Three-layer tablet formulation and preparation method therefor

Abstract

A three-layer tablet formulation capable of achieving an exponential release mode of initial slow release followed by rapid release. Said tablet formulation has three layers combined together in a stacked manner: a swelling retarding layer, comprising a sustained-release material, a filler, an adhesive, and a lubricant, having the characteristic of slowly expanding upon absorbing water, supporting a drug-containing sustained-release layer, and retarding the bottom surface of the drug-containing sustained-release layer from being in contact with a medium; the drug-containing sustained-release layer, comprising a sustained-release material, a filler, an adhesive, and a lubricant; and an erosion retarding layer, comprising a sustained-release material, a filler, an adhesive, and a lubricant, having the characteristic of slowly eroding or falling off upon absorbing water, and covering the top surface of the drug-containing sustained-release layer. The drug-containing sustained-release layer is sandwiched between the swelling retarding layer and the erosion retarding layer, and pharmaceutical ingredients in the drug-containing sustained-release layer are released in an exponential manner of initial slow release followed by rapid release.

Description

A three-layer tablet formulation and its preparation method Technical Field

[0001] This invention pertains to pharmaceutical technology, specifically relating to a three-layer tablet formulation capable of achieving an exponential release pattern that is initially slow and then accelerates, and its preparation method. Background Technology

[0002] Many diseases or conditions have a diurnal rhythm, such as asthma, hypertension, and angina. It is best to provide drug formulations that match the diurnal rhythm of these conditions to prevent attacks and improve blood drug concentration stability, efficacy, compliance, and safety.

[0003] Especially for asthma, which exhibits a pronounced pattern of nocturnal attacks, with more severe symptoms occurring from midnight to early morning, taking medication before bedtime for a slow onset and stable increase in blood drug concentration, thus ensuring sufficient blood drug concentration during midnight to early morning, can effectively prevent asthma attacks, improve medication safety, and reduce drug toxicity. Currently, although many medications exist for preventing or alleviating asthma attacks, taking medication at night can disrupt patient rest, or the blood drug concentration may gradually decrease, resulting in insufficient concentration during midnight to early morning attacks. While some sustained-release formulations can maintain sufficient and stable blood drug concentrations for a longer period, excessively high average blood drug concentrations can reduce medication safety. Patent CN103520130B describes a time-controlled release tablet of montelukast sodium and its preparation method, providing a chip-encapsulated formulation. After administration, the outer layer controls the drug release at a zero-order rate within a specific timeframe. During the peak of asthma attacks at midnight, the immediate-release core releases the drug in a sudden (pulsating) manner, generating a higher blood drug concentration, effectively suppressing asthma attacks. However, the dosage form provided by this patent has a complex preparation process, and the pulsed release causes a rapid increase in blood drug concentration, increasing the incidence of adverse reactions and reducing medication safety and compliance.

[0004] For conditions with similar asthma attack patterns, it is necessary to develop formulations with more suitable drug delivery modalities, better efficacy, safety, and compliance, and easier mass production. Currently, no drug formulations using trilayer tablet technology to achieve an exponential release pattern (slow initially, then rapid) have been found.

[0005] Summary of the Invention

[0006] This invention provides a three-layer tablet formulation that achieves an exponential release pattern of drug components, initially slow and then rapidly increasing. It is suitable for medications targeting symptoms similar to asthma attacks. Patients can take the medication before bedtime without affecting sleep. The drug components are released exponentially, gradually taking effect and then steadily increasing in blood concentration, reaching sufficient blood concentration between midnight and early morning. This improves medication safety, effectively prevents disease attacks, and reduces drug toxicity. Furthermore, the three-layer tablet manufacturing process is stable and convenient, facilitating industrial production. To achieve some or all of the above technical objectives, the technical solution of this invention is as follows:

[0007] A first aspect of the present invention provides a three-layer tablet formulation, characterized in that it comprises three layers stacked together:

[0008] The swelling barrier layer has the characteristic of slowly expanding after absorbing water. It supports the drug-containing sustained-release layer and prevents the bottom surface of the drug-containing sustained-release layer from contacting the medium; it contains sustained-release materials, fillers, binders and lubricants.

[0009] The drug-containing sustained-release layer contains sustained-release materials, fillers, binders, and lubricants;

[0010] The corrosion-inhibiting layer has the property of slowly dissolving or detaching by absorbing water, and covers the top surface of the drug-containing slow-release layer. It contains slow-release material, filler, binder and lubricant.

[0011] The drug-containing sustained-release layer is sandwiched between the swelling barrier layer and the erosion barrier layer;

[0012] The drug components in the drug-containing sustained-release layer are released in an exponential pattern, initially slowly and then rapidly.

