Tablets allowing segmented release of sleep regulating drugs and preparation method thereof

Abstract

The present invention "a tablet allowing segmented release of sleep-regulating drugs and a preparation method thereof" belongs to pharmaceutical technology and is characterized in that, in terms of structure, each tablet is composed of a drug-containing delayed-release core, a drug-free gastric-soluble coating, a drug-free enteric coating, a drug-containing quick-release outer shell, and an outer shell gastric-soluble coating from the inside to the outside; it can achieve an ideal dual-stage timed drug release mode, and is particularly suitable for sleep-regulating drugs, such as ramelteon.

Description

Technical Field

[0001] The invention relates to pharmaceutical technology, in particular to a tablet allowing segmented release of sleep regulating drugs and a preparation method thereof. Background Art

[0002] Some drugs, such as sleep-regulating drugs, need to be released quickly and take effect quickly after being ingested by the patient. However, the disadvantage is that it causes rapid fluctuations in blood drug concentrations and a high rate of adverse reactions. It is necessary to develop formulation technology to make the blood concentrations of such drugs more stable in the body, the drug effect disappears later, and the adverse reaction rate is lower.

[0003] Ramelteon ) is an oral hypnotic drug developed by Takeda Corporation of Japan and approved by the US FDA on July 22, 2005. It is the first melatonin receptor agonist used in the clinical treatment of insomnia. It is mainly used to treat insomnia with difficulty falling asleep, and it also has a definite effect on chronic insomnia and short-term insomnia. Ramelteon is the first prescription drug for insomnia with a new therapeutic mechanism in the past 35 years.

[0004] The mechanism of action of commonly used sleeping pills is generally to suppress the human brain nerve activity on a large scale. Ramelteon has a unique pharmacology, which selectively acts on two receptors in the suprachiasmatic nucleus (SCN) of the human hypothalamus. SCN is known as the "biological clock", which regulates the human body's 24-hour periodic biological rhythm, including the sleep-wake cycle. Research results show that there are no adverse reactions such as overuse, withdrawal reactions, drug dependence and "hangover" (aftereffects of the second day) after using this drug. The results of the Phase III clinical study showed that Ramelteon can effectively shorten the time it takes for patients to fall asleep, increase the total sleep time, improve sleep efficiency, and have little negative impact on work and study the next day. The recurrence rate after discontinuation is also very low. In one study, 472 patients took this product once a day for up to 1 year. According to recent clinical research results, this product is safe for elderly patients, patients with mild to moderate obstructive pulmonary disease (COPD) and patients with mild to moderate sleep apnea.

[0005] Most of the ramelteon preparations on the market are immediate-release preparations, which are released only once and can achieve a rapid onset of action and help people fall asleep quickly; however, they cannot prevent premature awakening and the blood drug concentration in the body is C max Large, easily increase the incidence of adverse reactions.

[0006] 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

[0007] 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.

[0008] The technical solution of the present invention is as follows:

[0009] 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.

[0010] 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).

[0011] 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%.

[0012] 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.

[0013] Preferably, the tablet is characterized in that the ratio of the content of the medicinal substance in the drug-containing rapid-release shell to that in the drug-containing delayed-release core is 1-3:1.

[0014] Preferably, the tablet is characterized in that the drug-containing delayed-release tablet core is a rapid-release preparation; in the drug-containing delayed-release tablet core, the weight percentage content of each excipient is 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.

[0015] 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 content of each excipient is 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.

[0016] Preferably, the tablet is characterized in that the material weight ratio of the drug-containing immediate-release shell to the drug-containing delayed-release core is ≥4, preferably 4-12 or 350:60.

[0017] Preferably, the tablet is characterized in that the gastric soluble coating of the outer shell increases by 2-5%, preferably 3%.

