Two-phase release control preparation and method for producing the same

Abstract

The present invention relates to a biphasic release control preparation composed of three layers, namely an immediate release layer, a core layer, and a barrier layer, and a method for producing the same. The immediate release layer rapidly elutes in vitro, and zero-order release in vitro is maintained by the combination of the remaining core layer and barrier layer. The preparation rapidly exerts an effect in vivo, quickly reaches the maximum blood concentration, then maintains a stable release, maintains a stable blood concentration, reduces the variation between the peak and trough, and rapidly elutes in vitro.

Description

Technical Field

[0001] The present invention relates to pharmaceutical technology, particularly to a biphasic release control formulation and a method for manufacturing the same.

Background Art

[0002] In recent years, with the in-depth theoretical research on drug delivery systems and the development of polymer material science, the research on drug delivery systems has been continuously increasing in terms of variety from items to dosage forms. Sustained-release formulations and release control formulations have been attracting attention so far. However, in some special pathological conditions, it may be difficult to meet clinical needs with conventional or single drug release modes. For example, it is difficult for ordinary immediate-release formulations to maintain the effect for a long time, and ordinary sustained-release formulations cannot exert the effect immediately. Therefore, the biphasic drug delivery system has been attracting more and more attention. The biphasic drug delivery system has two different release phases. For the special physicochemical and biopharmaceutical properties of drugs, the time rhythm and complexity of disease onset, rapid-acting / sustained drug release, pulse or delayed drug release can be achieved by specific formulation design or process technology, providing a more flexible dosing plan in clinical use.

[0003] In order to achieve the purpose of biphasic release, extensive research has been conducted to control the drug release at a predetermined time and rate, such as two-layer or multi-layer tablet systems, multi-particle systems, film coating systems, and time-controlled capsule systems. Compared with conventional general formulations, their formulations and manufacturing processes are relatively complex and require more advanced industrial manufacturing.

Summary of the Invention

[0004] The present invention manufactures a biphasic release control formulation that can rapidly exert an effect in vivo, maintain stable and uniform release over a long period of time, i.e., substantially zero-order release, reduce side effects, and improve patient compliance through dosage form design. Accordingly, the present invention claims protection for the following technical solutions.

[0005] It is composed of a drug-containing immediate-release layer (IR), a drug-containing sustained-release layer (SR), and a drug-free barrier layer (BL); The drug-containing sustained-release layer (SR) is wrapped between the drug-containing immediate-release layer (IR) and the barrier layer (BL); the drug-containing immediate-release layer (IR) is a biphasic release control preparation formed by compressing and covering the drug-containing sustained-release layer (SR) by a tabletting method.

[0006] Preferably, the drug-containing immediate-release layer (IR) is a biphasic release control preparation characterized by being composed of components such as an active substance, a filler, a binder, a disintegrant, a lubricant, and a glidant.

[0007] Preferably, the drug-containing sustained-release layer (SR) is composed of components such as an active substance, a sustained-release polymer, a filler, a binder, a lubricant, and a glidant; among them, the drug-containing sustained-release layer (SR) and the drug-free barrier layer (BL) form a partially open coating structure, and the drug-containing sustained-release layer (SR) functions as a core and the drug-free barrier layer (BL) functions as a partial coating layer. Preferably, the drug-containing immediate-release layer (IR) is a biphasic release control preparation characterized by being composed of components such as an active substance, a filler, a binder, a disintegrant, a lubricant, and a glidant.

[0008] Preferably, the drug-containing sustained-release layer (SR) is composed of components such as an active substance, a sustained-release polymer, a filler, a binder, a lubricant, and a glidant; the drug-containing sustained-release layer is wrapped between the drug-containing immediate-release layer and the barrier layer. A biphasic release control preparation characterized by this.

[0009] Preferably, the drug-free barrier layer (BL) is a biphasic release control preparation characterized by being composed of components such as a sustained-release polymer, a filler, a binder, a lubricant, and a glidant.

[0010] Preferably, The ratio of the mass of the drug-containing immediate-release layer (IR) to the mass of the drug-containing sustained-release layer (SR) is 5:1 to 1.5:1; The ratio of the mass of the drug-containing immediate-release layer (IR) to the mass of the barrier layer (BL) that does not contain the drug is 1:1 to 0.125:1; The biphasic release control preparation according to any one of the above, wherein the ratio of the mass of the drug-containing sustained-release layer (SR) to the mass of the barrier layer (BL) that does not contain the drug is 0.2:1 to 0.05:1.

[0011] Preferably, the compounding amount of the filler in the drug-containing sustained-release layer (SR) is 30 to 70%, preferably 50%; the filler is a brittle filler selected from the group consisting of lactose, sucrose, calcium sulfate, calcium carbonate, and calcium phosphate, etc., and preferably lactose. The biphasic release control preparation is characterized by this.

[0012] Preferably, here, as the compounding amount of the binder, it is 3 to 10% in the drug-containing immediate-release layer (IR) and 2 to 10% in the barrier layer (BL) that does not contain the drug. The binder is one or more selected from the group consisting of HPC, HPMC, povidone, and sodium carboxymethylcellulose; among them, the viscosity of HPC is 75 to 700 cps, and the viscosity of HPMC is 3 to 50 cps. The biphasic release control preparation is characterized by this.

[0013] Preferably, here, the compounding amount of the binder in the drug-containing immediate-release layer (IR) is 5%, and the material is composed of HPMC and HPC in a content ratio of 0 to 1:1. The biphasic release control preparation is characterized by this.

[0014] Preferably, here, the mass of the active substance in the drug-containing sustained-release layer is greater than the mass of the active substance in the drug-containing immediate-release layer, and the ratio of the mass of the active substance in the drug-containing sustained-release layer to the mass of the active substance in the drug-containing immediate-release layer is ≦4; preferably 4:1 to 1:1, preferably 2 or more and 4 or less. The biphasic release control preparation is characterized by this.

