The relationship between mucoadhesive polymers and surface coating in tablets for the controlled colonic delivery of a poorly water-soluble drug

Abstract

Background

The mucoadhesive polymers play an important role in targeted and controlled drug delivery.

Objectives

This study aimed to investigate the drug release behaviour and interpret the role of mucoadhesive polymers involved in the coating layer of mucoadhesive tablets for the sustained release of a poorly water-soluble drug.

Methods

A solid dispersion of prednisolone and zein was used in the core tablets created with two mucoadhesive polymers, which included Carbopol 940 and hydroxypropyl methylcellulose K4M. In addition, the properties of a single-layer coating, created from the combination of zein and Kollicoat MAE 100P to delay release through the upper parts of the gastrointestinal tract, were investigated in the presence of the above mucoadhesive polymers; these properties included drug dissolution, mucoadhesion, surface morphology, swelling and erosion.

Results

The mucoadhesive polymer concentrations and types were integrated not only into the core tablets through a swelling/erosion mechanism but also into the surface polymer coatings for controlled drug release. HPMC was preferred in the formulations due to the ability to form pores on the surface coating, allowing water uptake so that the coating could control drug release for a later stage via a swelling/erosion mechanism.

Conclusion

The proposed mechanism determined in this project could be beneficial in the selection of polymers for applications targeting the colon with coated mucoadhesive tablets.

Graphical abstract

Introduction

Oral administration is one of the most common approaches that researchers investigate for drug delivery, and after many studies, coatings of pharmaceutical dose forms have shown many benefits by improving product stability and modifying drug-release characteristics [1–5]. There are three reasons for applying such a coating layer onto a tablet: to protect the stomach from the drug, to protect the drug from the stomach, and to release the drug into organs that follow the stomach in the digestive track (e.g., the intestines) [6, 7]. In the case of colon delivery, the liberation of the active ingredients needs to be delayed during the degradation of the tablet during gastric residence and small intestinal transit [2, 8]. The coating used for selective large bowel delivery is usually more complicated than the other functional films used in oral modified release since this kind of coating needs to be able to degrade in the colon while resisting small intestine digestion [9]. Various natural or synthetic polymers have been proposed for colonic delivery [9–12].

After several evaluations, the mucoadhesion approach has shown benefits in increasing or harmonizing the residence time of drugs in the colon [13–15]. Therefore, mucoadhesive drug delivery systems can be used to target the drug to a particular region of the body—especially the colon—for the controlled release of the drug for extended periods of time [16]. A mucous gel layer, which is formed from hydrophilic polymers, has been shown to be able to adhere to the epithelial surface of the mucosal tissue in the colon. Carbopol and HPMC polymers are known to become sticky after coming into contact with water and create a strong bond with the mucosal membrane, which results in strong bioadhesion due to non-specific, non-covalent binding as well as specific binding to receptors on the mucosal surface [17–19]. Based on the mucoadhesive properties of these polymers, several designs for sustained release tablets with different concentrations of Carbopol and HPMC have been investigated. Furthermore, the sticking ability of these polymers has also been evaluated by determining the contact time between wet tablets and specific mucous membranes [20]. In a previous study, a single-layer film coating was successfully developed for colon-targeted oral delivery [21]. Zein in the tablet cores not only increased drug solubility in the colonic environment but also prevented drug release in the acidic environments; whereas, the outer coat further improved drug delivery to the colon because zein is insoluble at low pH conditions [21, 22]. The aim of this study was to prepare coated mucoadhesive tablets for improved colonic targeting and determine the relationship between the mucoadhesive polymers in the core tablets and the coating layer for controlled drug release.

Materials and methods

Materials

Zein (98%) was purchased from Acros Organics™ (USA). Kollicoat® MAE 100P (methacrylic acid-ethyl acrylate copolymer (1:1)) was provided by BASF (Germany). Polyethylene glycol (95%, PEG 6000) was obtained from Sino-Japan Chemical (Taiwan). Prednisolone (99%, PRL) was supplied by Tianjin Tianyao Pharmaceuticals Co., Ltd. (China). Hydroxypropyl methylcellulose K4M (~4000 cP, HPMC) was purchased from Sigma Aldrich (USA). Carbopol 940 (95%, Carbopol) was supplied from Sakshi Dyes and Chemicals Company (India). Mannitol (95%) was purchased from Roquette Pharma Company (France). Magnesium stearate (95%) was purchased from Nitika Pharmaceutical Specialities Pvt. Ltd. (India). Ethanol (90%) was provided by Guangdong Guanghua Sci-Tech Co., Ltd. (China). Methanol (99.9%, HPLC) was purchased from Fisher Scientific (USA).

