WO2024017411A1 - 一种双相控释制剂及其制备方法 - Google Patents

一种双相控释制剂及其制备方法 Download PDF

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WO2024017411A1
WO2024017411A1 PCT/CN2023/119277 CN2023119277W WO2024017411A1 WO 2024017411 A1 WO2024017411 A1 WO 2024017411A1 CN 2023119277 W CN2023119277 W CN 2023119277W WO 2024017411 A1 WO2024017411 A1 WO 2024017411A1
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drug
layer
release layer
release
sustained
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PCT/CN2023/119277
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English (en)
French (fr)
Inventor
黄小锋
张晨梁
闻晓光
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越洋医药开发(广州)有限公司
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Publication of WO2024017411A1 publication Critical patent/WO2024017411A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer

Definitions

  • the present invention relates to pharmaceutical technology, in particular to a biphasic controlled release preparation and its preparation method.
  • the biphasic drug release system has two different release phases, which can achieve quick/long-acting effects through specific prescription design or process technology based on the special physical and chemical properties and biopharmaceutical properties of the drug, as well as the rhythm and complexity of disease onset. Drug release, pulse or delayed drug release, thus providing a more flexible dosing regimen for clinical use.
  • the present invention prepares a biphasic controlled-release preparation through dosage form design, which can take effect quickly in the body and maintain stable and uniform release, that is, near zero-order release, for a long time. It can reduce adverse reactions and increase patient compliance. Accordingly, The present invention claims protection for the following technical solutions:
  • a biphasic controlled release preparation which is composed of a drug-containing immediate release layer (IR), a drug-containing sustained release layer (SR), and a drug-free blocking layer (BL);
  • the drug-containing sustained-release layer (SR) is wrapped between the drug-containing immediate-release layer (IR) and the retardant layer (SR); the drug-containing immediate-release layer (IR) is pressed and covered by tableting. Formed on the drug-containing sustained-release layer (SR).
  • the biphasic controlled release preparation is characterized in that the drug-containing immediate release layer (IR) is composed of the following components: active material, filler, binder, disintegrant, lubricant, auxiliary agent Flow agent.
  • IR immediate release layer
  • the biphasic controlled release preparation is characterized in that the drug-containing sustained release layer (SR) consists of the following components: Active substances, sustained-release polymers, fillers, adhesives, lubricants, and glidants; wherein the drug-containing sustained-release layer (SR) and the drug-free blocking layer (BL) constitute a partial package with an open side. coating structure, in which the drug-containing sustained-release layer (SR) serves as the tablet core, and the drug-free blocking layer (BL) functions as a partial coating layer.
  • the biphasic controlled release preparation is characterized in that the drug-containing immediate release layer (IR) is composed of the following components: active material, filler, binder, disintegrant, lubricant, auxiliary agent Flow agent.
  • the biphasic controlled-release preparation is characterized in that the drug-containing sustained-release layer (SR) is composed of the following components: active substance, sustained-release polymer, filler, adhesive, lubricant, Glidant; the drug-containing sustained-release layer is wrapped between the drug-containing immediate-release layer and the retardant layer.
  • SR drug-containing sustained-release layer
  • the biphasic controlled-release preparation is characterized in that the drug-free blocking layer (BL) is composed of the following components: sustained-release polymer, filler, adhesive, lubricant, flow aid agent.
  • BL drug-free blocking layer
  • the biphasic controlled release preparation according to any one of the above is characterized in that:
  • the mass ratio 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 mass ratio of the drug-containing immediate release layer (IR) to the mass of the drug-free blocking layer (BL) is 1:1 to 0.125:1;
  • the mass ratio of the drug-containing sustained-release layer (SR) to the mass of the drug-free blocking layer (BL) is 0.2:1 to 0.05:1.
  • the biphasic controlled release preparation is characterized in that the filler content in the drug-containing sustained release layer (SR) is 30 to 70%, preferably 50%; the filler material is a brittle filler, such as One or more of lactose, sucrose, calcium sulfate salt, calcium carbonate, and calcium phosphate salt, preferably lactose.
  • SR drug-containing sustained release layer
  • the biphasic controlled release preparation is characterized in that the adhesive content in the drug-containing immediate release layer (IR) is 3 to 10%, and the adhesive content in the drug-containing barrier layer (BL) is 3-10%. Content: 2 ⁇ 10%.
  • the binder is selected from one or more types of HPC, HPMC, povidone, and sodium carboxymethyl cellulose; the viscosity of HPC is 75-700 cps; the viscosity of HPMC is 3-50 cps.
  • the binder content 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 controlled release preparation is characterized in that 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-contained immediate-release layer, and the drug-containing sustained-release layer is The ratio of the mass of the active material in the layer to the mass of the active material in the drug-containing immediate-release layer is ⁇ 4; preferably 4:1 to 1:1, preferably: 2 ⁇ ratio ⁇ 4.
  • the biphasic controlled release preparation described in any one of the above is characterized in that the disintegrant in the drug-containing immediate release layer is selected from the group consisting of croscarmellose sodium, croscarmellose sodium, One or more of crospovidone PVPP and low-substituted hydroxypropylcellulose L-HPC; preferably croscarmellose sodium or croscarmellose sodium;
  • the lubricants in the drug-containing immediate release layer (IR), the drug-containing sustained release layer (SR) and the drug-free blocking layer (BL) are independently selected from magnesium stearate, stearic acid, stearyl fumarate Sodium behenate, glyceryl behenate, hydrogenated castor oil, and sodium lauryl sulfate One or more; 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 blocking layer (BL) are independently colloidal silica or talc; preferably colloidal Silica;
  • the sustained-release polymer (framework material) in the drug-containing sustained-release layer (SR) and the drug-free blocking layer (BL) is hydroxypropyl methylcellulose.
  • the biphasic controlled-release preparation is characterized in that 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 content of hydroxypropyl methylcellulose in the drug-free blocking layer (BL) is 20.00% to 60.00%, preferably 25.00% to 50.00%;
  • the biphasic controlled-release preparation is characterized in that the hydroxypropyl methylcellulose in the sustained-release polymer is selected from the group consisting of E30LV, E50LV, K100LV, K4M, K15M, K100M, and xanthan gum. kind or variety.
  • the active ingredients in the drug-containing immediate-release layer are dissolved within 45 minutes, and the active ingredients in the drug-containing sustained-release layer (SR) are dissolved within 1
  • the trend slope of the dissolution profile within ⁇ 10 hours was between 5.0 and 5.6, with release of at least 95% at 20 hours.
