (wt%)
Freezable bound water (wt%)
Non-freezable water (wt%)
85.7 90.9 88.6 83.2
70.6 76.1 81.3 79.6
5.1 0.8 1.9 0.0
10.0 14.0 5.4 3.6
MT:AG:PO 1.5:2.5:1 MT:BG:LU 1:3:3 BG:PO 4:1.5 MT:AG 3:5
Table 4 XRPD peak position and integral breadth parameters of xerogels. Sample
Peak position, (Å)
BG BG:PO 4:1.5 BG:MT:LU 1:3:3 AG AG:MT 5:3 AG:PO:MT 2.5:1:1.5
20.4 (1.1) – – 25.08 (3) 22.27 (1) 22.39 (1)
15.40 (8) 16.57 (5) 16.7 (2) 7.62 (5) 9.31 (6) 10.94 (3)
Integral breath, β = A/I0 12.4 (2) 12.08 (9) 9.9 (2) 6.14 (2) 6.46 (6) 7.73 (6)
10.72 (6) 10.44 (8) 8.3 (3) 4.80 (2) 4.84 (1) –
– – – 4.16 (2) 4.54 (2) –
415 (19) – – 116 (1) 33 (1) 39 (1)
22 74 15 143 185 135
(4) (3) (3) (10) (14) (10)
47 43 133 98 271 481
(5) (5) (19) (8) (22) (30)
70 (4) 14 (4) 32 (26) 210 (11) 47 (6) –
– – – 175 (14) 340 (12) –
Standard errors (given in parentheses) were calculated for each phase. Integral breadth (β) corresponds to the width of a rectangle with the same height I0 and area A as the diffraction peak.
ranges from 3.6 to 14% of the hydrogel mass (or 4.3–15.4% of the total water); the ternary gels have a higher portion of water present in nonfreezing form compared to binary gels. By comparing the amount of freezable and non-freezable bound water it follows that, in general, most of the hydration takes place in the primary shell of the polymer chains. 3.6. XRPD analysis The BG and AG polysaccharides have a polymer structure resulting in four or five very broad and overlapped peaks observed by XRPD. Similar patterns of pristine polysaccharides and corresponding xerogels, consisting of very broad overlapped peaks, exclude the possibility of their straightforward visual comparison and phase identification. Only free crystalline components of xerogel can be observed in diffraction pattern, if any. Therefore, we applied the line profile analysis to examine subtle differences in their diffraction patterns (Veverka et al., 2014; Veverka et al., 2016). Results of the line profile analysis are listed in Table 4. Each of four xerogel samples was graphically analyzed for the presence of residues of the crystalline components. For reasons of image clarity, diffractograms of well crystalline xerogel components (PO, LU) were adapted to significantly lower polysaccharide intensities. Results of the line-profile analysis of BG:PO 4:1.5 confirm the formation of new phases. The first diffraction line of pristine BG has disappeared and the second one is significantly shifted to lower angle 2θ. As it can be recognized from the line-profile analysis (see Figs. S1 and S2 in the Supplementary material), in the xerogel BG:PO 4:1.5 a small amount of crystalline PO was detected. Line-profile analysis of BG:MT:LU 1:3:3 sample due to the enormous peak broadening makes their separation somewhat ambiguous. Due to the strict overlap of BG and MT diffraction lines, the line-profile analysis is not sufficient to assess the formation of new phases. Unfortunately, xerogel contains a residual mark of LU phase, too. Line-profile analysis of AG:Methocel 5:3 unambiguously shows shift in peak positions and significant changes of integral breadth (β). It clearly indicates the formation of a new xerogel phase. Similarly, AG:PO:MT 2.5:1:1.5 forms a new phase. It can be stated on the base of peak shifts and changes of integral breadth (β) listed in Table 4.
Fig. 3. Release profile of TM from F1 dosage form in two different dissolution media. Solid lines are a least-squares fit to a first-order kinetic equation.
soluble polysaccharide led to a different pattern of water removal and caused increased irregularity of the matrices. Therefore, only a small number of pores survived the drying process. In the case of BG:PO 4:1.5 xerogel morphology, the micrograph (Fig. 2d) shows a different xerogel morphology where the channel type of pure BG xerogel is preserved. 3.5. Thermal behavior Thermal behavior of xerogels and corresponding hydrogels upon heating and cooling was studied by differential scanning calorimetry (DSC). Xerogel samples were swollen for 3 h in water and cooled down from 25 °C to −50 °C at 5 °C/min and allowed to equilibrate for 10 min. Afterwards, a heating run at 5 °C/min was done to observe melting of water confined in the gel matrix. The water was found to be present in three different forms: (i) non-interacting free water for which the melting is similar to that of bulk water, (ii) freezable bound water forming the secondary hydrating shell of the polymer chains which melts at slightly lower temperature, and (iii) non-freezing bound water which forms the primary hydrating shell and interacts with the gel matrix strongly so that it does not freeze upon cooling at all. DSC allows to quantify these water forms by comparing the corresponding peak area with the melting enthalpy of water (334 J/g); the results are summarized in Table 3. The most abundant is free water; this form represents 82–96 wt% of the total water content in hydrogels. The content of non-freezing water that strongly interacts with gel matrix
3.7. Controlled release of TM Representative dissolution release profiles of TM from the experimental solid dose formulations are shown in Fig. 3; numerical values for 137
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Table 5 Composition of TM dosage formulations and the corresponding parameters for first-order release kinetics. Ingredient
Composition (in wt%) F1
TM Microcrystalline cellulose (PH102) Lactose monohydrate (spray dried) MT:AG 3:5 BG:MT:LU 1:3:3 MT:AG:PO 1.5:2.5:1 BG:PO 4:1.5 Magnesium stearate Release rate constant, k (h−1) 0.1 M HCl 0.1 M HCl + 40% Alcohol Release half-time, t1/2 (h) 0.1 M HCl 0.1 M HCl + 40% Alcohol
F2
F3
F4
20 19 20 40 – – – 1
20 19 20 – 40 – – 1
20 19 20 – – 40 – 1
20 19 20 – – – 40 1
0.45 ± 0.02 0.21 ± 0.02
0.27 ± 0.02 0.20 ± 0.01
0.32 ± 0.02 0.19 ± 0.01
0.28 ± 0.01 0.19 ± 0.02
1.53 ± 0.06 3.31 ± 0.24
2.57 ± 0.20 3.52 ± 0.22
2.14 ± 0.13 3.65 ± 0.28
2.50 ± 0.11 3.61 ± 0.30