[0018] The filler is selected from one or more of microcrystalline cellulose, lactose, pregelatinized starch, starch, calcium hydrogen phosphate, mannitol, dextrin, etc.;

[0019] The binder is selected from one or more of povidone, copovidone, hydroxypropyl cellulose, hypromellose, etc.;

[0020] The disintegrant is selected from one or more of starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, etc.;

[0021] The sustained-release material is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, alginate, ethyl cellulose, vinyl acetate, xanthan gum, guar gum, cross-linked polyvinylpyrrolidone, and glyceryl behenate;

[0022] The antioxidant is selected from one or more of vitamin E, p-hydroxyanisole, butylated hydroxyanisole, dibutyltoluene phenol, sodium bisulfite, sodium metabisulfite and vitamin C;

[0023] The lubricant / glidant is selected from one or more of magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide, sodium lauryl sulfate, talc and the like.

[0024] Preferably, the tablet is characterized in that it is prepared by the following steps:

[0025] (1) preparing the materials for the drug-containing immediate-release shell: preparing the drug-containing immediate-release shell total mixed granules;

[0026] (2) Preparing a drug-containing delayed-release tablet core: preparing a total mixed granule of a drug-containing delayed-release tablet core, and obtaining a tablet core by a compression method; and sequentially performing a gastric coating and an enteric coating on the tablet core to obtain a drug-containing delayed-release tablet core;

[0027] (3) Fill a portion of the material of the drug-containing immediate-release 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 pre-compress; fill the remaining material of the drug-containing immediate-release shell as the third layer, and press into tablets.

[0028] Preferably, the tablet is characterized in that the pre-compression pressure is 0.02-1.5 kN, and the main pressure used for pressing into tablets is 15-35 kN.

[0029] Preferably, any of the above-mentioned tablets is characterized in that the sleep regulating drug is ramelteon.

[0030] The method for preparing any of the above tablets is characterized by comprising the following steps:

[0031] (1) preparing the materials for the drug-containing immediate-release shell: preparing the drug-containing immediate-release shell total mixed granules;

[0032] (2) Preparing a drug-containing delayed-release tablet core: preparing a total mixed granule of a drug-containing delayed-release tablet core, and obtaining a tablet core by a compression method; and sequentially performing a gastric coating and an enteric coating on the tablet core to obtain a drug-containing delayed-release tablet core;

[0033] (3) Fill a portion of the material of the drug-containing immediate-release 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 pre-compress; fill the remaining material of the drug-containing immediate-release shell as the third layer, and press into tablets.

[0034] Preferably, the preparation method is characterized in that the pre-pressing pressure is 0.02-1.5 kN, and the main pressure used for pressing into tablets is 15-35 kN.

[0035] The preparation of drug-containing delayed-release tablet core mixed granules and drug-containing immediate-release shell mixed granules is carried out by any of the following methods:

[0036] Method 1: Weigh the active substance and various sieved internal excipients according to the prescription amount, add the active substance and antioxidant into a certain amount of solvent to make a solution or suspension, spray it into the remaining internal excipients to complete wet granulation, add external excipients after drying, mix evenly, and obtain the corresponding total mixed granules;

[0037] Method 2: Weigh the active substance and various sieved internal excipients according to the prescription amount; add the active substance to a certain amount of solvent to make a solution or suspension, spray it into the internal excipients to complete wet granulation, add the external excipients after drying, mix evenly, and obtain the corresponding total mixed granules;

[0038] Method 3: Weigh the active substance and various sieved internal excipients according to the prescription amount, add the antioxidant or binder to a certain amount of solvent to make a solution or suspension, spray it into the mixed material of the active substance and the remaining internal excipients to complete wet granulation, add the external excipients after drying, mix evenly, and obtain the corresponding total mixed granules;

[0039] Method 4: Weigh the active substance and various sieved excipients according to the prescribed amount, mix the active substance and excipients evenly according to the equal amount addition method to obtain the corresponding total mixed granules.

[0040] The present invention studies the tablet structure, formula and tablet manufacturing process to obtain a tablet formula and its preparation process that allow the segmented release of active pharmaceutical ingredients, which is particularly suitable for sleep regulation drugs, and makes up for the lack of such tablets in the prior art.