  • the innovation of the present invention lies in the tablet structure and auxiliary material formula, which is suitable for any compound active drug that needs to obtain this kind of release mode.
  • Another aspect of the present invention provides a method for preparing the biphasic controlled release preparation described in any one of the above, which method includes the following steps:
  • sustained-release layer granules Prepare sustained-release layer granules according to the prescription and set aside;
  • sustained-release layer granules Place the sustained-release layer granules in the die of the tablet press and press them into plain tablet cores for later use;
  • steps a, b, c are as follows:
  • step e the pre-pressure is 0.1-0.5KN; the main pressure is 10-25KN.
  • the method wherein, when the binder material in the drug-containing immediate release layer (IR) and the blocking layer contains HPC, HPC is dissolved in the purification step used for the wet granulation. Add to water or alcohol solution.
  • the present invention has developed a new tablet structure, as well as an auxiliary material formula and process to enable the tablet structure to achieve ideal biphasic release; Compared with ordinary preparations, this tablet can reduce adverse reactions and increase patient compliance.
  • the immediate-release layer dissolves rapidly and is released in zero-order mode within 1 to 10 hours, achieving a smooth release effect. .
  • FIG. 1 Schematic diagram of the sheet structure of the present invention
  • Figure 4 In vitro dissolution curve and trend line of Example 2 tablets 2-2 escitalopram oxalate biphasic controlled release preparation for 1 to 10 hours;
  • Figure 8 In vitro dissolution curve and trend line of escitalopram oxalate biphasic controlled release preparation from 1 to 10 hours in Example 5;
  • Figure 9 In vitro dissolution curve and trend line of escitalopram oxalate biphasic controlled release preparation from 1 to 10 hours in Example 6;
  • Figure 10 In vitro dissolution curve and trend line of the biphasic controlled release preparation of escitalopram oxalate from 1 to 10 hours in Example 7;
  • the dissolution method conditions used in the following examples and comparative examples are as follows: "Chinese Pharmacopoeia” dissolution assay method 2, 50 rpm, medium 900 ml, pH 1.2, medium temperature 37 ⁇ 0.5°C.
  • the trend line of the dissolution curve within 1 to 10 hours was selected to evaluate the zero-order release rate.
  • the slope of the dissolution curve trend line between 5.0 and 5.6 is an ideal zero-order release effect, which can continuously maintain zero-order release.
  • the slope of the dissolution curve is too small (less than 5.0), indicating that the release rate of the sustained-release part of the drug is too slow, which will lead to incomplete drug absorption and affect bioavailability; the slope of the dissolution curve is too large (greater than 5.6), indicating that the release rate of the sustained-release part of the drug is too fast, which will cause the drug to be unable to maintain near zero-order release in the later period, affecting the sustained-release effect of the drug.
  • composition and weight of each component are as follows:
  • the method for preparing a biphasic controlled release preparation of escitalopram oxalate in Example 1 of the present invention includes the following steps:
  • IR immediate release layer
  • SR drug-containing sustained-release layer
  • BL blocking layer
  • Escitalopram oxalate control tablets are prepared, and the composition and weight of each component are as follows:
  • the method for preparing a biphasic controlled release preparation of escitalopram oxalate in Example 2 of the present invention includes the following steps:
  • a. Prepare the drug-containing immediate-release layer: Weigh escitalopram oxalate, corn starch, microcrystalline cellulose, croscarmellose sodium, and carboxymethylcellulose sodium and mix thoroughly, add purified water or alcohol solution The liquid is wet granulated, the wet granulation is passed through a 1000-8000 ⁇ m sieve, dried, the dry granulation is passed through a 1000-8000 ⁇ m sieve, talcum powder is added, premixed, and then stearin is added Mix the acid to prepare quick-release layer granules for later use;
  • b. Prepare the drug-containing sustained-release layer: Weigh escitalopram oxalate, HPMC K100LV, and lactose, mix them thoroughly, use purified water or alcohol solution for wet granulation, and pass the wet granulation through a 1000-8000 ⁇ m sieve, dry, and dry. Pass the granules through a 1000-8000 ⁇ m sieve, add talcum powder, premix, then add 0 stearic acid to mix to prepare sustained-release layer granules, and set aside;
  • Comparative Example 2 Tablet 2-1, Tablet 2-2, and Tablet 2-3 were inspected for appearance, fragmentation, friability, and dissolution.
  • the experimental data are as follows:
  • tablets 2-1, 2-2, and 2-3 are all qualified in terms of appearance and friability.
  • Comparative Example 4 Tablet 4-1 and Tablet 4-2 were inspected for appearance, fragmentation, friability, and in vitro dissolution.
  • the experimental data are as follows:
  • Tablet 4-1 is qualified in terms of appearance and friability.
  • Tablet 4-2 has a relatively small mass of BL layer, and cracking occurs during the pressing process. And the friability and appearance were substandard.
  • composition and weight of each component are as follows:
  • the preparation method is as follows
  • a. Prepare the drug-containing immediate-release layer: Weigh escitalopram oxalate, cross-linked povidone PVPP, pregelatinized starch, pregelatinized starch, HPMC K100LV and mix thoroughly, and add HPC-GF with purified water or alcohol solution. After dissolving, add liquid for wet granulation, add purified water or alcohol solution for wet granulation, pass the wet granules through a 1000-8000 ⁇ m sieve, dry, and dry the dry granules through a 1000-8000 ⁇ m sieve, add silica, and premix , then add sodium stearyl fumarate and mix to prepare immediate-release layer granules for later use;
  • b. Preparation of the drug-containing sustained-release layer Weigh escitalopram oxalate, HPMC K100M, and sucrose and mix thoroughly, use purified water or alcohol solution for wet granulation, pass the wet granulation through a 1000-8000 ⁇ m sieve, dry, and dry. Granules pass through 1000-8000 ⁇ m sieve Net, add silica, premix, then add sodium stearyl fumarate and mix to prepare sustained-release layer particles, set aside;
  • Example 6 Preparation of 1000 tablets of biphasic controlled-release preparation (HPMC 1%, HPC 4%, i.e. 1:4). Taking the preparation of 1000 tablets of escitalopram oxalate controlled tablets as an example, the ingredients and weight of each component are as follows:
  • the preparation method is the same as Example 5.