Methods

Preparation of the solid dispersion (SD) and core tablets

According to a previous study, an optimized PRL-to-zein ratio of 2:1.3 was chosen to prepare the SD for potential application in colonic delivery [22]. Briefly, zein was dissolved in an appropriate amount of 90% ethanol and stirred with a magnetic stirrer until the yellowish solution became clear. PRL was added to this solution and continually stirred until a clear solution was obtained, which was then dried to produce the final SD. To prepare the core tablets, mannitol (as a filler), magnesium stearate (as a lubricant), and HPMC (or Carbopol) were mixed with the above SD. Table 1 shows the differences in the ratios of specific formulations of the core tablets. The 200 mg tablets (9 mm in diameter) were compressed and controlled hardness at 62–72 N.

Table 1.

Formulation compositions of the core tablets

Formulation	Mannitol	Mg stearate	SD		HPMC	Carbopol	Total
			PRL	Zein
F1	142.5 mg	1 mg	10 mg	6.5 mg	40 mg		200 mg
F2	132.5 mg	1 mg	10 mg	6.5 mg	50 mg		200 mg
F3	112.5 mg	1 mg	10 mg	6.5 mg	70 mg		200 mg
F4	112.5 mg	1 mg	10 mg	6.5 mg		70 mg	200 mg

Preparation of coating solution and film coating process

Based on the results of our previous investigations, a coating solution was created using zein and Kollicoat® MAE 100P as the coating polymer and copolymer, respectively, and PEG 6000 was used as the plasticizer [21]. A 400 ml mixture of ethanol and water (ratio 6:4) was used for each formulation (Table 2); the weight of the coating mixture (zein and Kollicoat® MAE 100P) accounted for 6.25% (w/v) of the solvent, 150 ml was used to dissolve the zein–main coating component, 150 ml was used to dissolve the copolymer (Kollicoat® MAE 100P), and the plasticizer was dissolved into 100 ml of solvent. The final coating solution was the mixture of the three components. The core tablets were coated by using a pan coater. The coating process was set up with a pan coater (BYC-400, Taiwan) as follows: rotating speed 12 rpm, inlet temperature 40 °C, atomization pressure 1.04 kg/cm², and flow rate of the coating solution 2 rpm. The coating process was finished once the weight of the coated tablets reached a range of 8 ± 0.5% more than the weight of the uncoated tablet.

Table 2.

Formulation compositions of coating solution

Ratio of Zein and Kollicoat® MAE 100P	Zein (g)	Kollicoat® MAE 100P (g)	PEG 6000 (g)	Ethanol (ml)	Amount of coated film (%w/w of tablet)
4:6	10	15	2.5	400	8 ± 0.5%

In vitro release and mucoadhesive test

The in vitro drug release was assessed using a basket apparatus (75 rpm, 37 ± 0.5 °C) with 4 different stimulation environments [6, 23]. Initially, the coated tablets were placed in baskets at pH 1.2 for the first 2 h, followed by pH 4.6 for 2 h, pH 6.8 for 1 h and pH 7.4 for 6 h. At the end of each period, 1 ml of sample was withdrawn for analysis. However, at pH 7.4, 1 ml of sample was withdrawn at certain intervals and deposited in fresh medium. After that, all collected samples were analysed with high-performance liquid chromatography (HPLC) according to the methods from a previous study [21].

