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Back to Journal »Drug Design, Development and Treatment» Volume 13

The physicochemical properties and drug release mechanism of dual-release bilayer tablets of milaberone and fesoterodine fumarate

Author Lee HG, Park YS, Jeong JH, Kwon YB, Shin DH, Kim JY, Rhee YS, Park ES, Kim DW, Park CW 

Published on July 23, 2019, the 2019 volume: 13 pages 2459-2474

DOI https://doi.org/10.2147/DDDT.S212520

Single anonymous peer review

Editor who approved for publication: Dr. Guo Qiongyu

Hong-Goo Lee,*,1 Yun-Sang Park,*,1 Jin-Hyuk Jeong,1 Yong-Bin Kwon,1 Dae Hwan Shin,1 Ju-Young Kim,2 Yun-Seok Rhee,3 Eun-Seok Park, 4 Dong-Wook Kim, 5 Chun-Woong Park 1 1 School of Pharmacy, Chungbuk National University, Cheongju 28160, South Korea; 2 Faculty of Pharmacy, Pegatron University, Wanju 55338, South Korea; 3 School of Pharmacy and Pharmaceutical Research, Gyeongsang University, Jinju 52828, South Korea ; 4 School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea; 5 Department of Pharmaceutical Engineering, Cheongju University, Cheongju 28530, South Korea *These authors made equal contributions to this work. Introduction: In this study, one contains fumaric acid The dual-release bilayer tablets of fesoterodine (Fst) (Fst) 5 mg and Mirabegron (Mrb) 50 mg are intended to study the different release behavior of each drug in the bilayer tablet. Two-layer tablets were prepared based on the single-layer tablet formulation of each drug. Method: Based on a satisfactory similarity factor, the optimized bilayer tablet showed similar in vitro dissolution profiles to the commercial reference tablets Toviaz and Betmiga. The drug release kinetics of each drug in the bilayer tablet was evaluated based on the dissolution profile. Observe the surface of each layer by scanning electron microscope and measure the change of tablet weight and volume during dissolution to evaluate the drug release behavior. Fourier transform infrared spectroscopy imaging was also used to study the drug transfer between each layer by observing the cross-section of a double-layered tablet cut vertically during the dissolution process. Results: The release of Fst is very suitable for Higuchi model, and the release of Mrb is very suitable for Hixson-crowell model. Compared with the dissolution rate of each single-layer tablet, the dissolution rate of Fst in the double-layer tablet is slightly reduced (5%), but the dissolution rate of Mrb in the double-layer tablet is significantly reduced (20%). In addition, drug release studies confirmed that, compared with polymer erosion, polymer swelling dominates in the Fst layer, while degradation dominates in the MRB layer. Fourier transform infrared imaging and 3-D image reconstruction indicate that the drug transfer in the double-layer tablet is related to the result of the drug release behavior. Conclusion: These findings are expected to provide scientific insights for the development of dual-release dual-layer drug delivery systems for Fst and Mrb. Keywords: Mirabegron, fesoterodine fumarate, swelling, erosive, double-layer film, FT-IR imaging

Overactive bladder (OAB) is a complex symptom of lower urinary tract storage, with or without urge incontinence. In the absence of confirmed infections or other pathological conditions, it is usually accompanied by frequency and nocturia. 1 Antimuscarinic drugs are the main means of oral drug treatment for OAB. However, continued treatment is limited by insufficient efficacy and adverse events associated with antimuscarinic drugs. In this study, fesoterodine fumarate (Fst), which is commonly used in OAB, was selected as an antimuscarinic agent. The approval of the β3-adrenergic receptor agonist Mirabegron (Mrb) adds a new class of drug treatments to OAB. 2 Due to the different mechanisms of action, the combined use of β3-adrenergic receptor agonists and antimuscarinic drugs may improve the efficacy of OAB treatment. The appeal of the fixed-dose combination is not only its efficacy, but also its high patient compliance. Compared with monotherapy, the fixed-dose combination of Fst and Mrb can provide higher tolerability without affecting the efficacy. Preclinical models have demonstrated the potential of combination therapy to modulate bladder function. 2-4