  • Example 7 Preparation of 1000 tablets of biphasic controlled release preparation (HPMC 2%, HPC 3%, i.e. 2:3)
  • composition and weight of each component are as follows:
  • the preparation method is the same as Example 5.
  • Comparative Example 1 Prepare 1,000 tablets of biphasic controlled release preparation (check the IR binder content, the total amount exceeds 10%)
  • composition and weight of each component are as follows:
  • the method for preparing the biphasic controlled release preparation of escitalopram oxalate in the comparative example of the present invention includes the following steps:
  • a. Prepare the drug-containing immediate release layer: weigh 4g escitalopram oxalate, 90g pregelatinized starch, 119.75g microcrystalline cellulose, 7.5g cross-linked povidone PVPP, 12.5g HPMC-HF, 7.5g polyvitamin Mix the ketone thoroughly, add purified water or alcohol solution for wet granulation, pass the wet granules through a 1000-8000 ⁇ m sieve, dry, dry the whole granules through a 1000-8000 ⁇ m sieve, add 0.625g of silica, premix, and then Add 0.625g sodium stearyl fumarate and mix to prepare immediate-release layer granules and set aside;
  • b. Prepare the drug-containing sustained-release layer: Weigh 9.588g escitalopram oxalate, 18g HPMC K100M, and 31.212g sucrose, mix thoroughly, use purified water or alcohol solution for wet granulation, and pass the wet granulation through a 1000-8000 ⁇ m sieve. Dry, dry and whole granules pass through a 1000-8000 ⁇ m sieve, add 0.6g silica, premix, then add 0.6g sodium stearyl fumarate and mix to prepare sustained-release layer granules, set aside;
  • the prescribed amount of blocking layer particles in the die of the tablet press, place the plain tablet core layer in the center of the blocking layer particles, and perform pre-pressure (1KN)) to make the plain tablet core form the desired shape.
  • the drug-containing sustained-release layer (SR) is provided, and the plain tablet core is sunk into the retardant layer particles and all other surfaces except its top surface are surrounded by the retardant layer (BL) to form a partially coated structure with one side open; and then Place the prescribed amount of immediate-release layer particles in the die, apply main pressure (20KN), and make the immediate-release layer particles cover and adhere to the opening of the partial coating structure in a pressing manner to form the drug-containing immediate-release layer. (IR), the film is obtained;
  • the preparation method is the same as Example 1.
  • Comparative Example 2 of the present invention The method for preparing a biphasic controlled release preparation of escitalopram oxalate includes the following steps:
  • a. Prepare the drug-containing immediate release layer: weigh 4g escitalopram oxalate, 90g pregelatinized starch, 134.75g microcrystalline cellulose, 7.5g cross-linked povidone PVPP, 5g HPMC K4M, 7.5g povidone fully Mix, add liquid with purified water or alcohol solution for wet granulation, pass the wet granules through a 1000-8000 ⁇ m sieve, dry, dry and pass the dry granules through a 1000-8000 ⁇ m sieve, add 0.625g of silica, premix, and then add 0.625 g sodium stearyl fumarate is mixed to prepare immediate-release layer granules and set aside;
  • b. Prepare the drug-containing sustained-release layer: weigh 9.588g escitalopram oxalate, 18g HPMC K100M, and 31.212g microcrystals Mix the cellulose thoroughly, use purified water or alcohol solution for wet granulation, pass the wet granules through a 1000-8000 ⁇ m sieve, dry, and dry the granules through a 1000-8000 ⁇ m sieve, add 0.6g of silica, premix, and then add Mix 0.6g sodium stearyl fumarate to prepare sustained-release layer granules and set aside;
  • the prescribed amount of blocking layer particles in the die of the tablet press, place the plain tablet core layer in the center of the blocking layer particles, and perform pre-pressure (1KN)) to make the plain tablet core form the desired shape.
  • the drug-containing sustained-release layer (SR) is provided, and the core of the plain tablet is sunk into the retardant layer particles and all other surfaces except its top surface are surrounded by the retardant layer (BL) to form a partially coated structure with one side open; and then Place the prescribed amount of immediate-release layer particles in the die, apply main pressure (20KN), and make the immediate-release layer particles cover and adhere to the opening of the partial coating structure in a pressing manner to form the drug-containing immediate-release layer. (IR), the film is obtained.
  • brittle fillers that are not easily deformed must be selected, such as lactose, sucrose, calcium sulfate salts, calcium carbonate, and calcium phosphate salts.
  • the preparation method is the same as Example 5.
  • the sustained-release layer drug in the tablet maintains a zero-order release throughout the release process and releases at least 95% at 20 hours.
  • 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, which will lead to incomplete dissolution of the drug within 20 hours, affecting bioavailability
  • the slope of the dissolution curve is too large (greater than 5.6)
  • the drug release rate in the sustained-release part The drug will be released at a faster rate in the early stage, and the drug cannot maintain near zero-order release in the later stage, affecting the sustained release effect.
  • Tablet 2-1 released 97% in 12 hours because the API SR/IR was less than 2 and the immediate-release layer API accounted for 33% (completely released in 30-45 minutes), so in the first hour, the total The API has been released to 46%, so that it is almost completely released at the 12th hour of the post-sustained release phase, but it is near zero-level release during the entire process from 1 to 12 hours.

