Multi-dose-form program-release alprimilast double-layer tablet, preparation method and application of multi-dose-form program-release alprimilast double-layer tablet

Abstract

The invention relates to a multi-dose form program release alprimilast double-layer tablet and a preparation method and application thereof.The multi-dose form program release alprimilast double-layer tablet comprises a quick-release tablet layer containing enteric particles and a bioadhesive sustained-release tablet layer containing sustained-release enteric particles, and the enteric particles in the quick-release tablet layer comprise sugar balls, a drug polymer matrix and an enteric coating; the drug polymer comprises aprecilast and hydroxypropyl methyl cellulose, and the enteric coating comprises any one of phthalic acid hydroxypropyl methyl cellulose and a methacrylic acid copolymer. The alpramilast double-layer tablet has the effect of improving the high efficiency of the alpramilast double-layer tablet.

Description

Technical Field

[0001] This application relates to the field of apremilast drug delivery systems, and in particular to an apremilast bilayer tablet with multi-dose form programmed drug release, a preparation method thereof, and an application thereof. Background Art

[0002] Apremilast is a phosphodiesterase 4 (PDE4) inhibitor used to treat inflammations such as psoriasis and psoriatic arthritis. More importantly, apremilast needs to be taken once every 12 hours, and the dosage gradually increases in sequence. The first four doses are 10 mg, and the subsequent four doses are 20 mg and 30 mg to maintain treatment.

[0003] Each medication needs to be repeated every 12 hours, which brings inconvenience to patients, especially elderly patients. In addition, the traditional dosage forms of apremilast often lead to unsatisfactory treatment effects due to changes in drug absorption and patient compliance. Therefore, there is a need for a drug delivery system that can targetedly control the release of apremilast to improve efficacy, reduce side effects, and improve patient compliance. Summary of the Invention

[0004] To solve the above technical problems, this application provides an apremilast bilayer tablet with multi-dose form programmed drug release, a preparation method thereof, and an application thereof.

[0005] In the first aspect, an apremilast bilayer tablet with multi-dose form programmed drug release provided by this application adopts the following technical solution: An apremilast bilayer tablet with multi-dose form programmed drug release includes an immediate-release tablet layer containing enteric-coated granules and a bioadhesive sustained-release tablet layer containing sustained-release enteric-coated granules. The enteric-coated granules in the immediate-release tablet layer include sugar spheres, a drug polymer matrix, and an enteric coating. The drug polymer includes apremilast and hydroxypropyl methylcellulose, and the enteric coating includes any one of hydroxypropyl methylcellulose phthalate and methacrylic acid copolymer.

[0006] Preferably, the sustained-release enteric-coated granules in the bioadhesive sustained-release tablet layer include sugar spheres, a drug polymer matrix, an enteric coating, and a bioadhesive polymer coating prepared from a bioadhesive polymer. The bioadhesive polymer includes any one or a mixture of chitosan, polycarbophil, and sodium alginate.

[0007] Preferably, the immediate-release tablet layer includes apremilast, lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate.

[0008] Preferably, the bioadhesive sustained-release layer includes apremilast, poly(lactic-co-glycolic) acid, chitosan, lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate.

[0009] Preferably, the enteric-coated granules are prepared by the following method: The sugar spheres are coated with a drug-polymer matrix using the Wurster coating method, and then coated with an enteric coating to obtain enteric-coated granules.

[0010] Preferably, the sustained-release enteric-coated granules are prepared by the following method: The sugar spheres are coated with a drug-polymer matrix using the Wurster coating method, then coated with an enteric coating, and further coated with a bioadhesive polymer coating.

