Abstract
Pirfenidone (PRF) is an anti-fibrotic agent that has been approved by the Food and Drug Administration (FDA) for the treatment of mild to moderate idiopathic pulmonary fibrosis. However, the current oral administration dosing regimen of PRF is complex and requires high doses. Patients are instructed to take PRF three times daily, with each dose consisting of up to three capsules or tablets (600 mg/d or 1.8 g/d of PRF) taken with food. To improve the dosing regimen, efforts are being made to develop an extended-release tablet with a zero-order release pattern. In this study, two types of extended-release matrix tablets were compared: non-channeled extended-release matrix tablets (NChMT) and channeled extended-release matrix tablets (ChMT). In vitro release tests, swelling and erosion index, rheology studies, and X-ray microcomputed tomography (XRCT), were conducted. The results indicated that ChMT maintained a zero-order release pattern with a constant release rate, while NChMT exhibited a decreased release rate in the latter half of the dissolution. ChMT exhibited accelerated swelling and erosion compared to other formulations, and this was made possible by the presence of channels within the tablet. These channels allowed for thorough wetting and swelling throughout the entire depth of the tablet. The formation of channels was confirmed through XRCT images. In conclusion, the presence of channels in ChMT tablets increased the rate of swelling and erosion, resulting in a zero-order release pattern. This development offers the potential to improve the dosage of PRF and reduce its associated side effects.
Introduction
Idiopathic pulmonary fibrosis (IPF) is a condition with unknown etiology, which is unresponsive to treatment; however, IPF is the most common type of idiopathic interstitial pneumonia. IPF has been classified as an orphan disease and occurs at a frequency similar to that of stomach and brain cancers.1–6) Pirfenidone (PRF) was the first Food and Drug Administration (FDA)-approved anti-fibrotic agent for treating mild to moderate IPF. Although the mechanism of PRF action is unclear, it regulates transforming growth factor beta (TGF-β) and cytokines, which are key factors in IPF progression.7,8) The oral administration doses of PRF are extremely high and complex. One capsule or tablet is taken three times daily (600 mg/d of PRF) with food and as needed up to three capsules or tablets three times daily are recommended (1.8 g/d of PRF). High doses of PRF often induce various side effects such as gastrointestinal disorders, skin rashes due to phototoxicity, and hepatic dysfunction.9) Hence, preparing extended-release formulations is necessary to reduce the side effects and enhance patient compliance by decreasing the number of doses.
The extended-release matrix tablet (MT) is the most widely used formulation, which has improved therapeutic and nontoxic effects over the past three decades. The benefit of the MT dosage form compared to a conventional dosage form is the maintenance of effective plasma concentration, uniform therapeutic responses, extended action time, and reduced administration frequency.10–13) MT is a simple, diffusion-controlled system. However, conventional drug release depends on the presence of water in the gastro-intestinal (GI) tract.14,15) As water is poorly available in the colon, drug release from the MT dosage form is impeded in this part of the GI tract. Therefore, Yamanouchi developed a new MT system, the oral controlled absorption system (OCAS®), to ensure continuous and consistent drug release throughout the entire GI tract and to achieve consistent 24 h plasma concentrations.16)
MT containing channeling agents have been described in previous studies. Upon contact with the dissolution medium, the water-soluble particles of the channeling agent are rapidly dissolved, thus forming a network of channels in the extended-release matrix tablet, which facilitates drug dissolution and release from the tablet. The channeling effect rapidly wets the matrix tablet, inducing swelling. This enhances the sustained-release properties of the swelling agent during the initial release phase and facilitates complete wetting of the internal portion of the tablet during the later release phase, allowing for the drug to be fully released up to 100%. Thus, a constant drug release rate is achieved with zero-order kinetics.17–19) This drug delivery system, which uses a channeling agent, is useful for the delivery of drugs that are absorbed throughout the GI tract. Various water-soluble agents such as sodium chloride, polyethylene glycol (PEG), cyclodextrin, vinyl pyrrolidone and others have been used as channeling agents.20,21) Furthermore, significant efforts have been made to study the mechanism behind these agents. Therefore, the present study was undertaken to investigate the detailed role of channeling agents in drug release behavior from MT containing channeling agents, to optimize the formulation for achieving the desired release profiles.