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Abstract

一种双相控释制剂及其制备，在体内能够快速起效，快速达到血药浓度峰值，之后保持平稳的释放，维持稳定的血药浓度，减小波峰波谷之间的波动，该控释制剂由三个部分组成，速释层、片芯层、阻滞层。速释层在体外迅速溶出，剩余片芯层和阻滞层的组合可以保持体外的零级释放。

Description

一种双相控释制剂及其制备方法 技术领域
本发明涉及制药技术，特别是一种双相控释制剂及其制备方法。
背景技术
近年来，随着给药系统理论研究的深入进行和高分子材料科学的发展，药物传递系统的研究从品种到剂型都在不断地增多。缓控释制剂一直以来都为人们所关注，在某些特殊病理情况下，传统的或单一的释药模式有时很难满足临床需求，如普通速释制剂难以长时间维持药效，而普通缓释剂型则不能快速起效。因此，双相释药系统(Biphasic drug delivery system)日益引起人们的重视。双相释药系统有两个不同的释放相，可针对药物的特殊理化性质及生物药剂学性质、疾病发作的时辰节律性及复杂性，通过特定的处方设计或工艺技术，实现速效/长效释药、脉冲或延迟释药，从而为临床提供更加灵活的给药方案。
为实现双相释放的目的，人们开展了广泛的研究，控制药物在预定时间以预定速度释放，如双层或多层片系统，多颗粒系统、膜包衣系统和定时胶囊系统等。和常规普通制剂相比，其处方和生产工艺相对复杂，对工业化生产要求较高。
发明内容
本发明通过剂型设计，制备一种双相控释制剂，在体内既能够快速起效，又能长时间维持平稳匀速释放即近零级释放，可以降低不良反应，增加患者顺应性，据此，本发明请求保护以下技术方案：
一种双相控释制剂，该双相控释制剂由含药速释层(IR)、含药缓释层(SR)和不含药阻滞层(BL)组成；
所述含药缓释层(SR)包裹在所述含药速释层(IR)和阻滞层(SR)之间；所述含药速释层(IR)是通过压片方式压制并覆盖在所述含药缓释层(SR)上形成。
优选地，所述的双相控释制剂，其特征在于，所述含药速释层(IR)由以下组分组成：活性物质、填充剂、粘合剂、崩解剂、润滑剂、助流剂。
优选地，所述的双相控释制剂，其特征在于，所述含药缓释层(SR)由以下组分组成： 活性物质、缓释聚合物、填充剂、粘合剂、润滑剂、助流剂；其中所述含药缓释层(SR)和不含药的阻滞层(BL)构成一面开口的部分包衣结构，其中含药缓释层(SR)作为片芯，不含药阻滞层(BL)起到部分包衣层功能。优选地，所述的双相控释制剂，其特征在于，所述含药速释层(IR)由以下组分组成：活性物质、填充剂、粘合剂、崩解剂、润滑剂、助流剂。
优选地，所述的双相控释制剂，其特征在于，所述含药缓释层(SR)由以下组分组成：活性物质、缓释聚合物、填充剂、粘合剂、润滑剂、助流剂；所述含药缓释层包裹在所述含药速释层和阻滞层之间。
优选地，所述的双相控释制剂，其特征在于，所述不含药阻滞层(BL)由以下组分组成：缓释聚合物、填充剂、粘合剂、润滑剂、助流剂。
优选地，上述任一项所述的双相控释制剂，其特征在于，
所述含药速释层(IR)的质量与含药缓释层(SR)的质量之比为5:1～1.5:1；
所述含药速释层(IR)的质量与不含药阻滞层(BL)的质量之比为1:1～0.125:1；
所述含药缓释层(SR)的质量与不含药阻滞层(BL)的质量之比为0.2:1～0.05:1。
优选地，所述的双相控释制剂，其特征在于，所述含药缓释层(SR)中的填充剂含量为30～70％，优选50％；填充剂材料为脆性填充剂，比如乳糖、蔗糖、硫酸钙盐、碳酸钙、磷酸钙盐中的一种或多种，优选乳糖。
优选地，所述的双相控释制剂，其特征在于，其中含药速释层(IR)中粘合剂含量为3～10％，不含药阻滞层(BL)中的粘合剂含量为：2～10％。粘合剂选自HPC、HPMC、聚维酮、羧甲基纤维素钠中的一种或多种；其中HPC粘度为75-700cps；HPMC的粘度3-50cps。
优选地，所述的双相控释制剂，其中所述含药速释层(IR)中所述粘合剂含量为5％，材料由HPMC和HPC以0～1:1的含量比构成，。
优选地，所述的双相控释制剂，其特征在于，其中所述含药缓释层中活性物质的质量大于所述含药速释层中活性物质的质量，且所述含药缓释层中活性物质的质量与所述含药速释层中活性物质的质量的比值≤4；优选4:1～1:1，优选：2≤比值≤4。
优选地，上述任一所述的双相控释制剂，其特征在于，所述含药速释层中的崩解剂选自交联羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮PVPP和低取代羟丙基纤维素L-HPC中的一种或多种；优选为交联羧甲基淀粉钠或交联羧甲基纤维素钠；
所述含药速释层(IR)、含药缓释层(SR)和不含药阻滞层(BL)中的润滑剂独立地选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯、氢化蓖麻油和十二烷基硫酸钠中的一 种或多种；优选为硬脂酸镁或硬脂酸；
所述含药速释层(IR)、含药缓释层(SR)和不含药阻滞层(BL)中的助流剂独立地为胶态二氧化硅或滑石粉；优选为胶态二氧化硅；
所述含药缓释层(SR)和不含药阻滞层(BL)中的缓释聚合物(骨架材料)为羟丙甲基纤维素。
优选地，所述的双相控释制剂，其特征在于，所述含药缓释层(SR)的羟丙基甲基纤维素的含量为20.00～60.00％，优选为25.00％～50.00％；
所述不含药阻滞层(BL)羟丙基甲基纤维素的含量为20.00～60.00％，优选为25.00％～50.00％；
优选地，所述的双相控释制剂，其特征在于，所述缓释聚合物中的羟丙基甲基纤维素选自E30LV、E50LV、K100LV、K4M、K15M、K100M、黄原胶的一种或多种。
优选地，在体外溶解试验中，在体外溶解试验中，含药速释层(IR)中至少85％的活性成分在45min之内溶出，且含药缓释层(SR)中活性成分在1～10小时内的溶出曲线的趋势斜率在5.0～5.6之间，在20小时释放至少95％。
本发明的创新在于片形结构和辅料配方，适用于任何需要获得该类释放模式的化合物类活性药物。
本发明的另一方面，提供上述任一项所述的双相控释制剂的制备方法，该方法包括如下步骤：
a.按处方制备速释层颗粒，备用；
b.按处方制备缓释层颗粒，备用；
c.按处方制备阻滞层颗粒颗粒，备用；
d.将缓释层颗粒置于压片机的冲模内，压制成素片片芯，备用；
e.将处方量的阻滞层颗粒置于压片机的冲模内，将素片片芯层置于阻滞层颗粒的中央位置,进行预压，预压力为0.1-2KN，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层包围从而形成的一面开口的部分包衣结构；再将处方量的速释层颗粒置于冲模内，施加主压力，主压力为5-35KN，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，即得成片，片形结构如图1所示。
