WO2016050160A1 - 一种帕利哌酮口服控释片及其制备方法 - Google Patents

一种帕利哌酮口服控释片及其制备方法 Download PDF

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WO2016050160A1
WO2016050160A1 PCT/CN2015/090365 CN2015090365W WO2016050160A1 WO 2016050160 A1 WO2016050160 A1 WO 2016050160A1 CN 2015090365 W CN2015090365 W CN 2015090365W WO 2016050160 A1 WO2016050160 A1 WO 2016050160A1
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paliperidone
coating layer
controlled release
core
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French (fr)
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杜江永
李巧霞
施祥杰
胡李斌
陈浩
王红莲
胡功允
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浙江华海药业股份有限公司
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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Definitions

  • the invention relates to a drug controlled release preparation and a preparation method thereof, in particular to a paliperidone oral controlled release tablet and a preparation method thereof.
  • Paclipentone (9-hydroxyrisperidone) is a novel atypical antipsychotic that belongs to the class of benzoisoxazoles and is currently believed to act by blocking dopamine, serotonin and adrenergic receptors. It interferes with the signaling of neurotransmitters in the brain of patients.
  • the oral bioavailability of paliperidone is 28%, the plasma protein binding rate is 74%, the terminal elimination and half-life are about 23 hours, and it is clinically effective for schizophrenia.
  • the structural formula of paliperidone is as follows:
  • the main problems in the clinical application of drugs for the treatment of nervous system diseases are: large adverse reactions, especially in the early stage of taking the drug, the patient's tolerance is poor, easy to stop in the middle; the initial dose of the common preparation requires dose titration (ie slowly increase the dose) ) to reduce the occurrence of adverse reactions, but inconvenient to take.
  • controlled release preparations such as those prepared by osmotic pump controlled release technology have been developed, which have the pH of the medium, gastrointestinal motility, food, etc.
  • the influence of factors is small, the individual differences are small, the correlation between the body and the outside is good, the blood medicine is stable, the adverse reactions are small, the number of patients taking the medicine is small, and the compliance is high.
  • Paliperidone was developed by Johnson & Johnson, Inc., and was made into an osmotic pump controlled release formulation using Alza's osmotic pump technology.
  • Chinese Patent Application No. 03822948.X discloses a controlled release formulation of paliperidone.
  • the preparation adopts a three-layer osmotic pump tablet dosage form, and the preparation process is very complicated.
  • the three-layer osmotic pump sheet comprises a propelling layer and two drug-containing layers having different drug ratios.
  • the preparation process of the preparation is as follows: 1) First, the two drug-containing layer particles and the propellant layer particles are respectively granulated by a wet granulation process to obtain two drug-containing layer particles and a propellant layer particle respectively; 2) using a three-layer laminate The tablet machine compresses the two drug-containing layer particles and the propellant layer particles to obtain a pellipidone tri-layer tablet; 3) isolates the paliperidone tri-layer tablet; 4) the pellipidone three-layer tablet
  • the release coating of the sheet is coated with a cellulose acetate and polyethylene glycol for controlled release coating of the osmotic pump sheet, and the cellulose acetate is dissolved in acetone for coating during the coating, and the concentration of the coating liquid is 10 Within 5%; 5) laser perforation of the osmotic pump sheet to provide an outlet for drug release, requiring two laser holes on one side of the peliperone three-layer osmotic pump controlled release sheet; 6) for laser perforated The r
  • the technology has the following disadvantages: 1) the technology requires a special tableting machine, a three-layer tableting machine; 2) a controlled release coating of paliperidone with an organic solvent acetone, which requires not only a large amount of acetone but also At present, the coating equipment lacks the acetone recovery device, so only acetone can be directly discharged into the atmosphere, thereby causing pollution; 3) laser puncturing of the paliperidone tablets is required, and one side needs to be hit two Holes.
  • a double laminating machine or a three laminating machine is required to precisely control the tableting process to avoid the problem of excessive content uniformity, so the production cost High, the risk of producing defective films is high.