Immediate-release tablets have a risk of side effects because of the high Cmax of PRF. Further, the convenience of administration is reduced because of the complicated dosing methods and large amounts. These drawbacks can reduce patient compliance and treatment efficiency. We thus developed PRF extended-release tablets to decrease the Cmax, improve dosing regimens, and improve side effects and medication compliance. We applied the channeling effect to prepare an effective and predictable extended-release tablet. In this study, PEG 6000 was incorporated into hydroxypropyl methylcellulose (HPMC) matrix tablets. The effects of variables such as HPMC content and the PRF : HPMC : PEG ratio on the drug release characteristics were studied. The release kinetics were characterized using various release kinetic equations. Swelling, erosion, and textural analyses were performed to compare non-channeled extended-release matrix tablets (NChMT) and channeled extended-release matrix tablets (ChMT). Further, X-ray microcomputed tomography (XRCT) was used to quantitatively observe the inner state of swollen tablets.
Experimental
MaterialsPirfenidone (PRF) was purchased from Glenmark Pharmaceutical (Gujarat, India). Microcrystalline cellulose (MCC), commercially available as Avicel® 101, was obtained from FMC Corporation (Philadelphia, PA, U.S.A.). Magnesium stearate (Mg stearate) and PEG 6000 was purchased from Sigma-Aldrich Corporation (St. Louis, MO, U.S.A.). Hydroxyl propyl methylcellulose (HPMC) was obtained from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). PVP-K30 was obtained from BASF (Ludwigshafen, Germany). Ethanol and acetonitrile (Honeywell Burdick & Jackson, Muskegon, MI, U.S.A.) were of HPLC grade. Water was purified by filtration in the laboratory.
MethodsPreparation of Extended-Release Matrix Tablet Containing PirfenidoneUsing a high shear granulator (SPG-5TG, Dalton Corp., Tokyo, Japan) with ethanol as a binder solution, PRF and all excipients except magnesium stearate were granulated. After pre-blending with an impeller blade operating at 300 rpm for 3 min, the binder solution was added. Wet granulation was performed with an impeller at 300 rpm and a chopper blade at 1500 rpm. The granules dried to 1.5% by measuring the loss on drying using a moisture analyzer (MF-50, A&D Co., Ltd., Tokyo, Japan). All granules were passed through a sieve (#35 mesh) to remove aggregates and were then mixed with magnesium stearate. The formulations used are presented in Table 1. The tablets were prepared using a hydraulic press machine (Carver Lab Press, Carver Inc., Wabash, IN, U.S.A.) with a 15 mm round punch and die set. The compaction pressure was applied to each formulation to achieve a similar hardness of approximately 120 N, as measured using a hardness tester.
