1. Introduction
To date, one of the promising ways to improve the safety of drug carriers is the use of biopolymers. The most widespread are biopolymers of a polysaccharide nature: pectin, sodium alginate, starch, chitosan, inulin [
1,
2,
3,
4,
5,
6,
7,
8,
9,
10,
11]. Many studies have been conducted on the use of natural polysaccharides in drug delivery systems. Such studies include research of IPEC based on the biodegradable polymer starch and kappa carreginan [
12]. In other studies IPECs between naturally sulfated polysaccharides of the seaweed Polysiphonia nigrescens and cationized agaroses and Eudragit E were prepared, characterized, and explored for controlled drug release [
13]. Often in works, polyelectrolyte complexes are obtained by the interaction of oppositely charged polymers. So, polyelectrolyte complex film between pectin and chitosan was prepared by blending two polymer solutions and then solvent casting method [
14]. In addition, numerous studies have been conducted on the interaction of pectin and chitosan as drug delivery systems [
15,
16,
17,
18,
19]. There have also been studies on the interaction of cellulose derivatives - sodium carboxymethylcellulose [
20,
21].
Due to the fact that the present work studied systems based on pectin and a copolymer of acrylic and methacrylic acid, it is necessary to mention previously conducted studies involving these polymers.
Pectin is one of the most widespread and available polysaccharides in the plant world. In pharmaceutical technology, it is used as a binder [
1]. It should be noted that pectin belongs to biodegradable polymers. It is stable in the upper gastrointestinal tract (GIT) but is degraded by the microflora of the large intestine, mainly anaerobic bacteria such as Bifidobacterium, Bacteroides and lactobacilli of the genus Lactobacillus [
22].
Moreover, there are many oral drug delivery systems (DDS) containing pectin and calcium pectinate, such as tablets, particles, microparticles, pellets and beads, such forms are discussed and systematized in detail in a review on pectin-based delivery systems for the treatment of colon cancer [
4].
By the research group of Semde et.al. films based on pectin or calcium pectinate with cellulosic (Aquacoat® ESD 30, Surelase®) or acrylic (Eudragit® NE30D, RS30D) polymer dispersions were obtained and studied [
23]. The leaching of pectin from the obtained films was studied, a slowdown in the dissolution of pectin from films containing Eudragit® RS30D was noted, which is explained by the interaction of ionized carboxyl groups of pectin with quarter amino groups of Eudragit® RS30D [
23].
In addition, the same team of authors studied the effect of pectinolytic enzymes on the release of theophylline from dispersions containing pectin or calcium pectinate coated with cellulosic (Aquacoat® ESD 30, Surelase®) or acrylic (Eudragit® NE30D, RS30D) dispersions. The release of theophylline was found to be lower in the presence of pectinolytic enzymes. The authors attribute this to the ability of pectin to hydrate, swell, and form channels through which the hydrophilic drug substance easily diffuses into the environment. In the presence of pectinolytic enzymes, the hydration of pectin decreases, as a result of which the release level decreases. The release of the drug substance from the dosage form occurs due to the degradation of pectin [
24].
In the work of other authors (Ofori-Kwakye and Fell) films based on pectin, HPMC, chitosan were developed by the solvent cast method using 0.1 M hydrochloric acid or 0.1 M acetic acid [
25]. The leaching of pectin in a medium simulating the upper GIT was studied in the presence and absence of pectinolytic enzymes. In contrast to the previous work of the other authors (Semde et al.), the addition of enzymes led to an increase in the dissolution of pectin, which they explain as degradation of pectin from the obtained films [
24]. Attention is also drawn to the complex formation between the ionized carboxyl groups of pectin and the amino groups of chitosan, which is part of the dosage form [
25].
Biodegradable gels based on pectin and chitosan were obtained by a group of Khutoryansky, rheological properties, swelling ability of gels, degradation under the action of the enzyme and release of cisplatin were studied [
26].
Copolymers of methacrylic and acrylic acids are widely used as bases for matrices [
27,
28]. Among them, a special place is occupied by polymers under the common trade name "Eudragit", produced by the company "Evonik Ind.", Germany. They are organic solutions or aqueous dispersions of synthetic copolymers of methacrylic acid and its esters. Depending on the ratio of carboxyl and ether groups, these copolymers dissolve at different pH values and may differ in dissolution rate. They are used to obtain tablet coatings that allow you to control the release of the drug in desirable GIT. For example, Eudragit® E is a weak base used to develop coatings that are soluble in the stomach region [
18,
19,
20]. Many studies have been carried out on the production of systems based on polymethacrylates and oppositely charged ions [
31,
32,
33,
34,
35].
