Tablet allowing segmented release of sleep regulation drugs and preparation method thereof

Abstract

The invention relates to a tablet allowing segmented release of sleep regulating drugs and a preparation method thereof, which belong to the pharmaceutical technology, and are characterized in that each tablet structurally comprises a drug-containing delayed release tablet core, a drug-free gastric soluble coating, a drug-free enteric coating, a drug-containing quick release shell and a shell gastric soluble coating from inside to outside in sequence; an ideal double-section timed drug release mode can be realized, and the preparation is particularly suitable for sleep regulation drugs, such as ramelteon.

Description

[0001] This divisional application is based on a Chinese invention patent application with the application number 202110950477.6 and the filing date of August 18, 2021 as the parent case. Technical Field

[0002] The present invention relates to pharmaceutical technology, in particular to a tablet allowing for segmented release of sleep-regulating drugs and a preparation method thereof. Background Art

[0003] Some drugs, such as sleep-regulating drugs, need to be rapidly released and take effect quickly after being ingested by patients. However, the disadvantage is that it causes a sharp fluctuation in blood drug concentration, resulting in a high incidence of adverse reactions. It is necessary to develop formulation technologies to make the blood drug concentration of such drugs in the body more stable, the time for the drug effect to disappear later, and the incidence of adverse reactions lower.

[0004] Ramelteon ( ) is an oral hypnotic drug developed by Takeda Pharmaceutical Company of Japan and approved for marketing by the US FDA on July 22, 2005. It is the first melatonin receptor agonist applied clinically for the treatment of insomnia, mainly used for the treatment of insomnia with difficulty in falling asleep, and also has definite curative effects on chronic insomnia and short-term insomnia. Ramelteon is the first insomnia prescription drug with a new therapeutic mechanism in the past 35 years.

[0005] Currently, the mechanism of action of commonly used sleeping pills generally is to widely inhibit the nerve activities in the human brain. However, ramelteon has a unique pharmacology, that is, it selectively acts on two receptors in the suprachiasmatic nucleus (SCN) of the human hypothalamus. SCN is known as the "biological clock", which regulates the 24-hour periodic biological rhythm of the human body, including the sleep-wake cycle. Research results show that no adverse reactions such as overuse, withdrawal reactions, drug dependence, and "hangover" (the aftereffect on the next day) will occur after using this drug. The results of clinical phase III studies show that Ramelteon can effectively shorten the sleep onset time of patients, increase the total sleep time, improve sleep efficiency, and have less negative impact on work and study the next day, and the relapse rate after drug withdrawal is also very low. In one study, 472 patients took this product once a day for up to 1 year. According to the latest clinical research results, this product is safe for use in elderly patients, patients with mild to moderate certain obstructive pulmonary diseases (COPD), and patients with mild to moderate sleep apnea.

[0006] Most of the current ramelteon preparations on the market are immediate-release preparations, which can only be released once, achieving the effect of rapid onset and helping to fall asleep quickly; but it cannot prevent early awakening and the blood drug concentration C max is large, which is likely to increase the incidence of adverse reactions.

[0007] Although there are literature records of sleep-regulating drugs with dual-stage release modes, the characteristics of their preparations are that the drugs are made into quick-release and delayed-release pellets, the two pellets are mixed into capsules or pressed into tablets with fillers, and the two pellets achieve dual-stage release based on different dissolution characteristics; for example, CN00809487 records "timed dual-release dosage form containing short-acting hypnotic or its salt". Among them, the tablets made by first making pellets and then pressing them with fillers are prone to uneven mixing due to the difference in particle size, and there may be stratification during the pressing process, and there is a possibility that the pellets may be crushed during the pressing process, affecting the final release, and it is difficult to achieve an ideal two-stage release mode. Therefore, it is necessary to develop new tablets and tableting technologies. Summary of the invention

[0008] Based on the problems to be solved in the above-mentioned field, the present invention provides a tablet allowing two-stage drug release and a preparation method thereof, realizing an ideal two-stage timed drug release mode, and is particularly suitable for sleep regulating drugs, such as ramelteon.

[0009] The technical solution of the present invention is as follows:

[0010] A tablet that allows the segmented release of sleep-regulating drugs, characterized in that each tablet comprises, from the inside to the outside, a drug-containing delayed-release core, a drug-free enteric coating, a drug-containing immediate-release outer shell, and an outer shell gastric coating.

[0011] Preferably, the drug-free enteric coating has a weight gain of ≥4% relative to the drug-containing delayed-release tablet core (preferably a weight gain of 4%-12%, or 5%, 6%, 7%, 8%), and is soluble under dissolution conditions of pH 5 or above, preferably pH 7 or above, so that the delayed-release tablet core begins to release 0.5-4 hours after the drug-containing immediate-release shell is completely released and is completely released within 0.1-6 hours (0.5-4 hours).

[0012] Preferably, the tablet is characterized in that a non-drug gastric soluble coating is provided between the drug-containing delayed-release core and the non-drug enteric coating, and the non-drug gastric soluble coating has a weight gain of 2-5%, preferably 3% or 4%.