[0013] In the preferred embodiment, based on the weight of the three-layer tablet formulation, the swelling barrier layer accounts for more than 50%, and the corrosion barrier layer accounts for less than or equal to 25%.

[0014] In the preferred embodiment, based on the weight of the three-layer tablet formulation, the weight percentage of the sustained-release material contained in the swelling barrier layer is not less than 25%, preferably 30% to 60%; the weight percentage of the sustained-release material contained in the corrosion barrier layer is not more than 15%, preferably 3% to 15%; and the amount of sustained-release material in the drug-containing sustained-release layer is 2% to 15%.

[0015] In the preferred embodiment, the sustained-release material in the swelling barrier layer is a gel-skeleton type sustained-release material, which is selected from one or more of cellulose, high molecular polymers and non-cellulose polysaccharides.

[0016] The cellulose compounds include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and carboxymethyl cellulose; the polymers include povidone, polyacrylic acid resin, polyvinyl alcohol, and polyoxyethylene; and the non-cellulose polysaccharides include sodium alginate, xanthan gum, sophora bean gum, guar gum, tragacanth gum, agar, carbomer, and chitosan.

[0017] In a preferred embodiment, the sustained-release material of the drug-containing sustained-release layer and the corrosion-blocking layer is selected from one or more of cellulose, high molecular polymers, non-cellulose polysaccharides, and waxy materials;

[0018] The cellulose compounds include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and carboxymethyl cellulose; the polymers include povidone, polyacrylic acid resin, polyvinyl alcohol, and polyoxyethylene; the non-cellulose polysaccharides include sodium alginate, xanthan gum, sophora bean gum, guar gum, tragacanth gum, agar, carbomer, and chitosan; and the waxy materials include glyceryl behenate, carnauba wax, hydrogenated castor oil, stearic acid, stearyl alcohol, glyceryl monostearate, butyl stearate, and beeswax.

[0019] The study found that in the three-layer tablet formulation of the present invention, the sustained-release materials of the swelling retardation layer and the erosion retardation layer can be the same, and the desired characteristics of the swelling retardation layer and the erosion retardation layer can be achieved by adjusting the ratio of the sustained-release materials in the swelling retardation layer and the erosion retardation layer.

[0020] In a preferred embodiment, the filler in each layer is selected from one or more of calcium carbonate, microcrystalline cellulose, sucrose, lactose, dicalcium phosphate, dicalcium phosphate dihydrate, mannitol, and starch; the content of the filler in each layer (by layer weight) is 20% to 80%, preferably 30% to 60%.

[0021] In a preferred embodiment, the adhesive in each layer is selected from one or more of povidone, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, syrup, glue, and starch paste; the content of the adhesive in each layer is 1% to 8% by weight, preferably 1% to 6%, and more preferably 2% to 4%.

[0022] In a preferred embodiment, the lubricant in each layer is selected from one or more of calcium stearate, magnesium stearate, mineral oil, talc, sorbitol, stearic acid, zinc stearate, ethyl oleate, and ethyl laurate; the content of the lubricant in each layer is 1-2% by layer weight.

[0023] In a preferred embodiment, the weight ratio of the swelling barrier layer to the erosion barrier layer is ≥2, and more preferably ≥4.

[0024] In a preferred embodiment, the three layers stacked together have the same or different top and bottom surface areas.

[0025] In a preferred embodiment, the swelling barrier layer does not contain the drug; or it contains the drug, but may be the same as or different from the drug in the drug-containing sustained-release layer.

[0026] In a preferred embodiment, the erosion-blocking layer does not contain a drug; or it contains a drug, but the drug may be the same as or different from the drug in the drug-containing sustained-release layer.

[0027] In a preferred embodiment, the three-layer tablet further includes a coating layer; preferably, the coating layer contains a drug.

[0028] In a preferred embodiment, the drug in the drug-containing sustained-release layer is montelukast sodium.

[0029] Another aspect of the present invention provides a multilayer tablet, characterized in that, outside the swelling-blocking layer and / or erosion-blocking layer of any of the above-mentioned three-layer tablet formulations, there is an immediate-release layer, wherein the immediate-release layer contains a drug that is the same as or different from the drug-containing sustained-release layer.

[0030] In another aspect, the present invention provides a method for preparing any of the above-mentioned three-layer tablet formulations, characterized by comprising the following steps:

[0031] (1) Pre-made corrosion-resistant layer particles: Weigh the prescribed amount of slow-release material, binder and filler, mix for 2-5 minutes, and then pass them through a 20-40 mesh sieve with the lubricant. Mix again for 2-5 minutes to prepare corrosion-resistant layer particles for later use.

