Tablets that allow for the fractional release of sleep-regulating drugs and their preparation methods

Abstract

This invention, "a tablet that allows for the segmented release of sleep-regulating drugs and its preparation method," belongs to pharmaceutical technology. Its key feature is that each tablet, from the inside out, consists of a drug-containing delayed-release core, a drug-free gastric-coating coating, a drug-free enteric-coating coating, a drug-containing immediate-release outer shell, and an outer gastric-coating coating. This enables an ideal two-stage timed drug release mode, making it particularly suitable for sleep-regulating drugs such as rameltemid.

Description

[0001] This case is a divisional application of the Chinese invention patent application with application number 202110950477.6 and application date of 2021-08-18. Technical Field

[0002] This invention relates to pharmaceutical technology, and in particular to a tablet that allows for the fractional release of sleep-regulating drugs and a method for preparing the same. Background Technology

[0003] Some medications, such as sleep regulators, need to be released quickly and take effect rapidly after being ingested by the patient. However, this can lead to drastic fluctuations in blood drug concentration, resulting in a high rate of adverse reactions. Therefore, it is necessary to develop formulation technologies that can make the blood drug concentration of these drugs more stable, delay the onset of drug efficacy, and reduce the rate of adverse reactions.

[0004] Ramelteon Meretamide (Ramette) is an oral hypnotic drug developed by Takeda Pharmaceutical Company of Japan and approved by the US FDA on July 22, 2005. It was the first melatonin receptor agonist used clinically to treat insomnia, primarily for difficulty falling asleep, and also shows efficacy for chronic and short-term insomnia. Meretamide is the first prescription insomnia treatment with a novel mechanism of action in nearly 35 years.

[0005] Most commonly used sleeping pills work by broadly inhibiting neural activity in the brain. Ramelteon, however, has a unique pharmacological mechanism: it selectively acts on two receptors in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is known as the "biological clock," regulating the body's 24-hour circadian rhythm, including the sleep-wake cycle. Research shows that this drug does not cause overuse, withdrawal symptoms, drug dependence, or "hangover" (a lingering effect the following day). Phase III clinical trials showed that Ramelteon effectively shortens the time it takes for patients to fall asleep, increases total sleep time, improves sleep efficiency, and has minimal negative impact on work and study the next day, with a low relapse rate after discontinuation. In one study, 472 patients took the drug once daily for up to one year. Recent clinical studies indicate that this drug is safe for elderly patients, patients with mild to moderate obstructive pulmonary disease (COPD), and patients with mild to moderate sleep apnea.

[0006] Most ramelteamide formulations on the market are immediate-release formulations, releasing the drug in a single dose for rapid onset and to help patients fall asleep quickly; however, they do not prevent early awakening and may result in lower blood drug concentrations. max Larger sizes can increase the incidence of adverse reactions.

[0007] While some literature describes sleep-regulating drugs with a dual-release mechanism, their formulations typically involve making the drug into immediate-release and delayed-release microspheres, which are then mixed into capsules or compressed with a filler into tablets. The two microspheres achieve dual-release based on their different solubility properties; for example, CN00809487 describes a "timed dual-release dosage form containing a short-acting hypnotic agent or its salt." However, tablets made by first forming microspheres and then compressing them with a filler are prone to uneven mixing due to particle size differences. This can lead to stratification during compression and the possibility of microsphere breakage, affecting the final release and making it difficult to achieve the ideal dual-release mechanism. Therefore, it is necessary to develop new tablet and tablet manufacturing technologies. Summary of the Invention

[0008] Based on the problems that urgently need to be solved in the above-mentioned fields, the present invention provides a tablet that allows for two-stage drug release and a method for preparing the same, achieving an ideal two-stage timed drug release mode, which is especially suitable for sleep-regulating drugs, such as rameltemid.

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

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

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

[0012] Preferably, the tablet is characterized in that it further comprises a drug-free gastric coating between the drug-containing delayed-release tablet core and the drug-free enteric coating, wherein the drug-free gastric 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 in the drug-free enteric coating is selected from one or more of the following: acrylic resins I, II, and III; cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); cellulose acetate triterpenoid (CAT); acrylic resins EuS100 and EuL100; methacrylic acid-methyl methacrylate copolymer; and methacrylic acid-ethyl acrylate copolymer. Preferably, the film-forming material used is a copolymer of methacrylic acid and ethyl acrylate.

[0014] Preferably, the tablet is characterized in that the ratio of the active pharmaceutical ingredient in the immediate-release outer shell to the 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 formulation; in the drug-containing delayed-release tablet core, the weight percentage content of each excipient is as follows: 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 / flow aid 0.5-3%, preferably 0.5-1.5%, wherein the filler and antioxidant are internal excipients, the lubricant / flow aid is an external excipient, and the disintegrant can be either an internal or external excipient.