F1–F4 dosage forms are listed in Table S3 in the Supplementary Material. The release profiles approximately followed a first-order kinetics; the fitted parameters and composition of the formulations are listed in Table 5. In the absence of alcohol, TM release from formulation F1 (based on MT:AG 3:5 xerogel) was complete after 12 h; the release of TM from formulation F2 (BG:MT:LU 1:3:3) was 92.3%, from formulation F3 (MT:AG:PO 1.5:2.5:1) was 99.3% and from formulation F4 (BG:PO 4:1.5) 96.5% in the same period. These data indicate that under the dissolution conditions used in this study practically complete release of active ingredient was observed after 12 h in all cases. Similar release profiles were generated for all formulations, the release of TM is fastest from the F1 formulation with 50% of TM released during the first 90 min. The extended-release formulations contain large amounts of opiate active ingredient and therefore the release mechanism must be sufficiently robust to prevent any possibility of uncontrolled release leading to “dose dumping”. The ability of extended-release formulations to retain their respective intended delivery profiles in the presence of alcohol is of importance, given that some patients are likely to co-ingest alcohol with analgesic drugs either accidentally or deliberately. The release of TM from all the above mentioned xerogel formulations was significantly decreased by the presence of 40% (v/v) ethanol in the dissolution media. These release profiles show that co-administration of alcohol with extended-release xerogel tablets will result in a decreased liberation rate of TM from the tablet, as evidenced by significantly higher release half-times. This observation can be attributed to decreased rate of water diffusion into the xerogel matrix which results in slower drug release in presence of ethanol. This effect further guards the formulations against any potential dose dumping. Should a patient consume alcohol while taking the opioid drug, then reduced TM release rates would be desirable. In general, the controlled release of the guest drug from hydrogel is mainly governed by increased viscosity of the matrix which hinders drug dissolution and diffusion into the medium. Considering the possible drug–matrix interactions, hydrogen bonding and hydrophobic bonding can be expected (Xing et al., 2002). The presence of hydrogen donors in the form of phenolic hydroxyl group in tramadol suggests formation of hydrogen bonds. Since both compounds contain hydrophobic regions, the aromatic rings of tramadol and the aliphatic chains of polysaccharides, hydrophobic forces also could participate in the interaction phenomena. In addition, polar–polar interactions between the drug (a hydrochloride with polar groups) and polysaccharide matrix (with abundant hydroxyl groups) are also present in hydrophilic domains of the hydrogel (Hoare and Kohane, 2008).
4. Conclusions In this work, TM as a model API was successfully incorporated into a structurally optimized xerogel from which only therapeutic-level concentrations were released. The rate of drug release is not increased even if the dosage form is tampered with by a user. We have demonstrated the use of AG and BG polysaccharides with MT for preparing stable MT:AG and MT:BG hydrogels. Potential of xerogel matrices as a gelforming material for abuse-deterrent formulae of TM was tested. When a xerogel-based TM formulation is subjected to a liquid environment, a hydrogel is restored within a few seconds and the mixture becomes so thick that it cannot be drawn into a syringe. The swelling behavior was dependent on the extent of soluble polysaccharide in xerogel matrices, as well as the hydrophilicity of the restored hydrogel network. In the second part of this study, a novel approach regarding the improvement of TM delivery and the optimization of its efficacy was established. The dissolution/release results highlighted that the insoluble BG xerogel leads to alcohol resistant and prolonged-release profile across the 12hour period, while effect was somewhat inferior when MT:AG was present in the matrix. In general, addition of a second gel-forming material to the base hydrogel greatly improves control over TM release kinetics and abuse-deterrent properties. Acknowledgements Financial support from the Scientific Grant Agency of the Slovak Republic (VEGA 1/0592/15) is gratefully acknowledged (T. D., P. Š.). This work was also supported by the Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic for the Structural Funds of EU, OP R&D of ERDF by realization of the project “Evaluation of natural substances and their selection for prevention and treatment of lifestyle diseases”, ITMS 26240220040 (M. V.). The project “Research and development of active pharmaceuticals ingredients by stereoselective processes including development of finished dosage forms”, was supported by Ministry of Education, Science, Research and Sport of the Slovak Republic within provided incentives for research and development from State budget according to Act No 185/2009 on incentives for research and development and to completion of Act No 595/2003 about income tax as amended (M.V., Š. H.). Data statement The raw/processed data required to reproduce these findings are available from the authors upon request.
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Appendix A. Supplementary data
tissue engineering. Adv. Drug Deliv. Rev. 65 (9), 1172–1187. Matthews, F., Boehm, G., Tang, L., Liang, A., 2012. Abuse-deterrent multi-layer pharmaceutical composition comprising an opioid antagonist and an opioid agonist. US Patent US8158156. Mehling, T., Smirnova, I., Guenther, U., Neubert, R.H.H., 2009. Polysaccharide-based aerogels as drug carriers. J. Non-Cryst. Solids 355, 2472–2479. Micka, A., Feng, K., Lai, T.C., Gaik, J., 2016. Abuse deterrent immediate release formulations comprising non-cellulose polysaccharides. European Patent Application 2016/004170A1. Pellicer, J., Delegido, J., Dolz, J., Dolz, M., Hernández, M.J., Herráez, M., 2000. Influence of shear rate and concentration ratio on viscous synergism. Application to xanthanlocust bean gum mixtures. Food Sci. Technol. Int. 6, 415–423. Schaeffer, T., 2012. Abuse-deterrent formulations, an evolving technology against the abuse and misuse of opioid analgesics. J. Med. Toxicol. 8, 400–407. Sikora, M., Kowalski, S., Tomasik, P., 2008. Binary hydrocolloids from starches and xanthan gum. Food Hydrocoll. 22, 943–952. Synytsya, A., Novak, M., 2014. Structural analysis of glucans. Ann. Transl. Med. 2 (2), 17–30. Thomas, S., Durand, D., Chassenieux, C., Jyotishkumar, P. (Eds.), 2013. Handbook of Biopolymer-Based Materials: From Blends and Composites to Gels and Complex Networks. Wiley-VCH, Weinheim (875 pp). Toworfe, G.K., Anku, C., Radin, S., Zeiger, A., Ducheyne, P., 2016. Abuse prevention by controlled release of opioids from micro to nano-structured silica xerogel. In: Laudon, M., Romanowicz, B. (Eds.), TechConnect Briefs 2016: Advanced Materials. TechConnect.org, 978-0-9975-1170-3, pp. 174–180. Uthappa, U.T., Sriram, G., Brahmkhatri, V., Kigga, M., Jung, H.