Bilayer tablets are often used in fixed-dose combinations containing two active pharmaceutical ingredients (API). The basic structure of the double-layer sheet allows the minimum physical contact between the APIs to avoid unnecessary chemical reactions. 5-7 However, double-layer tablets containing Fst and Mrb have not been actively studied. One of the reasons for the lack of research is that both drugs require sustained release to obtain the best therapeutic effect. 8,9 Double-layer tablets have many problems in terms of controlled release drugs. First, one side may be blocked by another drug layer, thereby inhibiting the dissolution rate. Secondly, the drug may move to another layer, and the different release mechanism of the drug in the other layer will affect the diffusion and dissolution rate of the drug. For example, drug release can be delayed by the expansion of another layer. After the other layer is eroded to a critical level, the polymer matrix may also collapse, thereby delaying the release of the drug during the initial dissolution and leading to the rapid release of the drug during the post-dissolution. 10-12

In order to study drug release profiles, many researchers use the United States Pharmacopeia (USP) to monitor the amount of drug released from the tablet into the aqueous solution. This method provides a very useful way to characterize API releases. However, it provides limited information on the kinetics of drug release. Therefore, these studies are usually combined with mathematical models to prove the potential drug release mechanism. 13,14 A number of studies have been conducted during the dissolution of the tablet to study the swelling, erosion, and degradation behavior of each layer of the double-layer tablet. .10,15

Tracking and visualizing drug molecules is another way to reveal drug release behavior in double-layer tablets. Methods of visualizing drug molecules in tablets include nuclear magnetic resonance and Fourier transform infrared (FTIR) imaging. Both of these techniques can be used to monitor and study dissolving tablets. However, chemical specificity, spatial resolution, and acquisition time are very low and limited in MRI. 16,17 FTIR spectral imaging reveals the high resolution of chemical properties, allowing a wider range of drug analysis. In addition, FTIR images may be used for relatively high spatial resolution and accurate quantization. The short acquisition time required for FTIR imaging also allows time resolution in minutes. Based on these advantages, FTIR spectral imaging is very suitable for polymer wetting, swelling and erosion studies and drug transfer between each layer of bilayer tablets. 18,19

Although previous studies on double-layer tablets focused on delayed release, immediate release, stability and formulation, 20-23 this study tried to investigate the effects of different release behaviors on the release of double-layer tablets. The purpose of this study is to prepare and evaluate double-layer tablets based on single-layer tablets with different release behaviors. The dissolution profile of monolayer tablets containing Fst 4 mg is the same as that of commercially available Toviaz tablets, and the dissolution profile of monolayer tablets containing Mrb 50 mg is the same as that of commercially available Betmiga tablets. The morphology of the double-layer tablet during the predetermined time of dissolution was observed by camera image and scanning electron microscope (SEM). The swelling and erosion characteristics of each single-layer tablet were studied, and the influence of different release behaviors in each single-layer tablet was evaluated in the double-layer tablet. In addition, FTIR imaging and ImageJ image reconstruction were used to study the drug transfer between the layers in the bilayer tablet.

Fst and Mrb were purchased from Lupin Pharmaceuticals (Nagpur, India). Erythritol and magnesium stearate were purchased from Daejung Chemicals and Metals (Siheung, Korea). Ludipress and Kolliphor P188 were purchased from BASF (Ludwigshafen, Germany). Hydroxypropyl methylcellulose (HPMC) 4,000 cP (metolose 90 SH-4000 SR) and HPMC 100,000 cP (metolose 90 SH-100000 SR) were purchased from Shin-Etsu Chemical (Tokyo, Japan). Xantural gum (Xantural 180) was purchased from CP Kelco (Atlanta, GA, USA). Polyethylene oxide (PEO; Polyox WSR 301 LEO NF) was purchased from Colorcon Asia Pacific (Singapore). Glyceryl behenate (Compritol 888 ATO) was provided by Gattefossé (Saint-Priest, France). Talc and iron oxide red were purchased from Samchun Chemical (Pyeongtaek, South Korea). Hydroxypropyl cellulose (HPC; Klucel JF Pharm) was purchased from Ashland (Covington, KY, USA). Low replacement HPC (L-HPC) LH22 is provided by Huzhou Zhanwang Tianming Pharmaceutical (Zhejiang, China). Potassium phosphate and sodium hydroxide were purchased from Sigma-Aldrich. Use HPLC grade solvents for analysis.