[0016] Preferably, the tablet is characterized in that the drug-containing delayed-release tablet core is a sustained-release formulation; in the drug-containing delayed-release tablet core, the weight percentage content of each excipient is as follows: 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 / flow aid 0.5-3%, preferably 0.5-1.5%; wherein the filler, binder, and antioxidant are internal excipients, and the lubricant / flow aid is an external excipient.

[0017] Preferably, the tablet is characterized in that the weight ratio of the drug-containing immediate-release outer shell to 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 coating on the outer shell increases the weight by 2-5%, preferably 3%.

[0019] The filler is selected from one or more of the following: microcrystalline cellulose, lactose, pregelatinized starch, starch, dicalcium phosphate, mannitol, dextrin, etc.

[0020] The adhesive 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, crospovidone 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, and glyceryl behenate.

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

[0024] The lubricant / flow aid is selected from one or more of magnesium stearate, sodium stearate fumarate, colloidal silica, sodium dodecyl sulfate, talc, etc.

[0025] Preferably, the tablet is characterized by being prepared by the following steps:

[0026] (1) Materials for preparing the drug-containing immediate-release shell: according to the total mixed granules for preparing the drug-containing immediate-release shell;

[0027] (2) Preparation of drug-containing delayed-release tablet cores: Prepare a total mixed granule of drug-containing delayed-release tablet cores, and obtain tablet cores by compression; the tablet cores are then subjected to gastric coating and enteric coating to obtain drug-containing delayed-release tablet cores.

[0028] (3) A portion of the material containing the drug-releasing shell is filled into the middle mold as the first layer; the drug-releasing tablet core is placed on the first layer as the second layer, and then pre-compressed; the remaining material containing the drug-releasing shell is filled into the third layer and then compressed into tablets.

[0029] Preferably, the tablet is characterized in that: the pre-compression pressure is 0.02-1.5kN, and the main pressure used for compressing into tablets is 15-35kN.

[0030] Preferably, the tablet described above is characterized in that the sleep-regulating drug refers to ramelteamide.

[0031] The method for preparing any of the above tablets is characterized by comprising the following steps:

[0032] (1) Materials for preparing the drug-containing immediate-release shell: according to the total mixed granules for preparing the drug-containing immediate-release shell;

[0033] (2) Preparation of drug-containing delayed-release tablet cores: Prepare a total mixed granule of drug-containing delayed-release tablet cores, and obtain tablet cores by compression; the tablet cores are then subjected to gastric coating and enteric coating to obtain drug-containing delayed-release tablet cores.

[0034] (3) A portion of the material containing the drug-releasing shell is filled into the middle mold as the first layer; the drug-releasing tablet core is placed on the first layer as the second layer, and then pre-compressed; the remaining material containing the drug-releasing shell is filled into the third layer and then compressed into tablets.

[0035] Preferably, the preparation method is characterized in that: the pre-compression pressure is 0.02-1.5kN, and the main pressure used for compressing into sheets is 15-35kN.

[0036] The following methods can be used to prepare both the drug-containing delayed-release tablet core mixed granules and the drug-containing immediate-release shell mixed granules:

[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 to a certain amount of solvent to make a solution or suspension. Spray the solution or suspension into the remaining internal excipients to complete wet granulation. After drying, add 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 to a certain amount of solvent to make a solution or suspension, spray it into the internal excipients to complete wet granulation, dry it, add external excipients, mix evenly, and 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 to a certain amount of solvent to make a solution or suspension. Spray the solution or suspension into the mixture of active pharmaceutical ingredient and other internal excipients to complete wet granulation. After drying, add external excipients and mix evenly to obtain the corresponding total mixed granules.

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

[0041] This invention, through research on several dimensions including tablet structure, formulation, and manufacturing process, yields a tablet formulation and preparation process that allows for the segmented release of active pharmaceutical ingredients, making it particularly suitable for sleep-regulating drugs. This fills a gap in existing technologies regarding such tablets.

[0042] The tablets provided by this invention, in their dissolution test, yielded the following results: Figure 2 As shown in Figures 4 and 5, the drug-containing immediate-release outer shell completes the release within 10-30 minutes. Due to the protection of the drug-free enteric coating, no drug is released for a period of time afterward, such as 1.5-4 hours. Only then does the second-stage drug-containing delayed-release tablet core begin to release the drug, achieving a relatively ideal dual-stage release mode. When applied to sleep regulation drugs, it can take effect quickly after taking the medication to help people fall asleep quickly. After a period of time, the second-stage release is initiated to prevent early awakening and increase the total sleep time.

[0043] To obtain tablets that achieve the above-mentioned release mode, the present invention performs drug-free gastric coating and drug-free enteric coating on the drug-containing delayed-release tablet core in the tablet structure. During the research and development experiments of the present invention, it was found that because the enteric coating process requires a long time, the tablet core may be easily broken during the enteric coating process. Therefore, it is preferable to perform gastric coating before enteric coating to protect the tablet core. In the enteric environment, gastric coating does not delay the release of the tablet core.