Table 1. Formulation of Pirfenidone Extended-Release Matrix Tablets
| NChMT1 | NChMT2 | NChMT3 | NChMT4 | NChMT5 | ChMT1 | ChMT2 | ChMT3 | ChMT4 | ChMT5 | ChMT6 |
|---|
| PRF | 600 | 600 | 600 | 600 | 600 | 600 | 600 | 600 | 600 | 600 | 600 |
| PEG 6000 | — | — | — | — | — | 41.7 | 83.3 | 62.5 | 125 | 100 | 200 |
| Avicel® 101 | 120 | 120 | 120 | 120 | 120 | 120 | 120 | 120 | 120 | 120 | 120 |
| HPMC K15M | 50 | 75 | 85 | 100 | 120 | 50 | 50 | 75 | 75 | 120 | 120 |
| PVP-K30 | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 |
| Mg stearate | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
| Total | 800 | 825 | 835 | 850 | 870 | 841.7 | 883.3 | 887.5 | 950 | 970 | 1070 |
In vitro release studies were performed in 1000 mL distilled water thermostatically maintained at 37 ± 0.5 °C in a United States Pharmacopeia apparatus II. The rotational speed of the paddle was set to 50 rpm. The sampling time was set as 0.25, 0.5, 1, 2, 4, 6, 9, 12, 15, 18, 21, 23 and 24 h respectively. Samples (5 mL) were collected from each dissolution vessel and filtered through a 0.45 µm Polyvinylidene difluoride with glass micro fiber syringe filter (Whatman™, GE Healthcare Co., Ltd., Little Chalfont, Buckinghamshire, U.K.). The samples were then quantified and identified using HPLC analysis. All experiments were conducted in triplicate. The dissolution profiles were investigated to determine the mechanism of release using five kinetic models: zero-order, 1st-order, Higuchi, Hixon–Crowell, and Korsmeyer–Peppas equations. The zero-order rate Eq. 1 describes systems in which the drug release rate is independent of its concentration.22) The 1st-order Eq. 2 describes release from a system in which the release rate is concentration-dependent.23) Higuchi24) described the release of drugs from an insoluble matrix as the square root of a time-dependent process based on the Fickian diffusion Eq. 3. The Hixson–Crowell cube root law Eq. 4 describes the release from systems wherein there is a change in the surface area and diameter of the particles or tablets.25) Korsmeyer–Peppas (5) derived a simple relationship that describes drug release from a polymeric system equation.26) The mechanism of drug release was determined by fitting to the Korsmeyer–Peppas model.
 | (1) |
where K0 is the zero-order rate constant expressed in units of concentration/time and t is the time.
 | (2) |
where C0 is the initial concentration of the drug and K1 is the first-order constant.
 | (3) |
where, K is the constant reflecting the design variables of the system.
 | (4) |
where Qt is the amount of drug released at time t, Q0 is the initial amount of drug in the tablet, and KHC is the rate constant for the Hixson–Crowell rate equation.
 | (5) |
where Mt/M∞ is the fraction of the drug at time t, k is the rate constant, and n is the release exponent. The n value was used to characterize the different release mechanisms.
Characterization of Channeling EffectsSwelling and Erosion IndexSriamornsak et al. described how to measure the swelling and erosion rates of swollen tablets.27) The swelling and erosion indices of extended-release tablets were measured using the modified Sriamornsak method. In this study, we compared non-channeled extended-release matrix tablets (NChMT) and channeled extended-release matrix tablets (ChMT) using the formulations NChMT3 and ChMT6. We collected the tablets during the dissolution test under the same conditions as the dissolution test using distilled water mentioned earlier. Samples were harvested at 1, 2, 4, 6, 9, 12, and 18 h, respectively. The swelling index was measured as the percentage of weight gained by the dissolution medium. The erosion index was calculated using the weights of the tablets before and after the dissolution test. After a predetermined time, the swollen tablet was withdrawn from the dissolution medium, and its weight was measured. Wet samples were dried in an oven at 50 °C for 48 h. The experiment was performed in triplicate for each time point.
The swelling index was calculated using the following equation:
 | (6) |
where Wi is the initial weight of the tablet before the dissolution test and Wt is the weight of the tablet at time t before drying.
The erosion index was estimated from the following equation:
 | (7) |
where Wi is the initial weight of the tablet before the dissolution test and Wd is the weight of the tablet at time t after drying.