[0011] In a second aspect, the present application provides a method for preparing an apremilast bilayer tablet with programmed drug release in a dosage form, adopting the following technical solution: A method for preparing an apremilast bilayer tablet with programmed drug release in a dosage form, comprising the following steps: S1. Coating sugar spheres with a drug-polymer matrix and enteric coating to prepare enteric-coated granules; S2. Further coating the enteric-coated granules with a bioadhesive polymer to prepare sustained-release enteric-coated granules; S3. Mixing apremilast, excipients and enteric-coated granules to prepare an immediate-release tablet layer; S4. Mixing apremilast, bioadhesive polymer, excipients and sustained-release enteric-coated granules to prepare a bioadhesive sustained-release tablet layer; S5. Using a bilayer tablet press to compress the immediate-release tablet layer and the bioadhesive sustained-release tablet layer into a bilayer tablet to obtain the product.

[0012] In a third aspect, the present application provides an application of an apremilast bilayer tablet with programmed drug release in a dosage form, adopting the following technical solution: An application of an apremilast bilayer tablet with programmed drug release in a dosage form, wherein the apremilast bilayer tablet with programmed drug release in a multi-dose form is used for treating inflammation, including psoriasis and psoriatic arthritis.

[0013] In the present application, the immediate-release tablet layer containing enteric-coated granules is an immediate-release tablet containing apremilast and pharmaceutically acceptable excipients. It also contains enteric-coated granules, and the drug will be released after reaching the colon. The polymer is selected from phthalic acid polymers. The immediate-release tablet layer will release 10, 20 or 30 mg of the first-dose drug according to the protocol. The immediate-release pill further enters the intestine, and as the pH value increases, the second-dose drug starts to be released after 12 hours.

[0014] The bioadhesive sustained-release tablet layer contains a sustained-release component. The tablet contains a polymer matrix layer with strong bioadhesiveness, which can release the drug after swelling for 24 hours. The drug released after 24 hours is the third dose. It also contains enteric-coated pellets, and a bioadhesive sustained-release tablet layer is further coated on the pellets to enhance the retention in the stomach. After breaking the bioadhesive polymer, the particles coated with the bioadhesive polymer will be released in the stomach and remain in the stomach for 3 - 5 hours. Subsequently, it will enter the colon and release the fourth dose of the drug after 36 hours.

[0015] In enteric-coated granules, sugar spheres can serve as an inert carrier for the drug, providing a uniform surface for the coating of the drug and the polymer layer; ready-made spheres made of sugar or pharmaceutically acceptable materials are coated with a mixture of apremilast and a pharmaceutically acceptable polymer in a suitable carrier; in addition, the drug matrix-loaded spheres are coated with an enteric polymer coating using a pharmaceutically acceptable polymer.

[0016] The sustained-release enteric-coated granules are further coated with a bioadhesive material for retention and delayed release in the stomach. Subsequently, it will reach the colon and release the drug.

[0017] In summary, this application includes at least one of the following beneficial technical effects: 1. Combining the immediate-release tablet layer and the bioadhesive sustained-release tablet layer into a single double-layer tablet realizes the preset drug release curve of simulated pulsatile drug delivery. This product can ensure the controlled and targeted release of apremilast at specific time intervals, thereby improving the therapeutic effect, minimizing side effects, and improving patient compliance. 2. Using enteric-coated granules, bioadhesive polymers, and sugar spheres as inert carriers can precisely deliver the drug to the colon and other target sites. In vitro dissolution studies confirm that this system can release four doses of apremilast within 48 hours, indicating its potential to replace traditional multi-dose therapies. This innovation solves the problems of patient compliance and drug absorption variability, providing a more convenient and effective treatment option for inflammations such as psoriasis and psoriatic arthritis.

[0018] Description of the Drawings Figure 1 It is a cross-sectional schematic diagram of the apremilast double-layer tablet.

[0019] Figure 2 It is a cross-sectional schematic diagram of the enteric-coated granules.