[0044] In addition, this invention investigated the effect of enteric coating weight gain thickness on the release mode and found that if the enteric coating film is too thin, it cannot prevent the tablet core from being released 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 tablet core. The ideal enteric coating weight gain range was found to be 4-12%.

[0045] The research of this invention also found that some enteric coating materials are prone to breakage or gaps during tableting due to unsuitable toughness, leading to premature release of the delayed-release tablet core. Alternatively, some enteric coating materials have unsuitable film-forming materials, only ensuring insolubility below pH 4.0; for example... Figure 7 As shown, when the coating materials are Opadry enteric 94O680000 and 91O610002, the tablet core is released in a pH 5.0 environment, and 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 from the following group: acrylic resins I, II, and III, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl phthalate (PVAP), cellulose acetate triterpenoid (CAT), acrylic resins EuS100 and EuL100, methacrylic acid and methyl methacrylate copolymers, methacrylic acid and ethyl acrylate copolymers, etc., preferably methacrylic acid and ethyl acrylate copolymers; for example, when Eutec L100-55 is selected, the tablets prepared can achieve the ideal release effect.

[0047] The study of this invention also found that some parameters in the preparation process affect the yield of the tablets of this invention and whether the tablets achieve the target release mode, thereby affecting the practicality / promotability of the technology of this invention. For example, the pre-compression pressure and the main pressure of tableting in step (3) of the preparation method: when the pre-compression pressure is greater than 1.5kN, such as 2kN, most of the enteric coating of the tablet core is damaged, and the tablet core of the resulting tablet is released in acid. However, when the pre-compression pressure is between 0.02-1.5kN, the enteric coating of the tablet core is intact and is not released in acid for 4 hours, which helps to obtain the ideal release mode. When the main pressure is lower than 15kN, such as 10kN, the tablets are softer and easier to break, and the brittleness is not up to standard. When the main pressure is greater than 35kN, the tablets will crack at the top, and the enteric coating film of the tablet core will rupture, resulting in the release of the active drug in the tablet core in acid. The experiment showed that when the main pressure was in the range of 15-35kN, the brittleness was qualified, and the enteric coating of the tablet core was intact and did not release after 4 hours in acid.

[0048] When the active pharmaceutical ingredient is a sleep-regulating drug, this invention, through experimentation, has found that a drug-containing immediate-release shell to a drug-containing delayed-release core with a content ratio of 1-3:1 can achieve an ideal blood concentration. If the drug proportion in the delayed-release core is too high, it can lead to difficulty waking up later in the sleep cycle. If the drug proportion in the delayed-release core is too low and the proportion in the immediate-release shell is too high, it can lead to a rapid and excessively high blood drug concentration, followed by low blood drug concentration and excessive fluctuations in blood drug concentration later in the cycle. Attached Figure Description

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

[0050] Among them, 1-drug-containing delayed-release tablet core, 2-drug-free gastric-coated coating, 3-drug-free enteric-coated coating, 4-drug-containing immediate-release outer shell, and 5-outer shell gastric-coated coating.

[0051] Figure 2 Results of the tablet dissolution experiment obtained in Example 1;

[0052] Figure 3 Results of the tablet dissolution experiment obtained in Example 1;

[0053] Figure 3 The dissolution test results of the tablets obtained in Example 2;

[0054] Figure 4 The dissolution test results of the tablets obtained in Example 3;

[0055] Figure 5 The dissolution test results of the tablets obtained in Example 4;

[0056] Figure 6 The effect of pre-pressurization pressure on the tablet drug release model in the tablet preparation process of this invention;

[0057] Figure 7 The effect of main pressure on the tablet drug release model in the tablet preparation process of this invention;

[0058] Figure 8 The effect of enteric coating materials on the drug release model of the tablets of this invention;

[0059] Figure 9 The effect of the weight gain of the enteric coating material on the drug release model of the tablets of this invention;

[0060] Figure 10 Comparison of in vivo release data between the tablets of this invention and the reference formulation. Detailed Implementation

[0061] To make the objectives, technical solutions, and advantages of this application clearer, the technical solutions in the embodiments of this application will be described in more detail below with reference to the accompanying drawings.

[0062] like Figure 1 As shown,

[0063] 1. A tablet that allows for the fractional release of a drug, characterized in that it comprises, from the inside out, 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 gastrointestinal coating (5).

[0064] 2. Preferably, the tablet is characterized in that it further comprises a drug-free gastric 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 ≥2mm.

[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 2 and 6 mm, or 3 and 7 mm, or 4 and 8 mm.

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

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

[0073] 9. Preferably, the tablet is characterized in that, in the longitudinal cross-sectional direction of the tablet, the drug-containing delayed-release tablet core (1) is located in the geometric center region within 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 is a sleep-regulating drug, such as ramelteamide.

[0076] In a typical tablet example of this invention, the tablet core is pressed using a 5mm diameter die, so the theoretical diameter of the uncoated tablet core should be 5mm. The entire tablet is pressed using a 10mm diameter die, so the theoretical diameter of the uncoated tablet should be 10mm. The tablet core is theoretically located in the center of the entire tablet, so there may be slight errors in practice. The vertical distance between the outer edge of the tablet core and the outer edge of the tablet, ranging from 0.5 to 4.5mm, will not affect the final release curve.