-Y., Altalhi, T., Neelgund, G.M., Kurkuria, M.D., 2018. New J. Chem. 42 (14), 11964–11971. Varshosaz, J., Tavakoli, N., Kheirolahi, F., 2006. Use of hydrophilic natural gums in formulation of sustained-release matrix tablets of tramadol hydrochloride. AAPS PharmSciTech 7 (1), E168–E174. Vasanthan, T., Temelli, F., Ghotra, B.S., Wettasinge, M., 2006. Aqueous solutions containing beta-glucan and gums. US Patent Application 2006/0040036. Veverka, M., Dubaj, T., Gallovič, J., Jorík, V., Veverková, E., Mičušík, M., Šimon, P., 2014. Beta-glucan complexes with selected nutraceuticals: synthesis, characterization, and stability. J. Funct. Foods 8, 309–318. Veverka, M., Murányi, A., Bakoš, D., Kochan, J., Jorík, V., Omastová, M., 2016. Arabinogalactan:β-glucan as novel biodegradable carriers for recombinant human thrombin. J. Biomater. Sci. Polym. Ed. 27, 202–217. Veverka, M., Dubaj, T., Veverková, E., Šimon, P., 2017. Stabilization of conjugated linoleic acid via complexation with arabinogalactan and β-glucan. Eur. J. Lipid Sci. Technol. 119, 1600258. Veverka, M., Dubaj, T., Veverková, E., Šimon, P., 2018. Natural oil emulsions stabilized by β-glucan gel. Colloids Surf. A Physicochem. Eng. Asp. 537, 390–398. Webster, L.R., 2009. Update on abuse-resistant and abuse-deterrent approaches to opioid formulations. Pain Med. 10 (S2), S124–S133. Webster, L.R., 2011. Oxycodone extended-release using gel-cap technology to resist alteration and abuse for the treatment of moderate-to-severe pain. Pain Manag. 1 (5), 417–425. Wright, C., Oshlack, B., Breder, C., 2016. Pharmaceutical formulation containing gelling agent. US Patent 9517207. Xing, B., Yu, C.-W., Chow, K.-H., Ho, P.-L., Fu, D., Xu, B., 2002. Hydrophobic interaction and hydrogen bonding cooperatively confer a vancomycin hydrogel: a potential candidate for biomaterials. J. Am. Chem. Soc. 124 (50), 14846–14847. Xue, W., Champ, S., Huglin, M.B., Jones, T.G.J., 2004. Rapid swelling and deswelling in cryogels of crosslinked poly(N-isopropylacrylamide-co-acrylic acid). Eur. Polym. J. 40, 467–476.
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Beta-glucan and arabinogalactan-based xerogels for abuse-deterrent opioid formulations
T
Miroslav Veverkaa, Tibor Dubajb, , Eva Veverkovác, Peter Šimonb, Štefan Husárd,e, Katarína Tomanováb, Vladimír Joríkb ⁎
a
EUROFINS BEL/NOVAMANN Ltd., 940 02 Nové Zámky, Slovakia Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37 Bratislava, Slovakia c Faculty of Natural Sciences, Comenius University, 842 15 Bratislava, Slovakia d Saneca Pharmaceuticals, 920 27 Hlohovec, Slovakia e Faculty of Pharmacy, Department of Pharmaceutical chemistry, Comenius University, 832 32 Bratislava, Slovakia b
ARTICLE INFO
ABSTRACT
Keywords: Opioids Xerogel Drug delivery Drug abuse Release kinetics
Novel polysaccharide hydrogels based on Methocel and beta-glucan or arabinogalactan and corresponding xerogels were prepared and described. Phase stability of hydrogels was confirmed over multiple freeze–thaw cycles. Binary beta-glucan:Methocel hydrogels showed the highest freeze–thaw stability in terms of their syneresis. The viscosity of binary hydrogels was further increased by adding water-soluble resin. Freeze drying of polysaccharide gels yields xerogels suitable as abuse-deterrent vehicles for opioid delivery. The xerogels were characterized by infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, scanning electron microscopy and by their swelling behavior. As a model opioid, tramadol hydrochloride formulations were prepared with various xerogel matrices and dissolution-release profiles were determined. The xerogel matrix acts as a functional excipient that forms a viscous gel barrier with decreased rate of tramadol release. Moreover, slower drug release with no dose dumping is observed in the presence of ethanol. The release kinetics demonstrated that hydrophilic gels with beta-glucan or arabinogalactan are effective for controlling and prolonging the drug release for 12 h which could reduce the required number of administrations.
1. Introduction Controlled-release tablets enable patients to gain considerable control over their pain; however opioid drugs are a significant source of drug abuse. Therefore, many pharmaceutical companies are developing various abuse-resistant technologies to mitigate the potential abuse of their opioid formulations (Webster, 2009; Schaeffer, 2012). Formulations incorporating both physical and chemical barriers represent a promising approach that resists abuse patterns via forming ingestible high-viscosity material (Mastropietro and Omidian, 2015; Webster, 2011). Hydrogels are hydrophilic three-dimensional polymeric networks that can absorb and retain large quantities of water within their structure. Interpenetrating polymer network (IPN) technology is a suitable route for preparing hydrogels via physical crosslinking, chemical gelation, or self-assembly (Matricardi et al., 2013; Kim et al., 2003; Gupta and Srivastava, 1994; Hu et al., 2014). IPN hydrogels are usually
prepared by diffusing linear polymer chains into a preformed polymer network. While being physically interlocked, polymers within IPN are chemically independent of each other (Burugapalli et al., 2001; Sikora et al., 2008; Dragan, 2014). In this way, the mechanical stability of the hydrogels is improved due to physical entanglement and network interactions. Cellulose derivatives such as Methocel (MT) or their combination with a second polymer are frequently used as gel-forming polymers for hindering extraction of opioids from pharmaceutical formulations (Wright et al., 2016; Mastropietro and Omidian, 2015; Joshi and Somma, 2007; Micka et al., 2016). Only a comparatively few beta-glucans (BGs) form gels and these vary widely in gel character and texture so that they are suitable for food and cosmetic applications. For example, heating an aqueous suspension of curdlan yields a thermo-reversible gel with high strength and syneresis. Further, in contrasts to other polysaccharides multiple freeze–thaw cycles (FTCs) do not affect its properties (Thomas et al., 2013). To date, despite the ability of BGs to form viscous aqueous suspensions
Abbreviations: AG, arabinogalactan; BG, beta-glucan; MT, Methocel; PO, Sentry Polyox; LU, Lutrol; TM, tramadol hydrochloride ⁎ Corresponding author. E-mail addresses: [email protected] (M. Veverka), [email protected] (T. Dubaj). https://doi.org/10.1016/j.ejps.2019.01.003 Received 8 November 2018; Received in revised form 18 December 2018; Accepted 4 January 2019 Available online 06 January 2019 0928-0987/ © 2019 Elsevier B.V. All rights reserved.