Taking into account the ability of the studied polymers to interact, it becomes possible to obtain chemically new compounds as interpolyelectrolyte complexes (IPECs) in order to modify the properties of individual polymers [
39].
Earlier, the research group of Moustafine obtained and studied IPECs based on Eudragit® EPO and polysaccharide alginate [
29,
30]. In the research both physicochemical and swelling ability properties, the processes occurring during the swelling of matrices in the GIT environments were studied, and the drug release model of the diclofenac sodium was assessed [
30]. Several researches on the production of IPEC and encapsulation of such substances as fluorouracil, indomethacin has been conducted [
36,
37,
38].
The interaction of high and low viscosity alginate with Eudragit® EPO was also studied by researchers, where a comparative evaluation of the obtained IPECs with physical mixtures of these polymers was carried out, the interaction of these polymers and the slowing down of the release of diltiazem hydrochloride from tablets was proved [
40].
Another group of scientists conducted studies on the interaction of sodium alginate with quaternary polymethacrylates, obtained gel bids, and noted a slowdown in the release of the drug propranolol hydrochloride [
41].
IPECs obtained on the basis of pectin and Eudragit® E PO synthetic copolymer opens up the possibility of developing a drug delivery system for colon-targeting. Given that Eudragit® EPO and pectin are oppositely charged polyelectrolytes (PEs), one of the possible ways to modify their structure is to include them in an IPEC. Thus, taking into account the huge number of studies of DDS using pectin, well-known properties of pectin as the ability to hydrate, the aim of our research was to obtain and study IPECs based on pectin and Eudragit® E PO copolymer for developing modified oral DDS.
3. Discussion
Presented figures shows typical curves of turbidimetric titration of EPO and pectin solutions and conversely (pectin-EPO) in a medium of estimate pH values: 4.0, 5.0, 6.0, 7.0.
It should be noted that at pH=4, turbidity maximum is observed at a ratio of EPO/Pec polymers of 4:6, regardless of the mixing order during synthesis, both for apple and citrus pectins (
Figure 1a, b). At pH=5, in the case of PecC, the maximum is observed at a polymer ratio of 5:5, and for PecA, 4:6 (
Figure 1c, d). At pH = 6, the maxima are in both cases at a polymer ratio of 5:5 (
Figure 1e,f). And at pH = 7 - 6:4 is typical for PecC, and 8:2 for PecA (
Figure 1g,h). Therefore, most turbidity of system corresponds to maximum interaction between copolymers.
The results of the viscosity and gravimetric analysis from the copolymers combinations are shown in Figures. The decrease in viscosity of the supernatant of EPO-pectin mixture solutions observed in the system showed that the IPEC was formed in the investigated medium and was removed by centrifugation. According to the turbidimetry, viscosity, and gravimetry measurements optimal molar ratio of copolymers mixtures (EPO/pectin) were observed at pH=4.0 (1:1.5), pH 5.0 and 6.0 (1:1), pH 7.0 (1.5:1).
To assess the interaction of PEs, FTIR spectra of IPEC samples (
Figure 3a and
Figure 4a) and physical mixtures (
Figure 3b and
Figure 4b) of the same composition were recorded. FTIR spectra of the IPECs are characterized by increasing the intensity of the bands at 1610 cm
-1 and 1400 cm
-1, which can be assigned to the absorption band of the carboxylate groups that form the ionic bonds with the protonated dimethylamino groups of EPO. Furthermore, the presence in the complexes of the band at 2450 cm-1 corresponds to the absorption of ionized dimethylamino groups EPO relation to the polycomplex with the carboxylate groups of pectin. This band is absent in the FTIR spectra of the physical mixture. The polycomplexes are stabilized my macromolecular ionic bonds according to the presented scheme (
Figure 8).
According to the elemental analysis (
Table 1), the ratios obtained from the analysis are very close to the molar ratios at which the samples were synthesized. But it should be noted that in compare to citrus pectin IPECs a little more amount of apple pectin macromolecules is required due to its higher esterification values (73.0 ± 1.1).