[0013] Preferably, the tablet is characterized in that the film-forming material used for the drug-free enteric coating material is selected from one or more of acrylic resins No. I, No. II, and No. III, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate (CAT), acrylic resins EuS100, EuL100, methacrylic acid-methyl methacrylate copolymer, and methacrylic acid-ethyl acrylate copolymer, and the preferred film-forming material is methacrylic acid and ethyl acrylate copolymer.

[0014] Preferably, the tablet is characterized in that the content ratio of the active pharmaceutical ingredient in the drug-containing immediate-release shell to that in the drug-containing delayed-release tablet core is 1-3:1.

[0015] Preferably, the tablet is characterized in that the drug-containing delayed-release tablet core is an immediate-release preparation; in the drug-containing delayed-release tablet core, the weight percentage contents of the various excipients are respectively: filler 60-90%; disintegrant 2-10%, preferably 4-8%; binder 2-6%, preferably 2.5-5%; antioxidant 0.01-1%, preferably 0.05-1%; lubricant / glidant 0.5-3%, preferably 0.5-1.5%, wherein the filler and antioxidant are internal excipients, the lubricant / glidant is an external excipient, and the disintegrant can be an internal excipient or an external excipient.

[0016] Preferably, the tablet is characterized in that the drug-containing delayed-release tablet core is a sustained-release preparation; in the drug-containing delayed-release tablet core, the weight percentage contents of the various excipients are respectively: filler 60-90%; binder 2-6%, preferably 2.5-5%; sustained-release material 4-25%, preferably 5-20%; antioxidant 0.01-1%, preferably 0.05-1%; lubricant / glidant 0.5-3%, preferably 0.5-1.5%; wherein the filler, binder, and antioxidant are internal excipients, and the lubricant / glidant is an external excipient.

[0017] Preferably, the tablet is characterized in that the weight ratio of the material of the drug-containing immediate-release shell to that of the drug-containing delayed-release tablet core is ≥4, preferably 4-12 or 350:60.

[0018] Preferably, the tablet is characterized in that the gastric-soluble coating weight gain of the shell is 2-5%, preferably 3%.

[0019] The filler is selected from one or more of microcrystalline cellulose, lactose, pregelatinized starch, starch, calcium hydrogen phosphate, mannitol, dextrin, etc.;

[0020] The binder is selected from one or more of povidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc.;

[0021] The disintegrant is selected from one or more of starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, crospovidone, cross-linked sodium carboxymethyl cellulose, etc.;

[0022] The sustained-release material is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, alginate, ethyl cellulose, vinyl acetate, xanthan gum, guar gum, crospovidone, glyceryl behenate, etc.;

[0023] The antioxidant is selected from one or more of vitamin E, methoxyphenol, butylated hydroxyanisole, dibutylhydroxytoluene, sodium bisulfite, sodium metabisulfite and vitamin C;

[0024] The lubricant / glidant is selected from one or several of magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide, sodium lauryl sulfate, talc powder, etc.

[0025] Preferably, the tablet is characterized in that it is prepared by the following steps:

[0026] (1) Prepare the materials for the drug-containing immediate-release outer shell: Prepare the total mixed granules for the drug-containing immediate-release outer shell;

[0027] (2) Prepare the drug-containing delayed-release tablet core: Prepare the total mixed granules for the drug-containing delayed-release tablet core, and obtain the tablet core by pressing; The tablet core is sequentially coated with gastric-soluble coating and enteric coating to obtain the drug-containing delayed-release tablet core;

[0028] (3) Fill a part of the materials for the drug-containing immediate-release outer shell into the middle mold as the first layer; Place the drug-containing delayed-release tablet core on the first layer as the second layer, and then perform pre-pressing; Fill the remaining materials for the drug-containing immediate-release outer shell as the third layer, and perform tabletting.

[0029] Preferably, the tablet is characterized in that the pressure for pre-pressing is 0.02 - 1.5 kN, and the main pressure for tabletting is 15 - 35 kN.

[0030] Preferably, any of the above-mentioned tablets is characterized in that the sleep regulation drug refers to ramelteon.

[0031] The preparation method of any of the above-mentioned tablets is characterized in that it comprises the following steps:

[0032] (1) Prepare the materials for the drug-containing immediate-release outer shell: Prepare the total mixed granules for the drug-containing immediate-release outer shell;

[0033] (2) Prepare the drug-containing delayed-release tablet core: Prepare the total mixed granules for the drug-containing delayed-release tablet core, and obtain the tablet core by pressing; The tablet core is sequentially coated with gastric-soluble coating and enteric coating to obtain the drug-containing delayed-release tablet core;

[0034] (3) Fill a part of the materials for the drug-containing immediate-release outer shell into the middle mold as the first layer; Place the drug-containing delayed-release tablet core on the first layer as the second layer, and then perform pre-pressing; Fill the remaining materials for the drug-containing immediate-release outer shell as the third layer, and perform tabletting.

[0035] Preferably, the preparation method is characterized in that the pressure for pre-pressing is 0.02 - 1.5 kN, and the main pressure for tabletting is 15 - 35 kN.