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with shear-thinning flow behavior (Burkus and Temelli, 1998; Burkus and Temelli, 1999) its application to binary gels remains scarce, mainly because of lower viscosity in solution compared to gums and inferior gel-forming capacity. It was observed that solutions of BG and gums (iota carrageenan, xanthan gum, cellulose) exhibit enhanced rheological properties including increased shear tolerance (Vasanthan et al., 2006); however, the yeast-derived BG alone forms mechanically weak hydrogels. On the other hand, both BG and arabinogalactan (AG) exhibit very good complex-forming ability with various nutraceuticals (Veverka et al., 2014), conjugated linoleic acid (Veverka et al., 2017) and were proposed as carriers for recombinant human thrombin (Veverka et al., 2016). Moreover, BG-based gels form stable emulsions with various oils (Veverka et al., 2018). Tramadol hydrochloride (TM) is administered in the therapy of acute and chronic pain due to its specific mechanism of action which evokes a low incidence of adverse effects when compared to classical opioids such as morphine and fentanyl (Coluzzi and Mattia, 2007). Extended-release TM tablet formulated in a self-correcting hydrophilic controlled-release matrix is a secure-release once-daily formulation that cannot be crushed for abuse. For controlled TM delivery, double-phase hydrogels and hydrophilic natural gum-based tablets were described by Kamel et al. (2012) and Varshosaz et al. (2006). Gel applications for the above-mentioned goal via corresponding xerogels by swelling/rehydration are rare (Toworfe et al., 2016; Forsgren et al., 2011; Ahola et al., 2008). Xerogels are usually formed by removing liquid from a gel (Mehling et al., 2009; Gulrez et al., 2011). In general, the hydrophilic character of polysaccharide-based xerogels leads to moisture sensitivity and allows flexible renewability of gel (Xue et al., 2004; Khalid et al., 2002; Kuang et al., 2011). These xerogels swell to an equilibrium state that retains a significant amount of water; however, some formulations can only swell gradually due to slow water diffusion into a glassy polymer matrix. To achieve a highly viscous gel in liquid phase, a mixture of water-soluble/swellable cellulose derivatives, polysaccharides, poly(ethylene oxide), gums, clays and carbomers have been suggested (Wright et al., 2016; Micka et al., 2016; Bastin and Lithgow, 2001; Matthews et al., 2012). In addition to polysaccharide-based matrices, surface modified diatomaceous earth microparticles with silica xerogel were studied recently as a potential matrix for controlled drug release (Uthappa et al., 2018) The goal of this study was to prepare tablets with prolonged-release profile for opioids and evaluate their abuse-deterrent properties. Series of MT:AG and MT:BG hydrogels and xerogels were prepared in bulk form with a special focus to rapidly achieve a highly gelled state in a system reconstituted from xerogel. The effect of BG and AG mass ratio on viscosity of mother gel and the swelling behavior of xerogel was studied; the influence of the addition of another thickening excipient (Sentry Polyox WSR 303 or Lutrol F 127) was also studied.
2.1. Hydrogel preparation
2. Materials and methods
The powder X-ray diffraction pattern was collected within the 2θ range of 2–60° on a Brag-Brentano θ/θ focusing powder diffractometer Bruker AXS D8 Advance. The instrument was equipped with X-ray tube providing CuKα radiation (λ = 0.154062 nm). The experimental conditions were as follows: exciting voltage 40 kV; anode current 40 mA; step size 0.01°. Samples of xerogels were gently crushed using an agate mortar and pestle and pressed into a powder disk. The measurements were carried out at room temperature using a flat silicon zero-background sample holder.
To the water solution of AG an appropriate amount of MT as a sieved powder was carefully added at about 90 °C with mixing (a lumpy suspension can be formed transiently); mixture was stirred until all the MT particles were wetted. The reaction mixture was further stirred for 30 min without heating to reach room temperature until the MT powder completely hydrated and a smooth and clear gel was obtained. In case of ternary hydrogels, the third ingredient (PO or LU) was added according to the product specification. If not stated otherwise, gels containing 6.0 wt% MT were prepared. In case of the water-insoluble BG, the gel was prepared by a primary gelation of micronized BG in water for 48 h at 40 °C. The BG suspension was then stirred at 95 °C for 2 h with occasional homogenization using homogenizer (Ultra Turrax T18, IKA, Germany) at 4000 rpm and MT was finally added. The gel containing 4.0 wt% of BG was slightly turbid. 2.2. Viscosity measurements Viscosity was measured using a rotational viscometer (Anton Paar DV-1P, Berlin, Germany) equipped with a tempering bath. The measurements were carried out in triplicates at 22.0 ± 0.5 °C; the apparent viscosity was expressed in mPa·s. The viscosity of samples (approx. 20 g) was measured using spindle No. 4 in up/down cycles (0.3–60 rpm spindle speed) with each speed kept constant for 10 s before the measurement was made. 2.3. Syneresis A gel sample of about 12 g was sealed in a graduated centrifugal 15ml tube and placed into a refrigerator. Five FTCs were done where each of the hydrogel was stored at −10 °C for 12 h, followed by thawing at 25 °C for 6 h. The thawed samples were collected and tested for syneresis. Syneresis of the hydrogel after each FTC was determined by centrifuging the samples at 2200 rpm for 20 min in a centrifuge (WWR Compactstar CS4). The volume of exuded water was then determined. 2.4. Fourier transform infrared spectroscopy (FTIR) Attenuated total reflectance FTIR spectra were measured in 4000–580 cm−1 range using FTIR spectrometer Nicolet Impact 410-IR (Thermo Scientific, WI, USA). The ATR technique (diamond ATR crystal) was used with Omnic 5.2 software. Fifty scans were collected for each sample. The FTIR spectra of the materials prepared were compared with those of the parent polysaccharides. 2.5. X-ray diffraction (XRD)
BG (from Pleorotus ostreatus, purity 93%, MW 450 kDa) was obtained from Natures Ltd. (Trnava, Slovakia) as micronized particles with a mean diameter of 4.5 μm. AG (purity 98.7%; isolated from Larix sibirica) was obtained from the Favorskii Irkutsk Institute of Chemistry, Siberian Branch (Irkutsk, Russia). The active pharmaceutical ingredient (tramadol hydrochloride) was obtained from Saneca Pharmaceuticals (Hlohovec, Slovakia). MT (Methocel K15 Premium CR grade) was obtained from the Dow Chemical Company (Bay City, USA). Commercial poly(ethylene oxide) Sentry POLYOX WSR 303 (PO, MW 7 · 106 g mol−1) was manufactured by Dow chemical (Philadelphia, USA). Lutrol F 127, that is, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), (LU, MW 9840–14,600 g mol−1), was provided by BASF (Ludwigshafen, Germany). Other chemicals of analytical or Ph. Eur. grade were purchased locally and used as received. In all experiments, double distilled water was used.