[0020] Figure 3 It is a cross-sectional schematic diagram of the sustained-release enteric-coated granules. Detailed Description of the Invention

[0021] The following further elaborates on this application in conjunction with examples: Description of raw materials: All raw materials in the examples are commercially available; Example 1 The immediate-release tablet layer is composed of pharmaceutically acceptable components; the bioadhesive sustained-release tablet layer is composed of a drug-polymer matrix and other pharmaceutically acceptable components. The enteric-coated granules are composed of pharmaceutically acceptable spheres, on which a drug in a pharmaceutically acceptable polymer is coated, and then an enteric polymer is further coated. The sustained-release enteric-coated granules are composed of pharmaceutically acceptable spheres, in which a drug is coated in a pharmaceutically acceptable polymer, and then an enteric polymer is further coated. Then, a bioadhesive polymer is coated on the enteric-coated granules.

[0022] Example 2 The immediate-release tablet layer is composed of apremilast, lactose monohydrate, microcrystalline cellulose, C-tranexamic acid sodium, and magnesium stearate. The bioadhesive sustained-release tablet layer is composed of apremilast, polycarbophil, chitosan, lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl cellulose, and magnesium stearate. The enteric-coated granules are composed of sugar spheres, on which the drug is coated in a hydroxypropyl methylcellulose matrix, and then coated with hydroxypropyl methylcellulose phthalate. The sustained-release enteric-coated granules are composed of sugar spheres, on which the drug is coated in a hydroxypropyl methylcellulose matrix, and then further coated with hydroxypropyl methylcellulose phthalate. Then, chitosan, polylactic acid-polyglycolic acid, sodium alginate, polycarbophil, or a combination of any substances is coated on the enteric-coated granules.

[0023] Example 3 The immediate-release tablet layer is prepared by granulating a mixture of apremilast, lactose monohydrate, microcrystalline cellulose, C-chelate starch sodium, and magnesium stearate by a granulation method. The bioadhesive sustained-release tablet layer is composed of apremilast, polylactic acid-co-glycolic acid, chitosan, lactose monohydrate, microcrystalline cellulose, C-microcitrusin sodium, and magnesium stearate. The enteric-coated granules are composed of sugar spheres, on which the drug is coated in a hydroxypropyl methylcellulose matrix, and then coated with a layer of hydroxypropyl methylcellulose phthalate; all coating processes are carried out using a pusher coating method. The sustained-release enteric-coated granules are composed of sugar spheres, on which the drug is coated in a hydroxypropyl methylcellulose matrix, and then coated with hydroxypropyl methylcellulose phthalate. Then, a composition of chitosan and polylactic acid-co-glycolic acid is coated on the enteric-coated granules; all coating processes are carried out using a pusher coating method.

[0024] Example 4 Preparation of bilayer tablets: The enteric-coated granules were prepared by using sugar spheres as templates, coating the drug-polymer matrix, and then preparing the enteric coating using the wruster coating method and phthalic acid polymers; a part of the enteric-coated granules was further coated with bioadhesive polymers using the worm coating method. The various components were mixed and granulated, and then the granules were mixed with the enteric-coated granules to prepare the bulk powder of the immediate-release tablet layer. The bulk powder of the bioadhesive sustained-release tablet layer was prepared by mixing the raw materials, granulating, and mixing the granules with the sustained-release enteric granules. Tableting was performed using a bilayer tablet press to obtain the product.

[0025] Example 5 Preparation of bilayer tablets: Apremilast and hydroxypropyl methylcellulose dispersed in a suitable solvent were coated using sugar spheres as templates, and then enteric coating was performed using hydroxypropyl methylcellulose phthalate to prepare enteric-coated granules. A part of the enteric-coated granules was further coated with polycarbophil and chitosan polymers using the peristaltic coating method. Apremilast, lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl cellulose, and magnesium stearate were mixed to prepare the bulk powder of the immediate-release tablet layer, and these components were granulated and then the granules were mixed with the enteric-coated granules. Apremilast, poly(lactic-co-glycolic) acid, chitosan, lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl cellulose, and magnesium stearate were mixed, granulated, and the granules were mixed with the sustained-release enteric granules to prepare the bulk powder of the bioadhesive sustained-release tablet layer. Tableting was performed using a bilayer tablet press to obtain the product.