  • the general coating equipment does not have an organic solvent recovery system, so the acetone is directly discharged into the atmosphere, which is not environmentally friendly and pollutes the environment. Even with an organic solvent recovery system, the operating costs are high.
  • the present invention provides a paliperidone oral controlled release tablet comprising: a) a single layer core comprising paliperidone or a pharmaceutically acceptable salt or ester thereof; a first coating layer coated on a single layer core, wherein the first coating layer comprises 0 to 61% by weight of polyvinyl acetate, 22 parts by weight based on the total weight of the first coating layer % to 54% by weight of polyethylene glycol-polyvinyl alcohol copolymer, 12% to 40% by weight of talc and 2% to 7% by weight of triethyl citrate, with respect to single-layer core
  • the weight of the first coating layer is 5% by weight to 20% by weight;
  • the second coating layer is coated on the first coating layer, wherein the total weight of the second coating layer is
  • the second coating layer comprises 60.6 wt% to 69 wt% of polyvinyl acetate, 10 wt% to 18.2 wt% of polyethylene glycol-polyvinyl alcohol copoly
  • alipenemone oral controlled release tablets prepared by using polyoxyethylene as a gel skeleton and polyvinyl acetate as a membrane-control material have an increasing drug release behavior and are substantially consistent in release media of different pH values.
  • the release behavior that is, the release behavior independent of pH.
  • a paliperidone oral controlled release tablet having such an incremental release behavior is a single layer sheet, which does not require an expensive multi-laminate device; an aqueous dispersion coating does not require the use of an organic solvent; by adjusting the porogen ratio Adjust the release behavior without laser drilling. Therefore, compared with the prior art, the novel peliperone oral controlled release tablet production process is simpler, more environmentally friendly, and easier to industrialize.
  • the monolayer core of the paliperidone oral controlled release tablet of the present invention consists of paliperidone, a gel matrix polymeric material, and a lubricant.
  • the peliperone oral controlled release tablet of the present invention is in a single layer core
  • the amount of risperidone is from 1 mg to 12 mg.
  • the monolayer core of the paliperidone oral controlled release tablet of the present invention consists of paliperidone, polyoxyethylene and magnesium stearate or sodium stearyl fumarate.
  • the pellipidone oral controlled release tablet of the present invention has a single layer core of from 0.75% by weight to 6.7% by weight of paliperidone, 92% by weight relative to the total weight of the single layer core. 99% by weight of polyoxyethylene and 0.2% by weight to 2% by weight of magnesium stearate or sodium stearyl fumarate.
  • the monolayer core of the paliperidone oral controlled release tablet of the present invention has a polyoxyethylene having a molecular weight of 100,000 to 1,000,000 and may be one, two or more polyoxygens of different molecular weights. a mixture of ethylene. A single molecular weight polyoxyethylene is preferred.
  • the polyoxyethylene used in accordance with the present invention may contain from 0 to 3% by weight of silica, based on the total weight of the polyoxyethylene, preferably the product of the company Dow. Because it contains silica, the polyoxyethylene particles have good fluidity, so that the core of the invention can be produced by a direct compression process, thereby avoiding the use of a wet process which has higher energy consumption and has an influence on polyoxyethylene.
  • the pellet process produces a core.
  • the present invention provides a method for preparing a single layer core of a paliperidone oral controlled release tablet, comprising the steps of:
  • step b) adding magnesium stearate or sodium stearyl fumarate to a homogeneous mixture of paliperidone and polyoxyethylene obtained in step a) and continuing to mix;
  • step b) The mixture of the homogeneous paliperidone, polyoxyethylene, magnesium stearate or sodium stearyl fumarate obtained in step b) is tableted to obtain a paliperidone single-layer tablet core.