[0041] The tablet provided by the present invention has the following results in the dissolution test: Figure 2 As shown in Figures 4 and 5, the drug-containing rapid-release shell completes the release within 10-30 minutes. Due to the protection of the drug-free enteric coating, no drug is released within a period of time thereafter, such as within 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. It is applied to sleep-regulating drugs, which can take effect quickly after taking the medicine to help people fall asleep quickly. After a period of time, the second-stage release is started to prevent early awakening and increase the total sleep time.

[0042] In order to obtain tablets that achieve the above release mode, the present invention applies drug-free gastric coating and drug-free enteric coating to the drug-containing delayed-release tablet core in the tablet structure. In the research and development experiments of the present invention, it was found that since the enteric coating process takes a long time, the tablet core may be easily broken during the enteric coating process. Therefore, it is preferred to apply gastric coating before enteric coating to protect the tablet core. In the enteric environment, the gastric coating does not delay the release of the tablet core.

[0043] In addition, the present invention studies the effect of enteric coating weight gain thickness on the release pattern and finds 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, the process cost will be increased and the tablet core release will be delayed. It is found that the ideal enteric coating weight gain range is 4-12%.

[0044] The present invention also found that some enteric coating materials are not suitable for toughness, and the enteric coating is easy to break or produce gaps during tableting, resulting in premature release of the delayed-release tablet core, or the film-forming materials of some enteric coating materials are not suitable and can only ensure that they are insoluble 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 a two-stage release cannot be achieved.

[0045] In order to obtain tablets that achieve the target release pattern 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 groups: acrylic resin No. I, No. II, No. III, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl phthalate (PVAP), cellulose acetate trimellitate (CAT), acrylic resin EuS100, EuL100, methacrylic acid and methyl methacrylate copolymer, methacrylic acid and ethyl acrylate copolymer, etc., preferably methacrylic acid and ethyl acrylate copolymer; for example, when Eudragit L100-55 is selected, the prepared tablets can achieve an ideal release effect.

[0046] 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 achieve the target release pattern, thereby affecting the practicality / promotable value of the technology of the present invention, such as the pre-compression pressure in step (3) of the preparation method and the main pressure for tablet pressing: when the pre-compression pressure is greater than 1.5 kN, such as 2 kN, most of the enteric coating of the tablet core is damaged, and the tablet core of the obtained tablet is released in acid, while when the pre-compression pressure is 0.02-1.5 kN, the tablet core is completely wrapped in the enteric coating and is not released in acid for 4 hours, which helps to obtain the ideal release pattern; when the main pressure of less than 15 kN, such as 10 kN, is used for tablet pressing, the pressed tablets are soft and easy to break, and the friability is unqualified; when the main pressure is greater than 35 kN, the pressed tablets will crack, 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 test found that when the main pressure was within the range of 15-35 kN, the friability was acceptable, and the tablet core was completely coated with enteric coating and was not released in acid for 4 hours.

[0047] In the case where the active substance of the drug is a sleep regulating drug, the present invention has found through experiments that the content ratio of the active substance in the drug-containing immediate-release shell to the drug-containing delayed-release tablet core is 1-3:1, which can achieve an ideal blood concentration state. Too high a drug ratio in the drug-containing delayed-release tablet core can easily lead to difficulty in waking up in the later stage. Too low a drug ratio in the drug-containing delayed-release tablet core and too high a drug ratio in the immediate-release shell can easily lead to too high a blood drug concentration, too low a blood drug concentration in the later stage, and too large fluctuations in blood drug concentration. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 . A schematic diagram of the cross-sectional structure of a tablet of the present invention;

[0049] 1-drug-containing delayed-release core, 2-drug-free gastric-soluble coating, 3-drug-free enteric-soluble coating, 4-drug-containing immediate-release shell, 5-shell gastric-soluble coating

[0050] Figure 2 . The dissolution test results of the tablets obtained in Example 1;

[0051] Figure 3 . The dissolution test results of the tablets obtained in Example 2;

[0052] Figure 4 . The dissolution test results of the tablets obtained in Example 3;

[0053] Figure 5 . The dissolution test results of the tablets obtained in Example 4;