Rheological StudyThe swelling behavior of the tablets was also investigated using textural analysis. Swelling tablets were withdrawn at predetermined intervals. The tablets were then subjected to textural profiling using a texture analyzer, such as swollen height, hardness of swollen tablets, and total work of probe compression (Stable Microsystems, Ltd. Godalming, U.K.). All measurements were performed in triplicate for each time point, and the tablets were discarded. We collected the tablets during the dissolution test under the same conditions as the dissolution test using distilled water mentioned earlier. Samples were harvested at 2, 6, and 12 h, respectively. Textural analysis was performed using a TA texture analyzer equipped with a 5 kg load cell and Texture Exponent software (Texture Technologies Corporation, Hamilton, MA, U.S.A.). The force-displacement time profiles were monitored at a data acquisition rate of 200 points per second when the swollen tablet was compressed using a 75 mm round platen probe. The probe approached the sample at a rate of 1.0 mm/s. When the probe detected a trigger force of 10 g, measurement was initiated (upon contact of the probe with the tablet). The probe was advanced into the tablet at a rate of 1.0 mm/s until it destroyed the non-hydrated tablet core. The hardness of the tablet was determined to be 90% of the maximum force measured on the probe. The swollen height was determined by measuring the total probe displacement. The total work of compression was determined from the areas of the textural profiles.
X-ray Micro-computed Tomography (XRCT)The inner structure of the swollen tablet was investigated using a Quantum FX XRCT instrument (PerkinElmer, Inc., Waltham, MA, U.S.A.). It was equipped with a microfocus X-ray tube (L10101, Hamamatsu Photonics, Hamamatsu, Japan) and a flat panel detector (PaxScan 1313, Varian Medical Systems, Palo Alto, CA, U.S.A.). The X-ray tube and detector were placed opposite to each other on a rotating gantry around an animal bed at a distance of 265 mm. At the 1 × 1 and 2 × 2 detector binning modes, the pixel matrix was 1024 × 1024 and 512 × 512, and the frame rate was 10 frame per second (fps) and 30 fps, respectively.16,28) The samples were removed from the vessel at 2, 6, and 12 h, during the dissolution test with pH 6.8 buffer. The samples were then placed in a clear tube and held in place using spacers made of expanded polystyrene. XRCT allows complete reconstruction of a three-dimensional object through a series of cross-sectional images. We used ImageJ version 1.52, a public domain Java image processing program, to enhance contrast and separate the inner dry core, hydrated gel layer, and pores.
Results
In Vitro Dissolution Test of the Extended-Release Matrix TabletNon-channeled Extended-Release Matrix TabletHPMC K15M was used to prepare an extended-release matrix tablet for pirfenidone (PRF). The composition of each formulation is listed in Table 1. PRF is initially administered at 200 mg three times daily. We aimed to develop an extended-release tablet with 24-h delivery, providing a total dose of 600 mg per day as an initial dose. MCC, PVP-K30, and magnesium stearate were used as the excipient, binder, and lubricant, respectively. After fixing the weight of PRF with the other additives, five tablet formulations were prepared with increasing HPMC as 50, 75, 85, 100, and 120 mg, respectively. Each tablet was evaluated using an in vitro dissolution test, and the results are shown in Fig. 1(A). As expected, the larger the amount of HPMC, the higher was the extended-release effect. NChMT1, 2, 3, 4, and 5 showed 37.5, 15.8, 15.9, 12.6, and 8.7% release at 0.5 h, respectively. At 4 h, the difference in the release rate between all formulations became clearer, with release rates of 73.3, 42.6, 41.6, 33.9, and 28.0%, respectively. The dissolution rate of NChMT1 decreased after 60% and reached 100% after 12 h. Furthermore, the dissolution rate of NChMT5 was 87.5% at 18 h. In terms of the release rate constant of the Higuchi model, NChMT1 had the highest rate constant (40.0%), followed by NChMT2 (21.4%), NChMT3 (20.7%), NChMT4 (17.2%), and NChMT5 (17.0%) (Fig. 1(B)).