2.6. Differential scanning calorimetry Thermal behavior of hydrogels was studied using differential scanning calorimeter PerkinElmer DSC8500 equipped with an automatic cooling unit (IntraCooler II). Gel samples weighing 4–5 mg ( ± 0.01 mg) were placed in hermetically sealed aluminum pans; nitrogen was used as a purge gas. 133
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2.7. Gel drying
constant weight and potential matrix loss was evaluated gravimetrically.
A sample of approx. 100 g of hydrogel was transferred into a 300mL freeze-drying flask (ilShin Biobase, Korea) and frozen in an ultralow temperature freezer at −25 °C for 48 h. Subsequently, the flask was connected to a freeze-dryer (Coolsafe 55-4, Denmark) and freeze-dried at −55 °C under vacuum for 24 h to sublimate the solvent. The final desorption temperature was 20–22 °C after 24 h. Fluffy material was then pulverized using a coffee grinder for 30 s to obtain final powder. Moisture content in the xerogels was determined by Karl Fischer titration; the experiments were done in duplicate. Mass ratio of xerogel component is rounded to the nearest whole number.
2.12. Dissolution tests Drug release from the dosage formulations prepared was monitored according to Ph. Eur. (general chapters Section 2.9.3) using a paddle apparatus. The active pharmaceutical ingredient (TM) was mixed with powdered excipients and corresponding xerogels (see composition of TM dosage formulations in Table 5); the dry mixtures were compressed into round flat 0.2-ml tablets with a diameter of 6 mm using a manual tablet compression machine (UD Tablet Maker). All samples were compressed at the main compression force 124 bar which corresponds to force of 5.68 kN at the punch tip. For the dissolution test, 500 ml of medium was used in each dissolution vessel with a paddle rotation speed of 50 rpm. One tablet of experimental dosage formulations was put into each dissolution vessel and the collected samples were analyzed by HPLC. The dissolution media consisted of either 0.1-M HCl (pH = 1.2) or 40% ethanol in 0.1M HCl. Dissolution tests were carried out using 6 tablets (n = 6) for each of the four formulations over a 12-h period with samplings at 0.5, 1, 2, 4, 8, and 12 h.
2.8. pH measurement A digital pH meter (Mettler Toledo, Columbus, OH, USA) was used to measure the pH values at 20.0 ± 0.5 °C of samples immediately after preparation. 2.9. Conductivity measurement As the gel was prepared, it was tempered to 20 ± 0.5 °C and the conductivity was measured immediately (conductometer Mettler Toledo S230, Switzerland) using the 731 ISM electrode directly in a reaction glass beaker.
3. Results and discussion Using water as a solvent, two series of MT:AG and MT:BG gels were prepared by varying the AG or BG content from 2.5 to 10% and from 0.5 to 4%, respectively. The concentration of MT in the mixtures was fixed at 6.0 wt%. Apparent viscosity was measured for all hydrogels under study. For further evaluation by XRPD, FTIR, DSC, and swelling kinetics, representative formulations were selected from those with higher viscosity.
2.10. Scanning electron microscopy (SEM) Electron micrographs were obtained using JEOL 7500F (JEOL, Japan) at 15-kV accelerating voltage; all samples were covered by a thin gold/palladium layer to avoid charging effect. The measurements were performed in SEM at laboratory temperature and pressure of 4.5 · 10−4 Pa. The micrographs were acquired and analyzed using the PC SEM 3.0.1.8 package. For the cryo-EM, the technique described by Veverka et al. (2018) was employed.
3.1. Viscosity and syneresis Despite of no quantification of synergistic effects, it was evident that the viscosities of the mixed systems MT:AB and MT:BG are much higher than the viscosities of sole components, i.e., synergism can be expected (Pellicer et al., 2000). The hydrogel formed by BG and subsequent PO addition showed the strongest increase in viscosity among all the systems studied, ranging from 37.8 Pa·s before the treatment to 1160 Pa·s after polysaccharide addition (Table 1a). The viscosity continued to increase to 1524 Pa·s after LU addition. Similarly, the MT:AG combination also showed increased viscosity, however to a lesser extent (Table 1a). Generally, the effect of adding a third polymer (PO, LU) on the synergism observed in the two above-mentioned systems was clear. These ternary systems produce highly stable gels with improved water retention as confirmed freezing–thawing treatments. Prior to FT treatments, no syneresis was detected indicating good water-holding capacity of the hydrogels upon formation. After the fourth and fifth FTC, only low syneresis averaging 3.5% and 5.2% or 3.9% and 5.9% was detected in the MT:AG 5% and MT:BG 0.5% complexes, respectively. No syneresis was detected in other MT-containing hydrogels for up to five FTCs, indicating strong gels with stable water-holding ability.
2.11. Swelling experiments The xerogels prepared as powders are difficult to handle repeatedly; therefore, during the swelling experiments they were manipulated in tea bags. The kinetics of swelling of the xerogels was followed gravimetrically on an electronic balance (Mettler, Model ML 104, Switzerland). An empty wetted bag was used as a blank. Three xerogel samples of 0.3–0.5 g were used; the average values of these three measurements are reported. A xerogel sample of weight m0 was immersed in a tea bag in deionized water at 22 °C (pH = 7.1); after a certain time, the hydrogel was slightly dried using filter paper and weighed at regular time intervals to obtain m(t). The water uptake capacity is then defined as
m (t ) m 0 100%, meq
WUC(t ) =
(1)
where meq is the hydrogel weight at swelling equilibrium (24 h) at 22 °C. The equilibrium water content, EWC, was calculated as
EWC =
meq
m0
meq
100%.