[0036] The total mixed granules of the drug-containing delayed-release tablet core and the total mixed granules of the drug-containing immediate-release outer shell are prepared by any of the following methods:

[0037] Method 1: Weigh the active pharmaceutical ingredient and various internal excipients after sieving according to the prescription amount. Add the active pharmaceutical ingredient and antioxidant into a certain amount of solvent to make a solution or suspension, and spray it into the remaining internal excipients to complete wet granulation. After drying, add the external excipients and mix evenly to obtain the corresponding total mixed granules;

[0038] Method 2: Weigh the active pharmaceutical ingredient and various internal excipients after sieving according to the prescription amount. Add the active pharmaceutical ingredient into a certain amount of solvent to make a solution or suspension, and spray it into the internal excipients to complete wet granulation. After drying, add the external excipients and mix evenly to obtain the corresponding total mixed granules;

[0039] Method 3: Weigh the active pharmaceutical ingredient and various internal excipients after sieving according to the prescription amount. Add the antioxidant or binder into a certain amount of solvent to make a solution or suspension, and spray it into the mixed material of the active pharmaceutical ingredient and the remaining internal excipients to complete wet granulation. After drying, add the external excipients and mix evenly to obtain the corresponding total mixed granules;

[0040] Method 4: Weigh the active pharmaceutical ingredient and various excipients after sieving according to the prescription amount, and mix the active pharmaceutical ingredient and excipients evenly by the equal increment method to obtain the corresponding total mixed granules.

[0041] Through research on several dimensions of the tablet structure, formulation, and tablet-making process, the present invention obtains a tablet formulation and its preparation process that allow for segmented release of the drug active substance, which is particularly suitable for sleep regulation drugs. It makes up for the lack of such tablets in the prior art.

[0042] For the tablets provided by the present invention, in the dissolution test, the results are as Figure 2 , Figures 4 and 5 show that the drug-containing immediate-release outer shell completes release within 10 - 30 minutes. Due to the lack of protection of the drug-free enteric coating, there is no drug release within a subsequent period, such as within 1.5 - 4 hours. Only then does the second-stage drug-containing delayed-release tablet core start to release drugs, achieving an ideal two-stage release mode. When applied to sleep regulation drugs, it can take effect quickly after taking the medicine to help fall asleep quickly, and start the second-stage release after a period of time to prevent early waking and increase the total sleep time.

[0043] In order to obtain tablets that achieve the above release mode, the present invention performs a drug-free gastric-soluble coating and a drug-free enteric coating on the drug-containing delayed-release tablet core in the tablet structure. It is found in the R & D test of the present invention that due to the relatively long time required for the enteric coating process, the tablet core may be easily chipped during the enteric coating process. Therefore, it is preferably to perform a gastric-soluble coating before the enteric coating to protect the tablet core, and the gastric-soluble coating will not cause a delay in the release of the tablet core in the enteric environment.

[0044] In addition, the present invention studied the influence of the weight gain thickness of enteric coating on the release mode, and found that if the enteric coating film is too thin, it cannot prevent the core from releasing in the gastric acid environment, while if the coating film is too thick, it will increase the process cost and delay the release of the core. It was found that the ideal weight gain range of enteric coating is 4-12%.

[0045] The study of the present invention also found that due to unsuitable toughness, some enteric coating materials are prone to cracking or generating gaps during the tabletting process, resulting in premature release of the delayed-release core, or the film-forming materials of some enteric coating materials are not suitable, and can only ensure no dissolution below pH 4.0; for example Figure 7 As shown, when the coating materials are Opadry Enteric 94O680000 and 91O610002, the core is released in the pH 5.0 environment and the two-stage release cannot be achieved.

[0046] In order to obtain tablets that achieve the target release mode of the present invention, this study found that when the film-forming material of the selected enteric coating material is one or more materials in the following group: acrylic resin I, II, III, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl alcohol phthalate (PVAP), cellulose acetate trimellitate (CAT), acrylic resin EuS100, EuL100, copolymer of methacrylic acid and methyl methacrylate, copolymer of methacrylic acid and ethyl acrylate, etc., preferably the copolymer of methacrylic acid and ethyl acrylate is used; for example, when Eudragit L100-55 is selected, the tablets produced can achieve an ideal release effect.

[0047] The study of the present invention also found that some parameters in the preparation process affect the yield of the tablets of the present invention and whether the tablets reach the target release mode, thus affecting the practicality / promotability value of the technology of the present invention. For example, the pre-pressing pressure and the main pressure of tabletting in step (3) of the preparation method: when the pre-pressure is greater than 1.5 kN, such as 2 kN, most of the enteric coatings of the cores are damaged, and the cores of the obtained tablets are released in acid, while when the pre-pressure is between 0.02-1.5 kN, the enteric coatings of the cores are completely wrapped and not released in acid for 4 h, which helps to obtain an ideal release mode; when tabletting with a main pressure lower than 15 kN, such as 10 kN, the tablets formed are softer and easier to break, and the friability is unqualified; when the main pressure is greater than 35 kN, the tablets formed will have a top-cracking phenomenon, and the enteric coating film of the core will rupture, resulting in the release of the active drug in the core in acid. It was found through experiments that when the main pressure is in the range of 15-35 kN, the friability is qualified, and the enteric coatings of the cores are completely wrapped and not released in acid for 4 h.