Moreover, a mucoadhesive test was performed using the porcine colon as the model tissue section [24]. Briefly, an ex vivo mucoadhesive test was evaluated as follows: after dissolution in 3 different media (pH 1.2 for 2 h, pH 4.6 for 2 h and pH 6.8 for 1 h), the tablets were taken out and wetted with the pH 7.4 medium. Freshly excised pieces of pig intestinal mucosa of 2 cm² were mounted onto Petri dishes with glue. The tablets were hydrated on the surface by using the pH 7.4 medium and brought into contact with the mucosal membrane with an initial force equal to that of a finger press for 30 s. The Petri dishes were placed into a USP dissolution test apparatus II (paddle method, 75 rpm, 37 °C ± 0.5 °C). The time required for complete erosion or detachment of the tablets from the mucosal surface was recorded.

Swelling and erosion studies

The tablets were initially weighed to obtain baseline measurements (W₀). The method used was similar to the method of determining the in vitro dissolution profile as described above. However, for the swelling study, at predetermined periods, the tablets were removed from the baskets, lightly blotted with tissue paper to remove excess test liquid and then reweighed (W₁). For the erosion study, the tablets were dried to a constant weight and then reweighed (W_t).

The percentage increase in weight due to liquid or water uptake was estimated by

$$\mathit{\text{Swelling}}\left(\%\right)=\frac{W1-W0}{W0}\ast 100.$$

The percentage erosion (E) at time t was estimated with the following equation:

$$\mathit{\text{Erosion}}\left(\%\right)=\frac{W0-\mathit{Wt}}{W0}\ast 100$$

Scanning electron microscopy (SEM)

The optimized tablet formulations were removed from the dissolution apparatus at predetermined time intervals and dried to remove excess water. The samples were then placed on a sample holder. After that, the samples were coated with gold and visualized under a scanning electron microscope (JSM-IT100 Jeol Inc., Japan).

Statistical analysis

In vitro drug release data for the different formulations and the swelling and erosion studies were subjected to one-way analysis of variance (one-way ANOVA with 95% confidence intervals) to determine whether there was any significant difference among the formulations. Statistical analysis of the data was performed using SigmaPlot software version 12.5 (USA). The results are considered significantly different if p < 0.05.

Results and discussion

In vitro drug release studies

Overall, in the four formulations, after 5 h in the pH 1.2, pH 4.6 and pH 6.8 media, the single-coating layer demonstrated the properties shown in Fig. 1. There was no drug release in the first 5 h. After that, the tablets were moved into the last stimulated environment (pH 7.4), and no drug release occurred in the first 1 h in the SCF (simulated colonic fluid) either. Therefore, all of these formulations were able to prevent drug release in the upper parts of the GI tract, and the single-coating layer contributed to delayed drug release in microenvironmental conditions.

Fig. 1.

Dissolution profile of tablets containing HPMC at different concentrations. Statistically significant differences: (*) F1 vs F3, (**) F2 vs F3

To investigate the effects of increasing the concentrations of the mucoadhesive agents, HPMC 4000 formulations at three different ratios were evaluated to determine the best design for sustained release in the colon in terms of performance. After the 6 h immersion in the four environments, the drug started releasing in these formulations at rates of approximately 40% in F1, 30% in F2, and 10% in F3. When the testing time was extended for the three formulations, they demonstrated a similar release at each interval. F1 and F2 had greater drug release at each predetermined time and, consequently, less sustained release than F3, which had lower release due to the higher concentration of mucoadhesive agent. In detail, while F1 and F2 needed 3 h to completely release the drug, F3 was able to extend the duration of drug release up to 7 h, which was a consequence of the sustained release resulting from the longer residence time of the drug in the colon.

To compare HPMC 4000 and Carbopol 940, a concentration of 35% for the mucoadhesive agents was chosen for the evaluation. As detailed in Fig. 2, the two formulations both started releasing drug at 6 h after being moved to the last environment for 1 h. The difference between the two formulations can be seen in the duration for drug release to reach 100%; while F3, the HPMC formulation, needed 12 h for complete release, F4, containing Carbopol, completely released the drug in 10 h. At each interval, HPMC contributed to the stability of drug release during the period, and the rate of release was maintained between 15% and 25% each time. Meanwhile, the rates of release in F4 were significantly different; the drug released 10% at the first interval and increased rapidly to 20% in the next hour and 40% after 9 h total.

Fig. 2.