Channeled Extended-Release Matrix TabletThe channeling effect was applied by adding HPMC and PEG at a ratio of 1 : 0.83 and 1 : 1.67 to the NChMT composition evaluated previously. Figure 2(A) shows the dissolution profiles of tablets containing 50 mg of HPMC. An initial burst was observed from NChMT1, which was 23.1% at 0.5 h whereas that from ChMT1 and ChMT2 was less than 10%. At 4 h, the dissolution rate of NChMT1 was 57.9%, and that of the two ChMT formulations was 40.0 and 42.0%. Figure 2(B) shows the dissolution profile of tablets containing 75 mg of HPMC at a ratio of 1 : 0.83 and 1 : 1.67 to PEG as described above. At 0.5 and 4 h, all three formulations were very similar, with dissolution rates of approximately 8 and 33%. At 12h, the rates for NChMT2, ChMT3, and ChMT4 were 70.6, 74.9, and 80.19%, respectively. As the amount of PEG increased, the dissolution rate also increased. At 18 h, the dissolution rate was 85.8, 96.9, and 99.6%, for NChMT2, ChMT3, and ChMT4, respectively and the difference between the presence and absence of PEG was clear. In Fig. 2(C). The extended-release effect was excellent at approximately 5 and 25% at both 0.5 and 4 h. ChMT6 showed a dissolution rate of more than 90% at 18 h, and was considered suitable for the 24 h-release dosage form. The kinetic parameters of dissolution were calculated using a kinetic model (Table 2). The Korsmeyer–Peppas model had a high correlation in all formulations, and it was confirmed that the n value of NChMT1 was 0.46 and that dissolution occurred by Fickian diffusion. In contrast, ChMT6 had an n value of 0.85, which was the closest to 1 and showed a release pattern similar to the zero-order. Furthermore, as shown in Fig. 3, the dissolution of ChMT6 proceeded for 24 h at different pH values of the dissolution media, and the channelling effect was evaluated. No significant differences were detected in any of the four media tested.
Table 2. Dissolution Kinetic Parameters of Pirfenidone Extended-Release Matrix Tablets Containing Different Polyethylene Glycol (PEG) Ratios (
n = 3)
| PRF : HPMC : PEG | Zero order | First order | Hixson–Crowell | Higuchi | Korsmeyer–Peppas |
|---|
| R2 | R2 | R2 | R2 | R2 | n |
|---|
| NChMT1 | 12 : 1 : 0 | 0.900 | 0.945 | 0.982 | 0.993 | 0.997 | 0.46 |
| ChMT1 | 12 : 1 : 0.83 | 0.981 | 0.962 | 0.993 | 0.982 | 0.999 | 0.74 |
| ChMT2 | 12 : 1 : 1.67 | 0.986 | 0.910 | 0.975 | 0.975 | 0.999 | 0.81 |
| NChMT2 | 8 : 1 : 0 | 0.961 | 0.992 | 0.995 | 0.990 | 0.996 | 0.68 |
| ChMT3 | 8 : 1 : 0.83 | 0.984 | 0.912 | 0.980 | 0.981 | 0.998 | 0.67 |
| ChMT4 | 8 : 1 : 1.67 | 0.992 | 0.915 | 0.975 | 0.967 | 0.997 | 0.77 |
| NChMT3 | 5 : 1 : 0 | 0.986 | 0.994 | 0.999 | 0.979 | 0.999 | 0.74 |
| ChMT5 | 5 : 1 : 0.83 | 0.987 | 0.973 | 0.995 | 0.977 | 0.999 | 0.80 |
| ChMT6 | 5 : 1 : 1.67 | 0.992 | 0.950 | 0.987 | 0.971 | 0.999 | 0.85 |
The swelling and erosion indices are presented in Figs. 4(A) and 4(B), respectively. To clearly demonstrate the regions of increased and decreased swelling based on the presence or absence of channels, we added trend lines as a supplementary aid. At 1 h, the swelling index of ChMT6 was 56.8% and that of NChMT3 was 42.7%, indicating that ChMT6 swelled faster. From there, ChMT6 swelling occurred rapidly up to 4 h, whereas NChMT3 swelling was maintained until 6 h. Similar results were observed for the erosion index in Fig. 4(B); at the beginning of dissolution, the erosion index was similar for both ChMT6 and NChMT3, but after 4 h, the difference became evident. At 18 h, the erosion index of NChMT3 was 62.4%, indicating that most of the tablet matrix was intact and not eroded, whereas that of ChMT6 was 94.9%, and almost complete disintegration was observed.