[0048] In the case where the drug active substance is a sleep regulation drug, the present invention discovers through experiments that the content ratio of the drug in the drug-containing immediate-release outer shell to the drug in the drug-containing sustained-release tablet core is 1-3:1, which can achieve an ideal blood concentration state. If the drug ratio in the drug-containing sustained-release tablet core is too high, it is likely to cause difficulty in waking up later. If the drug ratio in the drug-containing sustained-release tablet core is too low and the ratio in the immediate-release outer shell is too high, it is likely to cause the blood drug concentration to increase too fast and too high, and the blood drug concentration will be low later, with too large fluctuations in the blood drug concentration. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 . Schematic cross-sectional structure diagram of the tablet of the present invention;

[0050] Where 1 - drug-containing sustained-release tablet core, 2 - drug-free gastric-soluble coating, 3 - drug-free enteric-soluble coating, 4 - drug-containing immediate-release outer shell, 5 - gastric-soluble coating of the outer shell

[0051] Figure 2 . Dissolution test results of the tablets obtained in Example 1;

[0052] Figure 3 . Dissolution test results of the tablets obtained in Example 1;

[0053] Figure 3 . Dissolution test results of the tablets obtained in Example 2;

[0054] Figure 4 . Dissolution test results of the tablets obtained in Example 3;

[0055] Figure 5 . Dissolution test results of the tablets obtained in Example 4;

[0056] Figure 6 . Influence of the pre-pressure on the drug release model of the tablets in the tablet preparation process of the present invention;

[0057] Figure 7 . Influence of the main pressure on the drug release model of the tablets in the tablet preparation process of the present invention;

[0058] Figure 8 . Influence of the enteric-soluble coating material on the drug release model of the tablets of the present invention;

[0059] Figure 9 . Influence of the weight gain of the enteric-soluble coating material on the drug release model of the tablets of the present invention;

[0060] Figure 10 . Comparison of in vivo release data between the tablets of the present invention and the reference preparation DETAILED DESCRIPTION OF THE INVENTION

[0061] To make the purpose, technical solutions, and advantages of the implementation of this application clearer, the following will describe the technical solutions in the embodiments of this application in more detail with reference to the accompanying drawings in the embodiments of this application.

[0062] As Figure 1 shown,

[0063] 1. A tablet that allows for segmented drug release, characterized in that it sequentially includes a drug-containing delayed-release tablet core (1), a drug-free enteric coating (3), a drug-containing immediate-release outer shell (4), and an outer shell gastric-soluble coating (5) from the inside to the outside.

[0064] 2. Preferably, the tablet is characterized in that there is also a drug-free gastric-soluble coating (2) between the drug-containing delayed-release tablet core (1) and the drug-free enteric coating (3).

[0065] 3. Preferably, the tablet is characterized in that the difference between the diameter of the tablet and the diameter of the drug-containing delayed-release tablet core (1) is ≥ 2 mm.

[0066] 4.. Preferably, the tablet is characterized in that the difference between the diameter of the tablet and the diameter of the drug-containing delayed-release tablet core (1) is between 2 and 8 mm or between 2 and 6 mm or between 3 and 7 mm or between 4 and 8 mm.

[0067] 5. The tablet according to claim 1, characterized in that the difference in thickness between the tablet and the drug-containing delayed-release tablet core (1) is ≥ 1 mm

[0068] 6. Preferably, the tablet is characterized in that the difference in thickness between the tablet and the drug-containing delayed-release tablet core (1) is between 1 and 8 mm or between 1.5 and 6 mm or between 2 and 6 mm.

[0069] 7. Preferably, the tablet is characterized in that the diameter of the tablet is 5 - 13 mm or 9.9 - 10.25 mm; the diameter of the drug-containing delayed-release tablet core (1) is 3 - 9 mm, or 4.9 - 5.25 mm;

[0070] 8. Preferably, the tablet is characterized in that

[0071] the thickness from the upper surface of the drug-containing delayed-release tablet core (1) to the narrower side of the upper surface of the tablet is ≥ 0.5 mm;

[0072] the thickness between the outer edge of the drug-containing delayed-release tablet core (1) and the outer edge of the tablet on the narrower side is ≥ 0.5 mm.

[0073] 9. Preferably, the tablet is characterized in that in the longitudinal section direction of the tablet, the drug-containing delayed-release tablet core (1) is located in the geometric center area inside the tablet;

[0074] In the cross-sectional direction of the tablet, the drug-containing delayed-release tablet core (1) is located in the geometric center region of the tablet.

[0075] 10. Preferably, the tablet is characterized in that the drug refers to a sleep regulation drug, such as ramelteon.