The formula of Fst single-layer tablet is shown in Table 1. It is prepared by wet granulation through trial and error. Mix Fst and erythritol, which have been sieved through a 355 µm sieve, with a sufficient amount of distilled water. The wet material is sieved through an 850 µm sieve, dried at 60°C for 3 hours, and then re-sieved through an 850 µm sieve. The dry granules are then mixed with Ludipress, HPMC and Compritol. Then the mixture is finally mixed with talc. Carver hydraulic press uses 11 mm rectangular punch and die set for tablet preparation. The tablets are compressed at 1,000 kg. Table 1 Formula of fesoterodine fumarate (Fst) sustained-release monolayer tablets (mg)

Table 1 Formula of fesoterodine fumarate (Fst) sustained-release monolayer tablets (mg)

The formula of Mrb monolayer tablet is shown in Table 2. It is prepared by direct compression through trial and error. PEO and HPC are prepared with sustained-release agents. Kollipor P188 is prepared with a plasticizer to penetrate tablets. L-HPC is used as a disintegrant or binder. Use iron oxide red as a colorant to observe the release behavior well. Carver hydraulic press uses 11 mm rectangular punch and die set for tablet preparation. The tablets are compressed at 1,000 kg. Table 2 Formula of Mirabegron (Mrb) sustained-release monolayer tablets (mg)

Table 2 Formula of Mirabegron (Mrb) sustained-release monolayer tablets (mg)

A bilayer tablet is prepared by pressing the Fst formulation and Mrb formulation together. First, a Carver hydraulic press with a 14 mm rectangular punch and die is used to compress the Mrb formula to 500 kg. Then, the Fst formula was added to the mold and then compressed at 1,000 kg.

The in vitro release study was modified based on USP dissolution. Each release study was conducted using the USP Dissolution Tester II (Vision 8 Elite, Hanson, Los Angeles, CA, USA). PBS (pH 6.8) is prepared by adding 6.81 g potassium dihydrogen phosphate and 0.9 g sodium hydroxide to 1 L of distilled water, and is used as a dissolution medium for enzyme-free simulated intestinal juice.

To evaluate the release of Fst, Fst monolayer tablets and reference tablets were immersed in 900 mL of dissolution medium and kept at 37°C with a paddle speed of 75 rpm. Take samples at 0.5, 1, 2, 4, 6, 8, 10, 12, and 20 hours. To evaluate Mrb release, Mrb monolayer tablets and reference tablets were immersed in the dissolution medium and kept at 37°C at a paddle speed of 100 rpm. Take samples at 1, 3, 5, 7 and 8.5 hours. To evaluate the dissolution of the double-layer tablet, the Fst-Mrb double-layer tablet and the reference tablet were immersed in 900 mL of dissolution medium and maintained at 37°C at a paddle speed of 75 rpm. The paddle speed is chosen to minimize the effect of paddle speed on the dissolution rate of the two drugs in the double-layer tablet. Take samples at 0.5, 1, 2, 4, 6, 8, 10, 12, and 20 hours. Use sinkers to sink all tablets. Samples (5 mL) were collected from all dissolution vessels and filtered through 0.45 μm polyvinylidene fluoride syringes with glass microfiber filters (Whatman; GE Healthcare, Little Chalfont, UK). These samples were diluted with mobile phase and then analyzed by HPLC.

The release profile of the best bilayer tablet was obtained, and three kinetic models were used to study the release mechanism: zero-order, first-order, Higuchi and Hixson-Crowell.

The zero-order equation 24 used is:

Where Q is the amount of drug released at time t, and ko is the zero-order release rate constant.

The Higuchi model 25 equation used is:

Where Mt and M∞ are the absolute cumulative amount of the drug released at time t and infinity, respectively, and kH is the release rate constant.

The equation of the Hixson-Crowell model 26 used is:

Where Qt is the amount of drug released in time t, Qo is the initial amount of drug in the tablet, and KHC is the release rate constant.

Use the similarity factor (f2) to compare the dissolution profiles of the single-layer and double-layer tablets with the dissolution profile of the reference tablet:

Where n is the number of sampling time points and the Rt and Tt percentages of the cumulative drug release of the reference sample and the test sample at time t. If f2>50, it is considered that the dissolution curve of the test sample is similar to that of the reference sample.

After 60 and 240 minutes of dissolution, the double-layer tablets were taken out of the dissolution container and gently blotted dry with filter paper to remove the surface medium. The original tablet computer and the tablet computer being released were taken at a certain distance with a digital SLR camera (EOS 80D; Canon, Tokyo, Japan). Set the length direction of the tablet to observe the overall dissolution behavior of the double-layer tablet.

After dissolving for a predetermined time-0, 60, 240 and 480 minutes for the Fst layer, 0, 30, 60 and 240 minutes for the Mrb layer-the double-layer tablet is taken out of the dissolution vessel and frozen at -75°C For 24 hours, then freeze-dry for 72 hours in a freeze dryer (FreeZone 2.5; Labconco, Kansas City, Missouri, USA) at -50°C and 0.07 mbar. After freeze-drying, the double-layer tablet was cut vertically from the center to observe the cross section. The cross-section of the tablet was coated with a gold film (600 Å) using sputter deposition, and observed with the same magnification (Ultra Plus; Carl Zeiss, Oberkochen, Germany) with SEM.