  • the present invention also provides a method for preparing a paliperidone oral controlled release tablet, the preparation method comprising the steps of:
  • the first coating layer comprises 0 to 61% by weight of polyvinyl acetate, 22% by weight, based on the total weight of the first coating layer ⁇ 54% by weight of polyethylene glycol- a polyvinyl alcohol copolymer, 12% to 40% by weight of talc and 2% to 7% by weight of triethyl citrate, wherein the weight of the first coating layer relative to the weight of the single layer core is 5 wt% to 20 wt%;
  • the second coating layer comprises from 0.66% by weight to 69% by weight of polyvinyl acetate based on the total weight of the second coating layer Ester, 10% by weight to 18.2% by weight of polyethylene glycol-polyvinyl alcohol copolymer, 12.9% by weight to 20% by weight of talc and 3% by weight to 7% by weight of triethyl citrate, wherein
  • step d) optionally coating the coated tablet obtained in step c) with a third outer protective coating layer, thereby preparing a paliperidone oral controlled release tablet, wherein the third outer protective coating layer is gastric-soluble Type coating.
  • the peliperone oral controlled release tablet of the present invention can be preferably prepared using a porous pan type coating machine.
  • fluidized bed coaters and spray coaters can also be used.
  • the first coating layer, the second coating layer, and the third outer protective coating layer each use water of the coating polymer. Coating in the form of a dispersion.
  • the second coating layer which functions as a sustained release, polyvinyl acetate is a film-forming material, and is coated with an aqueous dispersion of the brand name Kollicoat SR30D of BASF, and the sustained release effect can also be obtained without using an organic solvent.
  • the amount of polyvinyl acetate contained was calculated as 30% w/w of the amount of kollicoat SR30D; the polyethylene glycol-polyvinyl alcohol copolymer used the product of the trade name Kollicoat IR of BASF.
  • Figure 1 shows the release profile of a paliperidone double-layer osmotic pump controlled release tablet prepared according to the prior art (CN200910199425.9) in a release medium of pH 1.2;
  • Figure 2 shows the release profile of a paliperidone double-layer osmotic pump controlled release tablet prepared according to the prior art (CN200910199425.9) in four different release media at pH 1.2, pH 4.5, pH 6.8 and water;
  • Figure 3 is a graph showing the release profile of an oral controlled release tablet of paliperidone prepared according to Examples 1-5 of the present invention in a release medium of pH 1.0;
  • Figure 4 is a graph showing the release profile of alipenemone oral controlled release tablets prepared according to Example 6 of the present invention in a release medium of pH 1.0, pH 4.5 and pH 6.8, respectively;
  • Figure 5 is a graph showing the release profile of alipenemone orally controlled release tablets prepared according to Example 7 of the present invention in a release medium of pH 1.0, pH 4.5, and pH 6.8, respectively;
  • Figure 6 is a graph showing the release profile of an oral controlled release tablet of paliperidone prepared according to Examples 8-9 of the present invention in a release medium of pH 1.0.
  • polyvinyl acetate was used as an aqueous dispersion of the company KSF's trade name Kollicoat SR30D.
  • Polyethylene glycol-polyvinyl alcohol copolymers are available from the BASF company under the trade name Kollicoat IR.
  • Paliperidone uses products produced by Zhejiang Huahai Pharmaceutical.
  • Polyoxyethylene N80 is commercially available from DOW under the trade name POLYOX WSR N80.
  • Magnesium stearate was purchased from Merck's products.
  • Talc was purchased from IMI Fabi, LLC.
  • Triethyl citrate was purchased from Vertellus Performance Materials Inc. II coating powder was purchased from Shanghai Kalakang Company. The efficient coating machine was purchased from Manesty, UK.
  • Kollicoat SR30D is a 30% aqueous dispersion of Kollicoat SR, so when calculating the weight gain of the coating layer, multiplying the amount of Kollicoat SR30D by 30% is the weight gain of Kollicoat SR in the coating layer. with.
  • Example 1 The preparation method of Example 1 is:
  • step b) Magnesium stearate is added to a homogeneous mixture of paliperidone and polyoxyethylene N80 obtained in step a) and mixing is continued.
  • step b) a mixture of homogeneous paliperidone, polyoxyethylene N80, magnesium stearate obtained in step b) Tableting, thereby obtaining a peliperone monolayer core.