[0032] (2) Pre-made drug-containing sustained-release granules: Weigh the prescribed amount of API, sustained-release material, filler and binder, mix for 3 minutes, and then pass them through a 20-40 mesh sieve with the lubricant. Mix again for 2-5 minutes to prepare drug-containing sustained-release granules for later use.

[0033] (3) Pre-made swelling barrier layer particles: Weigh the prescribed amount of sustained-release material, binder and filler, mix for 3 minutes, and then pass them through a 20-40 mesh sieve with the lubricant. Mix again for 2-5 minutes to prepare swelling barrier layer particles for later use.

[0034] (4) Pressing multilayer tablets: Fill the tablet press with the prescribed amount of swelling and retardation layer particles and pre-press; continue to fill with the prescribed amount of drug-containing sustained-release layer particles and pre-press; finally fill with the prescribed amount of etch-retardation layer particles and adjust the main pressure to press into three-layer tablets.

[0035] In another aspect, the present invention provides a method for preparing any of the above-mentioned three-layer tablet formulations, characterized by comprising the following steps:

[0036] (1) Pre-made corrosion-resistant layer particles: Weigh the prescribed amount of sustained-release material, binder and filler, wet granulate with purified water, wet granulate through a 20-40 mesh sieve, dry, dry granulate through a 20-40 mesh sieve, add lubricant and mix again for 2-5 minutes to prepare corrosion-resistant layer particles for later use.

[0037] (2) Pre-made drug-containing sustained-release granules: Weigh the prescribed amount of API, sustained-release material, filler and binder, wet granulate with purified water, wet granulate through a 20-40 mesh sieve and dry; dry granulate through a 20-40 mesh sieve, add lubricant and mix again for 2-5 minutes to prepare drug-containing sustained-release granules for later use.

[0038] (3) Pre-made swelling barrier layer particles: Weigh the prescribed amount of sustained-release material, binder and filler, wet granulate with purified water, wet granulate through a 20-40 mesh sieve, dry, dry granulate through a 20-40 mesh sieve, add lubricant and mix for 2-5 minutes to prepare swelling barrier layer particles for later use.

[0039] (4) Pressing multilayer tablets: Fill with the prescribed amount of swelling and blocking layer particles, pre-press; continue to fill with the prescribed amount of drug-containing sustained-release layer particles, pre-press; finally fill with the prescribed amount of erosion blocking layer particles, adjust the main pressure and press into three-layer tablets.

[0040] The three-layer tablet provided by this invention has a typical structure as shown in Figure 1. By setting a dissolution-inhibiting layer in the top (or bottom) layer and a swelling-inhibiting layer in the bottom (or top) layer, the drug component in the middle drug-containing sustained-release layer is released in an exponential manner, first gradually taking effect and then steadily increasing the blood drug concentration. The release process of the three-layer tablet of this invention is shown in Figure 2:

[0041] Through the selection of sustained-release materials and formulations, the swelling retardation layer primarily serves as the support for the drug-containing sustained-release layer. During the drug release process, it gradually expands but is not easily eroded or erodes slowly; that is, even after the drug-containing sustained-release layer has been fully released, this layer remains undissolved and does not detach. The swelling retardation layer adheres to the drug-containing sustained-release layer, preventing drug aggregation (being encapsulated by gel-type sustained-release materials, making release difficult / slow). This ensures that the exposed surface of the drug-containing sustained-release layer remains intact during drug release. Simultaneously, the expansion of the swelling retardation layer extends the exposed surface of the drug-containing sustained-release layer, increasing the contact area with the medium, thus accelerating the later stages of drug release and promoting an exponential release pattern.

[0042] Similarly, through the selection of sustained-release materials and proportions, the erosion-blocking layer will gradually dissolve or detach after contact with the medium, causing the drug-containing sustained-release layer to gradually go from partial exposure to complete exposure, and the drug release will show a process from slow to fast; combined with the gradual expansion of the swelling-blocking layer, the exposed surface of the drug-containing sustained-release layer will be extended, thereby promoting the drug release of the drug-containing sustained-release layer to form an exponential release pattern throughout the process.

[0043] It is worth noting that the three-layer tablet formulation provided by this invention can be a final tablet product or part of a multilayer tablet. Additional drug-release units can be superimposed on the outside of the dissolution-blocking layer and / or swelling-blocking layer, such as adding a rapid-release layer of the same drug or other drugs. A drug-containing rapid-release coating layer can also be provided to encapsulate the three-layer tablet formulation. These are solutions that can be extended based on this invention and combined with conventional techniques in the art; the core effect remains the same: the drug-containing sustained-release layer in the three-layer tablet formulation achieves an exponential release pattern that is initially slow and then accelerates.