[0026] Preparation of enteric-coated granules: Table 1 Configuration table of enteric-coated granules Drug loading: Apremilast, sugar spheres, hydroxypropyl methylcellulose, and ethanol required for a 500-gram batch were prepared. The required amount of ethanol was added to the SS container and stirred to form a slight vortex. Apremilast was added under stirring and stirred until a uniform dispersion was prepared. Hydroxypropyl methylcellulose was added under stirring and stirred until uniformly dispersed. The solution was stirred throughout the drug layering process. The required amount of sugar spheres was added to the fluidized bed processor (GPCG 1.1), and the initial process parameters were set according to the following specifications, and the sugar spheres were preheated until the temperature reached 38 ± 4 °C. The remaining spray components were connected to the fluidized bed equipment, and the drug loading solution was started to be sprayed onto the granules according to the following parameters.

[0027] Table 2 Process parameters Number Process parameter Spraying Drying 1 Inlet temperature 50℃±10℃ 42℃±5℃ 2 Product temperature 38℃±4℃ 36℃±3℃ 3 Exhaust temperature 29℃±2℃ 29℃±2℃ 4 Atomizing air 1.2 bar Closed 5 Spray pump (rpm) 5 rpm ± 1 rpm Closed 6 Airflow 25％ 32％ Note to avoid the formation of twins due to too low temperature or too fast spraying speed. The spraying rate was monitored and recorded throughout the process. The yield was continuously monitored and spraying was continued until the target weight gain was achieved. The weight of the spraying solution and the obtained yield were recorded. The drug-loaded granules were dried.

[0028] Enteric coating: Prepare the required amounts of hydroxypropyl methylcellulose phthalate, castor oil, diacetylated monoglyceride, ethanol, dichloromethane, and purified water. Add the required amount of ethanol to an SS container and stir to form a gentle vortex. Then add hydroxypropyl methylcellulose phthalate while stirring the ethanol. Slowly add dichloromethane, castor oil, and diacetylated monoglyceride one by one to the above dispersion under stirring. The solution is kept under stirring throughout the enteric coating process. Transfer the required number of drug-loaded granules to a fluidized bed processor (GPCG 1.1) and preheat the granules until the temperature reaches 30 ± 5 °C. Set the remaining spraying components of the fluidized bed process and start spraying the enteric release coating solution onto the encapsulated granules according to the parameters mentioned below. Take care to avoid the formation of twins due to too low temperature or too fast spraying speed. Monitor and record the spraying rate throughout the process. Monitor the yield obtained and continue spraying until the target weight gain (30%) is reached. Record the weight of the spraying solution and the yield obtained. Dry the enteric granules according to the following parameters or settings.

[0029] Table 3 Drying Parameters of Enteric Granules Preparation of Sustained Release Enteric Granules: Table 4 Ingredient Table of Sustained Release Enteric Granules Use the enteric granules for further coating with a bioadhesive polymer. Screen the granules beforehand to remove fine particles, lumps, or oversized particles. Prepare the chitosan solution by dissolving chitosan in a suitable solvent of 3% acetic acid and water; prepare the poly(lactic-co-glycolic) acid solution by dissolving poly(lactic-co-glycolic) acid in dichloromethane and ethanol (mass ratio 1:1). Preheat the granules to the temperature of the Wurster coating chamber (30 - 40 °C). Adjust the air flow to enable uniform movement of the granules in the coating chamber. Spray the chitosan solution onto the fluidized granules using a Wurster coating nozzle and maintain a stable spraying rate and atomization pressure to ensure uniform coating. Control the inlet air temperature to gradually dry the chitosan layer (avoid over-drying or caking). Continue the process until the chitosan layer thickness is uniform. Let the chitosan-coated granules dry completely in the fluidized bed. Switch to the poly(lactic-co-glycolic) acid solution and spray it onto the chitosan-coated granules. Adjust the spraying speed and atomization pressure to ensure uniform spraying. Control the inlet air temperature to evaporate the organic solvent while avoiding damage to the chitosan layer. Continue the process until the poly(lactic-co-glycolic) acid coating thickness is uniform. Let the coated granules dry completely in the fluidized bed to remove any residual solvent. If necessary, cure the coated granules at a controlled temperature to improve the stability and integrity of the coating. Cool the system to room temperature using the ambient air in the fluidized bed to obtain the sustained release enteric granules.