优选地，所述的方法，其中步骤a，b，c具体如下：
a、称取制备含药速释层所需处方量的活性物质、填充剂、崩解剂、HPC之外的粘合剂充分混合，用纯化水或醇溶液加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥；干整 粒过1000-8000μm筛网，加入助流剂，预混合，再加入润滑剂混合，制得速释层颗粒，备用；
b、称取制备含药缓释层所需处方量的活性物质、缓释聚合物、填充剂，用纯化水或醇溶液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥；干整粒过1000-8000μm筛网，加入助流剂，预混合，再加入润滑剂混合制得缓释层颗粒，备用；
c、称取制备阻滞层所需处方量的缓释聚合物、填充剂、HPC之外的粘合剂充分混合，用纯化水或醇溶液加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥；干整粒过1000-8000μm筛网，加入助流剂，预混合，再加入润滑剂混合制得阻滞层颗粒，备用；
在步骤e中，所述预压力为0.1～0.5KN；，主压力为10～25KN。
优选地，所述的方法，其中，当所述含药速释层(IR)及阻滞层中的粘合剂材料包含HPC时，HPC以溶解在用于所述湿法制粒的所述纯化水或醇溶液中进行添加。
本发明的技术优势概括：
本发明为了实现活性药物双相释放即够快速起效又能长时间维持零级平稳释放，研发了新的片形结构，以及使该片形结构实现理想的双相释放的辅料配方及工艺；跟普通制剂比，该片剂，能达到降低不良反应，增加患者顺应性的效果，速释层在迅速溶出，并在1～10h内以零级模式释放，达到平稳释放的效果。。
附图说明：
图1.本发明片型结构示意图；
图2.实施例1片1-1草酸艾司西酞普兰双相控释制剂1～10h的体外溶出度曲线图及趋势线；
图3.实施例2片2-1草酸艾司西酞普兰双相控释制剂1～10h的体外溶出度曲线图及趋势线；
图4.实施例2片2-2草酸艾司西酞普兰双相控释制剂1～10h的体外溶出度曲线图及趋势线；
图5.实施例2片2-3草酸艾司西酞普兰双相控释制剂1～10h的体外溶出度曲线图及趋势线；
图6.实施例3片3-1草酸艾司西酞普兰双相控释制剂1～10h的体外溶出度曲线图及趋势线；
图7.实施例4片4-1草酸艾司西酞普兰双相控释制剂1～10h的体外溶出度曲线图及趋势线；
图8.实施例5草酸艾司西酞普兰双相控释制剂1～10h的体外溶出度曲线图及趋势线；
图9.实施例6草酸艾司西酞普兰双相控释制剂1～10h的体外溶出度曲线图及趋势线；
图10.实施例7草酸艾司西酞普兰双相控释制剂1～10h的体外溶出度曲线图及趋势线；
图11.对比例1草酸艾司西酞普兰双相控释制剂1～10h的体外溶出度曲线图及趋势线；
图12.脆碎度合格的片剂的0-20小时的体外溶出度数据。
具体实施例
下面通过具体实施例对本发明的技术方案作示例性说明，本领域技术人员可以理解，这些实施方案不应解读为对本发明保护范围的限制。
以下实施例及对比例采用的溶出方法条件如下：《中国药典》溶出测定法第二法，50rpm，介质为900ml，pH1.2，介质温度为37±0.5℃。
以下部分实施例及对比例溶出曲线，选取1～10h内溶出曲线的趋势线评价零级释放速率，溶出曲线趋势线斜率在5.0～5.6之间为较理想的零级释放效果，能持续维持零级释放，在，实现药物吸收完全；而溶出曲线斜率太小(小于5.0)，表明缓释部分药物释放速率太慢，会导致药物吸收不完全，影响生物利用度；溶出曲线斜率太大(大于5.6)，表明缓释部分药物释放速率太快，会导致药物后期无法维持近似零级释放，影响药物的缓释效果。
实施例1制备1000片双相控释制剂
以制备1000片草酸艾司西酞普兰控制片为例，其各组分成分及重量如下表：

本发明实施例1制备草酸艾司西酞普兰双相控释制剂的方法包括如下步骤：
a、制备含药速释层(IR)：按处方称取活性药物、崩解剂、填充剂、粘合剂充分混合，用纯化水或醇溶液加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入助流剂，预混合，再加入润滑剂混合，制得速释层颗粒，备用；
b、制备含药缓释层(SR)：按处方称取活性药物、缓释聚合物、填充剂充分混合，用纯化水或醇溶液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入助流剂，预混合，再加入润滑剂混合制得缓释层颗粒，备用；
c、制备阻滞层(BL)：按处方缓释聚合物和填充剂充分混合；将粘合剂HPC用纯化水或醇溶液溶解后加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入助流剂，预混合，再加入润滑剂混合制得阻滞层颗粒，备用；
d、将处方量的含所述缓释层颗粒置于压片机的冲模内，压制成素片片芯，备用；
e、将处方量的阻滞层颗粒置于压片机的冲模内，将素片片芯层置于阻滞层颗粒的中央位置,进行预压(1KN))，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层包围从而形成的一面开口的部分包衣结构；再将处方量的速释层颗粒置于冲模内，施加主压力(20KN)，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，即得成片1-1。
本发明双相控释制剂的片形结构如图1所示，后续实施例均相同。
对于实施例1片1-1外观、裂片情况、脆碎度、溶出情况进行考察，实验数据如下表：
由此可知，片1-1在外观和脆碎度方面均合格。对片1-1进行体外溶出实验，溶出曲线及趋势线见图2，零级释放速率(趋势线斜率)为5.49。
实施例2制备草酸艾司西酞普兰双相控释制剂，考察IR：SR不同比值的影响
制备草酸艾司西酞普兰控制片，其各组分成分及重量如下表：
本发明实施例2制备草酸艾司西酞普兰双相控释制剂的方法包括如下步骤：
a、制备含药速释层：称取草酸艾司西酞普兰、玉米淀粉、微晶纤维素、交联羧甲基纤维素钠、羧甲基纤维素钠充分混合，纯化水或醇溶液加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入滑石粉，预混合，再加入硬脂 酸混合，制得速释层颗粒，备用；
b、制备含药缓释层：称取草酸艾司西酞普兰、HPMC K100LV、乳糖充分混合，用纯化水或醇溶液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入滑石粉，预混合，再加入0硬脂酸混合制得缓释层颗粒，备用；
c、制备阻滞层：称取所需处方量的HPMCK4LV、预胶化淀粉、微晶纤维素充分混合，将HPC-GF用纯化水或醇溶液溶解后加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入1滑石粉，预混合，再加入硬脂酸混合制得阻滞层颗粒，备用；
d、将处方量的含所述缓释层颗粒置于压片机的冲模内，分别压制成40mg、50mg、80mg素片片芯，备用；