[0044] The three-layer tablets of this invention can be industrially scaled up using conventional tableting processes. The drug release pattern achieved is particularly suitable for medications targeting symptoms similar to asthma attack patterns (but not limited to this). Patients can take the medication before bedtime without affecting sleep. The drug components are released in an exponential pattern, meaning they gradually take effect and steadily increase blood drug concentration, reaching a sufficiently high blood drug concentration between midnight and early morning. This improves medication safety, effectively prevents symptom attacks, reduces drug toxicity and side effects, and the three-layer tablet preparation process is stable and convenient, facilitating industrial production.

[0045] The three-layer tablet provided by this invention enters the body first, then the stomach, and finally the intestines. The stomach is acidic, while the intestines are alkaline. The drug is released in an exponential manner, initially slowly and then rapidly. The faster drug release rate in the intestines results in a higher drug concentration in the bloodstream, which is more conducive to the long-term effectiveness of the drug.

[0046] Unless otherwise specified, all percentages mentioned in this invention refer to weight percentages. Attached Figure Description

[0047] Figure 1. Schematic diagram of the three-layer sheet structure of the present invention

[0048] Figure 2. Schematic diagram of the release principle and mechanism of the three-layer sheet of the present invention.

[0049] Figure 3 shows the in vitro dissolution curves of Examples 1-2 and Comparative Examples 1-2 of this application.

[0050] Figure 4. In vitro dissolution curves for Examples 3-4 and Comparative Examples 3-4 of this application.

[0051] Figure 5. In vitro dissolution curves for Examples 1-2 and Comparative Examples 5-6 of this application.

[0052] Figure 6. In vitro dissolution curves for Examples 5-6 and Comparative Examples 7-8 of this application.

[0053] Figure 7 shows the in vitro dissolution curves of Examples 7-8, Comparative Examples 2, and 9-10 of this application. Detailed Implementation

[0054] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention is further illustrated by the following exemplary embodiments. These embodiments are only used to illustrate the technical effects of the present invention and are not intended to limit the scope of protection of the present invention.

[0055] In the following examples and comparative examples, the effects were evaluated by in vitro dissolution curves. The dissolution method conditions used were as follows: Dissolution determination method II of the Chinese Pharmacopoeia, 50 rpm, medium of 900 ml, pH 1.2, and medium temperature of 37 ± 0.5 °C.

[0056] I. Investigation of the types of slow-release materials in the solution layer (Examples 1-2, Comparative Examples 1-2)

[0057] Example 1: Pressing 1000 three-layer sheets

[0058] The preparation method of the three-layer sheet in Example 1 of this invention (powder direct pressing method) is as follows:

[0059] (1) Dissolution barrier layer particles: Weigh out the prescribed amount of sustained-release material, binder and filler, mix for 3 minutes, and then pass them through a 40-mesh sieve with the lubricant. Mix again for 3 minutes to prepare dissolution barrier layer particles for later use.

[0060] (2) Drug-containing sustained-release granules: Weigh the prescribed amount of API, sustained-release material, filler and binder, mix for 3 minutes, and then pass them through a 40-mesh sieve with the lubricant. Mix again for 3 minutes to prepare drug-containing sustained-release granules for later use.

[0061] (3) Swelling barrier layer particles: Weigh out the prescribed amount of sustained-release material, binder and filler, mix for 3 minutes, and then pass them through a 40-mesh sieve with the lubricant. Mix again for 3 minutes to prepare swelling barrier layer particles for later use.

[0062] (4) Pressing multilayer tablets: Fill with the prescribed amount of swelling and blocking layer particles, pre-press; continue to fill with the prescribed amount of drug-containing sustained-release layer particles, pre-press; finally fill with the prescribed amount of erosion blocking layer particles, adjust the main pressure and press into three-layer tablets.

[0063] The structure of the resulting three-layer sheet is shown in Figure 1. Subsequent embodiments and comparative examples are the same.

[0064] Example 2: Pressing 1000 three-layer sheets

[0065] The method for preparing montelukast sodium three-layer tablets (wet granulation) in Example 2 of this invention is as follows:

[0066] (1) Dissolution barrier layer particles: Weigh the prescribed amount of sustained-release material, binder and filler, wet granulate with purified water, wet granulate through a 20-40 mesh sieve, dry, dry granulate through a 20-40 mesh sieve, add lubricant and mix again for 3 minutes to prepare dissolution barrier layer particles for later use.

[0067] (2) Drug-containing sustained-release layer granules: Weigh the prescribed amount of API, sustained-release material, filler and binder, wet granulate with purified water, wet granulate through a 20-40 mesh sieve, dry, dry granulate through a 20-40 mesh sieve, add lubricant and mix again for 3 minutes to prepare drug-containing sustained-release layer granules for later use.