[0076] In a typical tablet example of the present invention, the tablet core is pressed using a punch die with a diameter of 5 mm. Therefore, the theoretical diameter of the drug-containing tablet core without coating should be 5 mm. The whole tablet is pressed using a punch die with a diameter of 10 mm. Therefore, the theoretical diameter of the whole tablet without coating should be 10 mm. The tablet core is theoretically in the middle of the whole tablet. Therefore, theoretically, but there are some slight errors in reality. The vertical distance from the periphery of the tablet core to the periphery of the tablet within the range of 0.5 - 4.5 mm will not affect the final release curve.

[0077] Example 1 Preparation of tablets (the delayed-release tablet core is a rapid-release tablet)

[0078]

[0079]

[0080] The preparation method is as follows:

[0081] (1) Prepare a rapid-release composition. Weigh the sieved internal excipients (lactose, MCC, PVP / VA) according to the prescription amount. Add ramelteon and BHT to a certain amount of ethanol to make a solution, perform wet granulation, dry, add the sieved CCMC-Na and magnesium stearate, and mix evenly;

[0082] (2) Prepare a delayed-release composition. Weigh ramelteon according to the main drug prescription amount, weigh the sieved excipients according to the excipient formula, and mix them evenly by the equal increment method;

[0083] (3) Use the delayed-release preparation composition to press the tablet core, and perform gastric-soluble and enteric-coated;

[0084] (4) Use the rapid-release preparation composition as the outer shell and the delayed-release tablet core as the tablet core to press the coated tablet. Fill the rapid-release composition as the first layer into the middle mold; place the delayed-release tablet core on the first layer and perform pre-pressing (0.02 kN); fill the rapid-release composition again as the third layer and press into tablets with a main pressure of 20 kN.

[0085] The dissolution conditions are as follows: General Rules 0931, Method 2, paddle method, 50 rpm, 37 °C, 500 mL of pH 1.0 medium / pH 7.2 medium, and measure at 210 nm using UV ultraviolet spectrophotometry.

[0086] The dissolution test results are as Figure 2As shown, the immediate-release shell is released within 15 minutes; there is no drug release during the period from 15 minutes to 120 minutes, and the delayed-release tablet core is released within 30 minutes after the 120th minute.

[0087] Example 2 Preparation of Tablets (the delayed-release tablet core is sustained-release)

[0088]

[0089] The preparation method is as follows:

[0090] (1) Prepare the immediate-release composition. Weigh ramelteon and the sieved internal excipients (lactose, MCC, BHA) according to the prescription amount. Add PVP to a certain amount of water to make a binder, carry out wet granulation, dry, add the sieved cross-linked polyvinylpyrrolidone and magnesium stearate, and mix evenly;

[0091] (2) Prepare the delayed-release composition. Weigh ramelteon and the sieved internal excipients (calcium hydrogen phosphate, MCC, HPMC, BHA) according to the prescription amount. Add PVP to a certain amount of water to make a binder, carry out wet granulation, dry, add the sieved magnesium stearate, and mix evenly;

[0092] (3) Use the delayed-release preparation composition to press the tablet core, and carry out gastric-soluble and enteric coating;

[0093] (4) Use the immediate-release preparation composition as the shell and the delayed-release tablet core as the tablet core to press the coated tablet. Fill the middle mold with the immediate-release composition as the first layer; place the delayed-release tablet core on the first layer and carry out pre-pressing (0.04 kN); fill the immediate-release composition again as the third layer, and press into tablets with a main pressure of 25 kN.

[0094] The dissolution conditions are as follows: Method 2 of General Rules 0931 in Part IV of Chinese Pharmacopoeia 2015 Edition, paddle method at 50 rpm, 37 °C, 500 mL of pH 1.0 medium / pH 6.8 medium, and determine at 210 nm by UV-visible spectrophotometry.

[0095] The dissolution test results are as Figure 3 shown.

[0096] The immediate-release shell is released within 10 minutes; there is no drug release during the period from 15 minutes to 120 minutes, and the delayed-release tablet core starts to release the drug components after the 120th minute and continues until the 10th hour. Under this formulation, the proportion of the drug contained in the delayed-release tablet core is too high, and it is not easy for the taker to wake up later.

[0097] Example 3 Preparation of Tablets (the delayed-release tablet core is sustained-release)

[0098]

[0099]

[0100] The preparation method is as follows:

[0101] (1) Prepare the immediate-release composition. Weigh ramelteon according to the amount prescribed for the active ingredient, weigh the sieved excipients according to the excipient formula, and mix them thoroughly using the geometric dilution method;

[0102] (2) Prepare the delayed-release composition. Weigh ramelteon according to the amount prescribed in the formula, weigh the sieved excipients according to the excipient formula, and mix them thoroughly using the geometric dilution method;

[0103] (3) Use the delayed-release preparation composition to compress the tablet core, and perform gastric-soluble and enteric coating;

[0104] (4) Using the immediate-release preparation composition as the outer shell and the delayed-release tablet core as the tablet core, compress the coated tablet. Fill the middle mold with the immediate-release composition as the first layer; place the delayed-release tablet core on the first layer and perform pre-compression (0.02 kN); fill in the immediate-release composition again as the third layer, and compress into tablets with a main pressure of 17 kN.