[0015] Preferably, the disintegrant in the drug-containing immediate-release layer is at least one selected from the group consisting of sodium croscarmellose, croscarmellose sodium, crospovidone PVPP, and low-substituted hydroxypropyl cellulose L-HPC; preferably sodium croscarmellose or croscarmellose sodium; The lubricants in the drug-containing immediate-release layer (IR), the drug-containing sustained-release layer (SR), and the drug-free barrier layer (BL) are each independently at least one selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated castor oil, and sodium lauryl sulfate; preferably magnesium stearate or stearic acid; The glidants in the drug-containing immediate-release layer (IR), the drug-containing sustained-release layer (SR), and the drug-free barrier layer (BL) are each independently colloidal silica or talc; preferably colloidal silica; The sustained-release polymer (skeletal material) in the drug-containing sustained-release layer (SR) and the drug-free barrier layer (BL) is hydroxypropyl methylcellulose, and the biphasic release control preparation according to any one of the above.

[0016] Preferably, the content of hydroxypropyl methylcellulose in the drug-containing sustained-release layer (SR) is 20.00 to 60.00%, preferably 25.00 to 50.00%; The biphasic release control preparation is characterized in that the content of hydroxypropyl methylcellulose in the drug-free barrier layer (BL) is 20.00 to 60.00%, preferably 25.00 to 50.00%.

[0017] Preferably, the hydroxypropyl methylcellulose in the sustained-release polymer is at least one selected from the group consisting of E30LV, E50LV, K100LV, K4M, K15M, K100M, and xanthan gum, and the biphasic release control preparation is characterized by this.

[0018] Preferably, in the in vitro dissolution test, at least 85% of the active ingredient in the drug-containing immediate-release layer (IR) is dissolved within 45 minutes, and the slope of the dissolution curve of the active ingredient in the drug-containing sustained-release layer (SR) within 1 to 10 hours is 5.0 to 5.6, and at least 95% is released by 20 hours.

[0019] The innovation of the present invention is the tablet structure and the formulation of the additives, which is suitable for all compound-based active ingredients that require such a release pattern.

[0020] Another form of the present invention provides a method for manufacturing the biphasic release control preparation according to any of the above, and the following steps are included in this method. a. Manufacture and prepare the immediate-release layer granules according to the formulation; b. Manufacture and prepare the sustained-release layer granules according to the formulation; c. Manufacture and prepare the barrier layer granules according to the formulation; d. Put the sustained-release layer granules into the mold of the tableting machine and compress them into the core of the tablet blank for preparation; e. Put the prescribed amount of barrier layer granules into the mold of the tableting machine, place the core layer of the tablet blank in the center of the barrier layer granules, and perform pre-compression tableting with the pre-compression pressure of 0.1 to 2 KN, so that the core of the tablet blank forms the drug-containing sustained-release layer (SR), the core of the tablet blank sinks into the barrier layer granules, and the part with one open side surrounded by the barrier layer is formed except for its upper surface; further, put the prescribed amount of immediate-release layer granules into the mold, apply the main pressure, with the main pressure of 5 to 35 KN, and cover and adhere the immediate-release layer granules to the opening of the partial coating structure by the tableting method to form the drug-containing immediate-release layer (IR) and obtain the tablet. The tablet structure is shown in Figure 1.

[0021] Preferably, here, steps a, b, and c are as follows. a. Weigh the prescription amount of the active substance, filler, disintegrant, and binder other than HPC required to produce the drug-containing immediate-release layer, mix them thoroughly, add liquid with purified water or an alcohol solution, perform wet granulation, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, and dry them; pass the dried whole granules through a sieve with an aperture of 1000 - 8000 μm, add a glidant, perform preliminary mixing, and then add a lubricant and mix to obtain immediate-release layer granules, and set them aside; b. Weigh the prescription amount of the active substance, sustained-release polymer, and filler required to produce the drug-containing sustained-release layer, perform wet granulation with purified water or an alcohol solution, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, and dry them; pass the dried whole granules through a sieve with an aperture of 1000 - 8000 μm, add a glidant, perform preliminary mixing, and then add a lubricant and mix to obtain sustained-release layer granules, and set them aside; c. Weigh the prescription amount of the sustained-release polymer, filler, and binder other than HPC required to produce the barrier layer, mix them thoroughly, add liquid with purified water or an alcohol solution, perform wet granulation, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, and dry them; pass the dried whole granules through a sieve with an aperture of 1000 - 8000 μm, add a glidant, perform preliminary mixing, and then add a lubricant and mix to obtain barrier layer granules, and set them aside; In step e, the pre-pressure is set to 0.1 - 0.5 KN; the main pressure is set to 10 - 25 KN.

[0022] Preferably, here, when the binder material in the drug-containing immediate-release layer (IR) and the barrier layer contains HPC, a method of dissolving HPC in the purified water or alcohol solution for the wet granulation and adding it.

[0023] Summary of the technical advantages of the present invention:

[0024] The present invention develops a new tablet structure and the formulation and process of additives to achieve the biphasic release of active ingredients that can quickly exert effects and maintain zero-level stable release over a long period of time; compared with general formulations, this tablet reduces side effects and achieves the effect of improving patient compliance, the immediate-release layer dissolves rapidly and is released in a zero-order mode within 1 to 10 hours, achieving the effect of stable release.

Brief Description of the Drawings

[0025]

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Mode for Carrying Out the Invention

[0026] Hereinafter, the technical solution of the present invention will be described based on specific embodiments, but those skilled in the art can understand that these embodiments should not be construed as limiting the scope of the present invention.

[0027] The conditions of the dissolution method used in the following examples and comparative examples are as follows. "Chinese Pharmacopoeia" Dissolution Test Method No. 2, 50 rpm, 900 ml of test solution, pH 1.2, test solution temperature 37 ± 0.5 °C.