[0068] (3) Swelling barrier layer particles: Weigh the prescribed amount of sustained-release material, binder and filler, wet granulate with purified water, wet granulate through a 20-40 mesh sieve, dry, dry granulate through a 20-40 mesh sieve, add lubricant and mix for 3 minutes to prepare swelling barrier layer particles for later use.

[0069] (4) Pressing multilayer tablets: Fill with the prescribed amount of swelling and blocking layer particles, pre-press; continue to fill with the prescribed amount of drug-containing sustained-release layer particles, pre-press; finally fill with the prescribed amount of erosion blocking layer particles, adjust the main pressure and press into three-layer tablets.

[0070] Comparative Example 1: 1000 three-layer films pressed together

[0071] The method for preparing montelukast sodium triple-layer tablets in Comparative Example 1 of this invention is the same as in Example 2.

[0072] Compared with Examples 1 and 2, the etch-resistant layer in this three-layer sheet uses microcrystalline cellulose instead of HPMC K200M or xanthan gum.

[0073] Comparative Example 2: Pressing 1000 double-layer sheets

[0074] The method for preparing sodium montelukast bilayer sheets in Comparative Example 2 of this invention is the same as steps (2), (3), and (4) in Example 2. Compared with Examples 1 and 2, this bilayer sheet lacks a top etch-resistant layer.

[0075] In vitro dissolution experiments were conducted on the tablets obtained in Examples 1 and 2, and Comparative Examples 1 and 2. The in vitro dissolution curves are shown in Figure 3. The three-layer tablets of Examples 1 and 2 both achieved ideal exponential release of the drug-containing sustained-release layer.

[0076] In the experiments of this invention, it was found that when the sustained-release material in the erosion-blocking layer is selected from cellulose (including hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose), high molecular polymers (including povidone, polyacrylic acid resin, polyvinyl alcohol, polyoxyethylene), non-cellulose polysaccharides (including sodium alginate, xanthan gum, sophora japonica gum, guar gum, tragacanth gum, agar, carbomer, chitosan), and waxy materials (including glyceryl behenate, carnauba wax, hydrogenated castor oil, stearic acid, stearyl alcohol, glyceryl monostearate, butyl stearate, and beeswax), and the proportions are appropriate (the weight percentage of the sustained-release material in a three-layer tablet is not higher than 15%), the erosion-blocking layer will continuously dissolve or detach after contact with the medium, gradually exposing the drug-containing sustained-release layer, which gradually progresses from partial exposure to complete exposure.

[0077] In Comparative Example 1, the slow-release material in the erosion-blocking layer was replaced with microcrystalline cellulose, while Comparative Example 2 did not have a erosion-blocking layer. As a result, the drug-containing slow-release layer could not release the drug in a gradual exposure to full exposure manner, and therefore, exponential release was not achieved.

[0078] II. Investigate the proportion of slow-release material in the dissolution-retaining layer (Examples 3-4, Comparative Examples 3-4)

[0079] Example 3: Pressing 1000 three-layer sheets

[0080] The method for preparing montelukast sodium triple-layer tablets in Example 3 of this invention is the same as in Example 1.

[0081] Example 4: Pressing 1000 three-layer sheets

[0082] The method for preparing montelukast sodium triple-layer tablets in Example 4 of this invention is the same as in Example 1.

[0083] Comparative ratio 3 pressing of 1000 three-layer films

[0084] The method for preparing montelukast sodium triple-layer tablets in Comparative Example 3 of this invention is the same as in Example 1.

[0085] Comparative ratio 4: 1000 three-layer films pressed together

[0086] The method for preparing montelukast sodium triple-layer tablets in Comparative Example 4 of this invention is the same as in Example 1.

[0087] In vitro dissolution tests were conducted on the tablets obtained in Examples 3 and 4, and Comparative Examples 3 and 4. The in vitro dissolution curves are shown in Figure 4. The three-layer tablets of Examples 3 and 4 both achieved an ideal exponential release of the drug-containing sustained-release layer, and the drug was completely released within 24 hours.

[0088] In contrast, in Comparative Examples 3 and 4, the proportion of slow-release material in the dissolution barrier layer (based on three-layer tablets) exceeded 15%, the drug slow-release layer did not achieve exponential release, and the dissolution rate was only about 50% within 24 hours.

[0089] III. Investigation of the types of sustained-release materials in the swelling barrier layer (Examples 1-2, Comparative Examples 5-6)

[0090] Comparative ratio 5 pressing of 1000 three-layer films

[0091] The method for preparing montelukast sodium triple-layer tablets in Comparative Example 5 of this invention is the same as in Example 1.

[0092] Comparative ratio 6 pressing 1000 three-layer films

[0093] The method for preparing montelukast sodium triple-layer tablets in Comparative Example 6 of this invention is the same as in Example 1.