The swelling and erosion properties are important variables for the drug release of the bilayer tablet. Swelling is a related mechanism for delayed drug release, and erosion is also considered to be an ideal mechanism for drug delivery. 27 After the optimal bilayer tablets were prepared, the swelling and erosion of each monolayer tablet was studied using balance or gravimetric analysis. 13,28-32

Weigh the monolayer tablets (n=3) at time t=0 (initial), put them in the container of the device II with sinkers, and then immerse them in 900 mL at 37°C at a paddle speed of 75 rpm PBS (pH 6.8). After 2, 4, 8 and 20 hours for F1 and 2 and 4 hours for M3, the monolayer tablets were taken out of the dissolution cup, blotted gently with filter paper to remove the surface medium, and then reweighed (Wwet). Calculate the water absorption:

Wherein Wdried is the weight after drying in an oven at 60°C until it reaches a constant weight.

The tablet erosion at each time point is calculated as follows:

Calculate the percentage of tablets remaining after erosion:

The tablet volume was evaluated by measuring the three diameters of each monolayer tablet (n=3) during the predetermined time of dissolution to study the swelling and erosion characteristics in detail. After 2, 4, 8 and 20 hours for F1 and 2 and 4 hours for M3, the monolayer tablets were taken out of the container and gently blotted dry with filter paper to remove the surface medium. Then measure the length, width and height of the tablet with a caliper (Digimatic CD-20APX, Mitutoyo, Kawasaki, Japan).

Cary670 (main workbench) and Cary620 (microscope) were used to perform attenuated total reflection FTIR spectroscopy (Agilent Technologies) in the range of 500–4,000 cm-1. The FTIR spectra of the drugs, excipients, and physical mixtures in each layer were obtained, and the peaks that could trace the drug molecules were determined. In order to confirm the effect of freeze-drying, the physical mixture of each layer was also evaluated by FTIR after freeze-drying. FTIR imaging is performed using the same instrument. 17, 33, 34 After the predetermined time (30, 240, and 480 minutes for the two layers) dissolve, take the double-layer tablet out of the dissolution container, freeze it in a deep refrigerator at -75°C for 24 hours, and then place it in- Lyophilize for 72 hours in a lyophilizer (FreeZone 2.5; Labconco) at 50°C and 0.07 mbar. After freeze-drying, the double-layer tablet was cut vertically from the center to observe the cross section. Observe the profile of the cross-sectional layer under an infrared field of view of 325×325 and an infrared pixel size of 5.5×5.5. Use ImageJ (version 1.51j8) and Color Inspector 3-D version 2.0 (Internationale Medieninformatik, Berlin, Germany) plug-in to analyze each image, and generate a three-dimensional color space, giving an 8-bit red-green-blue value for each image easily Identify the distribution of each drug molecule.

Fst was analyzed using HPLC (Ultimate; Thermo Fisher Scientific, Waltham, MA, USA) and Spherisorb S5CN 5 µm 100 Å analytical column (250×4.6 mm; Supelco, Bellefonte, PA, USA). The mobile phase is acetonitrile: water: trifluoroacetic acid (550:450:1 v:v:v), and the flow rate is 0.8 mL/min. The UV detection was set at 220 nm to analyze the column effluent. The analysis is performed at a temperature of 35°C. Mrb's analysis was performed using Ultimate and Aegispak C18-L 5 µm 100 Å analytical column (150×4.6 mm; Young Jn Biochrom, Seongnam, South Korea). The mobile phase is acetonitrile: 0.01 M potassium dihydrogen PBS (30:70 v:v), and the flow rate is 0.1 mL/min. The UV detection was set at 249 nm to analyze the column effluent. The analysis is performed at a temperature of 30°C. The entire solution was filtered through a 0.45 µm membrane filter (Whatman) and degassed before use. Each sample (20 µL) was injected into the HPLC system for analysis.