[0105] The dissolution conditions are as follows: General Rules 0931, Method 2, paddle method, 50 rpm, 37 °C, 500 mL of pH 1.0 medium / pH 6.8 medium, and determine at 210 nm using UV-visible spectrophotometry.

[0106] The dissolution test results are as Figure 4 shown

[0107] The immediate-release outer shell is released within 10 minutes; there is no drug release during the period from 15 minutes to 120 minutes; the delayed-release tablet core starts to slowly release the drug component after 120 minutes and reaches 100% at the 5th hour, achieving an ideal release pattern.

[0108] Example 4 Preparation of tablets (the delayed-release tablet core is sustained-release)

[0109]

[0110] The preparation method is as follows:

[0111] (1) Prepare the immediate-release composition. Weigh the internal excipients (mannitol, MCC, PVP, VC, sodium carboxymethyl starch) after sieving according to the formula and mix them evenly. Dissolve ramelteon in a certain amount of ethanol to form a solution, perform wet granulation, dry, add the sieved sodium stearyl fumarate, and mix evenly;

[0112] (2) Prepare the delayed-release composition. Weigh ramelteon according to the amount prescribed for the active ingredient, weigh the sieved excipients according to the excipient formula, and mix them thoroughly using the geometric dilution method;

[0113] (3) using the delayed-release preparation composition to compress the tablet core, and then performing gastric and enteric coating;

[0114] (4) Using the immediate-release preparation composition as the outer shell and the delayed-release tablet core as the tablet core, a core is pressed and packaged, and the immediate-release composition is filled into the middle mold as the first layer; the delayed-release tablet core is placed on the first layer and pre-compressed with a pre-compression pressure (0.03 kN); the immediate-release composition is filled again as the third layer, and the main pressure is 20 kN to form a tablet.

[0115] The dissolution conditions are as follows: Chinese Pharmacopoeia 2015 edition Part IV General Rules 0931 Method 2, paddle method 50 rpm, 37° C., 500 mL of pH 1.0 medium / pH 7.2 medium, measured by UV spectrophotometry at 210 nm.

[0116] The dissolution test results are as follows Figure 5 As shown, the quick-release shell completes the release within 10 minutes; there is no drug release from 15 minutes to 120 minutes; the delayed-release core starts to release the drug ingredient after 120 minutes, and continues until 5.5 hours to reach 100% release, achieving a relatively ideal release pattern.

[0117] Test Example 1: Preload Pressure Test

[0118] During the research and development process, it was found that during the compression process of the tablet package: the pre-compression pressure affects the interface interaction and adhesion between the tablet core and the immediate-release shell, and also affects the integrity of the enteric coating film of the tablet core, thereby affecting the dissolution of the sample;

[0119] The prescription and preparation method of Example 4 were used to study the effect of different pre-pressures on the dissolution effect.

[0120] Different pre-compression pressures (0.02 kN, 0.5 kN, 1 kN, 2 kN) were used for pre-compression respectively; the quick-release composition was filled again as the third layer, and the main pressure was 20 kN to press into tablets.

[0121] The dissolution conditions are as follows: Chinese Pharmacopoeia 2015 edition Part IV General Rules 0931 Method 2, paddle method 50 rpm, 37°C, 500 mL of pH 1.0 medium / pH 6.8 medium, measured by UV spectrophotometry at 210 nm.

[0122] Figure 6 As shown, when the pre-compression pressure is 0.02, 0.5, and 1 kN, the tablet core is completely wrapped with enteric coating and is not released in acid for 4 hours. When the pre-compression pressure is greater than 1.5 kN, such as 2 kN, the tablet core is not completely wrapped with enteric coating and is damaged, and is released in acid.

[0123] Test Example 2: Main Pressure Test

[0124] During the R & D process, it was found that when the main pressure was within the range of 15 - 35 kN, the friability was qualified, and the enteric coating of the tablet core was completely wrapped, and no release occurred in acid within 4 h. Using the formulation and tablet-making process of Example 1, with the only difference being that the main pressure was set to 15, 20, 25, and 35 kN respectively, the effect of the main pressure on the dissolution effect was studied.

[0125] The dissolution conditions were as follows: Method 2 of General Chapter 0931, Volume IV, Chinese Pharmacopoeia 2015 Edition, paddle method at 50 rpm, 37 °C, 500 mL of pH 1.0 medium / pH 6.8 medium, and determined by UV ultraviolet spectrophotometry at 210 nm.

[0126] The test results were as Figure 7 shown that when tableting with a main pressure of 10 kN, the tablets cracked and the friability was unqualified. When the main pressure was greater than 35 kN (such as 35 kN), the enteric coating film of the tablet core cracked, resulting in the release of the active drug in the tablet core in acid.

[0127] Test Example 3 Comparison of Enteric Coating Materials

[0128] The effects of different enteric coating materials were compared.

[0129] Using the formulation process of Example 4, different enteric coating materials were investigated respectively.