e、将650mg阻滞层颗粒置于压片机的冲模内，将50mg素片片芯层置于阻滞层颗粒的中央位置,进行预压(1KN)，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层包围从而形成的一面开口的部分包衣结构；再将400mg的速释层颗粒置于冲模内，施加主压力(20KN)，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，即得成片2-1
将650mg阻滞层颗粒置于压片机的冲模内，将80mg素片片芯层置于阻滞层颗粒的中央位置,进行预压(1KN)，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层包围从而形成的一面开口的部分包衣结构；再将100mg的速释层颗粒置于冲模内，施加主压力(20KN)，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，即得成片2-2
将650mg阻滞层颗粒置于压片机的冲模内，将40mg素片片芯层置于阻滞层颗粒的中央位置,进行预压(1KN)，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层包围从而形成的一面开口的部分包衣结构；再将220mg的速释层颗粒置于冲模内，施加主压力(20KN)，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，即得成片2-3
对比实施例2片2-1、片2-2、片2-3的外观、裂片情况、脆碎度、溶出情况进行考察，实验数据如下表：
以上可知，在速释和缓释层重不同比值的情况下，片2-1、2-2、2-3在外观和脆碎度方面均合格。
对片2-1、2-2、2-3进行体外溶出实验，溶出曲线及趋势图分别见图3、4、5，对比其在1～10h的释放速率可知，片2-1、2-2、2-3的零级释放速率(趋势线斜率)分别为5.42、7.25和5.73；片2-2、2-3溶出速率偏快。
实施例3制备草酸艾司西酞普兰双相控释制剂(考察SR：BL不同比值)
按照实施例2的处方和工艺制备不同片层颗粒备用。
将800mg阻滞层颗粒置于压片机的冲模内，将40mg素片片芯层置于阻滞层颗粒的中央位置,进行预压(1KN)，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层(BL)包围从而形成的一面开口的部分包衣结构；再将200mg的速释层颗粒置于冲模内，施加主压力(20KN)，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，即得成片3-1，即IR:SR＝5:1,IR:BL＝1:4,SR:BL＝0.05:1；
将300mg阻滞层颗粒置于压片机的冲模内，将80mg素片片芯层置于阻滞层颗粒的中央位置,进行预压(1KN)，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层(BL)包围从而形成的一面开口的部分包衣结构；再将200mg的速释层颗粒置于冲模内，施加主压力(20KN)，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，即得成片3-2，即IR:SR＝2.5:1,IR:BL＝0.67:1,SR:BL＝0.27:1；
对比实施例3片3-1、片3-2的外观、裂片情况、脆碎度、体外溶出进行考察，实验数据如下表：
以上可知，在缓释和阻滞层重不同比值的情况下，片3-1外观和脆碎度均合格，片3-2 存在裂片现象且脆碎度不合格。对片3-1进行体外溶出实验，溶出曲线及趋势线见图6，零级释放速率(趋势线斜率)为5.46。
实施例4制备草酸艾司西酞普兰双相控释制剂(考察IR:BL不同比值)
按照实施例2的处方和工艺制备不同片层颗粒备用。
将200mg阻滞层颗粒置于压片机的冲模内，将40mg素片片芯层置于阻滞层颗粒的中央位置,进行预压(1KN)，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层(BL)包围从而形成的一面开口的部分包衣结构；再将200mg的速释层颗粒置于冲模内，施加主压力(20KN)，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，即得成片4-1；即IR:SR＝5:1,IR:BL＝1:1,SR:BL＝0.2:1；
将200mg阻滞层颗粒置于压片机的冲模内，将40mg素片片芯层置于阻滞层颗粒的中央位置,进行预压(1KN)，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层(BL)包围从而形成的一面开口的部分包衣结构；再将300mg的速释层颗粒置于冲模内，施加主压力(20KN)，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，即得成片4-2；即IR:SR＝7.5:1,IR:BL＝1.5:1,SR:BL＝0.2:1。
对比实施例4片4-1、片4-2的外观、裂片情况、脆碎度、体外溶出进行考察，实验数据如下表：
以上可知，在速释和阻滞层重不同比值的情况下，片4-1在外观和脆碎度方面均合格，片4-2由于BL层质量相对较小，压制过程中出现裂片现象，且脆碎度和外观不合格。
对片4-1进行体外溶出实验，溶出曲线及趋势线见图7，零级释放速率(趋势线斜率)为5.27。
以下实施例5-7及对比例3考察速释IR层中粘合剂材料的比例
实施例5制备1000片双相控释制剂(HPMC0％，HPC 5％，即0:5)
以制备1000片草酸艾司西酞普兰控制片为例，其各组分成分及重量如下表：
制备方法如下
a、制备含药速释层：称取草酸艾司西酞普兰、交联聚维酮PVPP、预胶化淀粉、预胶化淀粉、HPMC K100LV充分混合，将HPC-GF用纯化水或醇溶液溶解后加液进行湿法制粒，纯化水或醇溶液加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入二氧化硅，预混合，再加入硬脂富马酸钠混合，制得速释层颗粒，备用；
b、制备含药缓释层：称取草酸艾司西酞普兰、HPMC K100M、蔗糖充分混合，用纯化水或醇溶液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛 网，加入二氧化硅，预混合，再加入硬脂富马酸钠混合，制得缓释层颗粒，备用；
c、制备阻滞层：称取所需处方量的HPMC K4M、HPMC K15M、玉米淀粉、微晶纤维素MCC-PH101充分混合，将HPC-GF用纯化水或醇溶液溶解后加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入二氧化硅，预混合，再加入硬脂富马酸钠混合，混合制得阻滞层颗粒，备用；
d、将处方量的含所述缓释层颗粒置于压片机的冲模内，压制成素片片芯，备用；