[0054] Figure 6 . The effect of the predetermined pressure on the tablet drug release model in the tablet preparation process of the present invention;

[0055] Figure 7 .The effect of the main compression pressure on the tablet drug release model in the tablet preparation process of the present invention;

[0056] Figure 8 . The effect of enteric coating materials on the drug release model of the tablets of the present invention;

[0057] Fig. 9 . The effect of enteric coating material weight gain on the drug release model of the tablets of the present invention;

[0058] Fig.10 Comparison of in vivo release data of the tablets of the present invention and the reference preparation DETAILED DESCRIPTION

[0059] In order to make the purpose, technical solutions and advantages of the implementation of this application clearer, the technical solutions in the embodiments of this application will be described in more detail below in conjunction with the drawings in the embodiments of this application.

[0060] like Figure 1 As shown,

[0061] 1. A tablet that allows for segmented drug release, characterized in that it comprises, from inside to outside, 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 coating (5).

[0062] 2. Preferably, the tablet is characterized in that a non-drug gastric coating (2) is provided between the drug-containing delayed-release tablet core (1) and the non-drug enteric coating (3).

[0063] 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.

[0064] 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, 2 and 6 mm, 3 and 7 mm, or 4 and 8 mm.

[0065] 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

[0066] 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.

[0067] 7. Preferably, the tablet is characterized in that the diameter of the tablet is 5 to 13 mm or 9.9 to 10.25 mm; the diameter of the drug-containing delayed-release tablet core (1) is 3 to 9 mm, or 4.9 to 5.25 mm;

[0068] 8. Preferably, the tablet is characterized in that:

[0069] The thickness from the upper edge of the drug-containing delayed-release tablet core (1) to the narrower side of the upper surface of the tablet is ≥ 0.5 mm;

[0070] The thickness of the narrower side between the outer edge of the drug-containing delayed-release tablet core (1) and the outer edge of the tablet is ≥0.5 mm.

[0071] 9. Preferably, the tablet is characterized in that, in the longitudinal cross-sectional direction of the tablet, the drug-containing delayed-release core tablet (1) is located in the geometric center area of ​​the tablet;

[0072] In the cross-sectional direction of the tablet, the drug-containing delayed-release core tablet (1) is located in the geometric center area of ​​the tablet.

[0073] 10. Preferably, the tablet is characterized in that the drug is a sleep regulating drug, such as ramelteon.

[0074] In a typical tablet example of the present invention, the tablet core is compressed by a die with a diameter of 5 mm, so the theoretical diameter of the tablet core without coating should be 5 mm, and the entire tablet is compressed by a die with a diameter of 10 mm, so the theoretical diameter of the entire tablet without coating should be 10 mm. The tablet core is theoretically in the middle of the entire tablet, so there is a slight error in theory but in practice, and the vertical distance between the periphery of the tablet core and the periphery of the tablet in the range of 0.5 to 4.5 mm will not affect the final release curve.

[0075] Example 1 Preparation of tablets (delayed release tablet core is immediate release)

[0076]

[0077]

[0078] The preparation method is as follows:

[0079] (1) preparing an immediate-release composition, weighing the sieved internal excipients (lactose, MCC, PVP / VA) according to the prescription amount, adding ramelteon and BHT to a certain amount of ethanol to prepare a solution, wet granulating, drying, adding the sieved CCMC-Na and magnesium stearate, and mixing uniformly;

[0080] (2) preparing a delayed-release composition, weighing ramelteon according to the prescribed amount of the main drug, weighing the sieved excipients according to the excipient formula, and mixing them thoroughly and evenly according to the equal amount addition method;

[0081] (3) using the delayed-release preparation composition to compress the tablet core, and then performing gastric and enteric coating;

[0082] (4) Using the immediate-release preparation composition as the shell and the delayed-release tablet core as the tablet core, a core packing is performed, 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-pressed (0.02 kN); the immediate-release composition is filled again as the third layer, and the tablet is pressed into a tablet with a main pressure of 20 kN.

[0083] 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.