  • Kollicoat IR, triethyl citrate and talc powder were weighed according to the amount of the first coating layer, and uniformly dispersed in an appropriate amount of purified water, and then the dispersion was added to Kollicoat SR30D, and uniformly stirred to form a coating liquid.
  • step e) placing the paliperidone single-layer tablet core obtained in the step c) in a high-efficiency coating pan, coating with the coating liquid of the step d), obtaining the weight of the target coating and drying, and obtaining the first coating.
  • Kollicoat IR, triethyl citrate and talc powder were weighed according to the prescribed amount of the second coating layer, and uniformly dispersed in an appropriate amount of purified water, and then the dispersion was added to Kollicoat SR30D, and uniformly stirred to form a coating liquid.
  • step e) The paliperidone coated tablet obtained in step e) is placed in a high-efficiency coating pan, coated with the coating liquid of step f), and the target coating is dried and dried to obtain a first coating layer. And a second coating layer coated paliperidone coated tablet.
  • the paliperidone coated tablet obtained in the step g) is placed in a high-efficiency coating pan, and the protective coat is wrapped to achieve the weight gain of the target coating and dried, thereby obtaining an oral controlled release tablet of paliperidone.
  • the release profile of this example is shown in Figure 3.
  • the release medium is pH 1.0 [NaCl (0.2% w/w) in 0.0825 N HCl], and the volume of the release medium is 500 ml.
  • the release was measured by sampling at 2, 4, 6, 8, 12, 14, 18 and 24 hours.
  • the preparation process is as follows:
  • step b) Magnesium stearate is added to a homogeneous mixture of paliperidone and polyoxyethylene N80 obtained in step a) and mixing is continued.
  • Kollicoat IR, triethyl citrate and talc are weighed according to the amount of the first coating layer, and uniformly dispersed in an appropriate amount of purified water to form a coating liquid.
  • step e) placing the paliperidone single-layer tablet core obtained in the step c) in a high-efficiency coating pan, coating with the coating liquid of the step d), obtaining the weight of the target coating and drying, and obtaining the first coating.
  • Kollicoat IR, triethyl citrate and talc powder were weighed according to the prescribed amount of the second coating layer, and uniformly dispersed in an appropriate amount of purified water, and then the dispersion was added to Kollicoat SR30D, and uniformly stirred to form a coating liquid.
  • step e) The paliperidone coated tablet obtained in step e) is placed in a high-efficiency coating pan, coated with the coating liquid of step f), and the target coating is dried and dried to obtain a first coating layer. And the second coating layer Palipenone coated tablets.
  • the paliperidone coated tablet obtained in the step g) is placed in a high-efficiency coating pan, and the protective coat is wrapped to achieve the weight gain of the target coating and dried, thereby obtaining an oral controlled release tablet of paliperidone.
  • the release profile for this example is shown in Figure 4.
  • the release medium is pH 1.0, pH 4.5, and pH 6.8, and the release medium volume is 500 ml at 1, 2, 4, 6, and 8.
  • the release was measured at 12, 14, 18 and 24 hours.
  • the release profile of this example is shown in Figure 5.
  • the release medium is pH 1.0, pH 4.5, and pH 6.8 medium, and the volume of the release medium is 500 ml, at 1, 2, 4, 6,
  • the release was measured at 8, 12, 14, 18 and 24 hours.
  • the release profiles of Examples 8 and 9 are shown in Figure 6.
  • the release medium is pH 1.0 [NaCl (0.2% w/w) in 0.0825 N HCl], and the release medium volume is 500 ml.
  • the release was measured at 1, 2, 4, 6, 8, 12, 14, 18 and 24 hours.
  • the paliperidone oral controlled release tablet of Example 10 was prepared in the same manner as in Example 1 except that sodium stearyl fumarate was used instead of magnesium stearate. Using the method recommended by the FDA, using the paddle method, 50 rpm, the release medium is pH 1.0 [NaCl (0.2% w/w) in 0.0825 N HCl], the volume of the release medium is 500 ml, at 1, 2, 4, 6, 8, 12 Samples of Example 10 were taken at 14, 18 and 24 hours.