[0077] Example 1: Preparation of tablets (delayed-release tablet core is immediate-release)

[0078]

[0079]

[0080] The preparation method is as follows:

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

[0082] (2) Prepare the delayed-release composition. Weigh ramelteamide according to the prescription amount of the active drug and weigh the sieved excipients according to the excipient formula. Mix them thoroughly and evenly according to the equal addition method.

[0083] (3) Press tablet cores using a delayed-release formulation composition and perform gastric and enteric coating;

[0084] (4) Using the immediate-release formulation composition as the outer shell and the delayed-release tablet core as the core, press the tablet into a chip. Fill the middle mold with the immediate-release composition as the first layer; place the delayed-release tablet core on the first layer and pre-compress (0.02kN); fill the third layer with the immediate-release composition again and compress into a tablet with a main pressure of 20kN.

[0085] Dissolution conditions were as follows: Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II, paddle method, 50 rpm, 37℃, 500 mL of pH 1.0 / pH 7.2 medium, and determined by UV spectrophotometry at 210 nm.

[0086] Dissolution test results are as follows Figure 2As shown, the immediate-release capsule completes release within 15 minutes; no drug is released between 15 minutes and 120 minutes, while the delayed-release capsule completes release within 30 minutes after 120 minutes.

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

[0088]

[0089] The preparation method is as follows:

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

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

[0092] (3) Press tablet cores using a delayed-release formulation composition and perform gastric and enteric coating;

[0093] (4) Using the immediate-release formulation composition as the outer shell and the delayed-release tablet core as the core, press the tablet into a chip. Fill the middle mold with the immediate-release composition as the first layer; place the delayed-release tablet core on the first layer and pre-compress (0.04kN); fill the third layer with the immediate-release composition again and compress it into a tablet with a main pressure of 25kN.

[0094] Dissolution conditions were as follows: Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II, paddle method, 50 rpm, 37℃, 500 mL of pH 1.0 / pH 6.8 medium, and determined by UV spectrophotometry at 210 nm.

[0095] Dissolution test results are as follows Figure 3 As shown.

[0096] The immediate-release capsule releases the drug within 10 minutes; no drug is released between 15 and 120 minutes later. The delayed-release core begins to release the drug after 120 minutes, continuing until the 10th hour. With this formulation, the delayed-release core contains a high proportion of drug, making it difficult for the user to wake up later in the course of the medication process.

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

[0098]

[0099]

[0100] The preparation method is as follows:

[0101] (1) Prepare the immediate-release composition. Weigh ramelteamide according to the prescription amount of the active drug and weigh the sieved excipients according to the excipient formula. Mix them thoroughly and evenly according to the equal addition method.

[0102] (2) Prepare the delayed-release composition. Weigh ramelteamide according to the prescription amount and weigh the sieved excipients according to the excipient formula. Mix them thoroughly and evenly according to the equal addition method.

[0103] (3) Press tablet cores using a delayed-release formulation composition and perform gastric and enteric coating;

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

[0105] Dissolution conditions were as follows: Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II, paddle method, 50 rpm, 37℃, 500 mL of pH 1.0 / pH 6.8 medium, and determined by UV spectrophotometry at 210 nm.

[0106] Dissolution test results are as follows Figure 4 As shown

[0107] The immediate-release capsule releases the drug completely within 10 minutes; no drug is released between 15 and 120 minutes; the delayed-release capsule begins to release the drug after 120 minutes, continuing until 100% release by the 5th hour, achieving the ideal release pattern.

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

[0109]

[0110] The preparation method is as follows:

[0111] (1) Prepare an immediate-release composition. Weigh out the sieved internal excipients (mannitol, MCC, PVP, VC, sodium carboxymethyl starch) according to the prescription amount and mix them evenly. Add rameltein to a certain amount of ethanol to make a solution. Perform wet granulation, dry, add sieved sodium stearate, and mix evenly.

[0112] (2) Prepare the delayed-release composition. Weigh ramelteamide according to the prescription amount of the active drug and weigh the sieved excipients according to the excipient formula. Mix them thoroughly and evenly according to the equal addition method.

[0113] (3) Press tablet cores using a delayed-release formulation composition and perform gastric and enteric coating;

[0114] (4) Using the immediate-release formulation composition as the outer shell and the delayed-release tablet core as the core, press the tablet into a chip. Fill the middle mold with the immediate-release composition as the first layer; place the delayed-release tablet core on the first layer and pre-compress it with a pre-compression pressure (0.03kN); fill the third layer with the immediate-release composition again and compress it into a tablet with a main pressure of 20kN.

[0115] Dissolution conditions were as follows: Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II, paddle method, 50 rpm, 37℃, 500 mL of pH 1.0 / pH 7.2 medium, and determined by UV spectrophotometry at 210 nm.