[0084] The dissolution test results are as follows Figure 2 As shown, the immediate-release shell completed the release within 15 minutes; there was no drug release from 15 minutes to 120 minutes, and the delayed-release core completed the release within 30 minutes after the 120th minute.

[0085] Example 2 Preparation of tablets (delayed release tablet core is sustained release)

[0086]

[0087] The preparation method is as follows:

[0088] (1) preparing an immediate-release composition, weighing ramelteon and sieved internal excipients (lactose, MCC, BHA) according to the prescription amount, adding PVP to a certain amount of water to prepare a binder, wet granulating, drying, adding sieved cross-linked polyvinylpyrrolidone and magnesium stearate, and mixing uniformly;

[0089] (2) preparing a delayed-release composition, weighing ramelteon and sieved internal excipients (calcium hydrogen phosphate, MCC, HPMC, BHA) according to the prescription amount, adding PVP to a certain amount of water to prepare a binder, wet granulating, drying, adding sieved magnesium stearate, and mixing uniformly;

[0090] (3) using the delayed-release preparation composition to compress the tablet core, and then performing gastric and enteric coating;

[0091] (4) Using the immediate-release preparation composition as the shell and the delayed-release tablet core as the tablet core, a core packing is performed, 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-pressed (0.04 kN); the immediate-release composition is filled again as the third layer, and the main pressure is 25 kN to form a tablet.

[0092] 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.

[0093] The dissolution test results are as follows Figure 3 shown.

[0094] The immediate-release shell releases the drug within 10 minutes; no drug is released from 15 minutes to 120 minutes, and the delayed-release core starts to release the drug component after 120 minutes and continues until the 10th hour. Under this formula, the delayed-release core contains too high a proportion of drug, and it is not easy for the patient to wake up in the later stage.

[0095] Example 3 Preparation of tablets (delayed release tablet core is sustained release)

[0096]

[0097]

[0098] The preparation method is as follows:

[0099] (1) preparing an immediate-release composition, weighing ramelteon according to the prescribed amount of the main drug, weighing the sieved excipients according to the excipient formula, and mixing them thoroughly and uniformly according to the equal amount addition method;

[0100] (2) preparing a delayed-release composition, weighing ramelteon according to the prescribed amount, weighing the sieved excipients according to the excipient formula, and mixing them thoroughly and uniformly according to the equal amount addition method;

[0101] (3) using the delayed-release preparation composition to compress the tablet core, and then performing gastric and enteric coating;

[0102] (4) Using the immediate-release preparation composition as the outer shell and the delayed-release tablet core as the tablet core, a core packing is performed, 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-pressed (0.02 kN); the immediate-release composition is filled again as the third layer, and the main pressure is 17 kN to form a tablet.

[0103] 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.

[0104] The dissolution test results are as follows Figure 4 Shown

[0105] The quick-release shell completes the release within 10 minutes; no drug is released from 15 minutes to 120 minutes; the delayed-release core starts to release the drug ingredients after 120 minutes, and continues to release the drug ingredients in the fifth hour to reach 100%, achieving the ideal release pattern.

[0106] Example 4 Preparation of tablets (delayed release tablet core is sustained release)

[0107]

[0108]

[0109] The preparation method is as follows:

[0110] (1) preparing an immediate-release composition, weighing the sieved internal excipients (mannitol, MCC, PVP, VC, sodium carboxymethyl starch) according to the prescription amount and mixing them evenly, adding ramelteon to a certain amount of ethanol to prepare a solution, wet granulating, drying, adding the sieved sodium stearyl fumarate, and mixing evenly;

[0111] (2) preparing a delayed-release composition, weighing ramelteon according to the prescribed amount of the main drug, weighing the sieved excipients according to the excipient formula, and mixing them thoroughly and evenly according to the equal amount addition method;

[0112] (3) using the delayed-release preparation composition to compress the tablet core, and then performing gastric and enteric coating;

[0113] (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.

[0114] 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.

[0115] 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.