Thus, the results of physicochemical characterization confirm the formation of IPECs between oppositely charged PEs at pH values from 4.0 till 7.0. The structure of synthesized Eudragit EPO/pectin IPECs due to differences in starting change density of interacted macromolecules depends from the molar ratio of each component in the polyion mixture and correlate with their estimated stoichiometric compositions, showing change from 1:1.5 to 1.5:1.
According to the DSC analysis (
Figure 5), DSC thermograms were obtained with different Tg’s temperatures: for EPO Tg = 50.1°C, for the physical mixture EPO/PecC Tg = 53.4 °C, and for IPEC Tg = 57.3°C. Thus, with the addition of pectin in polycomplex structures, resulting Tg of the samples increases. It is interesting to note that in the thermogram of the physical mixture we do not see two glass transition temperatures, despite the fact that this is a mechanical mixture of two polymers: pectin and EPO, most likely due to the fact that pectin itself does not vitrify. However, the difference in Tg between the physical mixture and IPEC is observed due to the fact that the pectin macromolecules in IPEC structure is ionically bounded to EPO, unlike the physical mixture which were proved that IPEC was successfully synthesized (single Tg at 57.3°C higher that EPO with Tg at 50.1°C).
The next stage of research was an assessment of diffusion-transport properties, namely the kinetics of swelling of polymer matrices in mimicking the GIT conditions. According to the results, IPEC samples obtained at pH = 4.0 in a ratio of 1:1.5 based on citrus pectin (
Figure 6a) and at pH = 4.0 and pH = 5.0 in a ratio of 1:1.5 based on apple pectin (
Figure 6 b) are disintegrated: by the sixth hour (pH = 7.4) based on PeсC and by the second hour (pH = 5.8) based on PeсA. Possibly, due to the composition of these IPECs, which has contained excess amount of pectin in polycomplex structure. Since pectin is a hydrophilic polymer, it is easily hydrated in aqueous salt medium, and the tablet matrix is easily disintegrated. A similar result was described in a theophylline release studies [
24]. Perhaps apple pectin is more hydrophilic, since IPEC based on it is desintegrated faster - after 2-2.5 hours at pH = 5.8 (
Figure 6 b). In the physical mixture, the dimethylamino groups of Eudragit® E PO and the carboxyl group of pectin are in a free state, therefore they are easily ionized in the analyzed medium (pH = 5.8), contributing to the swelling of the hydrated matrix (
Figure 6 c, d). The subsequent decrease in swelling rates (at pH = 6.8) is due to the gradual dissolution of the polymers. At pH = 7.4, a slowdown in the dissolution of the physical mixture matrix is observed compared to pectin, which is apparently due to the formation of ionic bonds between two oppositely charged polymers. The profile of the pectin matrix is of a similar nature, but due to the intensity of dissolution of the polymer itself at pH = 7.4, it has lower values by the end of the experiment. It is interesting to note that the swelling ability of IPEC and physical mixtures based on apple pectin is significantly higher than that based on citrus pectin (
Figure 6 a, b, c, d). It should conclude, that all IPEC samples are suitable for further evaluation as carriers for oral drug release.
According to drug delivery results DS show ‘intestinal’ type of release profiles (
Figure 7 a, b). IPECs in this study belongs to pH- and time-dependent colon-specific DDS, because the release rate is minimal for a period of time, followed by comparatively rapid release of the drug at a site corresponding to the colon region [
42]. Swelling ability of matrixes, which were prepared from IPEC, can be tuned by their composition. This gives the possibility to tune the ratio of hydrophilic and hydrophobic sequences in the structure of IPECs. Similar studies based on sodium alginate and Eudragit® E have been reported in our research group previously [
30].
The highest release rates are shown by IPEC based on citrus pectin IPEC_EPO/PecC_1 and IPEC_EPO/PecC_4 (
Figure 7 a), which is also consistent with the swelling properties of these matrices, although the matrix based on IPEC_EPO/PecC_1 is destroyed at pH = 7.4, which may be due to the fact that the sample was obtained at a more acidic value pH=4.0. The mechanism of drug transport from the matrix can be characterized as Super Case II, since the release exponential is greater than 1. (
Table 3).