[0116] Dissolution test results are as follows Figure 5 As shown, the immediate-release capsule completes release within 10 minutes; no drug is released between 15 and 120 minutes; the delayed-release tablet core begins to release the drug component after 120 minutes, and reaches 100% release by 5.5 hours, achieving a relatively ideal release pattern.

[0117] Test Example 1: Preload Pressure Examination

[0118] During the research and development process, it was found that during the pressing and coating process, the pre-compression pressure affects the interfacial interaction and adhesion between the core and the immediate-release shell, and also affects the integrity of the enteric coating film of the core, thus affecting the dissolution of the sample.

[0119] Using the formulation and preparation method of Example 4, the effect of different pre-pressures on the dissolution effect was studied.

[0120] Pre-compression was performed using different pre-compression pressures (0.02kN, 0.5kN, 1kN, 2kN); then the immediate-release composition was filled in as a third layer, and the tablets were compressed under a main pressure of 20kN.

[0121] Dissolution conditions were as follows: Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II, paddle method, 50 rpm, 37℃, 500 mL of pH 1.0 / pH 6.8 medium, and determined by UV spectrophotometry at 210 nm.

[0122] Figure 6 As shown, when the pre-compression pressure is 0.02, 0.5, or 1 kN, the enteric coating of the tablet core is intact and does not release after 4 hours in acid. When the pressure is greater than 1.5 kN, such as 2 kN, the enteric coating of the tablet core is incomplete or damaged and releases in acid.

[0123] Test Example 2: Main Pressure Examination

[0124] During the research and development process, it was found that when the main pressure was within the range of 15-35 kN, the brittleness was acceptable, and the enteric coating of the tablet core remained intact, without release after 4 hours in acid. Using the formulation and tableting process of Example 1, with the only difference being that the main pressure was set to 15, 20, 25, and 35 kN, the effect of the main pressure on the dissolution effect was studied.

[0125] Dissolution conditions were as follows: Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II, paddle method, 50 rpm, 37℃, 500 mL of pH 1.0 / pH 6.8 medium, and determined by UV spectrophotometry at 210 nm.

[0126] The test results are as follows Figure 7 The results showed that when tablets were compressed with a main pressure of 10 kN, the tablets cracked, failing the brittleness test. When the main pressure exceeded 35 kN (e.g., 35 kN), the enteric coating of the tablet core ruptured, causing the active drug inside the tablet core to be released into the acid.

[0127] Comparison of enteric coating materials in Experiment Example 3

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

[0129] Different enteric coating materials were investigated using the formulation process of Example 4.

[0130] Dissolution method: Paddle method at 50 rpm, 37℃, 500 mL of pH 5.0 medium, and UV spectrophotometry at 210 nm.

[0131] The test results are as follows Figure 8 The results show that when the coating materials are Opadry enteric 94O680000 and 91O610002, the enteric coating film may have poor toughness or fail to remain insoluble at pH 5.0. However, when the coating material is such as Utec L100-55, whose main film-forming material is a copolymer of methacrylic acid and ethyl acrylate, ideal release effects can be achieved.

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

[0133] The formulation of Example 1 was used to compare the tableting effects of coating weight gain of 3%, 4%, 5%, 6%, 7%, 8%, 10%, and 12%.

[0134] Comparing the weight gain thickness of different enteric coatings, when the weight gain range is 4-12%, the dissolution is similar, and the second-stage release reaches a plateau within 0.5-1 hour, achieving the expected dissolution effect.

[0135] Dissolution conditions were as follows: Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II, paddle method, 50 rpm, 37℃, 500 mL of pH 1.0 / pH 6.8 medium, and determined by UV spectrophotometry at 210 nm.

[0136] The results are as follows Figure 9 The results showed that if the coating film was too thin, it would not be able to protect the tablet core from release in acid and would not achieve the enteric coating effect; if the coating film was too thick, the tablet production cost would increase.

[0137] In vivo data from Experimental Example 5

[0138] The sample (T) prepared in Example 1 was compared with the reference preparation (R) in a human trial, wherein the reference preparation (R) was rameltemosiderin tablets. Specification: 8mg, Batch No.: HH2012, Manufacturer: Takeda Pharmaceutical Co., Ltd., Japan, Storage conditions: Protect from light, seal tightly, store below 25℃.

[0139] A single-center, randomized, open-label, two-period, double-crossover, single-dose trial design was employed. The dosage was 1 tablet per person, with a 2-day washout period, and 8 subjects completed the trial.

[0140] The test results are as follows Figure 10 The sample (T) of this invention shows that it first releases C. max The sample (T) of this invention releases more than the reference formulation (R) after approximately 5 hours, which can effectively prevent premature awakening.