Dissolution profile of F3 and F4, comparing HPMC and Carbopol, respectively. Statistically significant difference: (*) F3 vs F4

Mucoadhesive testing

In this part of the study, the experiment simulated the activity of swollen tablets making contact with the colonic mucosa. By assessing the sticking duration between the tablets and the pig colonic membranes in appropriate media, this study evaluated the conditions that mucoadhesive agents would create to prolong drug release in the colon. These details are given in Fig. 3. Generally, the contact time of these tablets was significantly different among the different concentrations of HPMC. F1 and F2 had limited mucoadhesive characteristics; the tablets dropped down from the porcine colon membrane after 143 min and 158 min, respectively. F3, which had a higher concentration of HPMC, demonstrated its potential pharmacological applicability in the mucoadhesive testing; the tablets stuck to the mucous membrane for 380 min (> 6 h).

Fig. 3.

Mucoadhesive properties of F1, F2, F3 and F4. Statistically significant differences: (*) F1 vs F3, (**) F2 vs F3, (***) F3 vs F4

When compared with F4, which contains Carbopol, there is a statistically significant difference (p = 0.038) between F3 and F4. With approximately 350 min of contact time between the tablets and the colon mucosa membrane, F4 also showed potential for pharmacological application; however, for sustained drug release in the colon, this design is expected to provide a sustained release period of more than 6 h. Therefore, the HPMC formulation is more advantageous than that of Carbopol. Overall, the mechanisms of Carbopol and HPMC contributed to the extension of drug presence in the colon.

Swelling and erosion studies

The investigation of water uptake in the tablets demonstrated the rate of swelling, which can be used to determine how long the tablets took to erode, and indicated that swelling and erosion mechanisms might be operative during drug release. As seen in Fig. 4, there was no difference among the formulations (approximately 140–150% swelling) after insertion into the first medium. F1, F2, and F3 reached the highest swelling percentage after insertion into the second medium (pH 4.6; approximately 185–235%). At 5 h, the tablets were transferred to the next medium and the water uptake decreased; while F1 and F2 had similar swelling percentages (approximately 160%), F3 showed a marked improvement with a swelling of approximately 100%. Due to the higher concentration of HPMC, F3 formed a gel and covered the drug after the coating layer broke down to prevent the medium from entering the tablet core. Finally, in the last environment (pH 7.4), all formulations started to release the drug, and the swellings did not continue because of tablet deformation.

Fig. 4.

Swelling behaviours of F1, F2 and F3. Statistically significant difference: (*) F1 vs F3, (**) F2 vs F3

Figure 5 shows the details for the comparison between the results of the swelling experiments for HPMC and Carbopol. In general, the swelling results for the tablets containing HPMC and Carbopol were somewhat opposite. While HPMC reached the highest swelling after immersion into the two first media (approximately 170% in pH 1.2 and 210% in pH 4.6), Carbopol showed different results, with 20% after immersion in the pH 1.2 medium and 40% in the pH 4.6 medium. Furthermore, in the last two environments, while Carbopol reached the highest swelling percentage of approximately 275% in the pH 7.4 medium, the swelling of HPMC decreased and stayed at low percentages of approximately 100%. The different mechanisms of HPMC and Carbopol can be used to explain this situation. HPMC tends to form a gel and stick to the core tablets; therefore, at the beginning, when in contact with aqueous medium, a large amount of water was required for gel formation (in the first two environments). After that, the percentage of swelling decreased since the coating layer was destroyed and the gel containing the drug and HPMC started releasing. On the other hand, Carbopol had no response in the first two media; therefore, it prevented the core tablets from filling with water. When the coating layer was damaged in the next media, water could enter inside the tablet and increase the tablet weight.

Fig. 5.

