Crystalline cellulose (VIVAPUR101), lactose (Lactose-100M), calcium stearate, and HPMC (SE-06 and NE4000) were purchased from JRS Pharma (Tokyo, Japan), Glanbia Ireland (Kilkenny, Ireland), EIKA Corporation (Tokushima, Japan), and Shin-Etsu Chemical (Tokyo, Japan), respectively. Maltitol (Amalty-MR50) and sorbitol (Sorbit) were commercially obtained from Mitsubishi Corporation Life Sciences (Tokyo, Japan). Sucrose fatty acid ester (S-570) was purchased from Mitsubishi Chemical Cooperation (Tokyo, Japan). Starch (Perfiller102) and 10% ( w / w ) shellac solution (AQ shellac) were purchased from FREUND CORPORATION (Tokyo, Japan). Agar (disintegration grade), silicon dioxide (Sylopage), and psyllium husk powder were bought from Ina Food Industry (Nagano, Japan), Fuji Silysia Chemical (Aichi Japan), and Shikibo Cooperation (Osaka, Japan), respectively. All the additives used were food grade. A red-coloring agent (Allura Red AC) was obtained from San-Ei Gen F.F.I., Inc (Osaka, Japan). Hydrogen chloride, sodium chloride, sodium hydroxide, and potassium dihydrogen phosphate were commercially obtained from KANTO CHEMICAL CO., INC (Tokyo, Japan).
Tablet systems with the formulas shown in Table 1 were examined. Granulated lactose, starch, and maltitol, which are well-used excipients, were utilized. Additionally, calcium stearate and HPMC were added as a lubricant and gelling agent, respectively. Allura red AC was incorporated into each formula for the dissolution studies, and then the total weights of the formulas were maintained by adjustment when the amount of lactose was changed. All materials were mixed for one minute in laboratory plastic bags by hands at each batch size of 1500 g. Tableting was performed by employing a laboratory tableting machine (clean press correct 19K, KIKUSUI SEISAKUSHO LTD, Kyoto, Japan), which was equipped with round-shaped punches and dies of φ9 mm. The operating conditions were as follows; compression force: 1.0–1.2 kN; rotation speed: 35 rpm. Thereafter, the five kinds of tablets were individually coated using a laboratory coating machine (DRIACOATOR DRC-500, Powlex, Hyogo, Japan) until the average weights reached 357 mg/tablet. The coating layer was composed of shellac, sorbitol, and sucrose fatty acid ester (S-570) at a weight ratio of 5:1:1 with common conditions as follows: batch size: 1500 g; inlet temperature: 65–70 °C; outlet temperature: 50–53 °C; air flow: 3.5 Nm/min; atomizing air: 60 L/min; spray feed rate: approx. 50 g/min; pan revolutions: 13–14 rpm; diameter of spray nozzle: 1 mm.
The dissolution profiles of the tablets were evaluated in vitro by means of a dissolution test in accordance with Japanese Pharmacopoeia (17th edition). Briefly, a dissolution tester (NTR-3000, Toyama Sangyo Co., Ltd., Osaka, Japan) was used; the paddle rotations and the temperature of the tested fluids were set at 50 rpm and 37 °C, respectively. The test fluids were JP1 fluid (pH 1.2) for a model of gastric liquid, which was composed of 2 g/L NaCl and 7 mL/L HCl, and JP2 fluid (pH 6.8) for a model of gastrointestinal fluid, prepared from a mixture of 0.05 mol/L KH2PO4 and 23.6 mmol/L NaOH. A tablet of each formula prepared was added in the JP1 fluid for two hours at first; then, it was immediately moved to the JP2 fluid and tested for nine hours. Sampling (5 mL) was performed at regular intervals, and fresh fluids heated to 37 °C were supplied each time to maintain the total volume at 1000 mL. After the filtration of the samples, their absorbances at 510 nm were measured to detect the Allura red AC eluted from each tablet, employing a spectrophotometer (U-2900, HITACHI, Tokyo, Japan). The dissolution rates of the tablets were calculated with a standard curve given by several concentrations of Allura red AC diluted in the JP2 fluid.
Kinetic analysis was performed for the five kinds of systems using the following equations:
Qt = K0
t
,(1)
t is the amount of Allura red AC released in timet
, and K0 represents the zero-order release rate constant.Zero-order equation:where Qis the amount of Allura red AC released in time, and Krepresents the zero-order release rate constant.
Qt = Q0·e−K1
t
,(2)
t is the amount of Allura red AC released in timet
, Q0 is the initial amount of the coloring agent, and K1 represents the first-order release rate constant.First-order equation:where Qis the amount of Allura red AC released in time, Qis the initial amount of the coloring agent, and Krepresents the first-order release rate constant.
Qt/Q∞ = Kkp·
t
n,(3)
t/Q∞ is the cumulative release ratio of the Allura red AC released at timet
, and Kkp represents the release rate constant. The n value is used to characterize different release mechanisms.Korsmeyer–Peppas equation:where Q/Qis the cumulative release ratio of the Allura red AC released at time, and Krepresents the release rate constant. The n value is used to characterize different release mechanisms.
Unique tablets that were visually detectable under X-ray exposure were formulated using barium sulfate (baribriteLV, Kaigen pharma Co., Ltd., Osaka, Japan). With a batch size of 1500 g, the six formulas shown in Table 2 were tableted in the same way as described above, and their weights were controlled to be approx. 683.4 mg/tablet. Tablets 6a and 6b were not coated, and tablets 7a, 7b, 8a, and 8b were coated with shellac solutions, for which 50 g of sorbitol, 50 g of sucrose fatty acid ester, and/or 117 g of HPMC (SE-06) were dissolved in a 2500 g shellac solution, using the same instrument and conditions as described above. The coating process was finished when the average weight of each tablet reached 731.2 mg. Next, tablets 6a, 7a, and 8a were used for dissolution tests, the details of which are mentioned above, and tablets 6b, 7b, and 8b were subjected to a human volunteer study described below.
The protocol used in this study was approved by a research ethics committee (application number: ULS202003, 2020), which was organized by User Life Science Co., Ltd., (Fukuoka, Japan), and the whole study was conducted in the Takahira internist clinic under proper doctor’s advice. Written informed consent was obtained from all the participants in accordance with the Helsinki Declaration revised in Fortaleza, Brazil, 2013. Three healthy volunteers (20–28 years old; male only) were selected for this study after giving informed written consent. They had fasted without drinking from 21:00 on the day before the study, and then, tablets 6b, 7b, and 8b were administrated to each person with 150 mL of water in the morning from 6:30 to 9:00. They rested calmly until 12:30; in the meantime, X-ray scans were performed four times. The X-ray examinations were strictly restricted to a maximum of four times a day because of radiation exposure.
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