[0028] Regarding the dissolution curves of the following partial examples and comparative examples, the trend line of the dissolution curve within 1 to 10 h was selected to evaluate the zero-order release rate. When the slope of the trend line of the dissolution curve was between 5.0 and 5.6, it was an ideal zero-order release effect, and the zero-order release could be continuously maintained to achieve complete drug absorption. However, when the slope of the dissolution curve was too small (less than 5.0), it indicated that the drug release rate in the sustained-release part was too slow, resulting in incomplete drug absorption and affecting bioavailability. When the slope of the dissolution curve was too large (exceeding 5.6), it indicated that the drug release rate in the sustained-release part was too fast, and the drug could hardly maintain zero-order release in the later stage, affecting the sustained-release effect.

[0029] Example 1 Manufacture of 1000 tablets of two-phase release controlled formulation

[0030] Taking the production of 1000 control tablets of escitalopram oxalate as an example, the components and weights are as shown in the following table.

[0031]

Table 1

[0032] The manufacturing method of the biphasic release control preparation of escitalopram oxalate in Example 1 of the present invention includes the following steps.

[0033] a. Manufacture of the drug-containing immediate-release layer (IR): Weigh the active ingredient, disintegrant, filler, and binder according to the formulation, mix them thoroughly, add a liquid with purified water or an alcohol solution, perform wet granulation, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, dry them, pass the dry whole granules through a sieve with an aperture of 1000 - 8000 μm, add a glidant, perform preliminary mixing, and then add a lubricant and mix to obtain immediate-release layer granules, and set them aside;

[0034] b. Manufacture of the drug-containing sustained-release layer (SR): Weigh the active ingredient, sustained-release polymer, and filler according to the formulation, mix them thoroughly, perform wet granulation with purified water or an alcohol solution, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, dry them, pass the dry whole granules through a sieve with an aperture of 1000 - 8000 μm, add a glidant, perform preliminary mixing, and then add a lubricant and mix to obtain sustained-release layer granules, and set them aside;

[0035] c. Manufacture of the barrier layer (BL): Weigh the sustained-release polymer and filler according to the formulation, mix them thoroughly, dissolve the binder HPC in purified water or an alcohol solution, then add the liquid and perform wet granulation, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, dry them, pass the dry whole granules through a sieve with an aperture of 1000 - 8000 μm, add a glidant, perform preliminary mixing, and then add a lubricant and mix to obtain barrier layer granules, and set them aside;

[0036] d. Put the above-mentioned sustained-release layer granules in the amount of the formulation into the mold of a tableting machine, compress and form them into the core of the plain tablet, and set them aside;

[0037] e. Put the barrier layer granules of the prescribed amount into the mold of the tableting machine, place the core layer of the tablet core in the center of the barrier layer granules, perform pre-compression tableting (1 KN), the core of the tablet core forms the drug-containing sustained release layer (SR), the core of the tablet core sinks into the barrier layer granules, and the one-sided open partial coating structure is formed where the other surfaces except the upper surface are surrounded by the barrier layer; further, put the immediate release layer granules of the prescribed amount into the mold, apply the main pressure (20 KN), and cover and adhere the immediate release layer granules to the opening of the partial coating structure by tableting method to form the drug-containing immediate release layer (IR) and obtain tablet 1-1.

[0038] The tablet structure of the biphasic release control preparation in the present invention is shown in Fig. 1, and the same applies to the following examples.

[0039] Examine the appearance, crack situation, abrasion degree, and dissolution situation of tablet 1-1 in Example 1, and the experimental data are as shown in the following table.

[0040] [Table 2]

[0041] From this, it is considered that tablet 1-1 passes in terms of appearance and abrasion degree. An in vitro dissolution test was carried out on tablet 1-1, and the dissolution curve and trend line are shown in Fig. 2, and the zero-order release rate (the slope of the trend line) was 5.49.

[0042] Example 2 Manufacture a biphasic release control preparation of escitalopram oxalate and examine the influence of different IR:SR ratios

[0043] Manufacture escitalopram oxalate, and the components and weights are as shown in the following table.

[0044] [Table 3]

[0045] The manufacturing method of the biphasic release control preparation of escitalopram oxalate in Example 2 of the present invention includes the following steps.

[0046] a. Manufacture of the drug-containing immediate release layer: Weigh escitalopram oxalate, corn starch, crystalline cellulose, croscarmellose sodium, and sodium carboxymethyl cellulose, mix them thoroughly, add a liquid with purified water or an alcohol solution, perform wet granulation, pass the wet whole granules through a sieve with a mesh opening of 1000 - 8000 μm, dry them, pass the dried whole granules through a sieve with a mesh opening of 1000 - 8000 μm, add talc, perform preliminary mixing, and then add stearic acid and mix to obtain immediate release layer granules and set them aside;

[0047] b. Manufacture of the drug-containing sustained release layer: Weigh escitalopram oxalate, HPMC K100LV, and lactose, mix them thoroughly, perform wet granulation with purified water or an alcohol solution, pass the wet whole granules through a sieve with a mesh opening of 1000 - 8000 μm, dry them, pass the dried whole granules through a sieve with a mesh opening of 1000 - 8000 μm, add talc, perform preliminary mixing, and then add 0 stearic acid and mix to obtain sustained release layer granules and set them aside;

[0048] c. Manufacture of the barrier layer: Weigh the required prescription amount of HPMCK4LV, pregelatinized starch, and crystalline cellulose, mix them thoroughly, dissolve HPC - GF with purified water or an alcohol solution, then add the liquid and perform wet granulation, pass the wet whole granules through a sieve with a mesh opening of 1000 - 8000 μm, dry them, pass the dried whole granules through a sieve with a mesh opening of 1000 - 8000 μm, add 1 talc, perform preliminary mixing, and then add stearic acid and mix to obtain barrier layer granules and set them aside;