If we compare the data on swelling and release of IPEC on PeсA (
Figure 7 b), we can note that matrices based on samples IPEC_EPO/PecA_1 and IPEC_EPO/PecA_2 swell and collapse in a slightly acidic environment pH = 5.8, and when assessing the release, they show a low level of DS release. IPEC_EPO/PecA_3 and IPEC_EPO/PecA_4 swell well, IPEC_EPO/PecA_4 especially when transferred to pH = 7.4, and also surpasses other samples based on apple pectin in terms of release level. This IPEC was obtained at pH=7.0, which may be why swelling and release are higher than other samples. According to the mathematical calculation (
Table 3), IPEC_EPO/PecA_3 and IPEC_EPO/PecA_4 have a release exponent greater than 1 (n>1), so the mechanism of drug transport from the matrix is Super Case II [
43]. Super Case-II release is the drug transport mechanism associated with stresses and state transition in hydrophilic polymers which swell in GIT mimicking fluids. Anomalous (non-Fickian release) is typical for IPEC_EPO/PecA_1 and IPEC_EPO/PecA_2 (0.5<n<1) [
43].
Thus, the resulting systems are suitable for colon-specific drug delivery; since they show a characteristic lag phase in the first hours of release in stomach mimicking fluids, followed by an increase in the amount of DS release after moving to the intestinal mimicking conditions with pH of 6.8 and 7.4 values.
Figure 1.
Dependence of the degree of turbidity on the composition of the reaction medium. (a) – at pH=4.0 EPO/PecC, PecC/EPO, (b) - at pH=4.0 EPO/PecA, PecA/EPO, (c) - at pH=5.0 EPO/PecC, PecC/EPO, (d) - at pH=5.0 EPO/PecA, PecA/EPO , (e) - at pH=6.0 EPO/PecC, PecC/EPO, (f) - at pH=6.0 EPO/PecA, PecA/EPO, (g) - at pH=7.0 EPO/PecC, PecC/EPO, (h) - at pH=7.0 EPO/PecA, PecA/EPO.
Figure 1.
Dependence of the degree of turbidity on the composition of the reaction medium. (a) – at pH=4.0 EPO/PecC, PecC/EPO, (b) - at pH=4.0 EPO/PecA, PecA/EPO, (c) - at pH=5.0 EPO/PecC, PecC/EPO, (d) - at pH=5.0 EPO/PecA, PecA/EPO , (e) - at pH=6.0 EPO/PecC, PecC/EPO, (f) - at pH=6.0 EPO/PecA, PecA/EPO, (g) - at pH=7.0 EPO/PecC, PecC/EPO, (h) - at pH=7.0 EPO/PecA, PecA/EPO.
Figure 2.
Dependence of the viscosity and gravimetry on the composition of the reaction medium. (a) – at pH=4.0 EPO/PecC, PecC/EPO, (b) - at pH=4.0 EPO/PecA, PecA/EPO, (c) - at pH=5.0 EPO/PecC, PecC/EPO, (d) - at pH=5.0 EPO/PecA, PecA/EPO , (e) - at pH=6.0 EPO/PecC, PecC/EPO, (f) - at pH=6.0 EPO/PecA, PecA/EPO, (g) - at pH=7.0 EPO/PecC, PecC/EPO, (h) - at pH=7.0 EPO/PecA, PecA/EPO.
Figure 2.
Dependence of the viscosity and gravimetry on the composition of the reaction medium. (a) – at pH=4.0 EPO/PecC, PecC/EPO, (b) - at pH=4.0 EPO/PecA, PecA/EPO, (c) - at pH=5.0 EPO/PecC, PecC/EPO, (d) - at pH=5.0 EPO/PecA, PecA/EPO , (e) - at pH=6.0 EPO/PecC, PecC/EPO, (f) - at pH=6.0 EPO/PecA, PecA/EPO, (g) - at pH=7.0 EPO/PecC, PecC/EPO, (h) - at pH=7.0 EPO/PecA, PecA/EPO.
Figure 3.
The FTIR spectrum of the IPECs and of the physical mixtures: (a) IPEC EPO/PecC, (b) Physical mixture EPO/PecC.
Figure 3.
The FTIR spectrum of the IPECs and of the physical mixtures: (a) IPEC EPO/PecC, (b) Physical mixture EPO/PecC.
Figure 4.
The FTIR spectrum of the IPECs and of the physical mixtures: (a) IPEC EPO/PecA, (b) Physical mixture EPO/PecA.
Figure 4.
The FTIR spectrum of the IPECs and of the physical mixtures: (a) IPEC EPO/PecA, (b) Physical mixture EPO/PecA.
Figure 5.
Results of DSC analysis of the IPEC EPO/PecC_4 sample, physical mixture IPEC EPO/PecC_1.5:1 and individual polymers.
Figure 5.