[0116] Test Example 1: Preload Pressure Test

[0117] 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;

[0118] The prescription and preparation method of Example 4 were used to study the effect of different pre-pressures on the dissolution effect.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] Test Example 2: Main Pressure Test

[0123] During the research and development process, it was found that when the main pressure was within the range of 15-35 kN, the friability was qualified, and the tablet core was completely enteric coated and not released in acid for 4 hours. The prescription and tableting process of Example 1 were used, except that the main pressure was set to 15, 20, 25, and 35 kN, respectively, to study the effect of the main pressure on the dissolution effect.

[0124] 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.

[0125] The test results are as follows Figure 7 It is shown that when the main pressure of 10 kN is used for tableting, the tablet breaks and the friability is unqualified. When the main pressure is greater than 35 kN (such as 35 kN), the enteric coating film of the tablet core breaks, resulting in the release of the active drug in the tablet core in the acid.

[0126] Comparison of enteric coating materials in Test Example 3

[0127] The effects of different enteric coating materials were compared.

[0128] The formulation and process of Example 4 were used to investigate different enteric coating materials.

[0129] Dissolution method: Paddle method 50 rpm, 37°C, 500 mL of pH 5.0 medium, measured by UV spectrophotometry at 210 nm.

[0130] The test results are as follows Figure 8 The results show that when the coating material is Opadry Enteric 94O680000 and 91O610002, the enteric coating film may have poor toughness or fail to remain insoluble at pH 5.0. When the coating material is Eudragit L100-55, whose main film-forming material is methacrylic acid and ethyl acrylate copolymer, an ideal release effect can be achieved.

[0131] Test Example 4 Comparison of Enteric Coating Weight Gain Thickness

[0132] The formulation of Example 1 was used to compare the tableting effects of coating weight gain of 3%, 4%, 5%, 6%, 7%, 8% and 10%, 12%.

[0133] Comparing the thickness of different enteric coating weight gain, when the weight gain range is 4-12%, the dissolution is similar, and the second stage release reaches a platform within 0.5-1h, which can achieve the expected dissolution effect.

[0134] 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.

[0135] The results are as follows Fig. 9 It shows that if the coating film is too thin, it cannot protect the tablet core from being released in acid and cannot achieve the enteric effect; if the coating film is too thick, the tablet production cost will increase.

[0136] Experimental Example 5 In vivo data

[0137] The sample (T) prepared in Example 1 was compared with the reference preparation (R) in a human test, wherein the reference agent (R) was ramelteon tablets. Specification: 8 mg, Batch number: HH2012, Manufacturer: Takeda Pharmaceutical Co., Ltd., Japan, Storage conditions: Light-proof, sealed, stored below 25°C.

[0138] A single-center, randomized, open, two-period, double-crossover, single-dose trial design was used. The dosage was 1 tablet per person, with a washout period of 2 days, and 8 subjects completed the trial.

[0139] The test results are as follows Fig.10 It shows that the sample (T) of the present invention releases C for the first time. max The sample (T) of the present invention has a release rate of about 5 hours compared with the reference preparation (R), which can effectively prevent premature awakening.

Claims

1. A tablet that allows the segmented release of sleep-regulating drugs, characterized in that: In terms of structure, each tablet is composed of a drug-containing delayed-release core, a drug-free gastric-soluble coating, a drug-free enteric-soluble coating, a drug-containing immediate-release outer shell, and an outer shell coating from the inside to the outside. The segmented release means that after the drug-containing rapid-release shell is completely released, the drug-containing delayed-release core begins to release 0.5-4 hours later and is completely released within 0.1-6 hours; The tablet is prepared by the following steps: (1) Preparing the materials for the drug-containing immediate-release shell: preparing the drug-containing immediate-release shell total mixed granules according to the formula; (2) preparing a total mixed granule of drug-containing delayed-release tablet cores, and obtaining tablet cores by compression; and sequentially performing gastric coating and enteric coating on the tablet cores; (3) filling a portion of the material of the drug-containing immediate-release shell into the middle mold as the first layer; placing the material obtained in step (2) on the first layer as the second layer, and then pre-pressing; filling the remaining material of the drug-containing immediate-release shell as the third layer, and pressing into tablets; The pre-pressing pressure is 0.02-1.5 kN, and the main pressure used for pressing into tablets is 15-25 kN; The film-forming material used in the drug-free enteric coating material is selected from one or more of acrylic resins No. Ⅰ, No. Ⅱ, No. Ⅲ, cellulose acetate phthalate CAP, hydroxypropyl methylcellulose phthalate HPMCP, polyvinyl acetate phthalate PVAP, cellulose acetate trimellitate CAT, acrylic resins EuS100, EuL100, and methacrylic acid-ethyl acrylate copolymer; The non-drug enteric coating increases in weight by 4%-12% relative to the drug-containing delayed-release tablet core and is soluble under dissolution conditions of pH 5 or above; The drug-containing delayed-release tablet core contains the following excipients by weight percentage: Filler 60-90%; Adhesive 2-6%; Among them, fillers and adhesives are added auxiliary materials; 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 hypromellose.