[0049] d. Put the above-mentioned sustained release layer granules in the amount of the prescription into the mold of a tableting machine and compress them into cores of tablets of 40 mg, 50 mg, and 80 mg respectively and set them aside;

[0050] e. Put 650 mg of barrier layer granules into the mold of a tableting machine, place 50 mg of the core layer of the tablet core in the center of the barrier layer granules, perform pre-compression tableting (1 KN), so that the core of the tablet core forms the drug-containing sustained-release layer (SR), the core of the tablet core sinks into the barrier layer granules, and the other surfaces except its upper surface are surrounded by the barrier layer to form a partially coated structure with one open side; further, put 400 mg of immediate-release layer granules into the mold, apply the main pressure (20 KN), and cover and adhere the immediate-release layer granules to the opening of the partially coated structure by tableting method to form the drug-containing immediate-release layer (IR), and obtain tablet 2-1

[0051] Put 650 mg of barrier layer granules into the mold of a tableting machine, place 80 mg of the core layer of the tablet core in the center of the barrier layer granules, perform pre-compression tableting (1 KN), so that the core of the tablet core forms the drug-containing sustained-release layer (SR), the core of the tablet core sinks into the barrier layer granules, and the other surfaces except its upper surface are surrounded by the barrier layer to form a partially coated structure with one open side; further, put 100 mg of immediate-release layer granules into the mold, apply the main pressure (20 KN), and cover and adhere the immediate-release layer granules to the opening of the partially coated structure by tableting method to form the drug-containing immediate-release layer (IR), and obtain tablet 2-2

[0052] Put 650 mg of barrier layer granules into the mold of a tableting machine, place 40 mg of the core layer of the tablet core in the center of the barrier layer granules, perform pre-compression tableting (1 KN), so that the core of the tablet core forms the drug-containing sustained-release layer (SR), the core of the tablet core sinks into the barrier layer granules, and the other surfaces except its upper surface are surrounded by the barrier layer to form a partially coated structure with one open side; further, put 220 mg of immediate-release layer granules into the mold, apply the main pressure (20 KN), and cover and adhere the immediate-release layer granules to the opening of the partially coated structure by tableting method to form the drug-containing immediate-release layer (IR), and obtain tablet 2-3

[0053] Examine the appearance, cracking situation, abrasion degree, and dissolution situation of tablets 2-1, 2-2, and 2-3 in Example 2. The experimental data are as shown in the following table.

[0054]

Table 4

[0055] From the above, in the case of the weight ratio of different immediate-release layers and sustained-release layers, it is considered that tablets 2-1, 2-2, and 2-3 are qualified in terms of appearance and wear degree.

[0056] In vitro dissolution tests were carried out on tablets 2-1, 2-2, and 2-3. The dissolution curves and trend lines are shown in Figures 3, 4, and 5 respectively. When comparing the release rates at 1-10 h, the zero-order release rates (the slopes of the trend lines) of tablets 2-1, 2-2, and 2-3 are 5.42, 7.25, and 5.73 respectively. It is considered that the dissolution rates of tablets 2-2 and 2-3 are faster.

[0057] Example 3 Preparation of a biphasic release-controlled formulation of escitalopram oxalate (investigation of different IR:SR ratios)

[0058] According to the formulation and process of Example 2, granules of different tablet layers were prepared.

[0059] 800 mg of barrier layer granules were placed in the mold of a tableting machine, and 40 mg of the core layer of the plain tablet was placed in the center of the barrier layer granules. Pre-compression tableting was carried out (1 KN), and the core of the plain tablet formed the drug-containing sustained-release layer (SR). The core of the plain tablet sank into the barrier layer granules, and the one-sided open partial coating structure was formed with the other surfaces except the upper surface surrounded by the barrier layer (BL); further, 200 mg of immediate-release layer granules were placed in the mold, and full pressure (20 KN) was applied. The immediate-release layer granules were covered and adhered to the opening of the partial coating structure by the tableting method to form the drug-containing immediate-release layer (IR), and tablet 3-1 was obtained, that is, IR:SR = 5:1, IR:BL = 1:4, SR:BL = 0.05:1;

[0060] Put 300 mg of barrier layer granules into the mold of a tableting machine, place 80 mg of the core layer of the tablet core in the center of the barrier layer granules, and perform pre-compression tableting (1 KN). The core of the tablet core forms the drug-containing sustained-release layer (SR), the core of the tablet core sinks into the barrier layer granules, and the other surfaces except its upper surface are surrounded by the barrier layer (BL), forming a partially coated structure with one side open; furthermore, put 200 mg of immediate-release layer granules into the mold, apply a main pressure (20 KN), and cover and adhere the immediate-release layer granules to the opening of the partially coated structure by tableting method to form the drug-containing immediate-release layer (IR), obtaining tablet 3-2, that is, IR:SR = 2.5:1, IR:BL = 0.67:1, SR:BL = 0.27:1;

[0061] Examine the appearance, crack situation, wear degree, and in vitro dissolution situation of tablets 3-1 and 3-2 in Example 3. The experimental data are as shown in the following table.

[0062]

Table 5

[0063] From the above, in the case of different weight ratios of the immediate-release layer and the barrier layer, it is considered that tablet 3-1 passes in terms of appearance and wear degree, while tablet 3-2 has cracks and fails in terms of wear degree. An in vitro dissolution test was carried out on tablet 3-1, and the dissolution curve and trend line are shown in Figure 6. The zero-order release rate (the slope of the trend line) was 5.46.

[0064] Example 4 Preparation of a biphasic release control preparation of escitalopram oxalate (examination of different IR:BL ratios)

[0065] According to the formulation and process of Example 2, granules of different tablet layers were prepared.