The first monolayer tablet was prepared based on the formula in Table 1. The in vitro release study was conducted in PBS (pH 6.8) for 20 hours. The dissolution curves of Fst single-layer tablets and reference tablets are shown in Figure 1. F1 is composed of two kinds of HPMC as slow-release agents. F2 is composed of xanthan gum, and F3 and F4 are composed of xanthan gum and PEO in different proportions as sustained-release agents. F2 composed only of xanthan gum showed the longest sustained release. The dissolution rate increases as the amount of xanthan gum decreases, while the amount of PEO increases. F1 is composed of two types of HPMC, and its dissolution rate is slightly higher than that of the reference tablet. The similarity factor is evaluated by comparing the dissolution profile of the reference tablet. The similarity factors of f1, f2, f3, and f4 compared with the reference tablet are 69.7, 44.8, 72.8, and 59.1, respectively. The dissolution profiles of F1 and F3 are most similar to those of the reference tablet. Figure 1 Comparison of the dissolution profiles of fesoterodine fumarate monolayer tablets and the commercial reference tablet Toviaz. The tablets were immersed in PBS (pH 6.8) for 20 hours (n=3, mean ± SD).

Figure 1 Comparison of the dissolution profiles of fesoterodine fumarate monolayer tablets and the commercial reference tablet Toviaz. The tablets were immersed in PBS (pH 6.8) for 20 hours (n=3, mean ± SD).

Based on the formula in Table 2, Mrb monolayer tablets were prepared. The in vitro release study was conducted in PBS (pH 6.8) for 8.5 hours. The dissolution curves of Mrb monolayer tablets and reference tablets are shown in Figure 2. Mrb preparations are prepared with different ratios of HPC and L-HPC. As the amount of HPC decreases and the amount of L-HPC increases, the dissolution rate increases. The similarity factor is evaluated by comparing the dissolution profile of the reference tablet. The similarity factors of m1, m2, and m3 are 73.5, 52.0, and 36.7, respectively. The dissolution profile of M1 is most similar to the dissolution profile of the reference tablet. Figure 2 Comparison of the dissolution profile of Mirabegron monolayer tablet and the commercial reference tablet Betmiga. The tablets were immersed in PBS (pH 6.8) for 8.5 hours (n=3, mean ± SD).

Figure 2 Comparison of the dissolution profile of Mirabegron monolayer tablet and the commercial reference tablet Betmiga. The tablets were immersed in PBS (pH 6.8) for 8.5 hours (n=3, mean ± SD).

The bilayer tablets are prepared based on F1, F3 and M1 formulations and have a higher f2 value compared to each reference tablet. The dissolution rate of Fst in the double-layer tablet is slightly reduced by about 5%. Therefore, compared with the double-layer tablet based on the F3 formula, the double-layer tablet based on the F1 formula shows a more similar dissolution profile with the reference tablet. The dissolution rate of Mrb in the bilayer tablet is reduced by about 20%. Therefore, in contrast to the dissolution profile of the single-layer tablet, the dissolution profile of the bilayer tablet based on the M3 formulation and the reference tablet showed a more similar dissolution profile than the bilayer tablet based on the M1 formulation. The dissolution profile of the optimized bilayer tablets (F1-M3) and each reference tablet is shown in Figure 3. Compared with the reference tablet, the similarity factors of f1 and m3 are 75.67 and 72.30, respectively. Figure 3 Comparison of the dissolution profiles of fesoterodine fumarate-miraberone bilayer tablets and commercial reference tablets Toviaz and Betmiga. The tablets were immersed in PBS (pH 6.8) for 20 hours (n=3, mean ± SD).

Figure 3 Comparison of the dissolution profiles of fesoterodine fumarate-miraberone bilayer tablets and commercial reference tablets Toviaz and Betmiga. The tablets were immersed in PBS (pH 6.8) for 20 hours (n=3, mean ± SD).

The release curve of the optimized two-layer tablet (F1-M3) is suitable for various mathematical models to evaluate the release kinetics of each layer. The drug release kinetics, including the coefficient of determination and the release rate constant, are evaluated for up to 12 hours, which is the main release time of the two layers. The results are summarized in Table 3. The release of Fst in the double-layer tablet fits well with the Higuchi model (R2=0.9880), and the release of Mrb in the double-layer tablet fits well with the Hixson-Crowell model (R2=0.9942). The Higuchi model can be used to describe changes in drug release through diffusion, such as certain matrix tablets containing water-soluble drugs. 25,35,36 Higuchi model can also be applied to swellable matrix formulations, such as F1-based matrix formulations. On the swelling polymer HPMC. The Hixson-Crowell model can be used to evaluate drug release as a function of surface area or tablet diameter. Therefore, the Hixson-Crowell model can be applied to the erodible matrix formulation, which indicates that the M3 layer is eroded at a relatively constant rate. 26,36,37 Table 3 Mathematical model and drug release kinetics layer of fesoterodine fumarate and Mirabegron

Table 3 Mathematical model and drug release kinetics of Fesoterodine fumarate layer and Mirabegron layer