Swelling behaviour of F3 and F4. Statistically significant difference: (*) F3 and F4

To evaluate the rate of tablet degradation, erosion studies were performed to provide an overview of tablet damage in multiple environments. Generally, when comparing the swelling and erosion data, the three formulations demonstrated the same rates of erosion at pH 1.2, pH 4.6 and pH 6.8. Particularly, after pH 4.6, there was a slight drop in the erosions of the three formulations (Fig. 6), which represented the dissolution of HPMC in the core tablets, filling the pores and slowing down the erosion of these formulations. In the last medium, there were significant differences in erosion. F3, with a higher concentration of HPMC, showed the slowest erosion, while F1 and F2 eroded faster. Corroborating the details of drug release described earlier at pH 1.2 and pH 4.6, the coating layer played an important role in delaying the release of drug from the tablets; therefore, the erosion remained at a low rate (mainly involving the breaking of the coating layer). There were some changes in swelling and erosion in these media; however, they mainly acted inside the core tablets (forming a gel with HPMC). In the next media, the coating layer was broken down, but HPMC had formed a gel in the previous media. At this stage, drug release was only prevented in the first hour and then occurred slowly over the next hours.

Fig. 6.

Erosion as a function of time for F1, F2 and F3. Statistically significant differences: (*) F1 vs F3, (**) F2 vs F3

Due to the dramatic inversion in the swelling of HPMC and Carbopol, there were considerable differences in their erosion as well (Fig. 7). In the first two media, F3 had greater erosion than F4 since HPMC formed a gel at these stages and reduced the weight of the tablets, while Carbopol prevented the hydration of the tablets and kept the core tablet dry. In the next medium, the coating layer was broken down; the Carbopol started to erode and form a smooth layer on the outside of the tablet, completely covering the drug at first such that no drug was released at pH 6.8. In the last medium, the Carbopol shield separated slowly, creating space for contact between the drug and the environment. More details on swelling and erosion in terms of tablet morphology are described in the section below.

Fig. 7.

Erosion as a function of time for F3 and F4. Statistically significant difference: (*) F3 vs F4

Morphology of swollen tablets

The morphologies of F1 and F2 had similar characteristics due to only slight differences in the HPMC concentration; after the swelling in the first medium, the surfaces of the tablets were rough and contained many large pores (Fig. 8). This indicated the ability of the coating layer to prevent contact between the core tablet and the environment. Water went inside the core tablets through the pores, resulting in high water intake by the tablets. After immersion in the pH 4.6 medium, the surface was smoother than in the first medium and the pores became larger. This suggests that the maximum swelling of the tablet was a result of the dissolving of the HPMC, which made the surface smoother. In the last medium, the coating layer was dissolved completely, and the surfaces showed the appearance of a gel, which was a combination of HPMC and drug. Some cones can be seen, which indicate the flow of gel at small concentrations of zein that could not dissolve at this pH and instead floated to the surface of the gel.

Fig. 8.

SEM photographs (500 X) of matrix tablets in the dry state and after immersion in several different media

Compared with F1 and F2, in the first 2 environments, F3 had fewer pores, and the tablets took up water but could not release it, leading to greater swelling. After immersion in the pH 4.6 medium, given the higher concentration of HPMC, F3 had fewer pores than F1 and F2 because the HPMC dissolved and filled some of the pores on the surface. In the last medium, F3 showed large pieces of coating layer since the greater concentration of HPMC contributed to the prevention of coating layer dissolution; the pieces instead lied on the surface of the tablet.

Due to its lower swelling, the surface of the Carbopol tables was not significantly different from that of the HPMC tablets. In the first medium, there were many pores on the surface of the Carbopol tablets; however, these had fewer pores than the HPMC-based tablets, leading to lower swelling. While HPMC took water inside the tablet to form a gel, the Carbopol prevented water from entering inside tablets. Similarly, in the pH 4.6 medium, the Carbopol dissolved and filled the pores, leading to the lower swelling at this stage. In the last medium, the Carbopol covered the outside of the tablet, creating a layer; at this time, the tablet erosion observed above consisted of the erosion of this layer.

Conclusion

This study developed and investigated the drug release behaviour of mucoadhesive tablets with a single-coating layer for sustained drug release in the colon. The optimized formulation with HPMC-based tablets showed the potential for not only delaying drug release in the gastrointestinal tract but also sustaining drug release in the colon. Moreover, polymers such as HPMC and Carbopol-based tablets offer a promising strategy for formulating mucoadhesive materials. Although the mucoadhesive properties of the Carbopol-based tablets were close to those of the HPMC-based tablets, the dissolution profile was satisfactory with HPMC through its roles in swelling, erosion and polymer coating during the dissolution process for controlled drug release.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.