[0066] Put 200 mg of barrier layer granules into the mold of a tableting machine, place 40 mg of the core layer of the tablet in the center of the barrier layer granules, and perform pre-compression tableting (1 KN). The core of the tablet forms the drug-containing sustained release layer (SR). The core of the tablet sinks into the barrier layer granules, and the other surfaces except the upper surface are surrounded by the barrier layer (BL), forming a partially coated structure with one side open; further, put 200 mg of immediate release layer granules into the mold, apply the main pressure (20 KN), and cover and adhere the immediate release layer granules to the opening of the partially coated structure by tableting method to form the drug-containing immediate release layer (IR), obtaining tablet 4-1, that is, IR:SR = 5:1, IR:BL = 1:1, SR:BL = 0.2:1;

[0067] Put 200 mg of barrier layer granules into the mold of a tableting machine, place 40 mg of the core layer of the tablet in the center of the barrier layer granules, and perform pre-compression tableting (1 KN). The core of the tablet forms the drug-containing sustained release layer (SR). The core of the tablet sinks into the barrier layer granules, and the other surfaces except the upper surface are surrounded by the barrier layer (BL), forming a partially coated structure with one side open; further, put 300 mg of immediate release layer granules into the mold, apply the main pressure (20 KN), and cover and adhere the immediate release layer granules to the opening of the partially coated structure by tableting method to form the drug-containing immediate release layer (IR), obtaining tablet 4-2, that is, IR:SR = 7.5:1, IR:BL = 1.5:1, SR:BL = 0.2:1;

[0068] Examine the appearance, crack situation, wear degree, and in vitro dissolution situation of tablets 4-1 and 4-2 in Example 4. The experimental data are as follows in the table.

[0069]

Table 6

[0070] From the above, in the case of different weight ratios of the immediate release layer and the barrier layer, tablet 4-1 passes in terms of appearance and wear degree. For tablet 4-2, since the mass of the BL layer is relatively small, cracks occur during compression, and it is considered that the wear degree and appearance are unqualified.

[0071] An in vitro dissolution test was carried out on tablet 4-1, and the dissolution curve and trend line are shown in Figure 7. The zero-order release rate (the slope of the trend line) was 5.27.

[0072] For the following Examples 5 to 7 and Comparative Example 3, the ratio of the binder raw material in the immediate-release IR layer was examined.

[0073] Example 5 Production of 1000 tablets of a biphasic release controlled preparation (HPMC 0%, HPC 5%, i.e., 0:5)

[0074] Taking the production of 1000 control tablets of escitalopram oxalate as an example, the components and weights are as shown in the following table.

[0075]

Table 7

[0076] The manufacturing method is as follows.

[0077] a. Production of the drug-containing immediate-release layer: Weigh escitalopram oxalate, crospovidone PVPP, pre-gelatinized starch, pre-gelatinized starch, and HPMC K100LV, mix well, dissolve HPC-GF in purified water or an alcohol solution, add the solution, perform wet granulation, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, dry, pass the dry whole granules through a sieve with an aperture of 1000 - 8000 μm, add silicon dioxide, perform preliminary mixing, and then add sodium stearyl fumarate and mix to obtain immediate-release layer granules, and set aside.

[0078] b. Production of the drug-containing sustained-release layer: Weigh escitalopram oxalate, HPMC K100M, and sucrose, mix well, perform wet granulation with purified water or an alcohol solution, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, dry, pass the dry whole granules through a sieve with an aperture of 1000 - 8000 μm, add silicon dioxide, perform preliminary mixing, and then add sodium stearyl fumarate and mix to obtain sustained-release layer granules, and set aside.

[0079] c. Manufacture of the barrier layer: Weigh the required prescription amounts of HPMC K4M, HPMC K15M, corn starch, and crystalline cellulose MCC-PH101, mix them thoroughly, dissolve HPC-GF in purified water or an alcohol solution, add the solution, perform wet granulation, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, dry them, pass the dry whole granules through a sieve with an aperture of 1000 - 8000 μm, add silicon dioxide, perform preliminary mixing, and then add sodium stearyl fumarate and mix to obtain barrier layer granules for later use;

[0080] d. Put the said sustained-release layer granules in the mold of a tableting machine, compress and form them into the core of the plain tablet for later use;

[0081] e. Put the barrier layer granules in the mold of a tableting machine, place the core layer of the plain tablet in the center of the barrier layer granules, perform pre-compression tableting (1 KN), so that the core of the plain tablet forms the drug-containing sustained-release layer (SR), the core of the plain tablet sinks into the barrier layer granules, and the one-sided open partial coating structure is formed with the other surfaces except the upper surface surrounded by the barrier layer; furthermore, put the immediate-release layer granules into the mold, apply the main pressure (20 KN), and cover and adhere the immediate-release layer granules to the opening of the said partial coating structure by the tableting method to form the drug-containing immediate-release layer (IR), and obtain tablets respectively

[0082] Example 6 Manufacture of 1000 tablets of a biphasic release control preparation (HPMC 1%, HPC 4%, i.e., 1:4)

[0083] Taking the manufacture of 1000 control tablets of escitalopram oxalate as an example, the components and weights are as shown in the following table.

[0084]

Table 8

[0085] The manufacturing method is the same as that of Example 5.

[0086] Example 7 Manufacture of 1000 tablets of a biphasic release control preparation (HPMC 2%, HPC 3%, i.e., 2:3)

[0087] Taking the manufacture of 1000 control tablets of escitalopram oxalate as an example, the components and weights are as shown in the following table.

[0088]

Table 9

[0089] The manufacturing method is the same as that of Example 5.

[0090] Comparative Example 1 Manufacture of 1000 tablets of a biphasic release control preparation (examining the blending amount of the IR binder, total amount exceeding 10%)

[0091] Taking the manufacture of 1000 control tablets of escitalopram oxalate as an example, the components and weights are as shown in the following table.

[0092]

Table 10

[0093] The manufacturing method is the same as that of Example 5

[0094] The manufacturing method of the biphasic release control preparation of escitalopram oxalate in the comparative example of the present invention includes the following steps.