[0030] Preparation of immediate-release tablet layer powder: Table 5 Formulation of immediate-release tablet layer powder Note: *The enteric-coated granules are prepared at the strength equivalent to apremilast. Preparation steps: Dispense each ingredient into a polyethylene bag and seal it tightly after dispensing; Sieving: Pass apremilast, lactose monohydrate, microcrystalline cellulose, and sodium carbocysteine through a 30-mesh sieve using an electric sieve, and then collect the mixture in a polyethylene bag; Mixing: Transfer the mixture to a stirrer, then add the enteric-coated granules and stir at a speed of 5 - 25 rpm for 10 - 20 minutes; Lubrication: Sieve magnesium stearate through a 60-mesh sieve, add it to the stirrer in the previous step, and stir for 10 - 20 minutes to obtain the powder.

[0031] Preparation of bioadhesive sustained-release tablet layer powder: Table 6 Formulation of bioadhesive sustained-release tablet layer powder Note: *The enteric-coated granules are prepared at the strength equivalent to apremilast. Preparation method: Ingredient preparation: Dispense each ingredient into a polyethylene bag and seal it tightly after dispensing; Sieving: Pass apremilast, lactose monohydrate, chitosan, polylactic acid, microcrystalline cellulose, and sodium carboxymethylcellulose through a 30-mesh sieve using an electric sieve, and then collect the mixture in a polyethylene bag; Mixing: Transfer the mixture to a stirrer, add the enteric-coated granules coated with a bioadhesive polymer, and stir for 10 - 20 minutes; Lubrication: Sieve magnesium stearate through a 60-mesh sieve, add it to the stirrer in the previous step, and stir at a speed of 5 - 25 RPM for 10 - 20 minutes to obtain the bioadhesive sustained-release tablet layer powder.

[0032] Tabletting: Use a double-layer tabletting machine to tablet the powders prepared in Example 3 and Example 4 to cover tablets and apremilast with sufficient strength. The tabletting speed is maintained at 20 - 60 tablets per minute.

[0033] Dissolution study: Conduct a dissolution study using a dissolution study instrument II (paddle type) at a speed of 60 rpm. The first dissolution medium is the acidic stage (A): 100 mM HCl; the buffer stage (B): phosphate buffer pH 6.4; the buffer solution stage (C): phosphate buffer pH 7.2.

[0034] Table 7 Schematic table of dissolution Medium Example 1 Example 2 Example 3 Example 4 Acidic phase (A): 0.85％ 0.00％ 101％ 98.93％ 100 mmol hydrochloric acid 1.21％ 0.18％ 0.95％ 2.07％ Buffering phase (B): 96.23％ 98.47％ 97.21％ 98.54％ Each formulation example demonstrated excellent release performance within the target medium and time. The enteric-coated granules and sustained-release enteric-coated granules showed the least drug release in acidic and pH 6.8 buffer solutions, while the maximum drug release occurred in pH 7.2 phosphate buffer solution. The immediate-release tablet layer containing the enteric-coated granule powder released the drug for the first time under acidic conditions and for the second time in pH 7.2 phosphate buffer solution. The same was true for the bioadhesive sustained-release powder, except that there was a certain lag time in drug release.

[0035] Tablet dissolution study: According to the target dissolution time, the compressed tablets of Example 5 were immersed in different media. The tablets were carefully separated into two layers to keep each layer intact without breaking and were divided into two sieve baskets with a size smaller than the particle size. Initially, the tablet layer was immersed in 750 m 100 mM HCl. After 4 hours, the immediate-release layer was transferred to pH 6.8 phosphate buffer solution. After 8 hours, the immediate-release granules at pH 6.8 were transferred to pH 7.2 phosphate buffer solution. The bioadhesive tablet layer was kept in 100 mM HCl for 28 hours, and then the exposed basket containing the granules was transferred to pH 6.8 phosphate buffer solution for another 8 hours. After 8 hours, the immediate-release granules at pH 6.8 were transferred to pH 7.2 phosphate buffer solution.