e、将阻滞层颗粒置于压片机的冲模内，将素片片芯层置于阻滞层颗粒的中央位置,进行预压(1KN)，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层包围从而形成的一面开口的部分包衣结构；再将速释层颗粒置于冲模内，施加主压力(20KN)，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，分别得成片。
实施例6制备1000片双相控释制剂(HPMC 1％，HPC 4％，即1:4)以制备1000片草酸艾司西酞普兰控制片为例，其各组分成分及重量如下表：

制备方法同实施例5。
实施例7制备1000片双相控释制剂(HPMC 2％，HPC 3％，即2:3)
以制备1000片草酸艾司西酞普兰控制片为例，其各组分成分及重量如下表：

制备方法同实施例5。
对比例1制备1000片双相控释制剂(考察IR粘合剂含量，总量超过10％)
以制备1000片草酸艾司西酞普兰控制片为例，其各组分成分及重量如下表：
制备方法同实施例5
本发明对比例制备草酸艾司西酞普兰双相控释制剂的方法包括如下步骤：
a、制备含药速释层：称取4g草酸艾司西酞普兰、90g预胶化淀粉、119.75g微晶纤维素、7.5g交联聚维酮PVPP、12.5gHPMC-HF、7.5g聚维酮充分混合，用纯化水或醇溶液加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入0.625g二氧化硅，预混合，再加入0.625g硬脂富马酸钠混合，制得速释层颗粒，备用；
b、制备含药缓释层：称取9.588g草酸艾司西酞普兰、18gHPMC K100M、31.212g蔗糖充分混合，用纯化水或醇溶液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入0.6g二氧化硅，预混合，再加入0.6g硬脂富马酸钠混合制得缓释层颗粒，备用；
c、制备阻滞层：称取所需处方量的260g HPMCK4M、65g HPMCK15M、97.5g玉米淀粉、172.25g微晶纤维素充分混合，将52gHPC用纯化水或醇溶液溶解后加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入1.625二氧化硅，预混合，再加入1.625g硬脂富马酸钠混合制得阻滞层颗粒，备用；
d、将处方量的含所述缓释层颗粒置于压片机的冲模内，压制成素片片芯，备用；
e、将处方量的阻滞层颗粒置于压片机的冲模内，将素片片芯层置于阻滞层颗粒的中央位置,进行预压(1KN))，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层(BL)包围从而形成的一面开口的部分包衣结构；再将处方量的速释层颗粒置于冲模内，施加主压力(20KN)，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，即得成片；
对于对比例1压制的双相控释制剂外观、裂片情况、脆碎度、溶出情况进行考察，实验数据如下表：
以上可知，对比例1压制的双相控释制剂无裂片情况，脆碎度合格，但外观较粗糙。将对比例1压制的双相控释制剂进行体外溶出实验，溶出曲线见图11。
对比其在1～10h的释放速率可知，对比例1的双相控释制剂在体外1～10h溶出速度过慢，零级释放速率(趋势线斜率)为4.84，未达到理想的释放模式。
对比例2制备1000片双相控释制剂(考察SR填充剂材料选择)
制备方法同实施例1。
本发明对比例2制备草酸艾司西酞普兰双相控释制剂的方法包括如下步骤：
a、制备含药速释层：称取4g草酸艾司西酞普兰、90g预胶化淀粉、134.75g微晶纤维素、7.5g交联聚维酮PVPP、5gHPMC K4M、7.5g聚维酮充分混合，用纯化水或醇溶液加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入0.625g二氧化硅，预混合，再加入0.625g硬脂富马酸钠混合，制得速释层颗粒，备用；
b、制备含药缓释层：称取9.588g草酸艾司西酞普兰、18gHPMC K100M、31.212g微晶 纤维素充分混合，用纯化水或醇溶液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入0.6g二氧化硅，预混合，再加入0.6g硬脂富马酸钠混合制得缓释层颗粒，备用；
c、制备阻滞层：称取所需处方量的260g HPMCK4M、65g HPMCK15M、97.5g玉米淀粉、191.75微晶纤维素充分混合，将32.5gHPC用纯化水或醇溶液溶解后加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入1.625二氧化硅，预混合，再加入1.625g硬脂富马酸钠混合制得阻滞层颗粒，备用；
d、将处方量的含所述缓释层颗粒置于压片机的冲模内，压制成素片片芯，备用；
e、将处方量的阻滞层颗粒置于压片机的冲模内，将素片片芯层置于阻滞层颗粒的中央位置,进行预压(1KN))，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层(BL)包围从而形成的一面开口的部分包衣结构；再将处方量的速释层颗粒置于冲模内，施加主压力(20KN)，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上形成所述含药速释层(IR)，即得成片。
对于对比例2压制的双相控释制剂外观、裂片情况、脆碎度、溶出情况进行考察，实验数据如下表：
以上可知，压制对比例2的过程中出现裂片现象，是因为微晶纤维素为非脆性填充剂，受压后易产生黏弹性形变，导致速释层被顶开，因此脆碎度和外观不合格。
综合研发中的实验数据发现，针对本发明的片形结构，须选择不易形变的脆性填充剂，例如乳糖、蔗糖、硫酸钙盐、碳酸钙、磷酸钙盐。
对比例3制备1000片双相控释制剂(HPMC 3％，HPC 2％，即3:2)以制备1000片草酸艾司西酞普兰控制片为例，其各组分成分及重量如下表：

制备方法同实施例5。
实施例5、6、7和对比例3的外观、裂片情况、脆碎度、体外溶出进行考察，实验数据如下表：
通过以上数据对比可知，当速释层粘合剂HPMC：HPC大于1(对比例3)时，片子外观粗糙、麻面，且脆碎度不合格。
对实施例5～7压制的双相控释制剂进行体外溶出实验，溶出曲线及趋势线见图8～10，零级释放速率(趋势线斜率)分别为5.49、5.51和5.5，可见脆碎度和体外溶出都能达到理想状态。
对实施例1～7所得制片过程不裂片脆碎度合格的片剂统计0～20小时各时间节点的体外溶出度％统计如下表，溶出曲线见图12。
可以看出，当1-10小时的溶出曲线的趋势斜率在5～5.6之间时，片剂中缓释层药物整个释放过程中维持似零级释放，并在20小时释放至少95％。但是当溶出曲线斜率太小(小于5.0)，缓释部分药物释放速率太慢，会导致在20小时内药物溶出不完全，影响生物利用度；溶出曲线斜率太大(大于5.6)，缓释部分药物前段将以较快速率释放，药物后期无法维持近似零级释放，影响缓释效果。