[0095] a. Preparation of the immediate-release drug-containing layer: Weigh 4 g of escitalopram oxalate, 90 g of pregelatinized starch, 119.75 g of crystalline cellulose, 7.5 g of crospovidone PVPP, 12.5 g of HPMC-HF, and 7.5 g of povidone, mix them thoroughly, add a liquid with purified water or an alcohol solution, perform wet granulation, pass the wet granules through a sieve with an aperture of 1000 - 8000 μm, dry them, pass the dried granules through a sieve with an aperture of 1000 - 8000 μm, add 0.625 g of silicon dioxide, premix, and then add 0.625 g of sodium stearyl fumarate and mix to obtain immediate-release layer granules for later use;

[0096] b. Preparation of the sustained-release drug-containing layer: Weigh 9.588 g of escitalopram oxalate, 18 g of HPMC K100M, and 31.212 g of sucrose, mix them thoroughly, perform wet granulation with purified water or an alcohol solution, pass the wet granules through a sieve with an aperture of 1000 - 8000 μm, dry them, pass the dried granules through a sieve with an aperture of 1000 - 8000 μm, add 0.6 g of silicon dioxide, premix, and then add 0.6 g of sodium stearyl fumarate and mix to obtain sustained-release layer granules for later use;

[0097] c. Preparation of the barrier layer: Weigh 260 g of HPMC K4M, 65 g of HPMC K15M, 97.5 g of corn starch, and 172.25 g of crystalline cellulose in the required formulation amounts, mix them thoroughly, dissolve 52 g of HPC in purified water or an alcohol solution, then add the solution and perform wet granulation, pass the wet granules through a sieve with an aperture of 1000 - 8000 μm, dry them, pass the dried granules through a sieve with an aperture of 1000 - 8000 μm, add 1.625 g of silicon dioxide, premix, and then add 1.625 g of sodium stearyl fumarate and mix to obtain barrier layer granules for later use;

[0098] d. Put the sustained-release layer granules in the required formulation amount into the mold of a tableting machine and compress them into the core of a tablet for later use;

[0099] e. Put the barrier layer granules of the prescribed amount into the mold of the tableting machine, place the core layer of the tablet in the center of the barrier layer granules, and perform pre-compression tableting (1 KN). The core of the tablet forms the drug-containing sustained-release layer (SR), the core of the tablet sinks into the barrier layer granules, and the structure with an open side formed with other surfaces except the upper surface surrounded by the barrier layer (BL); furthermore, put the immediate-release layer granules of the prescribed amount into the mold, apply the main pressure (20 KN), and cover and adhere the immediate-release layer granules to the opening of the partial coating structure by the tableting method to form the drug-containing immediate-release layer (IR) and obtain the tablets.

[0100] Examine the appearance, crack situation, abrasion degree, and dissolution situation of the compressed biphasic release control preparation in Comparative Example 1. The experimental data are as shown in the following table.

[0101]

Table 11

[0102] From the above, it is considered that the compressed biphasic release control preparation in Comparative Example 1 has no cracks and the abrasion degree is qualified, but the appearance is rough. An in vitro dissolution test was carried out on the compressed biphasic release control preparation in Comparative Example 1, and the dissolution curve is shown in Figure 11.

[0103] When comparing the release rates at 1 - 10 h, the in vitro dissolution rate of the biphasic release control preparation in Comparative Example 1 at 1 - 10 h is too slow, and the zero-order release rate (the slope of the trend line) is 4.84, not reaching the ideal release mode.

[0104] Manufacture of 1000 tablets of the biphasic release control preparation in Comparative Example 2 (examination of SR filler raw materials)

[0105]

Table 12

[0106] The manufacturing method is the same as that in Example 1.

[0107] The manufacturing method of the biphasic release control preparation of escitalopram oxalate in Comparative Example 2 of the present invention includes the following steps.

[0108] a. Manufacture of the drug-containing immediate release layer: Weigh 4 g of escitalopram oxalate, 90 g of pregelatinized starch, 134.75 g of crystalline cellulose, 7.5 g of crospovidone PVPP, 5 g of HPMC K4M, and 7.5 g of povidone, mix well, add liquid with purified water or alcohol solution, perform wet granulation, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, dry, pass the dried whole granules through a sieve with an aperture of 1000 - 8000 μm, add 0.625 g of silicon dioxide, perform preliminary mixing, and then add 0.625 g of sodium stearyl fumarate and mix to obtain immediate release layer granules, and set aside;

[0109] b. Manufacture of the drug-containing sustained release layer: Weigh 9.588 g of escitalopram oxalate, 18 g of HPMC K100M, and 31.212 g of crystalline cellulose, mix well, perform wet granulation with purified water or alcohol solution, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, dry, pass the dried whole granules through a sieve with an aperture of 1000 - 8000 μm, add 0.6 g of silicon dioxide, perform preliminary mixing, and then add 0.6 g of sodium stearyl fumarate and mix to obtain sustained release layer granules, and set aside;

[0110] c. Manufacture of the barrier layer: Weigh 260 g of HPMC K4M, 65 g of HPMC K15M, 97.5 g of corn starch, and 191.75 of crystalline cellulose in the required formulation amounts, mix well, dissolve 52 g of HPC in purified water or alcohol solution, then add the liquid and perform wet granulation, pass the wet whole granules through a sieve with an aperture of 1000 - 8000 μm, dry, pass the dried whole granules through a sieve with an aperture of 1000 - 8000 μm, add 1.625 g of silicon dioxide, perform preliminary mixing, and then add 1.625 g of sodium stearyl fumarate and mix to obtain barrier layer granules, and set aside;

[0111] d. Put the sustained release layer granules in the required formulation amount into the mold of a tableting machine and compress and form them into the core of a plain tablet, and set aside;

[0112] e. Place the barrier layer granules of the prescribed amount into the mold of the tableting machine, place the core layer of the tablet core in the center of the barrier layer granules, perform pre-compression tableting (1 KN), so that the core of the tablet core forms the drug-containing sustained release layer (SR), the core of the tablet core sinks into the barrier layer granules, and the part with the other surfaces except its upper surface surrounded by the barrier layer (BL) forms a partially open coating structure; further, place the immediate release layer granules of the prescribed amount into the mold, apply the main pressure (20 KN), and cover and adhere the immediate release layer granules to the opening of the partially coated structure by tableting to form the drug-containing immediate release layer (IR) and obtain tablets.