3.2. FTIR spectra
(2)
The FTIR spectra of xerogels (Fig. 1) consisted of broad absorption bands of the hydroxyl group of both pristine polysaccharides (about 3330 cm−1, strong and wide OeH stretch), 2900 cm−1 corresponding to CeH stretch, and broad bands at about 1370 and 1035 cm−1 of glucopyranose ring. Tables S1 and S2 in the Supplementary Material list several characteristic absorption bands for AG, MT, BG and representative xerogels. Apparent differences in the spectrum of starting polysaccharides and xerogels should arise from any intermolecular interactions between MT and polysaccharide in the matrices. In the series
Similarly, swelling ratio, SR, and equilibrium swelling ratio, SReq, were calculated as
SR(t ) =
SR eq =
m (t ) m 0 m0
meq m0
(3a)
m0 (3b)
Afterwards, the swelled material was dried (55 °C, 2 kPa) to 134
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of the xerogel samples there was observable fact that FTIR spectrum does not change from one to the other and is quite reproducible except for the difference in band intensities due to increasing amount of AB or BG in the xerogel. For structural characterization of polysaccharides two spectral regions are important. These are “sugar region” (1200–950 cm−1) and “anomeric region” (950–750 cm−1). The highly overlapping intense bands of CeO and CeC stretching vibrations in glycosidic bonds and pyranoid ring predominate in the former region (Synytsya and Novak, 2014). In xerogels, CeO vibrations were slightly shifted to 1350 cm−1 and 1100 cm−1. An increase in peak intensity appeared at 1100 cm−1 due to an increase in the extent of hydrogen bonding. Compared to pristine polysaccharide, the xerogel showed a weak broadened absorption band for ν(OH). The observed broadening and asymmetry of the ν(OH) band in the spectra of MT:AG and MT:BG samples suggests formation of a new type of hydrogen bonds by interactions between MT and polysaccharides. The shifts in spectra imply that new hydrogen-bonding interaction is formed between polysaccharide and MT in the MT:AG or MT:BG series. The FTIR spectra of the corresponding physical mixtures did not show such changes (data not shown).
Table 1 Composition and physico-chemical properties of AG (a) and BG (b) gels determined 2 h after preparation. (a) MT in base gel (wt%)
AG (wt %)
PO (wt %)
Viscositya (mPa·s)
Conductivity (μS/ cm)
pH
6.0 6.0 6.0 6.0 6.0
– 5.0 5.0 10.0 10.0
– – 4.0 – 4.0
37,750 141,250 358,940 288,649 470,120
nc 0.30 nc 0.21 0.35
nc 3.3 nc 3.4 3.4
(b) MT in base gel (wt%)
BG (wt%)
PO (wt%)
LU (wt%)
6.0 6.0 6.0 6.0 6.0 –
– 0.5 2.0 2.0 2.0 4.0
– – – 6.0 – 1.5
– – – – 6.0 –
Viscosity (mPa·s) 37,750 720,410 874,945 1,158,924 1524 195 1,020,450
Conductivity (μS/ cm)
pH
nc 0.88 0.90 1.00 0.95 1.10
nc 5.4 6.0 5.7 5.2 5.5
3.3. Swelling studies
nc test not conducted. a Apparent value.
For practical xerogel applications the kinetics of water absorption is indicative to determine how quickly a hydrogel is restored. From a practical point of view, fast swelling of the xerogel prevents intravenous route of administration: a thick hydrogel is restored within a short time and the mixture cannot be drawn into a syringe. As the indicative criteria, swelling ratio and water uptake after 10 min (SR10 and WU10, respectively) were chosen; the time interval of 10 min might correspond to initial stage of swelling. The swelling rate depends mostly on xerogel composition and structure and on the nature of mutual interaction of polysaccharides. All xerogels showed similar hydration profiles, swelling data for representative xerogels are shown in Table 2. Clearly the AG-containing xerogels are quickly hydrated (see WU10 and SR10 values). When the weight ratio of AG in the xerogel is increased over the range 1 to 5 to the MT, the equilibrium swelling ratio SR10 was increased substantially. The observed results may be explained by the fact that an increased AG content in xerogel renders the network more hydrophilic and henceforth, the degree of water sorption and swelling ratio increases. In addition, the water-soluble AG particles may form a porous microstructure of MT:AG xerogel which is able to transport water into the matrix bulk. On the other hand, AG is more soluble than MT itself, however, its gel forming ability is negligible. It should be noted that swelling of AG-containing xerogels is probably accompanied by a partial loss of water-soluble AG which leads to a decreased final water content (comparing SReq data). Results in BG series may be attributed to the fact that BG is a hydrophilic gel-forming polymer and increasing its amount in the xerogel Table 2 Properties of representative MT:AG and MT:BG xerogels. Measurements were done in duplicates, mean values are listed. Xerogel (wt. ratio) MT:AG 3:5 MT:AG 6:5 MT:AG:PO 1.5:2.5:1 MT:BG 3:1 BG:PO 4:1.5 MT:BG:LU 3:1:3
Fig. 1. FTIR spectra (from top to bottom): AG, BG, MT, AG:PO:MT 2.5:1:1.5, BG:MT:LU 1:3:3, AG:MT 5:3, BG:PO 4:1.5.