  • the release profile of the risperidone oral controlled release tablet was similar to that of the aliskipone oral controlled release tablet of Example 1.
  • Figure 1 shows the release profile of a paliperidone double-layer osmotic pump controlled release tablet prepared according to the prior art (CN200910199425.9) in a release medium of pH 1.2;
  • Figure 2 shows according to the prior art (CN200910199425) .9) Release profile of the prepared paliperidone double osmotic pump controlled release tablets in four different release media at pH 1.2, pH 4.5, pH 6.8 and water.
  • the release profile of the aliskipone oral controlled release tablet prepared according to the embodiment 1-10 of the present invention is compared with the release curve of the paliperidone double-layer osmotic pump controlled release tablet prepared according to the prior art. It can be seen that the release profile of the paliperidone oral controlled release tablet according to the present invention in a release medium of pH 1.0 is similar to the release profile of the paliperidone double-layer osmotic pump controlled release tablet according to the prior art, see FIG.
  • the preparation process of the paliperidone oral controlled release tablet according to the present invention does not require a multi-laminate device, does not require the use of an organic solvent, and does not require laser drilling. Therefore, the paliperidone oral controlled release tablet production process according to the present invention is simpler, more environmentally friendly, and easier to industrialize than the prior art.

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Abstract

本发明提供一种帕利哌酮口服控释片，该口服控释片包含：含有帕利哌酮的单层片芯，以及包被在该单层片芯上起到控制药物释放作用的由一种或多种包衣聚合物形成的第一包衣层和第二包衣层，以及任选地由一种或多种包衣聚合物形成的第三外保护包衣层。本发明还提供该帕利哌酮口服控释片的制备方法。本发明应用凝胶骨架和膜控包衣两种控释机制联用的方法来控制帕利哌酮释放，生产工艺更简单，且生产过程中不使用有机溶剂，绿色环保，更利于工业化生产。

Description

一种帕利哌酮口服控释片及其制备方法
本申请要求于2014年10月1日提交中国专利局、申请号为201410543391.1发明名称为“一种帕利哌酮控释片及其制备方法”的中国专利申请的优先权，其全部内容通过引用并入本申请中。
技术领域
本发明涉及一种药物控释制剂及其制备方法，特别是涉及一种帕利哌酮口服控释片及其制备方法。
背景技术
帕利哌酮(9-羟基利培酮)是新型非典型抗精神病药物，属于苯并异噁唑类的衍生物，目前认为其作用机制是通过阻断多巴胺、5-羟色胺和肾上腺素受体而干扰患者脑内神经递质的信号传导。帕利哌酮的口服生物利用度为28％，血浆蛋白结合率是74％，末端消除和半衰期约为23小时，临床用于精神***症有较好的疗效。帕利哌酮的结构式如下：
Figure PCTCN2015090365-appb-000001
治疗神经***疾病的药物在临床应用中存在的问题主要有：不良反应大，尤其是服药初期不良反应明显，患者耐受性差，易中途停用；普通制剂服用初期需要剂量滴定(即缓慢增加剂量)以减小不良反应的发生，但服用不便。为解决以上临床应用问题，将多种控释技术应用于神经***用药，开发出了控释制剂，如利用渗透泵控释技术制备的制剂，具有受介质环境pH值、胃肠蠕动以及食物等因素的影响小，个体差异小，且体内外相关性好，血药平稳，不良反应小，患者服药次数少，顺应性高等优点。
帕利哌酮由美国强生公司开发，采用Alza公司的渗透泵技术制成渗透泵控释制剂。中国专利申请第03822948.X号(发明名称为用于控制释放帕潘立酮的方法和剂型)公开了一种帕利哌酮控释制剂。该制剂采用三层渗透泵片的剂型，制备工艺非常复杂，三层渗透泵片包括一个推进层，两个药物比例不同的含药层。该制剂制备过程如下：1)首先用湿法造粒工艺对两个含药层颗粒和推进层颗粒进行分别造粒，分别获得两个含药层颗粒和推进层颗粒；2)使用三层压片机对两个含药层颗粒和推进层颗粒进行压片，获得帕利哌酮三层片；3)对帕利哌酮三层片进行隔离包衣；4)在帕利哌酮三层片的隔离包衣外用醋酸纤维素和聚乙二醇进行渗透泵片的控释包衣，在该包衣过程中须将醋酸纤维素溶于丙酮进行包衣，且包衣液的浓度在10％以内；5)对渗透泵片进行激光打孔，提供药物释放的出口，需要对帕利哌酮三层渗透泵控释片的一面打两个激光孔；6)对经过激光打孔的帕利哌酮渗透泵片进行外保护层的包衣。该技术存在以下缺点：1)该技术需要特殊的压片设备三层压片机；2)需使用有机溶剂丙酮对帕利哌酮进行控释包衣，这不仅需要耗费大量的丙酮，而且由于目前包衣设备缺少丙酮回收装置，因此只能将丙酮直接排入大气中，由此造成污染；3)需要使用激光打孔机对帕利哌酮片进行激光打孔，且一个面需要打两个孔。
因三层压片对设备精度要求非常高，有文献对帕利哌酮控释片进行工艺改进。例如，中国专利申请第200910199425.9号(发明名称为一种苯并异噁唑类衍生物的控释制剂及其制备方法)公开了一种帕利哌酮双层渗透泵片及其制备方法。但是，该工艺仍需特殊的压片设备即双层压片机和有机溶剂即丙酮进行控释包衣。
目前公开的帕利哌酮控释片的制备过程中均需要使用双层压片机或三层压片机，从而精确控制压片过程，以避免产生含量均匀度过大的问题，因此生产成本高，产生不合格片的风险大。另外，还需要将半透膜材料醋酸纤维素溶于丙酮，需要使用大量的有机溶剂，目前一般包衣设备没有有机溶剂回收***，因此将丙酮直接排放到大气中，不环保，污染环境。即使有有机溶剂回收***，运行费用也很高昂。此外，需要对帕利哌酮渗透泵片进行激光打孔，但是国内激光打孔设备并不成熟，容易造成漏打孔和打孔深度不够等 问题，产品容易有质量隐患。
因此，目前仍有必要提供一种新的解决方案来克服以上缺点，使得帕利哌酮口服控释片的片面美观，质量合格。同时，帕利哌酮具有良好的稳定性和溶出行为，且价格低廉，有利于商业化生产。