片剂2-1在12小时即释放至97％，是因为API SR/IR不足2，速释层API占33％(在30-45分钟时已经完全释放)，所以在第1个小时，总API已经释放至46％，以至于后缓释阶段第12小时时差不多完全释放，但是在1-12小时内整个过程中是近零级释放。

Claims (16)

  1. 一种双相控释制剂，该双相控释制剂由含药速释层(IR)、含药缓释层(SR)和不含药阻滞层(BL)组成；
    所述含药缓释层(SR)包裹在所述含药速释层(IR)和阻滞层(SR)之间；所述含药速释层(IR)是通过压片方式压制并覆盖在所述含药缓释层(SR)上形成。
  2. 根据权利要求1所述的双相控释制剂，其特征在于，所述含药速释层(IR)由以下组分组成：活性物质、填充剂、粘合剂、崩解剂、润滑剂、助流剂。
  3. 根据权利要求1所述的双相控释制剂，其特征在于，所述含药缓释层(SR)由以下组分组成：活性物质、缓释聚合物、填充剂、粘合剂、润滑剂、助流剂；所述含药缓释层(SR)和不含药的阻滞层(BL)构成一面开口的部分包衣结构，其中含药缓释层(SR)作为片芯，不含药阻滞层(BL)起到部分包衣层功能。
  4. 根据权利要求1所述的双相控释制剂，其特征在于，所述不含药阻滞层(BL)由以下组分组成：缓释聚合物、填充剂、粘合剂、润滑剂、助流剂。
  5. 根据权利要求1-4中任一项所述的双相控释制剂，其特征在于，
    所述含药速释层(IR)的质量与含药缓释层(SR)的质量之比为5:1～1.5:1；
    所述含药速释层(IR)的质量与不含药阻滞层(BL)的质量之比为1:1～0.125:1；
    所述含药缓释层(SR)的质量与不含药阻滞层(BL)的质量之比为0.2:1～0.05:1。
  6. 根据权利要求5所述的双相控释制剂，其特征在于，所述含药缓释层(SR)中的填充剂含量为30～70％，优选50％；填充剂材料选自乳糖、蔗糖、硫酸钙盐、碳酸钙、磷酸钙盐中的一种或多种，优选乳糖。
  7. 根据权利要求5所述的双相控释制剂，其特征在于，其中含药速释层(IR)中粘合剂含量为3～10％，不含药阻滞层(BL)中的粘合剂含量为：2～10％，粘合剂选自HPC、HPMC、聚维酮、羧甲基纤维素钠中的一种或多种；其中HPC粘度为75-700cps，HPMC的粘度3-50cps。
  8. 根据权利要求7所述的双相控释制剂，其中所述含药速释层(IR)中所述粘合剂含量为5％，材料由HPMC和HPC以0～1:1的含量比构成。
  9. 根据权利要求1所述的双相控释制剂，其特征在于，其中所述含药缓释层中活性物质的质量大于所述含药速释层中活性物质的质量，且所述含药缓释层中活性物质的质量与所述含药速释层中活性物质的质量的比值≤4；优选4:1～1:1。
  10. 根据权利要求3～9所述的双相控释制剂，其特征在于，所述含药速释层中的崩解剂选 自交联羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮PVPP和低取代羟丙基纤维素L-HPC中的一种或多种；优选为交联羧甲基淀粉钠或交联羧甲基纤维素钠；
    所述含药速释层(IR)、含药缓释层(SR)和不含药阻滞层(BL)中的润滑剂独立地选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯、氢化蓖麻油和十二烷基硫酸钠中的一种或多种；优选为硬脂酸镁或硬脂酸；
    所述含药速释层(IR)、含药缓释层(SR)和不含药阻滞层(BL)中的助流剂独立地为胶态二氧化硅或滑石粉；优选为胶态二氧化硅；
    所述含药缓释层(SR)和不含药阻滞层(BL)中的缓释聚合物(骨架材料)为羟丙甲基纤维素。
  11. 根据权利要求10所述的双相控释制剂，其特征在于，所述含药缓释层(SR)的羟丙基甲基纤维素的含量为20.00～60.00％，优选为25.00％～50.00％；
    所述不含药阻滞层(BL)羟丙基甲基纤维素的含量为20.00～60.00％，优选为25.00％～50.00％；
  12. 根据权利要求10所述的双相控释制剂，其特征在于，所述缓释聚合物中的羟丙基甲基纤维素选自E30LV、E50LV、K100LV、K4M、K15M、K100M、黄原胶的一种或多种。
  13. 根据权利要求1-12任一所述的双相控释制剂，其特征在于，在体外溶解试验中，含药速释层(IR)中至少85％的活性成分在45min之内溶出，且含药缓释层(SR)中活性成分在1～10小时内的溶出曲线的趋势斜率在5.0～5.6之间，在20小时释放至少95％。
  14. 一种制备权利要求1至13任一项所述的双相控释制剂的方法，该方法包括如下步骤：
    a.按处方制备速释层颗粒，备用；
    b.按处方制备缓释层颗粒，备用；
    c.按处方制备阻滞层颗粒颗粒，备用；
    d.将缓释层颗粒置于压片机的冲模内，压制成素片片芯，备用；
    e.将处方量的阻滞层颗粒置于压片机的冲模内，将素片片芯层置于阻滞层颗粒的中央位置,进行预压，预压力为0.1-2KN，使得素片片芯形成所述含药缓释层(SR)，且素片片芯陷入阻滞层颗粒中且除了其顶面外其它面均被阻滞层包围从而形成的一面开口的部分包衣结构；再将处方量的速释层颗粒置于冲模内，施加主压力，主压力为5-35KN，使速释层颗粒以压制方式覆盖和粘附在所述部分包衣结构的开口上，形成所述含药速释层(IR)，即得成片
  15. 根据权利要求14所述的方法，其中步骤a，b，c具体如下：
    a、称取制备含药速释层所需处方量的活性物质、填充剂、崩解剂、HPC之外的粘合剂材料充分混合，用纯化水或醇溶液加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入助流剂，预混合，再加入润滑剂混合，制得速释层颗粒，备用；
    b、称取制备含药缓释层所需处方量的活性物质、缓释聚合物、填充剂，用纯化水或醇溶液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入助流剂，预混合，再加入润滑剂混合制得缓释层颗粒，备用；
    c、称取制备阻滞层所需处方量的缓释聚合物、填充剂、HPC之外的粘合剂充分混合，用纯化水或醇溶液加液进行湿法制粒，湿整粒过1000-8000μm筛网，干燥，干整粒过1000-8000μm筛网，加入助流剂，预混合，再加入润滑剂混合制得阻滞层颗粒，备用；
    步骤e中，所述预压力为0.1～0.5KN；主压力为10～25KN。
  16. 根据权利要求15所述的方法，其中，当所述含药速释层(IR)及阻滞层中的粘合剂材料包含HPC时，HPC以溶解在用于所述湿法制粒的所述纯化水或醇溶液中进行添加。
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