Claims

1. A tablet that allows for the fractional release of sleep-regulating drugs to treat insomnia, characterized in that, Structurally, each tablet consists of, from the inside out, a drug-containing delayed-release core, a drug-free gastric-coating coating, a drug-free enteric-coating coating, a drug-containing immediate-release outer shell, and an outer shell coating. The segmented release refers to the following: after the immediate-release drug-containing outer shell has completely released its contents, the delayed-release drug-containing tablet core begins to release its contents 0.5-4 hours later and is completely released within 0.1-6 hours. The tablets are prepared using the following steps: (1) Material for preparing the drug-containing immediate-release shell: Prepare total mixed particles containing the drug-containing immediate-release shell according to the formula; (2) Preparation of drug-containing delayed-release tablet cores: Prepare total mixed granules containing drug-containing delayed-release tablet cores, and obtain tablet cores by compression method; the tablet cores are subjected to gastric coating and enteric coating in sequence to obtain drug-containing delayed-release tablet cores; (3) Fill a portion of the material containing the drug-releasing shell into the middle mold as the first layer; place the drug-releasing tablet core prepared in step (2) on the first layer as the second layer, and then pre-press it; fill the remaining material containing the drug-releasing shell as the third layer, and press it into a tablet; The pre-compression pressure is 0.02-1.5kN, and the main pressure used for compressing into sheets is greater than 15kN but not greater than or equal to 35kN; The drug-free enteric coating material uses a film-forming material selected from acrylic resins I, II, and III; cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); cellulose acetate triterpenoid (CAT); acrylic resins EuS100 and EuL100; methacrylic acid-methyl methacrylate copolymer; and methacrylic acid-ethyl acrylate copolymer. The non-drug enteric coating is 4%-12% heavier than the drug-containing delayed-release tablet core, and it is soluble under dissolution conditions above pH 5; The treatment of insomnia refers to treating insomnia caused by difficulty falling asleep and early awakening, thereby increasing total sleep time; wherein the rapid release of the drug-containing fast-release shell is used to treat difficulty falling asleep, and the drug-containing delayed-release tablet core is used to treat early awakening symptoms.

2. A tablet that allows for the fractional release of sleep-regulating drugs to treat insomnia, characterized in that, Structurally, each tablet consists of, from the inside out, a drug-containing delayed-release core, a drug-free gastric-coating coating, a drug-free enteric-coating coating, a drug-containing immediate-release outer shell, and an outer shell coating. The tablets are prepared using the following steps: (1) Material for preparing the drug-containing immediate-release shell: Prepare total mixed particles containing the drug-containing immediate-release shell according to the formula; (2) Preparation of drug-containing delayed-release tablet cores: Prepare total mixed granules containing drug-containing delayed-release tablet cores, and obtain tablet cores by compression method; the tablet cores are subjected to gastric coating and enteric coating in sequence to obtain drug-containing delayed-release tablet cores; (3) Fill a portion of the material containing the drug-releasing shell into the middle mold as the first layer; place the drug-releasing tablet core prepared in step (2) on the first layer as the second layer, and then pre-press it; fill the remaining material containing the drug-releasing shell as the third layer, and press it into a tablet; The pre-compression pressure is 0.02-1.5kN, and the main pressure used for compressing into sheets is greater than 15kN but not greater than or equal to 35kN; The drug-free enteric coating material uses a film-forming material selected from acrylic resins I, II, and III; cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); cellulose acetate triterpenoid (CAT); acrylic resins EuS100 and EuL100; methacrylic acid-methyl methacrylate copolymer; and methacrylic acid-ethyl acrylate copolymer. The non-drug enteric coating is 4%-12% heavier than the drug-containing delayed-release tablet core, and it is soluble under dissolution conditions above pH 5; The segmented release in vitro is characterized as follows: under in vitro dissolution test conditions, the immediate-release outer shell containing the drug completes release within 10 to 15 minutes; no drug is released between 15 minutes and 120 minutes; the delayed-release tablet core begins to release the drug component after 120 minutes, reaching 100% release within 5 to 5.5 hours. The in vitro dissolution test conditions refer to: Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II: Paddle method, 50 rpm, 37ºC, 500 mL of pH 1.0 / pH 6.8 medium, determined by UV spectrophotometry at 210 nm. The treatment of insomnia refers to treating insomnia caused by difficulty falling asleep and early awakening, thereby increasing total sleep time; wherein the rapid release of the drug-containing fast-release shell is used to treat difficulty falling asleep, and the drug-containing delayed-release tablet core is used to treat early awakening symptoms.