Results of DSC analysis of the IPEC EPO/PecC_4 sample, physical mixture IPEC EPO/PecC_1.5:1 and individual polymers.
Figure 6.
Kinetics of swelling of the studied samples. (a), (b) – IPEC samples, (c),(d) – Physical mixtures and pectine.
Figure 6.
Kinetics of swelling of the studied samples. (a), (b) – IPEC samples, (c),(d) – Physical mixtures and pectine.
Figure 7.
Kinetics of drug release of a model drug substance from IPEC matrices: (a) - based on EPO/PecC, (b) - based on EPO/PecA.
Figure 7.
Kinetics of drug release of a model drug substance from IPEC matrices: (a) - based on EPO/PecC, (b) - based on EPO/PecA.
Figure 8.
Scheme of interaction between EPO and pectin.
Figure 8.
Scheme of interaction between EPO and pectin.
Table 1.
Elementary analysis results
Table 1.
Elementary analysis results
pH |
ЕРО/РecC (mole/mole) |
EРО/РecA (mole/mole) |
4,0 |
1 : 1,74 |
1 : 1,8 |
5,0 |
1 : 1,41 |
1 : 1,67 |
6,0 |
1 : 1,35 |
1 : 1,38 |
7,0 |
1,4: 1 |
1,78 : 1 |
Table 2.
Sample symbols.
Sample symbol |
Molar ration of polymers EPO/Pec |
pH at which IPEC was obtained |
IPEC EPO/PecC_1 |
1:1.5 |
4.0 |
IPEC EPO/PecC_2 |
1:1 |
5.0 |
IPEC EPO/PecC_3 |
1:1 |
6.0 |
IPEC EPO/PecC_4 |
1.5:1 |
7.0 |
IPEC EPO/PecА_1 |
1:1.5 |
4.0 |
IPEC EPO/PecА_2 |
1:1.5 |
5.0 |
IPEC EPO/PecА_3 |
1:1 |
6.0 |
IPEC EPO/PecА_4 |
4:1 |
7.0 |
Table 3.
Results of mathematical modeling of drug release from IPEC matrices according to the Korsemeyer-Peppas equation.
Table 3.
Results of mathematical modeling of drug release from IPEC matrices according to the Korsemeyer-Peppas equation.
Parameters |
IPEC_EPO/PecC_1 |
IPEC_EPO/PecC_2 |
IPEC_EPO/PecC_3 |
IPEC_EPO/PecC_4 |
Exponential release (n) |
14.032±1.849 |
4.762±0.751 |
8.415±0.908 |
16.366±1.637 |
Constant release (k) |
0.766±0.064 |
1.032±0.074 |
0.818±0.052 |
0.658±0.049 |
Correlation coefficient (R2) |
0.93828 |
0.95789 |
0.96337 |
0.94553 |
Transport mechanism |
Super Case II |
Super Case II |
Super Case II |
Super Case II |
|
IPEC_EPO/PecA_1 |
IPEC_EPO/PecA_2 |
IPEC_EPO/PecA_3 |
IPEC_EPO/PecA_4 |
Exponential release (n) |
0.526±0.123 |
0.819±0.178 |
2.612±0.632 |
5.149±0.808 |
Constant release (k) |
2.186±0.129 |
1.884±0.122 |
1.453±0.139 |
1.287±0.091 |
Correlation coefficient (R2) |
0.98515 |
0.98119 |
0.9588 |
0.97361 |
Transport mechanism |
Anomalous transport |
Anomalous transport |
Super Case II |
Super Case II |
Table 4.
Order and mixing ratios of polymers for turbidity measurements
Table 4.
Order and mixing ratios of polymers for turbidity measurements
Mixing order |
Polymer ratio |
EPO/PecC(or PecA)* |
9:1 |
8:2 |
7:3 |
6:4 |
5:5 |
4:6 |
3:7 |
2:8 |
1:9 |
PecC(or PecA)/EPO* |
9:1 |
8:2 |
7:3 |
6:4 |
5:5 |
4:6 |
3:7 |
2:8 |
1:9 |
Table 5.
Molar ratio of polymers for viscosity measurements
Table 5.
Molar ratio of polymers for viscosity measurements
Molar ratio EPO/ PecС(or PecA) |
6:1 |
5:1 |
4:1 |
3:1 |
2:1 |
1,5:1 |
1:1 |
1:1,5 |
1:2 |
1:3 |
1:4 |
1:5 |
1:6 |