Take camera images to confirm the behavior of each layer of the optimized two-layer tablet (F1-M3) during the dissolution process. Figure 4 shows the tablet images of the optimized two-layer tablet (F1–M3) before dissolution, 60 minutes after dissolution, and 240 minutes after dissolution. Compared with the initial F1 layer (Figure 4A), the subsequent F1 layer exhibits a greater degree of swelling during the dissolution process than the M3 layer (Figure 4, B and C). Compared with the initial M3 layer (Figure 4A), the subsequent M3 layer showed erosion over time during the dissolution process, and slight swelling was also observed (Figure 4, B and C). Figure 4 After dissolving (A) 0, (B) 60 and (C) 240 minutes of the double-layer tablet.

Figure 4 After dissolving (A) 0, (B) 60 and (C) 240 minutes of the double-layer tablet.

Take SEM images to confirm the internal polymer behavior of each layer in the optimized double-layer tablet (F1-M3) during the dissolution process. Figure 5 shows the SEM of the F1 layer slice in the double-layer tablet, taken before dissolution, after 60 minutes of dissolution, after 240 minutes of dissolution, and after 480 minutes of dissolution. Before dissolution, the Fst layer is densified (Figure 5A). After 60 minutes (Figure 5B), stalk-shaped holes were formed in the Fst layer. After 240 minutes, the holes in the layer grew along the shape of the stem to distinguish the outer expanded layer from the inner layer (Figure 5C). After 480 minutes, the pores began to grow and the outer expansion layer developed further (Figure 5D). Figure 6 shows the SEM of the M3 layer slices of the bilayer tablet before, after 30 times, (c) 60 minutes, and 240 minutes after dissolution. Before dissolution, the M3 layer is as dense as the Fst layer (Figure 6A). After 30 minutes, no holes were formed, but the surface appeared rough (Figure 6B). After 60 minutes, pores are formed and their size increases from the outer layer to the inner layer (Figure 6C). This is related to the slight expansion of the M3 layer in Figure 4B. After 240 minutes, the size of these pores in the outer layer also increased, and due to erosion, the particles appeared to fall off in the form of straw (Figure 6D). Figure 5 Scanning electron microscope of the F1 layer in the double-layer film after dissolving (A) 0, (B) 60, (C) 240 and (D) 480 minutes. The magnification is 200 times. Figure 6 Scanning electron microscope of the M33 layer in the double-layer film after dissolving (A) 0, (B) 30, (C) 60 and (D) 240 minutes. The magnification is 200 times.

Figure 5 Scanning electron microscope of the F1 layer in the double-layer film after dissolving (A) 0, (B) 60, (C) 240 and (D) 480 minutes. The magnification is 200 times.

Figure 6 Scanning electron microscope of the M33 layer in the double-layer film after dissolving (A) 0, (B) 30, (C) 60 and (D) 240 minutes. The magnification is 200 times.

Morphological studies confirmed the behavior of each layer of the optimized double-layer tablet (F1-M3) during the dissolution process. Water absorption, residual rate and tablet volume studies were also conducted to study the swelling and erosion behavior of Fst and Mrb monolayer tablets that constitute the best bilayer tablets (F1-M3).

The water absorption rate indicates the swelling rate of the polymer when it absorbs the surrounding fluid, and the rest indicates the erosion rate when the polymer disintegrates in the fluid during the dissolution process. 13 The water absorption and remaining amount of the monolayer tablet of each drug during the dissolution process are shown in Figure 7. As shown in Figure 4 and Figure 5, the F1 monolayer tablet swelled greatly within 20 hours. The water absorption rate of F1 monolayer sheet was 286.9%±15.4% for 2 hours, 476.5%±45.7% for 4 hours, 701.7%±36.3% for 8 hours, and 988.7%±97.3% for 20 hours. The rest are 70.9%±1.2% for 2 hours, 58.5%±3.0% for 4 hours, 45.1%±0.8% for 8 hours, and 28.1%±4.6% for 20 hours (Figure 7A). These results indicate that polymer swelling plays a leading role in the dissolution of F1 monolayer tablets. As shown in Figures 4 and 6, the M3 monolayer tablet showed great erosion within 4 hours. The water absorption rate of M3 monolayer sheet is 152.0%±21.0% for 2 hours, 302.1%±64.5% for 4 hours, 60.7%±1.4% for the remaining 2 hours, and 14.9%±1.0% for 4 hours (Figure 7B). These results indicate that the polymer Erosion dominates the dissolution of M3 monolayer tablets. Figure 7 (A) F1 monolayer tablet and (B) 3 monolayer tablet water absorption (%) and residual curve (n=3, mean ± SD).