[0094] In vitro dissolution tests were conducted on the tablets obtained in Examples 1 and 2, namely Comparative Examples 5 and 6. The in vitro dissolution curves are shown in Figure 5. Compared with the three-layer tablets of Examples 1 and 2, the sustained-release material of the swelling retardation layer in Comparative Examples 5 and 6 was replaced with KSR and glyceryl behenate. The dissolution curves show that Comparative Examples 5 and 6 both exhibited zero-order release and did not achieve exponential release.

[0095] The swelling barrier layer supports the drug-containing sustained-release layer. Upon contact with the medium, it must expand but not detach, and be difficult to dissolve or dissolve slowly. This prevents the drug components from agglomerating (being encapsulated by gel-type sustained-release materials, making release difficult / slow). This ensures that the exposed surface remains intact during drug release. At the same time, the expanding swelling barrier layer extends the exposed surface of the drug-containing sustained-release layer, increasing the contact area with the medium, thereby accelerating the drug release rate in the later stages and forming an exponential release pattern.

[0096] During the development of this invention, it was discovered that when the sustained-release material in the swelling retardation layer is made of cellulose (including hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose), high molecular polymers (including povidone, polyacrylic acid resin, polyvinyl alcohol, polyoxyethylene), or non-cellulose polysaccharides (including sodium alginate, xanthan gum, sophora bean gum, guar gum, tragacanth gum, agar, carbomer, chitosan) in appropriate proportions (the proportion of sustained-release material contained in the swelling retardation layer is not less than 25%, preferably 30% to 60%), the swelling retardation layer can meet the requirements and thus support the exponential release of the drug-containing sustained-release layer in the three-layer tablet.

[0097] IV. Investigate the proportion of slow-release material in the dissolution-inhibiting layer (Examples 1-2, 5-6 and Comparative Examples 7-8)

[0098] Example 5: Pressing 1000 three-layer sheets

[0099] The method for preparing montelukast sodium triple-layer tablets in Example 5 of this invention is the same as in Example 1.

[0100] Example 6: Pressing 1000 three-layer sheets

[0101] The method for preparing montelukast sodium triple-layer tablets in Example 6 of this invention is the same as in Example 1.

[0102] Comparative ratio 7 pressing of 1000 three-layer films

[0103] The method for preparing montelukast sodium triple-layer tablets in Comparative Example 7 of this invention is the same as in Example 1.

[0104] Comparative ratio 8 pressing of 1000 three-layer films

[0105] The method for preparing montelukast sodium triple-layer tablets in Comparative Example 8 of this invention is the same as in Example 1.

[0106] In vitro dissolution tests were conducted on the tablets obtained in Examples 5 and 6, and Comparative Examples 7 and 8. The in vitro dissolution curves are shown in Figure 6. In the three-layer tablets of Examples 1 and 2 (Figure 3) and Examples 5 and 6, the sustained-release material in the swelling retardation layer was higher than 25%, which promoted exponential release. However, in Comparative Examples 7 and 8, the proportion of sustained-release material in the swelling retardation layer was lower than 25%, and the dissolution curves showed that exponential release was not achieved.

[0107] V. Investigate the swelling / dissolution layer weight ratio (Examples 7-8, Comparative Example 2, Comparative Example 9-10)

[0108] Example 7: Pressing 1000 three-layer sheets

[0109] The method for preparing montelukast sodium three-layer tablets in Example 7 of this invention is the same as in Example 1. The specific gravity of the swelling barrier layer and the etching barrier layer is 6.

[0110] Example 8: Pressing 1000 three-layer sheets

[0111] The method for preparing montelukast sodium three-layer tablets in Example 8 of this invention is the same as in Example 1. The specific gravity of the swelling barrier layer and the etch barrier layer is 4.

[0112] Comparative ratio 9 pressing of 1000 three-layer films

[0113] The method for preparing sodium montelukast triple-layer tablets in Comparative Example 9 of this invention is the same as in Example 1. The specific gravity of the swelling barrier layer and the etch barrier layer is 1.

[0114] Comparative ratio 10 pressing of 1000 three-layer films

[0115] The method for preparing montelukast sodium triple-layer tablets in Comparative Example 10 of this invention is the same as in Example 1.

[0116] Comparative Example 10 has the same formulation as Example 8, except that the ratio of the swelling barrier layer to the erosion barrier layer is 1, while it is 4 in Example 8.

[0117] In vitro dissolution experiments were conducted on the tablets obtained in Examples 7-8, Comparative Examples 2, and Comparative Examples 9-10. The dissolution data are shown in Figure 7: When the layer weight ratio of the swelling barrier layer to the erosion barrier layer is higher than 2 (for example, the ratio is 6 in Example 7 and 4 in Example 8), it can promote the achievement of an ideal exponential release pattern.