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

3. The tablet according to claim 1, characterized in that The drug-free enteric coating increases in weight by 5%, 6%, 7% or 8% relative to the drug-containing delayed-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 increases in weight by 2-5%.

5. The tablet according to claim 1, characterized in that The content ratio of the medicinal substance in the drug-containing rapid-release shell to the drug-containing delayed-release core tablet is 1-3:

1.

6. The tablet according to claim 1, characterized in that The drug-containing delayed-release tablet core is a quick-release preparation, and the drug-containing delayed-release tablet core further contains the following excipients by weight percentage: Disintegrant 2-10%; Antioxidants 0.01-1%; Lubricant / glidant 0.5-3%; The antioxidant is an internal excipient, the lubricant / glidant is an external excipient, and the disintegrant is an internal or external excipient; The disintegrant is selected from one or more of starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose; The antioxidant is selected from one or more of vitamin E, p-hydroxyanisole, butylated hydroxyanisole, dibutyltoluene phenol, 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.

7. The tablet according to claim 6, characterized in that In the drug-containing delayed-release tablet core, the weight percentage content of each excipient is: Filler 60-90%; Disintegrant 4-8%; Adhesive 2.5-5%; Antioxidants 0.05-1%; Lubricant / glidant 0.5-1.5%.

8. The tablet according to claim 1, characterized in that The drug-containing delayed-release tablet core is a sustained-release preparation, and the drug-containing delayed-release tablet core further contains, by weight percentage: Sustained release material 4-25%; Antioxidants 0.01-1%; Lubricant / glidant 0.5-3%; Among them, antioxidants are internal excipients, and lubricants / glidants are external excipients; The sustained-release material is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, alginate, ethyl cellulose, vinyl acetate, xanthan gum, guar gum, cross-linked polyvinylpyrrolidone, and glyceryl behenate; The antioxidant is selected from one or more of vitamin E, p-hydroxyanisole, butylated hydroxyanisole, dibutyltoluene phenol, 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.

9. The tablet according to claim 8, characterized in that In the drug-containing delayed-release tablet core, the weight percentage contents of the excipients are respectively: Filler 60-90%; Adhesive 2.5-5%; Sustained release material 5-20%; Antioxidants 0.05-1%; Lubricant / glidant 0.5-1.5%.

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

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

60.

12. The tablet according to any one of claims 1 to 9, characterized in that: The sleep regulating drug refers to ramelteon.

13. The method for preparing a tablet according to any one of claims 1 to 12, characterized in that: The following steps are involved: (1) Preparing the materials for the drug-containing immediate-release shell: preparing the drug-containing immediate-release shell total mixed granules according to the formula; (2) preparing a total mixed granule of drug-containing delayed-release tablet cores, and obtaining tablet cores by compression; and sequentially performing gastric coating and enteric coating on the tablet cores; (3) filling a portion of the material of the drug-containing immediate-release shell into the middle mold as the first layer; placing the material obtained in step (2) on the first layer as the second layer, and then pre-pressing; filling the remaining material of the drug-containing immediate-release shell as the third layer, and pressing into tablets; The pre-pressing pressure is 0.02-1.5 kN, and the main pressure used for pressing into tablets is 15-25 kN.

Images