Rheology StudyFigure 5(A) shows the profile of NChMT3. After the start of dissolution, the tablet was removed at 2, 6, and 12 h, and the hardness was measured using a texture analyzer. At 2 h, erosion and swelling were minimal, and the hardness was the highest at 607.4N. The tablet height was measured at 5.7 ± 0.1 mm. However, at 6 h, the hardness decreased to 245.2N compared to the hardness at 2 h, while the height remained similar at 6.0 ± 0.3 mm. In the profile of ChMT6 shown in Fig. 5(B), the hardness was much lower than that of NChMT3 at 2 h and decreased sharply to 19.6 N at 6 h. On the contrary, the height of ChMT6 was 7.2 and 8.0 mm at 2 and 6 h, respectively, which were higher than that of NChMT3. The hardness of ChMT6 was 0.7N at 12 h, which was the lowest, and its height was 3.7 mm, which was also the lowest among all the measurements.
X-Ray Micro-Computed Tomography (XRCT)Figure 6 depicts the observed changes in swelling and erosion of the formulation during the dissolution process. In Fig. 7, The tablets were investigated at 0 (initial), 2, 6, and 12 h after dissolution, and different colors were observed inside the tablets. Clear white areas indicated parts where complete wetting and swelling had occurred, while gray areas indicated parts that were still incompletely wetted, representing the core where swelling had not yet occurred. Black areas indicated where no substance was present.16) Figures 6 and 7(A) show that the NChMT3 tablet size slightly increased due to swelling at 2 h. However, only the tablet edges were completely swollen and appeared white. At 6 h, the tablet size slightly decreased due to erosion, but a large core that was not completely swollen remained inside the tablet. At 12 h, erosion caused a clear decrease in the tablet size, and the internal core remained largely unswollen, with only the edges appearing completely swollen. While the boundaries were completely swollen at 2, 6, and 12 h, the internal core remained incompletely swollen due to the slow erosion process. In contrast, Fig. 7(B) shows that the ChMT6 tablet had a very small inner core with a pale colour at 2 h. This was because a large amount of water penetrated and swelling progressed rapidly. Additionally, a part that appeared completely black was observed inside the tablet, which could be considered a channel. At 6 h, the tablet was completely swollen and smaller than the NChMT3 tablet, with several channels observed. At 12 h, the ChMT6 tablet was clearly smaller, and the channels had significantly increased.
Discussion
In Vitro Dissolution Test of the Extended-Release Matrix TabletNon-channeled Extended-Release Matrix TabletNChMT1 showed a rapid initial burst of release due to the low amount of HPMC, whereas higher amounts of HPMC resulted in slower early dissolution, leading to successful extended release. However, all formulations showed rapid release within 2 h after the start of the dissolution test, indicating a high probability of an initial burst. The results were consistent with the release rate constant of the Higuchi model (Fig. 1(B)). Although increased HPMC contributed to the extended-release effect, the difference in release rate constants between NChMT1 and NChMT2 was approximately 2 times, while NChMT4 and NChMT5 showed the same constant despite a difference in HPMC amount. Thus, there seems to be a limit to solving rapid dissolution in the early stage by increasing HPMC alone.