3. A tablet that allows for the fractional release of sleep-regulating drugs to treat insomnia, characterized in that, Structurally, each tablet consists of, from the inside out, a drug-containing delayed-release core, a drug-free gastric-coating coating, a drug-free enteric-coating coating, a drug-containing immediate-release outer shell, and an outer shell coating. The tablets are prepared using the following steps: (1) Material for preparing the drug-containing immediate-release shell: Prepare total mixed particles containing the drug-containing immediate-release shell according to the formula; (2) Preparation of drug-containing delayed-release tablet cores: Prepare total mixed granules containing drug-containing delayed-release tablet cores, and obtain tablet cores by compression method; the tablet cores are subjected to gastric coating and enteric coating in sequence to obtain drug-containing delayed-release tablet cores; (3) Fill a portion of the material containing the drug-releasing shell into the middle mold as the first layer; place the drug-releasing tablet core prepared in step (2) on the first layer as the second layer, and then pre-press it; fill the remaining material containing the drug-releasing shell as the third layer, and press it into a tablet; The pre-compression pressure is 0.02-1.5kN, and the main pressure used for compressing into sheets is greater than 15kN but not greater than or equal to 35kN; The drug-free enteric coating material uses a film-forming material selected from acrylic resins I, II, and III; cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); cellulose acetate triterpenoid (CAT); acrylic resins EuS100 and EuL100; methacrylic acid-methyl methacrylate copolymer; and methacrylic acid-ethyl acrylate copolymer. The non-drug enteric coating is 4%-12% heavier than the drug-containing delayed-release tablet core, and it is soluble under dissolution conditions above pH 5; The segmented release in vitro is characterized by the following: under in vitro dissolution test conditions, the immediate-release drug-containing outer shell completes release within 10-15 minutes; no drug is released between 15 minutes and 120 minutes; and the delayed-release drug-containing tablet core completes release within 30 minutes after 120 minutes. The in vitro dissolution test conditions refer to: Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II: Paddle method, 50 rpm, 37ºC, 500 mL of pH 1.0 / pH 6.8 medium, determined by UV spectrophotometry at 210 nm. The treatment of insomnia refers to treating insomnia caused by difficulty falling asleep and early awakening, thereby increasing total sleep time; wherein the rapid release of the drug-containing fast-release shell is used to treat difficulty falling asleep, and the drug-containing delayed-release tablet core is used to treat early awakening symptoms.

4. A tablet that allows for the fractional release of sleep-regulating drugs to treat insomnia, characterized in that, Structurally, each tablet consists of, from the inside out, a drug-containing delayed-release core, a drug-free gastric-coating coating, a drug-free enteric-coating coating, a drug-containing immediate-release outer shell, and an outer shell coating. The tablets are prepared using the following steps: (1) Material for preparing the drug-containing immediate-release shell: Prepare total mixed particles containing the drug-containing immediate-release shell according to the formula; (2) Preparation of drug-containing delayed-release tablet cores: Prepare total mixed granules containing drug-containing delayed-release tablet cores, and obtain tablet cores by compression method; the tablet cores are subjected to gastric coating and enteric coating in sequence to obtain drug-containing delayed-release tablet cores; (3) Fill a portion of the material containing the drug-releasing shell into the middle mold as the first layer; place the drug-releasing tablet core prepared in step (2) on the first layer as the second layer, and then pre-press it; fill the remaining material containing the drug-releasing shell as the third layer, and press it into a tablet; The pre-compression pressure is 0.02-1.5kN, and the main pressure used for compressing into sheets is greater than 15kN but not greater than or equal to 35kN; The drug-free enteric coating material uses a film-forming material selected from acrylic resins I, II, and III; cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); cellulose acetate triterpenoid (CAT); acrylic resins EuS100 and EuL100; methacrylic acid-methyl methacrylate copolymer; and methacrylic acid-ethyl acrylate copolymer. The non-drug enteric coating is 4%-12% heavier than the drug-containing delayed-release tablet core, and it is soluble under dissolution conditions above pH 5; The treatment of insomnia refers to treating insomnia caused by difficulty falling asleep and early awakening, thereby increasing total sleep time; The rapid release of the drug-containing fast-release outer shell is used to treat difficulty falling asleep, while the drug-containing delayed-release core is used to treat early awakening symptoms. The plasma drug concentration data generated after it was administered to subjects at a daily dose showed a biphasic pattern of two releases. A peak value occurs 10-15 minutes after administration; a second peak value occurs 5-5.5 hours after administration.

5. The tablet according to any one of claims 1 to 4, characterized in that, The drug-free enteric coating material uses a copolymer of methacrylic acid and ethyl acrylate as the film-forming material.

6. The tablet according to any one of claims 1 to 4, characterized in that, The non-drug enteric coating increases the weight of the drug-containing delayed-release tablet core by 5%, 6%, 7%, or 8%, and is soluble under dissolution conditions above pH 5.

7. The tablet according to any one of claims 1 to 4, characterized in that, The non-drug-containing gastric coating increases weight by 2-5%.

8. The tablet according to any one of claims 1 to 4, characterized in that, The non-drug-containing gastric coating increased in weight by 3%.

9. The tablet according to any one of claims 1 to 4, characterized in that, The non-drug-containing gastric coating increased in weight by 4%.

10. The tablet according to any one of claims 1 to 4, characterized in that, The ratio of the active pharmaceutical ingredient content in the immediate-release outer shell to that in the delayed-release tablet core is 1-3:

1.