[0118] Comparative Example 10 and Example 8 have the same formulation, except that the ratio of the swelling barrier layer to the erosion barrier layer is 1 in Comparative Example 10, while it is 4 in Example 8. The dissolution curves show that Example 8 achieved an ideal exponential release, while Comparative Example 10 had a zero-order release and a significantly lower dissolution rate than Example 8 within 24 hours.

[0119] In Comparative Example 2, due to the lack of a dissolution barrier layer, the drug was rapidly released in zero-order mode within the contact time with the medium. In Comparative Example 9, the ratio of the swelling barrier layer to the dissolution barrier layer was less than 2, and its dissolution curve was similar to that of Comparative Example 10, which was a zero-order release. Moreover, the dissolution rate within 24 hours was significantly lower than that of Examples 7 and 8, resulting in the inability to achieve an effective blood drug concentration.

Claims

1. A three-layered tablet formulation, characterized in that: The three layers are combined together in a stacked manner: a swelling retardant layer, which has the property of slowly swelling after absorbing water, supports the drug-containing sustained-release layer and retards the contact between the bottom surface of the drug-containing sustained-release layer and the medium; the swelling retardant layer contains a sustained-release material, a filler, a binder and a lubricant; a drug-containing sustained-release layer, which contains a sustained-release material, a filler, a binder and a lubricant; an erosion retardant layer, which has the property of slowly eroding or falling off after absorbing water, covers the top surface of the drug-containing sustained-release layer, and contains a sustained-release material, a filler, a binder and a lubricant; the drug-containing sustained-release layer is sandwiched between the swelling retardant layer and the erosion retardant layer; the drug component in the drug-containing sustained-release layer is released in an exponential manner, which is slow at first and then fast.

2. The three-layer tablet formulation according to claim 1, characterized in that: The swelling retardant layer accounts for more than 50% of the weight of the three-layer tablet formulation, and the erosion retardant layer accounts for no more than 25% of the weight of the three-layer tablet formulation.

3. The three-layer tablet formulation according to claim 1, characterized in that: The swelling retardant layer contains a sustained-release material in an amount of no less than 25% by weight based on the weight of the three-layer tablet formulation; the erosion retardant layer contains a sustained-release material in an amount of no more than 15% by weight based on the weight of the three-layer tablet formulation; and the drug-containing sustained-release layer contains a sustained-release material in an amount of 2-15% by weight based on the weight of the three-layer tablet formulation.

4. The three-layer tablet formulation according to claim 1, characterized by: The swelling retardant layer contains a sustained-release material in an amount of 30-60% by weight based on the weight of the three-layer tablet formulation; the erosion retardant layer contains a sustained-release material in an amount of 3-15% by weight based on the weight of the three-layer tablet formulation; and the drug-containing sustained-release layer contains a sustained-release material in an amount of 2-15% by weight based on the weight of the three-layer tablet formulation.

5. The three-layer tablet formulation according to claim 1, characterized in that: The swelling retardant layer contains a sustained-release material in an amount of 30-60% by weight based on the weight of the three-layer tablet formulation; the erosion retardant layer contains a sustained-release material in an amount of 3-15% by weight based on the weight of the three-layer tablet formulation; and the drug-containing sustained-release layer contains a sustained-release material in an amount of 2-15% by weight based on the weight of the three-layer tablet formulation. The sustained-release material in the swelling retardant layer is a gel matrix type sustained-release material selected from one or more of cellulose, a high molecular polymer and a non-cellulose polysaccharide; 6. The three-layer tablet formulation according to claim 1, characterized in that: The cellulose includes hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose and carboxymethyl cellulose; the high molecular polymer includes povidone, polyacrylic acid resin, polyvinyl alcohol and polyoxyethylene; and the non-cellulose polysaccharide includes sodium alginate, xanthan gum, locust bean gum, guar gum, tragacanth gum, agar, carbomer and chitosan. The sustained-release material in the drug-containing sustained-release layer and the erosion retardant layer is selected from one or more of cellulose, a high molecular polymer, a non-cellulose polysaccharide and a waxy material; 7. The three-layer tablet formulation according to claim 1, characterized by: The cellulose includes hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose and carboxymethyl cellulose; the high molecular polymer includes povidone, polyacrylic acid resin, polyvinyl alcohol and polyoxyethylene; the non-cellulose polysaccharide includes sodium alginate, xanthan gum, locust bean gum, guar gum, tragacanth gum, agar, carbomer and chitosan; and the waxy material includes glyceryl behenate, carnauba wax, hydrogenated castor oil, stearic acid, octadecanol, glyceryl monostearate, butyl stearate and beeswax.