Figure 7 (A) F1 monolayer tablet and (B) 3 monolayer tablet water absorption (%) and residual curve (n=3, mean ± SD).

In order to evaluate swelling and erosion in detail, three measurements were taken for each monolayer tablet during the dissolution process. The diameter of the tablet length, width, and height of the F1 monolayer tablet was evaluated (Figure 8A). The length of F1 single-layer film increased by 21.1%±1.6% at 2 hours, 25.7%±1.1% at 4 hours, 31.9%±2.9% at 8 hours, and 22.3%± at 20 hours 9.6%. The tablet width increased by 28.8%±3.3% at 2 hours, 33.6%±2.3% at 4 hours, 46.0%±6.2% at 8 hours, and 53.5%±9.4% at 20 hours . Tablet height increased by 74.0%±9.3% at 2 hours, 111.8%±15.2% at 4 hours, 104.3%±12.5% ​​at 8 hours, and 86.9%±13.0% at 20 hours . These results differ in radial variation due to the influence of shear strength during compression and dissolution. The height of a tablet that is longer than the initial length in 4 hours has a very large increase in height and is not suitable for swelling studies because it is too affected by compression. Since the tablet length was initially too long, the increase was relatively small, indicating that the swelling study was insufficient. The width of the tablet is less affected by compression, and the swelling is stable. Therefore, the radial variation of width is considered suitable for swelling and erosion studies of F1 monolayer tablets. The swelling occurred actively during the first 2 hours and continued to slow down to 20 hours. Figure 8 (A) F1 single-layer sheet and (B) M3 single-layer sheet radial changes (n=3, average ± SD).

Figure 8 (A) F1 single-layer sheet and (B) M3 single-layer sheet radial changes (n=3, average ± SD).

The tablet length, width, and height of M3 monolayer tablets were evaluated during dissolution (Figure 8B). The length decreased by 0.8%±0.6% at 2 hours and 33.8%±1.2% at 4 hours. The width increased by 11.7%±5.6% at 2 hours, but decreased by 15.1%±3.4% at 4 hours. The height increased by 52.8%±2.1% at 2 hours and 10.9%±1.3% at 4 hours. For the same reason as the F1 single-layer sheet, the M3 single-layer sheet has the largest height expansion value and the smallest length. Therefore, the radial change in the width direction is considered suitable for swelling and erosion studies of M3 monolayer tablets. Sales occurred for up to 2 hours, after which erosion dominated for up to 4 hours.

Figure 9 shows the correlation between the water absorption (Figure 7A) and the radial change in width (Figure 8A) of the F1 monolayer tablet during the 20-hour dissolution period (n=3). There is a significant correlation (R2=0.9882), indicating that the two swelling parameters show the same trend, confirming that the drug release in F1 is dominated by swelling. Figure 9 Correlation between water absorption in a single-layer tablet and the change in width and diameter of the tablet (n=3, mean ± SD).

Figure 9 Correlation between water absorption in a single-layer tablet and the change in width and diameter of the tablet (n=3, mean ± SD).

Obtain FTIR spectra (Figure 10) to identify peaks that can track drug molecules in IR images. Figure 10A shows the FTIR spectra of Fst and excipients in the F1 formulation. The FTIR spectra of F1 before and after freeze-drying were also studied. The COO¯ group peak at 1,757 cm-1 is only observed in the FTIR spectra of Fst and F1. In order to determine the effect of freeze-drying on the FTIR spectrum, the physical mixture after freeze-drying was also evaluated. The COO¯ base peak at 1,757 cm-1 is slightly reduced, but it is observed in the physical mixture after freeze-drying. Therefore, a wavenumber of 1757 cm-1 was chosen to track the Fst molecule in the drug transfer study. Figure 10B shows the FTIR spectra of Mrb and excipients in the M3 formulation. The FTIR spectra of M3 before and after freeze-drying were also studied. Only in the FTIR spectra of Mrb and M3, the peak of the C-NH2 group was observed at 1,646 cm-1. In order to determine the effect of freeze-drying on the FTIR spectrum, the physical mixture after freeze-drying was also evaluated. The C-NH2 group peak at 1,646 cm-1 is slightly reduced, but it is observed in the physical mixture after freeze-drying. Therefore, a wavenumber of 1,646 cm-1 was chosen to track Mrb molecules in the drug transfer study. Fig. 10 Fourier transform infrared spectra of drugs, excipients, physical mixtures and freeze-dried physical mixtures in (A) F1 layer and (B) M3 layer.