11. The tablet according to claim 3, characterized in that, The drug-containing delayed-release tablet core is an immediate-release formulation. The weight percentage content of each excipient in the drug-containing delayed-release tablet core is as follows: Filler 60-90%; Disintegrant 2-10%; Adhesive 2-6%; Antioxidant 0.01-1%; Lubricant / flow aid 0.5-3%; The fillers and antioxidants are internal excipients, the lubricants / flow aids are external excipients, and the disintegrants can be either internal or external excipients.

12. The tablet according to claim 11, characterized in that, In the drug-containing delayed-release tablet core, the weight percentage content of each excipient is as follows: Filler 60-90%; Disintegrant 4-8%; Adhesive 2.5-5%; Antioxidant 0.05-1%; Lubricant / flow aid 0.5-1.5%.

13. The tablet according to claim 1, 2, or 4, characterized in that, The drug-containing delayed-release tablet core is a sustained-release formulation, and the weight percentage content of each excipient in the drug-containing delayed-release tablet core is as follows: Filler 60-90%; Adhesive 2-6%; Sustained-release material 4-25%; Antioxidant 0.01-1%; Lubricant / flow aid 0.5-3%; Fillers, binders, and antioxidants are internal additives, while lubricants / flow aids are external additives.

14. The tablet according to claim 13, characterized in that, In the drug-containing delayed-release tablet core, the weight percentage content of each excipient is as follows: Filler 60-90%; Adhesive 2.5-5%; Sustained-release material 5-20%; Antioxidant 0.05-1%; Lubricant / flow aid 0.5-1.5%.

15. The tablet according to any one of claims 1-4, characterized in that, The weight ratio of the drug-containing immediate-release outer shell to the drug-containing delayed-release tablet core is ≥4.

16. The tablet according to any one of claims 1-4, characterized in that, The weight ratio of the drug-containing immediate-release outer shell to the drug-containing delayed-release tablet core is 4~12.

17. The tablet according to any one of claims 1-4, characterized in that, The weight ratio of the drug-containing immediate-release outer shell to the drug-containing delayed-release tablet core is 350:

60.

18. The tablet according to any one of claims 11-12, or 14, characterized in that, The filler is selected from one or more of microcrystalline cellulose, lactose, pregelatinized starch, starch, dicalcium phosphate, mannitol, and dextrin; The adhesive is selected from one or more of povidone, copovidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; The disintegrant is selected from one or more of starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, crospovidone, and crospovidone carboxymethyl cellulose. 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, and glyceryl behenate. The antioxidant is selected from one or more of vitamin E, p-hydroxyanisole, butylated hydroxyanisole, dibutylcresol, sodium bisulfite, sodium metabisulfite, and vitamin C; The lubricant / flow aid is selected from one or more of magnesium stearate, sodium stearate fumarate, colloidal silica, sodium dodecyl sulfate, and talc.

19. The tablet according to any one of claims 1-4, characterized in that: The sleep-regulating drug mentioned refers to ramelteamide.

20. A method for preparing a tablet according to any one of claims 1-19, characterized in that, Includes the following steps: (1) Material for preparing the drug-containing immediate-release shell: Prepare total mixed particles containing the drug-containing immediate-release shell according to the formula; (2) Preparation of drug-containing delayed-release tablet cores: Prepare total mixed granules containing drug-containing delayed-release tablet cores, and obtain tablet cores by compression method; the tablet cores are subjected to gastric coating and enteric coating in sequence to obtain drug-containing delayed-release tablet cores; (3) Fill a portion of the material containing the drug-releasing shell into the intermediate mold as the first layer; The drug-containing delayed-release tablet core is placed on the first layer as the second layer, and then pre-compressed; the remaining material containing the drug-containing immediate-release outer shell is filled in as the third layer, and then compressed into a tablet; The pre-compression pressure is 0.02-1.5kN, and the main pressure used for compressing into sheets is greater than 15kN and less than 35kN.

21. The preparation method according to claim 20, characterized in that, The preparation of the drug-containing delayed-release tablet core mixed granules and the drug-containing immediate-release shell mixed granules shall be carried out by any of the following methods: 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 to a certain amount of solvent to make a solution or suspension. Spray the solution or suspension into the remaining internal excipients to complete wet granulation. After drying, add external excipients and mix evenly to obtain the corresponding total mixed granules. Method 2: Weigh the active pharmaceutical ingredient and various internal excipients after sieving according to the prescription amount; add the active pharmaceutical ingredient to a certain amount of solvent to make a solution or suspension, spray it into the internal excipients to complete wet granulation, dry it, add external excipients, mix evenly, and 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 make a solution or suspension. Spray the solution or suspension into the mixture of active pharmaceutical ingredient and other internal excipients to complete wet granulation. After drying, add external excipients and mix evenly to obtain the corresponding total mixed granules. Method 4: Weigh the active pharmaceutical ingredient and the various excipients after sieving according to the prescription amount, and mix the active pharmaceutical ingredient and excipients evenly according to the equal addition method to obtain the corresponding total mixed granules; The excipients include internal excipients and external excipients; The internal additives refer to fillers, adhesives, and antioxidants, while the external additives refer to lubricants and flow aids.

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