8. The three-layer tablet formulation according to claim 1, characterized by: The filler in each layer is selected from one or more of calcium carbonate, microcrystalline cellulose, sucrose, lactose, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, mannitol and starch; and the content of the filler in each layer is 20-80% or 30-60% by weight based on the weight of the layer. The binder in each layer is selected from one or more of povidone, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, sugar syrup, gum syrup and starch syrup; and the content of the binder in each layer is 1-8%, or 1-6%, or 2-4% by weight based on the weight of the layer.

9. The three-layer tablet formulation according to claim 1, characterized in that: The lubricant in each layer is selected from one or more of calcium stearate, magnesium stearate, mineral oil, talc, sorbitol, stearic acid, zinc stearate, ethyl oleate, ethyl laurate; the content of the lubricant in each layer is 1-2% based on the weight of the layer.

10. The three-layer tablet formulation according to claim 1, characterized in that: The ratio of the layer weight of the swelling retardant layer to the erosion retardant layer is ≥2, preferably the ratio of the layer weight is ≥4.

11. The tri-layer tablet formulation according to claim 1, further having one or more of the following features: (i) the three layers combined together in a stack have the same or different top and bottom surface areas; (ii) the swelling retardant layer is free of drug; or contains drug, but the drug is the same as or different from the drug in the drug-containing sustained release layer; (iii) the erosion retardant layer is free of drug; or contains drug, but the drug is the same as or different from the drug in the drug-containing sustained release layer; (iv) the tri-layer tablet further comprises a coating layer; preferably, the coating layer contains drug; (v) the drug in the drug-containing sustained release layer is montelukast sodium.

12. A multi-layer tablet characterized by, The outer surface of the swelling retardant layer and / or the erosion retardant layer of the tri-layer tablet formulation according to any one of claims 1-11 further has a immediate release layer, which contains the same or different drug as the drug-containing sustained release layer.

13. A process for the preparation of a tri-layer tablet formulation according to any one of claims 1 to 11, characterized in that The method comprises the following steps: (1) Preparing the erosion retardant layer granules: the prescription amount of sustained release material, binder, filler is mixed for 2-5 minutes, then passed through a 20-40 mesh sieve with lubricant, mixed again for 2-5 minutes, to prepare the erosion retardant layer granules; (2) Preparing the drug-containing sustained release layer granules: the prescription amount of API, sustained release material, filler, binder is mixed for 3 minutes, then passed through a 20-40 mesh sieve with lubricant, mixed again for 3 minutes, to prepare the drug-containing sustained release layer granules; (3) Preparing the swelling retardant layer granules: the prescription amount of sustained release material, binder, filler is mixed for 3 minutes, then passed through a 20-40 mesh sieve with lubricant, mixed again for 3 minutes, to prepare the swelling retardant layer granules; (4) Pressing into multi-layer tablets: filling the prescription amount of swelling retardant layer granules in the tablet press, pre-pressing; continue to fill the prescription amount of drug-containing sustained release layer granules, pre-pressing; finally fill the prescription amount of erosion retardant layer granules, adjust the main pressure to press into tri-layer tablets.

14. A process for the preparation of a tri-layer tablet formulation according to any one of claims 1 to 11, characterized in that The method comprises the following steps: (1) Preparing the erosion retardant layer granules: the prescription amount of sustained release material, binder, filler is mixed for 2-5 minutes, then passed through a 20-40 mesh sieve with lubricant, mixed again for 2-5 minutes, to prepare the erosion retardant layer granules; (2) Preparing the drug-containing sustained release layer granules: the prescription amount of API, sustained release material, filler, binder is mixed for 3 minutes, then passed through a 20-40 mesh sieve with lubricant, mixed again for 3 minutes, to prepare the drug-containing sustained release layer granules; (3) Preparing the swelling retardant layer granules: the prescription amount of sustained release material, binder, filler is mixed for 3 minutes, then passed through a 20-40 mesh sieve with lubricant, mixed again for 3 minutes, to prepare the swelling retardant layer granules; (4) Pressing into multi-layer tablets: filling the prescription amount of swelling retardant layer granules in the tablet press, pre-pressing; continue to fill the prescription amount of drug-containing sustained release layer granules, pre-pressing; finally fill the prescription amount of erosion retardant layer granules, adjust the main pressure to press into tri-layer tablets. (4) Compression of multilayer tablets: fill the prescription amount of swell- retard layer granules, pre-press; continue to fill the prescription amount of drug-containing sustained-release layer granules, pre-press; finally fill the prescription amount of erodible retard layer granules, adjust the main pressure to compress into three-layer tablets.

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