Fig. 10 Fourier transform infrared spectra of drugs, excipients, physical mixtures and freeze-dried physical mixtures in (A) F1 layer and (B) M3 layer.

Obtain two-layer cross-sectional FTIR images to track drug transfer. The 3D reconstruction was visualized using ImageJ software based on FTIR imaging (Figures 11 and 12). The FTIR image was taken at 30 minutes, representing the first phase, 240 minutes representing the dissolution phase, and 480 minutes representing the end phase of dissolution. As shown in Figure 11, the FTIR image and 3-D Color Inspector show that the amount of Fst in the F1 layer gradually decreases over time, while it gradually increases in the M3 layer. The F1 layer expands (Figure 5) and increases over time, resulting in a decrease in Fst in the F1 layer (Figure 11A), and an increase in Fst in the M3 layer (Figure 11B). As a result, the expansion in F1 transfers Fst to M3, eventually delaying the release of Fst. Although the release of Fst is blocked by M3 in the double-layer tablet, the dissolution profile of Fst is not significantly reduced (5%) compared with the single-layer tablet, which is different from the Mrb dissolution profile (Figures 1 and 3). This can be achieved by transfer First through swelling. As shown in Figure 12A, the FTIR image and 3-D Color Inspector show that the amount of Mrb in M3 is relatively constant during the dissolution process compared with the amount of Fst in F1, which shows a large change because Mrb in M3 is released with erosion . As shown in Figure 12B, the FTIR image and the 3-D Color Inspector show that Mrb is almost invisible in the Fst layer during the dissolution process, which indicates that Mrb has hardly transferred to the Fst layer. In addition, the results indicate that Mrb release is blocked by the Fst layer. The dissolution profile of Mrb in the double-layer tablet shows the blocking effect of the Fst layer on the release of Mrb. Compared with the single-layer tablet, the dissolution rate is significantly reduced (20%) (Figures 2 and 3). In addition, as shown in Figure 12B, the small amount of Mrb transferred to the Fst layer during the dissolution process seems to accumulate in the swelling of the Fst layer, which leads to further suppression of Mrb release in the double-layer tablet compared to the single-layer tablet. In summary, although the layers in the double-layer tablet block each other, the release of Fst is less affected by F1 swelling when the single-layer tablet is changed to a double-layer tablet, and the release of Mrb is affected when the single-layer tablet is changed to a double-layer tablet. Significantly inhibited. Due to erosion in M3. Figure 11 Fourier transform infrared image and reconstruction (3-D color checker) image tracking fesoterodine fumarate after a predetermined time after the dissolution of (A) F1 and (B) M3 layers. Figure 12 Fourier transform infrared image and reconstruction (3-D color checker) image tracking mirabegron after a predetermined time of dissolution in (A) M3 and (B) F1 layers.

Figure 11 Fourier transform infrared image and reconstruction (3-D color checker) image tracking fesoterodine fumarate after a predetermined time after the dissolution of (A) F1 and (B) M3 layers.

Figure 12 Fourier transform infrared image and reconstruction (3-D color checker) image tracking mirabegron after a predetermined time of dissolution in (A) M3 and (B) F1 layers.

The purpose of this study was to investigate the difference in the dissolution patterns of double-layer tablets based on single-layer tablets. A double-release drug delivery system was used to successfully prepare a double-layer tablet containing Mrb and Fst. Compared with commercial reference tablets based on similar factor f2, these bilayer tablets have similar in vitro dissolution profiles. Morphological studies using camera images and SEM confirmed the behavior of the bilayer tablet over time during the dissolution process. A number of swelling and erosion studies have confirmed that Fst is mainly released through swelling and Mrb is mainly released through erosion. In particular, the relationship between the amount of water absorption and the radial variation of the tablet width was determined. In addition, the transfer of Fst and Mrb is visualized in the double-layer tablet by FTIR imaging and 3-D image reconstruction. The visualization of drug molecular tracking reveals the transfer of each drug during the dissolution process, and provides a basic principle for the different dissolution profiles of double-layer tablets and single-layer tablets. In summary, the release of bilayer tablets based on monolayer tablets with different release behaviors shows that the swollen monolayer is slightly affected, while the eroded monolayer is significantly affected. These findings provide scientific insights for the development of dual-release bilayer tablet drug delivery systems.

This research was funded by the National Research Foundation of Korea and was funded by the Korean government (NRF-2017R1A5A2015541, NRF-2018R1A1A1A05023012 and 2018R1D1A1B07050538).

The authors report no conflicts of interest in this work.

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