发明内容
在一个方面中，本发明提供一种帕利哌酮口服控释片，该口服控释片包含：a)含有帕利哌酮或其药学上可接受的盐或酯的单层片芯；b)第一包衣层，其包被在单层片芯上，其中以所述第一包衣层总重量计所述第一包衣层包含0～61重量％的聚醋酸乙烯酯、22重量％～54重量％的聚乙二醇-聚乙烯醇共聚物、12重量％～40重量％的滑石粉和2重量％～7重量％的柠檬酸三乙酯，其中相对于单层片芯的重量所述第一包衣层的重量为5重量％～20重量％；c)第二包衣层，其包被在第一包衣层上，其中以所述第二包衣层总重量计所述第二包衣层包含60.6重量％～69重量％的聚醋酸乙烯酯、10重量％～18.2重量％的聚乙二醇-聚乙烯醇共聚物、12.9重量％～20重量％的滑石粉和3重量％～7重量％的柠檬酸三乙酯，其中相对于单层片芯的重量所述第二包衣层的重量为5重量％～20重量％；d)任选地第三外保护包衣层，其包被在第二包衣层上，其中所述第三外保护包衣层为胃溶型包衣。
本发明人发现采用聚氧乙烯为凝胶骨架，聚醋酸乙烯酯为膜控材料制备的帕利哌酮口服控释片具有递增的药物释放行为，且在不同pH值的释放介质中具有基本一致的释放行为，即具有与pH无关的释放行为。具有这样的递增释放行为的帕利哌酮口服控释片为单层片，不需要昂贵的多层压片设备；使用水分散体包衣，不需要使用有机溶剂；通过调整致孔剂比例可以调整释放行为，不需要进行激光打孔。因此，与现有技术相比，该新型帕利哌酮口服控释片生产工艺更简单、更环保、更易产业化。
在一个实施方案中，本发明的帕利哌酮口服控释片的单层片芯由帕利哌酮、凝胶骨架高分子材料以及润滑剂组成。
在另一个实施方案中，本发明的帕利哌酮口服控释片的单层片芯中的帕 利哌酮的用量为1mg至12mg。
在又一个实施方案中，本发明的帕利哌酮口服控释片的单层片芯由帕利哌酮、聚氧乙烯和硬脂酸镁或硬脂富马酸钠组成。
在另一个实施方案中，本发明的帕利哌酮口服控释片的单层片芯由相对于单层片芯总重量的0.75重量％～6.7重量％的帕利哌酮、92重量％～99重量％的聚氧乙烯和0.2重量％～2重量％的硬脂酸镁或硬脂富马酸钠组成。
在一个实施方案中，本发明的帕利哌酮口服控释片中的单层片芯所用的聚氧乙烯分子量为100000到1000000，可以是一种、两种或两种以上不同分子量的聚氧乙烯的混合物。优选单一分子量的聚氧乙烯。根据本发明所用的聚氧乙烯，可含有相对于聚氧乙烯总重量的0-3重量％的二氧化硅，优选DOW公司的商品名是保益乐的产品。因为含有二氧化硅，所以聚氧乙烯颗粒具有很好的流动性，使得本发明的片芯可以采用直接压片工艺生产，从而避免使用耗能更高且对聚氧乙烯有影响的湿法造粒工艺生产片芯。
在另一个方面中，本发明提供了一种帕利哌酮口服控释片的单层片芯的制备方法，包括以下步骤：
a)将帕利哌酮和聚氧乙烯混合，过筛，混合；
b)将硬脂酸镁或硬脂富马酸钠加入步骤a)得到的帕利哌酮和聚氧乙烯的均匀的混合物中并继续混合；
c)将步骤b)得到的均匀的帕利哌酮、聚氧乙烯、硬脂酸镁或硬脂富马酸钠的混合物压片，从而得到帕利哌酮单层片芯。
在又一个方面中，本发明还提供了一种帕利哌酮口服控释片的制备方法，该制备方法包括以下步骤：
a)将帕利哌酮、聚氧乙烯、硬脂酸镁或硬脂富马酸钠混合、过筛、混合，然后直接压片以制备单层片芯；
b)用第一包衣层包被该单层片芯，其中以所述第一包衣层总重量计所述第一包衣层包含0～61重量％的聚醋酸乙烯酯、22重量％～54重量％的聚乙二醇- 聚乙烯醇共聚物、12重量％～40重量％的滑石粉和2重量％～7重量％的柠檬酸三乙酯，其中相对于单层片芯的重量所述第一包衣层的重量为5重量％～20重量％；
c)用第二包衣层包被步骤b)得到的包衣片，其中以所述第二包衣层总重量计所述第二包衣层包含60.6重量％～69重量％的聚醋酸乙烯酯、10重量％～18.2重量％的聚乙二醇-聚乙烯醇共聚物、12.9重量％～20重量％的滑石粉和3重量％～7重量％的柠檬酸三乙酯，其中相对于单层片芯的重量所述第二包衣层的重量为5重量％～20重量％；
d)任选地用第三外保护包衣层包被步骤c)得到的包衣片，由此制成帕利哌酮口服控释片，其中所述第三外保护包衣层为胃溶型包衣。