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Particle size, mean ± SD (μm)
Residual water (wt %)
Swelling parameters WU10 (%)
SR10
SReq
EWC (%)
128 ± 33 103 ± 29 105 ± 20
2.9 3.3 3.0
82.8 78.8 77.5
65.5 64.4 61.4
67.21 70.80 66.50
98.6 98.8 98.8
130 ± 22 99 ± 28 131 ± 38
3.8 3.5 4.8
65.9 70.5 73.6
61.5 59.8 60.1
86.61 79.26 79.14
99.5 99.5 99.7
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Fig. 2. Scanning electron micrographs of xerogel surfaces: MT:AG:PO 1.5:2.5:1, BG:MT:LU 1:3:3, MT:AG 3:5, BG:PO 4:1.5, BG, and pure BG (2 wt%) hydrogel.
matrices will obviously increase the gelling; thus, an increase in the swelling ratio is expected. On the other hand, higher volume of waterinsoluble BG in the MT:BG xerogel hinders water diffusion so that swelling is slower and the corresponding WU10 and SR10 parameters are lower. The EWC values for BG-containing formulations are slightly higher (≥99.5%) compared to AG series. However, some variation in the EWC and SReq values is expected due to inevitable manipulation losses of the xerogel mass in swelling experiments which is true mainly for soluble AG, especially after long swelling periods. Thus, for all AGbased xerogels the SR10 and WU10 swelling parameters are higher than those for BG xerogels; for equilibrium parameters SReq and EWC the opposite is true. However, as the LU was added to the BG:MT matrices, WU10 increased from 65.9% to 73.6%; the difference can be explained by increased hydrophilic nature of the xerogel matrix (Table 2). It is hypothesized that the intermolecular interactions between the BG and LU chains keep the components of the matrix in the largely amorphous form and so accelerate the swelling kinetics (Khalid et al., 2002).
3.4. Xerogel morphology Morphology of the xerogels prepared can be described as a structure consisting of high-density material. The interior morphologies of the xerogels and the BG hydrogel are shown in Fig. 2 (a–f). As depicted on representative micrograph for BG-based formulation (Fig. 2f), hydrogels exhibit a highly interconnected porous structure with uniform pore distribution. Moreover, the pure BG xerogel exhibited inter-connected a highly porous and fibrous structure with uniform and deep pore distribution. (Fig. 2e). Thus, for MT:AG and MT:BG xerogels a similar surface pattern and the pore sizes can be expected as identical preparation technique and conditions were used. However, in these xerogels the cracks in the particles happened probably due to various rates of water removal by evaporation from different matrices. Variable extents of the pores and channels were observed; xerogels have many pores with interconnecting capillary channels in their inner surface (Fig. 2 a–c). Probably the MT:AG system combining both swellable and
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Table 3 Quantification of water forms present in rehydrated xerogels. Formulation
Total water (wt%)
Free water (wt%)
Freezable bound water (wt%)
Non-freezable water (wt%)
85.7 90.9 88.6 83.2
70.6 76.1 81.3 79.6
5.1 0.8 1.9 0.0
10.0 14.0 5.4 3.6
MT:AG:PO 1.5:2.5:1 MT:BG:LU 1:3:3 BG:PO 4:1.5 MT:AG 3:5
Table 4 XRPD peak position and integral breadth parameters of xerogels. Sample
Peak position, (Å)
BG BG:PO 4:1.5 BG:MT:LU 1:3:3 AG AG:MT 5:3 AG:PO:MT 2.5:1:1.5
20.4 (1.1) – – 25.08 (3) 22.27 (1) 22.39 (1)
15.40 (8) 16.57 (5) 16.7 (2) 7.62 (5) 9.31 (6) 10.94 (3)
Integral breath, β = A/I0 12.4 (2) 12.08 (9) 9.9 (2) 6.14 (2) 6.46 (6) 7.73 (6)
10.72 (6) 10.44 (8) 8.3 (3) 4.80 (2) 4.84 (1) –
– – – 4.16 (2) 4.54 (2) –
415 (19) – – 116 (1) 33 (1) 39 (1)
22 74 15 143 185 135
(4) (3) (3) (10) (14) (10)
47 43 133 98 271 481
(5) (5) (19) (8) (22) (30)
70 (4) 14 (4) 32 (26) 210 (11) 47 (6) –
– – – 175 (14) 340 (12) –
Standard errors (given in parentheses) were calculated for each phase. Integral breadth (β) corresponds to the width of a rectangle with the same height I0 and area A as the diffraction peak.
ranges from 3.6 to 14% of the hydrogel mass (or 4.3–15.4% of the total water); the ternary gels have a higher portion of water present in nonfreezing form compared to binary gels. By comparing the amount of freezable and non-freezable bound water it follows that, in general, most of the hydration takes place in the primary shell of the polymer chains. 3.6. XRPD analysis The BG and AG polysaccharides have a polymer structure resulting in four or five very broad and overlapped peaks observed by XRPD. Similar patterns of pristine polysaccharides and corresponding xerogels, consisting of very broad overlapped peaks, exclude the possibility of their straightforward visual comparison and phase identification. Only free crystalline components of xerogel can be observed in diffraction pattern, if any. Therefore, we applied the line profile analysis to examine subtle differences in their diffraction patterns (Veverka et al., 2014; Veverka et al., 2016). Results of the line profile analysis are listed in Table 4. Each of four xerogel samples was graphically analyzed for the presence of residues of the crystalline components. For reasons of image clarity, diffractograms of well crystalline xerogel components (PO, LU) were adapted to significantly lower polysaccharide intensities. Results of the line-profile analysis of BG:PO 4:1.5 confirm the formation of new phases. The first diffraction line of pristine BG has disappeared and the second one is significantly shifted to lower angle 2θ. As it can be recognized from the line-profile analysis (see Figs. S1 and S2 in the Supplementary material), in the xerogel BG:PO 4:1.5 a small amount of crystalline PO was detected. Line-profile analysis of BG:MT:LU 1:3:3 sample due to the enormous peak broadening makes their separation somewhat ambiguous. Due to the strict overlap of BG and MT diffraction lines, the line-profile analysis is not sufficient to assess the formation of new phases. Unfortunately, xerogel contains a residual mark of LU phase, too. Line-profile analysis of AG:Methocel 5:3 unambiguously shows shift in peak positions and significant changes of integral breadth (β). It clearly indicates the formation of a new xerogel phase. Similarly, AG:PO:MT 2.5:1:1.5 forms a new phase. It can be stated on the base of peak shifts and changes of integral breadth (β) listed in Table 4.