Channeled Extended-Release Matrix TabletThe dissolution rates of NChMT1 were similar to those at the end of dissolution, but were different at the beginning compared to ChMT1 and 2. Both ChMT1 and 2 formulations containing PEG showed lower early dissolution rates. In ChMT1, the extended-release effect increased with PEG addition. This result was the opposite of the expected channeling effect. PEG was expected to act as small fine particles to form channels by dissolution, but instead, it acted as a binder in the early stages, increasing the binding force of the tablet and slowing the dissolution rate. When HPMC is insufficient and release control is inadequate, the binder role of PEG becomes more prominent than its channeling effect. The release rate between 9 and 15 h tended to increase as the amount of PEG increased, but the channeling effect could not be confirmed because there was no significant difference. Unlike Fig. 2A, both ChMT3 and ChMT4 formulations containing PEG increased in the second half of dissolution, which did not make a big difference to the initial dissolution. Furthermore, the second-half dissolution rate increased with increasing PEG. Similar results were observed in Fig. 2C. The extended-release effect was excellent at approximately 5 and 25% at both 0.5 and 4 h. However, NChMT3, which did not contain PEG, had a very low dissolution rate in the second half. In contrast, ChMT5 and ChMT6, which contained PEG, showed a high release rate, which was approximately 10% higher than that of NChMT3 at 12 and 18 h. Based on these results, when HPMC was abundant and the extended-release effect was excellent, dissolution was suppressed, and the drug was not released in the latter half. Under these conditions, the channeling effect of PEG was clearly confirmed. Regardless of the amount of HPMC, the higher the PEG content, the higher the correlation in the zero-order, showing a dissolution profile close to a linear release pattern. This was because the channeling effect increased the late dissolution rate suppressed by the drug trapped in the HPMC matrix. Moreover, among formulations with the same amount of HPMC, those without PEG showed the best fit with the Higuchi model, which is a diffusion release model from the matrix. The channeling effect was not pH-dependent (Fig. 3). The dissolution rate of ChMT6 reached 100% at 24 h in all four media. Furthermore, ChMT6 showed linearity in the dissolution of different pH values and had a release pattern close to the zero-order; thus, even when administered to the human body, the drug is continuously and uniformly released in the gastrointestinal tract for 24 h.29,30) In conclusion, the channeling effect of PEG was confirmed. We expected that the channeling effect would be revealed by dissolving PEG, creating small pores in the tablet, which would act as channels, facilitating water penetration. In the second half, the drug trapped in the matrix may diffuse and be released from the tablet.31,32)
Characterization of the Channeling EffectSwelling and Erosion StudyIn this study, we investigated how the channeling effect influenced the release pattern and dissolution profile of two different types of tablets: NChMT3 and ChMT6. First, we characterized the release mechanism using swelling and erosion indices. Equation 6 provided a measure of the swelling index, which indicated the extent to which the tablet absorbed water and swelled. As shown in Fig. 4(A), after the peak point of the swelling index, swelling decreased, and erosion occurred at a faster rate,33) causing the swelling index to sharply decrease. These results suggested that swelling occurred immediately in ChMT6 because the PEG contained in the tablet rapidly dissolved and formed pores, acting as a channel that allowed water to easily penetrate the tablet. In contrast, since NChMT3 did not contain a channeling agent, water was believed to exist only in the outer shell and did not penetrate deep into the tablet. As a result, swelling occurred only in the early stage and did not increase further. Because of these differences in properties, NChMT3 exhibited a phenomenon where the drug was trapped in the inner matrix of the tablet and was not released in the latter half of dissolution. However, as ChMT6 underwent swelling due to the permeation of water deep into the tablet, drug release was facilitated in the latter half of dissolution. The results in Fig. 4(B) were also attributed to the channeling agent. The PEG formed channels after rapid dissolution, which reduced the binding force of the tablet, and the shear by the rotating paddle eroded from the outer shell of the tablet, ultimately resulting in almost complete disintegration. However, in NChMT3, because there was no channel, the binding force inside the matrix was stronger than that in ChMT6. Furthermore, NChMT3 required more time for water to penetrate deeply and sufficient swelling to occur, resulting in slower erosion progression. In summary, NChMT3 did not undergo swelling and erosion as water did not penetrate deep into the tablet. Therefore, the drug was confined to the internal matrix and was not released in the latter half of dissolution. In contrast, in ChMT6, the PEG rapidly dissolved and formed a channel, facilitating water uptake, and leading to relatively quick swelling and erosion, allowing drug release in the latter half of dissolution.