[0036] Table 8 Schematic table of tablet dissolution The dissolution curves of the tablets and the sealants showed that the drug release at different positions after every 12 hours was similar to that of the pulsatile drug delivery system. In vitro dissolution confirmed that four doses of apremilast tablets could be combined into one tablet, and the drug was released in vivo once every 12 hours.

[0037] This specific embodiment is merely an interpretation of the present application and does not limit the present application. Through the above description, relevant staff can make various changes and modifications completely within the scope without deviating from the technical idea of this application. The technical scope of this application is not limited to the content in the specification and must be determined according to the scope of the claims.

Claims

1. A multi-dose programmed release apremilast bilayer tablet, characterized in that: The invention comprises a quick-release tablet layer containing enteric granules and a bioadhesive sustained-release tablet layer containing sustained-release enteric granules. The enteric granules in the quick-release tablet layer comprise sugar spheres, a drug polymer matrix and an enteric coating. The drug polymer matrix comprises apremilast and hydroxypropyl methylcellulose. The enteric coating comprises any one of hydroxypropyl methylcellulose phthalate and methacrylic acid copolymer.

2. The multi-dose programmed release apremilast bilayer tablet according to claim 1, characterized in that: The sustained-release enteric granules in the bioadhesive sustained-release tablet layer include sugar spheres, a drug polymer matrix, an enteric coating and a bioadhesive polymer coating prepared from a bioadhesive polymer, wherein the bioadhesive polymer includes any one or more of chitosan, polycarbophil and sodium alginate.

3. The multi-dose programmed release apremilast bilayer tablet according to claim 1, characterized in that: The immediate release tablet layer includes apremilast, lactose monohydrate, microcrystalline cellulose, sodium methylcellulose and magnesium stearate.

4. The multi-dose programmed release apremilast bilayer tablet according to claim 1, characterized in that: The bioadhesive sustained-release layer includes apremilast, poly(lactic-co-glycolic) acid, chitosan, lactose monohydrate, microcrystalline cellulose, sodium methylaminosuccinate and magnesium stearate.

5. The multi-dose programmed release apremilast bilayer tablet according to claim 1, characterized in that: The enteric-coated granules are prepared by the following method: The sugar spheres were coated with the drug polymer matrix using the Wurster coating method and then coated with an enteric coating to obtain enteric granules.

6. The multi-dose programmed release apremilast bilayer tablet according to claim 1, characterized in that: The sustained-release enteric-coated granules are prepared by the following method: The sugar spheres were coated with a drug polymer matrix using the Wurster coating method, applied with an enteric coating, and coated with a bioadhesive polymer coating.

7. A method for preparing apremilast bilayer tablets for programmed drug release in dosage form according to any one of claims 1 to 6, characterized in that: The steps include: S1, coating the sugar spheres with a drug polymer matrix and an enteric coating to prepare enteric granules; S2, further coating the enteric granules with a bioadhesive polymer to prepare sustained-release enteric granules; S3, Apremilast, excipients and enteric-coated granules are mixed to prepare an immediate-release tablet layer; S4, mixing apremilast, bioadhesive polymer, excipients and sustained-release enteric granules to prepare a bioadhesive sustained-release tablet layer; S5. Use a double-layer tablet press to compress the immediate-release tablet layer and the bioadhesive sustained-release tablet layer into a double-layer tablet to obtain a product.

8. Use of a premilast bilayer tablet with programmed drug release in a multi-dose form according to any one of claims 1 to 7, characterized in that: The multiple-dose programmed-release apremilast bilayer tablet is useful for treating inflammatory diseases, including psoriasis and psoriatic arthritis.

Images