[0130] Dissolution method: paddle method at 50 rpm, 37 °C, 500 mL of pH 5.0 medium, and determined by UV ultraviolet spectrophotometry at 210 nm.

[0131] The test results were as Figure 8 shown that when the coating materials were Opadry Enteric 94O680000 and 91O610002, the enteric coating film might have poor toughness or could not remain insoluble at pH 5.0. When the coating material was used such as Eudragit L100 - 55, whose main film-forming material was a copolymer of methacrylic acid and ethyl acrylate, an ideal release effect could be achieved.

[0132] Test Example 4 Comparison of Enteric Coating Weight Gain Thickness

[0133] Using the formulation of Example 1, the tablet-making effects of coating weight gains of 3%, 4%, 5%, 6%, 7%, 8%, and 10%, 12% were studied for comparison.

[0134] Comparing different enteric coating weight gain thicknesses, when the weight gain range was 4 - 12%, the dissolution was similar, and the second-stage release reached a plateau within 0.5 - 1 h, and the expected dissolution effect could be achieved.

[0135] The dissolution conditions are as follows: General Chapter 0931, Method 2, paddle method at 50 rpm, 37 °C, 500 mL of pH 1.0 medium / pH 6.8 medium, and measured at 210 nm by UV-visible spectrophotometry.

[0136] The results are as Figure 9 shown that the coating film is too thin to protect the tablet core from releasing in acid and cannot achieve the enteric coating effect; if the coating film is too thick, the production cost will increase.

[0137] Test Example 5 In vivo data

[0138] The sample (T) prepared in Example 1 was compared with the reference preparation (R) in a human trial, where the reference reagent (R) was ramelteon tablets Specification: 8 mg, batch number: HH2012, manufacturer: Takeda Pharmaceutical Company Limited, Japan, storage conditions: protected from light, sealed, stored below 25 °C.

[0139] A single-center, randomized, open-label, two-period, double-cross, single-dose administration trial design method was adopted. The dosing dose was 1 tablet per person, the washout period was 2 days, and 8 subjects completed the trial.

[0140] The test results are as Figure 10 shown that for the sample (T) of the present invention, the first release C max is less than that of the reference preparation (R), which can reduce the incidence of adverse reactions, and there is another release of the sample (T) of the present invention compared with the reference preparation (R) at about 5 h, which can effectively prevent early awakening.

Claims

1. A tablet that allows for the segmented release of sleep-regulating drugs, characterized in that, Structurally, each tablet from the inside out consists of a medicated sustained-release tablet core, a drug-free gastric-soluble coating, a drug-free enteric-soluble coating, a medicated immediate-release outer shell, and an outer shell coating in sequence; The segmented release means that: after the medicated immediate-release outer shell is completely released, after a lapse of 0.5 - 4 hours, the medicated sustained-release tablet core begins to release and is completely released within 0.1 - 6 hours; The tablet is prepared by the following steps: (1) Configure the materials for the medicated immediate-release outer shell: prepare the total mixed granules of the medicated immediate-release outer shell according to the formula; (2) Prepare the medicated sustained-release tablet core: prepare the total mixed granules of the medicated sustained-release tablet core, and obtain the tablet core by the pressing method; perform gastric-soluble coating and enteric-soluble coating on the tablet core in sequence to obtain the medicated sustained-release tablet core; (3) Fill a part of the materials for the medicated immediate-release outer shell into the middle mold as the first layer; Place the medicated sustained-release tablet core on the first layer as the second layer, and then perform pre-pressing; fill the remaining materials for the medicated immediate-release outer shell as the third layer, and perform tabletting; Among them, the pressure for pre-pressing is 0.02 - 1.5 kN, and the main pressure for tabletting is 15 - 35 kN; The film-forming materials used for the drug-free enteric-soluble coating material are selected from one or more of acrylic resin type I, type II, type III, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate (CAT), acrylic resin EuS100, EuL100, methyl methacrylate-methyl methacrylate copolymer, methyl methacrylate-ethyl acrylate copolymer; Among them, the drug-free enteric-soluble coating has a weight gain of 4% - 12% relative to the medicated sustained-release tablet core and is soluble under dissolution conditions of pH 5 or above.

2. The tablet according to claim 1, characterized in that, The film-forming material used for the drug-free enteric-soluble coating material is a copolymer of methacrylic acid and ethyl acrylate.

3. The tablet according to claim 1, characterized in that, Among them, the drug-free enteric-soluble coating has a weight gain of 5%, 6%, 7% or 8% relative to the medicated sustained-release tablet core and is soluble under dissolution conditions of pH 5 or above.

4. The tablet according to claim 1, characterized in that, The drug-free gastric-soluble coating has a weight gain of 2 - 5%, 3% or 4%.

5. The tablet according to claim 1, characterized in that, The content ratio of the active pharmaceutical ingredient in the medicated immediate-release outer shell to that in the medicated sustained-release tablet core is 1 - 3:

1.