[0113] Examine the appearance, cracking situation, wear degree, and dissolution situation of the compressed biphasic release control preparation in Comparative Example 2, and the experimental data are as shown in the following table.

[0114]

Table 13

[0115] From the above, it is considered that crystalline cellulose is a non-brittle filler, and when it is subjected to pressure, viscoelastic deformation is likely to occur, and the immediate release layer is pushed open. Therefore, due to the cracking during compression in Comparative Example 2, the wear degree and appearance are unqualified.

[0116] By integrating the experimental data in research and development, it was found that for the tablet structure of the present invention, it is necessary to select brittle fillers that are difficult to deform, such as lactose, sucrose, calcium sulfate, calcium carbonate, calcium phosphate, etc.

[0117] Comparative Example 3 Production of 1000 tablets of biphasic release control preparation (HPMC 3%, HPC 2%, that is, 3:2)

[0118] Taking the production of 1000 control tablets of escitalopram oxalate as an example, the components and weights are as shown in the following table.

[0119]

Table 14

[0120] The manufacturing method is the same as that of Example 5.

[0121] The appearance, crack situation, wear degree, and in vitro dissolution situation of Examples 5, 6, 7 and Comparative Example 3 were examined, and the experimental data are as shown in the following table.

[0122]

Table 15

[0123] From the comparison of the above data, when the HPMC:HPC of the immediate release layer binder is greater than 1 (Comparative Example 3), it is considered that the appearance of the tablets is rough, there are rough surfaces, and the wear degree is unqualified.

[0124] For the compressed biphasic release controlled preparations in Examples 5 to 7, in vitro dissolution tests were carried out, and the dissolution curves and trend lines are shown in Figures 8 to 10. The zero-order release rate (the slope of the trend line) is 5.49, 5.51 and 5.5 respectively. It is considered that the wear degree and in vitro dissolution can reach an ideal state.

[0125] For the tablets obtained in Examples 1 to 7 without cracks during manufacturing and with qualified wear degree, the results of aggregating the in vitro dissolution rate % at each time point from 0 to 20 hours are shown in the following table, and the dissolution curve is shown in Figure 12.

[0126]

Table 16

[0127] When the slope of the dissolution curve for 1 to 10 hours is between 5 and 5.6, it was confirmed that the sustained-release layer drug in the tablet maintained approximately zero-order release throughout the entire release process and was at least 95% released at 20 hours. However, if the slope of the dissolution curve is too small (less than 5.0), the drug release rate in the sustained-release part is too slow, resulting in incomplete drug dissolution within 20 hours and affecting bioavailability. If the slope of the dissolution curve is too large (exceeding 5.6), the drug in the sustained-release part is released at a faster rate in the initial stage and cannot maintain approximately zero-order release in the later stage, affecting the sustained-release effect.

[0128] Tablet 2-1 is released 97% at 12 hours because the API SR / IR is less than 2 and the immediate-release layer API accounts for 33% (completely released in 30 to 45 minutes). Therefore, 46% of the total API is released at the 1st hour, and at the 12th hour in the later sustained-release stage, it is almost completely released, but it is approximately zero-order release throughout the entire process within 1 to 12 hours.

Claims

1. It is composed of a drug-containing immediate-release layer (IR), a drug-containing sustained-release layer (SR), and a drug-free barrier layer (BL); The drug-containing sustained-release layer (SR) is wrapped between the drug-containing immediate-release layer (IR) and the barrier layer (BL); The drug-containing immediate-release layer (IR) is a biphasic release control preparation formed by compressing and covering the drug-containing sustained-release layer (SR) by a tabletting method.

2. The drug-containing immediate-release layer (IR) is composed of components of an active substance, a filler, a binder, a disintegrant, a lubricant, and a glidant. The biphasic release control preparation according to Claim 1, characterized in that.

3. The drug-containing sustained-release layer (SR) is composed of components of an active substance, a sustained-release polymer, a filler, a binder, a lubricant, and a glidant; The drug-containing sustained-release layer (SR) and the drug-free barrier layer (BL) form a partially open coating structure, and the drug-containing sustained-release layer (SR) functions as a core and the drug-free barrier layer (BL) functions as a partial coating layer. The biphasic release control preparation according to Claim 1, characterized in that.

4. The drug-free barrier layer (BL) is composed of components of a sustained-release polymer, a filler, a binder, a lubricant, and a glidant. The biphasic release control preparation according to Claim 1, characterized in that.

5. The ratio of the mass of the drug-containing immediate-release layer (IR) to the mass of the drug-containing sustained-release layer (SR) is 5:1 to 1.5:1; The ratio of the mass of the drug-containing immediate-release layer (IR) to the mass of the drug-free barrier layer (BL) is 1:1 to 0.125:1; The ratio of the mass of the drug-containing sustained-release layer (SR) to the mass of the drug-free barrier layer (BL) is 0.2:1 to 0.05:

1. The biphasic release control preparation according to any one of Claims 1 to 4, characterized in that.

6. The compounding amount of the filler in the drug-containing sustained-release layer (SR) is 30 to 70%, preferably 50%; The filler is one or more selected from the group consisting of lactose, sucrose, calcium sulfate, calcium carbonate, and calcium phosphate, preferably lactose. The biphasic release control preparation according to Claim 5, characterized in that.