Rheology StudyThe rheology of the tablets was evaluated to confirm the effect of the channel (Fig. 5 and Table 3). As mentioned earlier, we manufactured all formulation to have a hardness of 120 N as measured using a hardness tester. However, after dissolution, it can be confirmed that there is a difference of more than 2 times depending on the presence or absence of the channeling agent. The tablets swelled as much as they eroded from 2 to 6 h. As a result, the height of the tablets remained almost the same, but the hardness decreased by less than half. The lowest hardness and height were observed at 12 h, which was due to increased swelling. The hardness of ChMT6 was the lowest at 12 h, indicating that erosion occurred after the height decreased due to maximum swelling, leading to lowest hardness. Similar to the previous results of the swelling and erosion indices, ChMT6, which contained the channeling agent PEG, swelled faster than NChMT3, leading to an increase in height and a decrease in hardness. In the second half of dissolution, erosion occurred more rapidly, leading to a significant decrease in height. In conclusion, channel formation promotes swelling and erosion, and in the latter half of dissolution, the drug is released without being trapped in the tablet.
Table 3. Texture Analysis Results for NChMT3 and ChMT6 during the Dissolution Test (
n = 3)
| Time (h) | Hardness (N) | Total work (N × mm) | Sample height (mm) |
|---|
| NChMT3 | 2 | 607.4 (±9.5) | 930.1 (±29.2) | 5.7 (±0.1) |
| 6 | 245.2 (±11.4) | 247.7 (±15.2) | 6.0 (±0.3) |
| 12 | 6.3 (±1.4) | 7.9 (±2.9) | 4.7 (±1.6) |
| ChMT6 | 2 | 312.7 (±63.0) | 475.2 (±115.8) | 7.2 (±0.4) |
| 6 | 19.6 (±5.1) | 20.4 (±4.7) | 8.0 (±0.5) |
| 12 | 0.7 (±0.7) | 1.2 (±0.8) | 3.7 (±0.3) |
Figures 6 and 7 display the appearance and XRCT images of NChMT3 and ChMT6 tablets during the dissolution test. Magnified images of NChMT3 and ChMT6 at 12 h showed that the size of ChMT6 was smaller, swelling had progressed completely throughout the entire tablet with no gray areas found, and a black area representing a channel was observed. This result was highly correlated with the swelling and erosion indices mentioned earlier. In conclusion, XRCT analyses confirmed that channels were formed by adding PEG, which caused rapid swelling to occur inside the tablet in the early stage of dissolution, and rapid erosion in the latter half of dissolution. Unlike tablets without PEG, the release rate did not decrease due to rapid erosion in the latter half of dissolution.34) Due to these characteristics, it is considered that the release rate in the latter half does not decrease, and the pattern is close to zero order.
Conclusion
In this study, we aimed to develop an extended-release tablet with a zero-order release pattern by utilizing the channeling effect. We compared the characteristics of channeled matrix tablet (ChMT) and non-channeled matrix tablet (NChMT) and investigated the mechanism of the channeling effect. After conducting in vitro dissolution tests, we selected the composition of the most effective extended-release ChMT6 and NChMT3 and confirmed the differences in their dissolution patterns. ChMT6 and NChMT3 showed similar release rates in the early stages within 3 h, but after 4 h, NChMT3 released slowly while ChMT3 maintained a zero-order release rate. We examined the swelling and erosion indices to investigate the cause of these differences, which showed that the presence of channels led to a faster swelling and erosion rate. Rheology studies showed that the height of the channeled tablet decreased rapidly due to erosion in the latter half of dissolution. Finally, XRCT confirmed that the channeled tablet swelled uniformly throughout its entire structure, while the non-channeled tablet had an unswollen core. In conclusion, we developed an extended-release tablet containing pirfenidone that belongs to revise to Biopharmaceutical Classification System (BCS) class I and has a zero-order release pattern. This formulation can improve dosing convenience and patient compliance, while reducing the side effects caused by a decreased Cmax. We believe that this study can contribute to improving the efficacy of lung fibrosis treatment.
Acknowledgments
This research was supported by the Chungbuk National University and Korea National University Development Project (2022).
Conflict of Interest
The authors declare no conflict of interest.
Data Availability
Data will be made available on request.
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