6. The tablet according to claim 1, characterized in that, The medicated sustained-release tablet core is an immediate-release preparation. In the medicated sustained-release tablet core, the weight percentage contents of each excipient are respectively: Filler 60 - 90%; Disintegrant 2 - 10%; Binder 2 - 6%; Antioxidant 0.01 - 1%; Lubricant / glidant 0.5 - 3%; Among them, the filler and antioxidant are internal excipients, the lubricant / glidant is an external excipient, and the disintegrant can be an internal excipient or an external excipient.

7. The tablet according to claim 6, characterized in that, In the medicated sustained-release tablet core, the weight percentage contents of each excipient are respectively: Filler 60 - 90%; Disintegrant 4 - 8%; Binder 2.5 - 5%; Antioxidant 0.05 - 1%; Lubricant / glidant 0.5 - 1.5%.

8. The tablet according to claim 1, characterized in that, The medicated sustained-release tablet core is a sustained-release preparation. In the medicated sustained-release tablet core, the weight percentage contents of each excipient are respectively: Filler 60 - 90%; Binder 2 - 6%; Sustained-release material 4 - 25%; Antioxidant 0.01 - 1%; Lubricant / glidant 0.5 - 3%; Among them, the filler, binder, and antioxidant are internal excipients, and the lubricant / glidant is an external excipient.

9. The tablet according to claim 8, characterized in that, In the medicated delayed-release tablet core, the weight percentage contents of each excipient are as follows: Filler 60 - 90%; Binder 2.5 - 5%; Sustained-release material 5 - 20%; Antioxidant 0.05 - 1%; Lubricant / glidant 0.5 - 1.5%.

10. The tablet according to any one of claims 1-9, characterized in that, The weight ratio of the material of the medicated immediate-release shell to the material of the medicated delayed-release tablet core is ≥4.

11. The tablet according to any one of claims 1-9, characterized in that, The weight ratio of the material of the medicated immediate-release shell to the material of the medicated delayed-release tablet core is 4 - 12 or 350:

60.

12. The tablet according to any one of claims 6-9, characterized in that, The filler is selected from one or more of microcrystalline cellulose, lactose, pregelatinized starch, starch, calcium hydrogen phosphate, mannitol, and dextrin; The binder is selected from one or more of povidone, copovidone, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose; The disintegrant is selected from one or more of starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, crospovidone, and cross-linked sodium carboxymethyl cellulose; The sustained-release material is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, alginate, ethyl cellulose, vinyl acetate, xanthan gum, guar gum, crospovidone, and glyceryl behenate; The antioxidant is selected from one or more of vitamin E, p-hydroxyanisole, butylated hydroxyanisole, dibutylhydroxytoluene, sodium bisulfite, sodium metabisulfite, and vitamin C; The lubricant / glidant is selected from one or more of magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide, sodium lauryl sulfate, and talc.

13. The tablet according to any one of claims 1-12, characterized in that: The sleep-regulating drug refers to ramelteon.

14. The method for preparing the tablet according to any one of claims 1-13, characterized in that, Comprising the following steps: (1) Prepare the material of the medicated immediate-release shell: Prepare the total mixed granules of the medicated immediate-release shell according to the formula; (2) Prepare the medicated delayed-release tablet core: Prepare the total mixed granules of the medicated delayed-release tablet core, and obtain the tablet core by pressing method; The tablet core is sequentially coated with gastric-soluble coating and enteric coating to obtain the medicated delayed-release tablet core; (3) Fill a part of the material of the medicated immediate-release shell into the middle mold as the first layer; Place the medicated delayed-release tablet core on the first layer as the second layer, and then perform pre-pressing; Fill the remaining material of the medicated immediate-release shell as the third layer, and perform tabletting; The pressure for pre-pressing is 0.02 - 1.5 kN, and the main pressure for tabletting is 15 - 35 kN.

15. The preparation method according to claim 14, characterized in that, The following any one method is adopted to prepare the total mixed granules of the medicated delayed-release tablet core and the total mixed granules of the medicated immediate-release shell: Method 1: Weigh the active ingredient and various internal excipients after sieving according to the prescription amount. Add the active ingredient and antioxidant to a certain amount of solvent to make a solution or suspension, and spray it into the remaining internal excipients to complete wet granulation. After drying, add the external excipient and mix evenly to obtain the corresponding total mixed granules; Method 2: Weigh the active ingredient and various internal excipients after sieving according to the prescription amount; Add the active ingredient to a certain amount of solvent to make a solution or suspension, and spray it into the internal excipients to complete wet granulation. After drying, add the external excipient and mix evenly to obtain the corresponding total mixed granules; Method 3: Weigh the active pharmaceutical ingredient and various internal excipients after sieving according to the prescription amount. Add the antioxidant or binder to a certain amount of solvent to prepare a solution or suspension, and spray it into the mixed material of the active pharmaceutical ingredient and the remaining internal excipients to complete wet granulation. After drying, add the external excipients and mix evenly to obtain the corresponding total mixed granules. Method 4: Weigh the active pharmaceutical ingredient and various excipients after sieving according to the prescription amount, and mix the active pharmaceutical ingredient and excipients evenly by the equal increment method to obtain the corresponding total mixed granules.

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