7. Here, as the blending amount of the binder, it is 3 to 10% in the drug-containing immediate-release layer (IR) and 2 to 10% in the drug-free barrier layer (BL), and the binder is one or more selected from the group consisting of HPC, HPMC, povidone, and sodium carboxymethylcellulose; among them, the viscosity of HPC is 75 to 700 cps, and the viscosity of HPMC is 3 to 50 cps. The biphasic release control preparation according to claim 5, characterized in that.

8. Here, the blending amount of the binder in the drug-containing immediate-release layer (IR) is 5%, and the material is composed of HPMC and HPC in a content ratio of 0 to 1:

1. The biphasic release control preparation according to claim 7.

9. Here, the mass of the active substance in the drug-containing sustained-release layer is greater than the mass of the active substance in the drug-containing immediate-release layer, and the ratio of the mass of the active substance in the drug-containing sustained-release layer to the mass of the active substance in the drug-containing immediate-release layer is ≦ 4; preferably 4:1 to 1:

1. The biphasic release control preparation according to claim 1, characterized in that.

10. The disintegrant in the drug-containing immediate-release layer is one or more selected from the group consisting of sodium croscarmellose, croscarmellose sodium, crospovidone PVPP, and low-substituted hydroxypropyl cellulose L-HPC; preferably sodium croscarmellose or croscarmellose sodium; The lubricants in the drug-containing immediate-release layer (IR), the drug-containing sustained-release layer (SR), and the drug-free barrier layer (BL) are independently one or more selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated castor oil, and sodium lauryl sulfate; preferably magnesium stearate or stearic acid; The glidants in the drug-containing immediate-release layer (IR), the drug-containing sustained-release layer (SR), and the drug-free barrier layer (BL) are independently colloidal silica or talc; preferably colloidal silica; The sustained-release polymer (skeletal material) in the drug-containing sustained-release layer (SR) and the drug-free barrier layer (BL) is hydroxypropyl methylcellulose. The biphasic release control preparation according to any one of claims 3 to 9, characterized in that.

11. The compounding amount of hydroxypropylmethylcellulose in the drug-containing sustained-release layer (SR) is 20.00 to 60.00%, preferably 25.00% to 50.00%; The biphasic release control preparation according to claim 10, wherein the compounding amount of hydroxypropylmethylcellulose in the barrier layer (BL) containing no drug is 20.00 to 60.00%, preferably 25.00% to 50.00%.

12. The biphasic release control preparation according to claim 10, wherein the hydroxypropylmethylcellulose in the sustained-release polymer is one or more selected from the group consisting of E30LV, E50LV, K100LV, K4M, K15M, K100M, and xanthan gum.

13. In the in vitro dissolution test, at least 85% of the active ingredient in the drug-containing immediate-release layer (IR) is dissolved within 45 min, and the tendency slope of the dissolution curve of the active ingredient in the drug-containing sustained-release layer (SR) within 1 to 10 hours is 5.0 to 5.6, and at least 95% is released by 20 hours. The biphasic release control preparation according to any one of claims 1 to 12, characterized in that.

14. The following steps are included. a. Manufacture and prepare immediate-release layer granules according to the formulation; b. Manufacture and prepare sustained-release layer granules according to the formulation; c. Manufacture and prepare barrier layer granules according to the formulation; d. Put the sustained-release layer granules into the mold of a tableting machine and compress them into the core of a tablet blank for preparation; e. Put the prescribed amount of barrier layer granules into the mold of a tableting machine, place the core layer of the tablet blank in the center of the barrier layer granules, perform pre-compression tableting, set the pre-compression pressure to 0.1 to 2 KN, so that the core of the tablet blank forms the drug-containing sustained-release layer (SR), the core of the tablet blank sinks into the barrier layer granules, and the part with one side open surrounded by the barrier layer except for its upper surface is formed; further, put the prescribed amount of immediate-release layer granules into the mold, apply the main pressure, set the main pressure to 5 to 35 KN, and cover and adhere the immediate-release layer granules to the opening of the partial coating structure by tableting to form the drug-containing immediate-release layer (IR) to obtain a tablet. A method for manufacturing a biphasic controlled-release preparation according to any one of claims 1 to 13.

15. Here, steps a, b, and c are as follows. a. Weigh the prescription amount of the active substance, filler, disintegrant, and binder raw material other than HPC required to produce the drug-containing immediate-release layer, mix them thoroughly, add liquid with purified water or an alcohol solution, perform wet granulation, pass the wet total granules through a sieve with an aperture of 1000 - 8000 μm, dry them, pass the dried total granules through a sieve with an aperture of 1000 - 8000 μm, add a glidant, perform preliminary mixing, and then add a lubricant and mix to obtain the immediate-release layer granules and set them aside; b. Weigh the prescription amount of the active substance, sustained-release polymer, and filler required to produce the drug-containing sustained-release layer, perform wet granulation with purified water or an alcohol solution, pass the wet total granules through a sieve with an aperture of 1000 - 8000 μm, dry them, pass the dried total granules through a sieve with an aperture of 1000 - 8000 μm, add a glidant, perform preliminary mixing, and then add a lubricant and mix to obtain the sustained-release layer granules and set them aside; c. Weigh the prescription amount of the sustained-release polymer, filler, and binder other than HPC required to produce the barrier layer, mix them thoroughly, add liquid with purified water or an alcohol solution, perform wet granulation, pass the wet total granules through a sieve with an aperture of 1000 - 8000 μm, dry them, pass the dried total granules through a sieve with an aperture of 1000 - 8000 μm, add a glidant, perform preliminary mixing, and then add a lubricant and mix to obtain the barrier layer granules and set them aside; The method according to claim 14, wherein in step e, the pre-pressure is 0.1 - 0.5 KN and the main pressure is 10 - 25 KN.

16. The method according to claim 15, wherein when the binder material in the drug-containing immediate-release layer (IR) and the barrier layer contains HPC, HPC is dissolved in the purified water or alcohol solution for the wet granulation and then added.

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