Fig. 3. Release profile of TM from F1 dosage form in two different dissolution media. Solid lines are a least-squares fit to a first-order kinetic equation.
soluble polysaccharide led to a different pattern of water removal and caused increased irregularity of the matrices. Therefore, only a small number of pores survived the drying process. In the case of BG:PO 4:1.5 xerogel morphology, the micrograph (Fig. 2d) shows a different xerogel morphology where the channel type of pure BG xerogel is preserved. 3.5. Thermal behavior Thermal behavior of xerogels and corresponding hydrogels upon heating and cooling was studied by differential scanning calorimetry (DSC). Xerogel samples were swollen for 3 h in water and cooled down from 25 °C to −50 °C at 5 °C/min and allowed to equilibrate for 10 min. Afterwards, a heating run at 5 °C/min was done to observe melting of water confined in the gel matrix. The water was found to be present in three different forms: (i) non-interacting free water for which the melting is similar to that of bulk water, (ii) freezable bound water forming the secondary hydrating shell of the polymer chains which melts at slightly lower temperature, and (iii) non-freezing bound water which forms the primary hydrating shell and interacts with the gel matrix strongly so that it does not freeze upon cooling at all. DSC allows to quantify these water forms by comparing the corresponding peak area with the melting enthalpy of water (334 J/g); the results are summarized in Table 3. The most abundant is free water; this form represents 82–96 wt% of the total water content in hydrogels. The content of non-freezing water that strongly interacts with gel matrix
3.7. Controlled release of TM Representative dissolution release profiles of TM from the experimental solid dose formulations are shown in Fig. 3; numerical values for 137
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Table 5 Composition of TM dosage formulations and the corresponding parameters for first-order release kinetics. Ingredient
Composition (in wt%) F1
TM Microcrystalline cellulose (PH102) Lactose monohydrate (spray dried) MT:AG 3:5 BG:MT:LU 1:3:3 MT:AG:PO 1.5:2.5:1 BG:PO 4:1.5 Magnesium stearate Release rate constant, k (h−1) 0.1 M HCl 0.1 M HCl + 40% Alcohol Release half-time, t1/2 (h) 0.1 M HCl 0.1 M HCl + 40% Alcohol
F2
F3
F4
20 19 20 40 – – – 1
20 19 20 – 40 – – 1
20 19 20 – – 40 – 1
20 19 20 – – – 40 1
0.45 ± 0.02 0.21 ± 0.02
0.27 ± 0.02 0.20 ± 0.01
0.32 ± 0.02 0.19 ± 0.01
0.28 ± 0.01 0.19 ± 0.02
1.53 ± 0.06 3.31 ± 0.24
2.57 ± 0.20 3.52 ± 0.22
2.14 ± 0.13 3.65 ± 0.28
2.50 ± 0.11 3.61 ± 0.30
F1–F4 dosage forms are listed in Table S3 in the Supplementary Material. The release profiles approximately followed a first-order kinetics; the fitted parameters and composition of the formulations are listed in Table 5. In the absence of alcohol, TM release from formulation F1 (based on MT:AG 3:5 xerogel) was complete after 12 h; the release of TM from formulation F2 (BG:MT:LU 1:3:3) was 92.3%, from formulation F3 (MT:AG:PO 1.5:2.5:1) was 99.3% and from formulation F4 (BG:PO 4:1.5) 96.5% in the same period. These data indicate that under the dissolution conditions used in this study practically complete release of active ingredient was observed after 12 h in all cases. Similar release profiles were generated for all formulations, the release of TM is fastest from the F1 formulation with 50% of TM released during the first 90 min. The extended-release formulations contain large amounts of opiate active ingredient and therefore the release mechanism must be sufficiently robust to prevent any possibility of uncontrolled release leading to “dose dumping”. The ability of extended-release formulations to retain their respective intended delivery profiles in the presence of alcohol is of importance, given that some patients are likely to co-ingest alcohol with analgesic drugs either accidentally or deliberately. The release of TM from all the above mentioned xerogel formulations was significantly decreased by the presence of 40% (v/v) ethanol in the dissolution media. These release profiles show that co-administration of alcohol with extended-release xerogel tablets will result in a decreased liberation rate of TM from the tablet, as evidenced by significantly higher release half-times. This observation can be attributed to decreased rate of water diffusion into the xerogel matrix which results in slower drug release in presence of ethanol. This effect further guards the formulations against any potential dose dumping. Should a patient consume alcohol while taking the opioid drug, then reduced TM release rates would be desirable. In general, the controlled release of the guest drug from hydrogel is mainly governed by increased viscosity of the matrix which hinders drug dissolution and diffusion into the medium. Considering the possible drug–matrix interactions, hydrogen bonding and hydrophobic bonding can be expected (Xing et al., 2002). The presence of hydrogen donors in the form of phenolic hydroxyl group in tramadol suggests formation of hydrogen bonds. Since both compounds contain hydrophobic regions, the aromatic rings of tramadol and the aliphatic chains of polysaccharides, hydrophobic forces also could participate in the interaction phenomena. In addition, polar–polar interactions between the drug (a hydrochloride with polar groups) and polysaccharide matrix (with abundant hydroxyl groups) are also present in hydrophilic domains of the hydrogel (Hoare and Kohane, 2008).
4. Conclusions In this work, TM as a model API was successfully incorporated into a structurally optimized xerogel from which only therapeutic-level concentrations were released. The rate of drug release is not increased even if the dosage form is tampered with by a user. We have demonstrated the use of AG and BG polysaccharides with MT for preparing stable MT:AG and MT:BG hydrogels. Potential of xerogel matrices as a gelforming material for abuse-deterrent formulae of TM was tested. When a xerogel-based TM formulation is subjected to a liquid environment, a hydrogel is restored within a few seconds and the mixture becomes so thick that it cannot be drawn into a syringe. The swelling behavior was dependent on the extent of soluble polysaccharide in xerogel matrices, as well as the hydrophilicity of the restored hydrogel network. In the second part of this study, a novel approach regarding the improvement of TM delivery and the optimization of its efficacy was established. The dissolution/release results highlighted that the insoluble BG xerogel leads to alcohol resistant and prolonged-release profile across the 12hour period, while effect was somewhat inferior when MT:AG was present in the matrix. In general, addition of a second gel-forming material to the base hydrogel greatly improves control over TM release kinetics and abuse-deterrent properties. Acknowledgements Financial support from the Scientific Grant Agency of the Slovak Republic (VEGA 1/0592/15) is gratefully acknowledged (T. D., P. Š.). This work was also supported by the Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic for the Structural Funds of EU, OP R&D of ERDF by realization of the project “Evaluation of natural substances and their selection for prevention and treatment of lifestyle diseases”, ITMS 26240220040 (M. V.). The project “Research and development of active pharmaceuticals ingredients by stereoselective processes including development of finished dosage forms”, was supported by Ministry of Education, Science, Research and Sport of the Slovak Republic within provided incentives for research and development from State budget according to Act No 185/2009 on incentives for research and development and to completion of Act No 595/2003 about income tax as amended (M.V., Š. H.). Data statement The raw/processed data required to reproduce these findings are available from the authors upon request.
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Appendix A. Supplementary data
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