在根据本发明的帕利哌酮口服控释片的制备方法的一个实施方案中，可优选使用多孔锅型包衣机来制备本发明的帕利哌酮口服控释片。作为替代方案，也可使用流化床包衣机和喷雾包衣机。
在根据本发明的帕利哌酮口服控释片的制备方法的另一个实施方案中，第一包衣层、第二包衣层以及第三外保护包衣层均使用包衣聚合物的水分散体的形式涂覆。尤其是起到缓释作用的第二包衣层，聚醋酸乙烯酯为成膜材料，使用BASF公司的商品名为Kollicoat SR30D的水分散体包衣，不使用有机溶剂，同样可以取得缓释效果，其含有的聚醋酸乙烯酯量按kollicoat SR30D用量的30％w/w计算；聚乙二醇-聚乙烯醇共聚物使用BASF公司的商品名为Kollicoat IR的产品。
附图说明
为了更清楚地说明本发明实施例和现有技术的技术方案，下面对实施例和现有技术中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1示出了根据现有技术(CN200910199425.9)制得的帕利哌酮双层渗透泵控释片在pH 1.2的释放介质中的释放曲线；
图2示出了根据现有技术(CN200910199425.9)制得的帕利哌酮双层渗透泵控释片在pH 1.2、pH 4.5、pH 6.8和水四种不同释放介质中的释放曲线；
图3示出了根据本发明实施例1-5制得的帕利哌酮口服控释片在pH 1.0的释放介质中的释放曲线；
图4示出了根据本发明实施例6制得的帕利哌酮口服控释片分别在pH 1.0、pH 4.5和pH 6.8的释放介质中的释放曲线；
图5示出了根据本发明实施例7制得的帕利哌酮口服控释片分别在pH 1.0、pH 4.5和pH 6.8的释放介质中的释放曲线；
图6示出了根据本发明实施例8-9制得的帕利哌酮口服控释片在pH 1.0的释放介质中的释放曲线。
具体实施方式
为使本发明的目的、技术方案、及优点更加清楚明白，以下参照附图并举实施例，对本发明进行进一步的详细说明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
在以下实施例中，聚醋酸乙烯酯使用BASF公司的商品名为Kollicoat SR30D的水分散体。聚乙二醇-聚乙烯醇共聚物使用BASF公司的商品名为Kollicoat IR的产品。帕利哌酮使用浙江华海药业生产的产品。聚氧乙烯N80购自DOW公司的商品名为POLYOX WSR N80的产品。硬脂酸镁购自默克公司的产品。滑石粉购自IMI Fabi，LLC。柠檬酸三乙酯购自Vertellus Performance Materials Inc。
Figure PCTCN2015090365-appb-000002
II包衣粉购自上海卡乐康公司。高效包衣机购自英国Manesty公司。
实施例1：
Figure PCTCN2015090365-appb-000003
备注：其中*Kollicoat SR30D是Kollicoat SR的30％水分散体，因此当计算包衣层增重重量时，将Kollicoat SR30D的用量乘以30％即为包衣层中Kollicoat SR的增重重量，下同。
实施例1的制备方法为：
a)将帕利哌酮和聚氧乙烯N80混合，过筛，混合。
b)将硬脂酸镁加入步骤a)得到的帕利哌酮和聚氧乙烯N80的均匀的混合物中并继续混合。
c)将步骤b)得到的均匀的帕利哌酮、聚氧乙烯N80、硬脂酸镁的混合物 压片，从而得到帕利哌酮单层片芯。
d)按第一包衣层处方量称取Kollicoat IR、柠檬酸三乙酯和滑石粉，并均匀分散在适量纯化水中，再将分散液加入Kollicoat SR30D中，搅拌均匀形成包衣液。
e)将步骤c)得到的帕利哌酮单层片芯置于高效包衣锅中，使用步骤d)的包衣液包衣，达到目标包衣增重后干燥，得到经第一包衣层包衣的帕利哌酮包衣片。
f)按第二包衣层处方量称取Kollicoat IR、柠檬酸三乙酯和滑石粉，并均匀分散在适量纯化水中，再将分散液加入Kollicoat SR30D中，搅拌均匀形成包衣液。
g)将步骤e)得到的帕利哌酮包衣片置于高效包衣锅中，使用步骤f)的包衣液包衣，达到目标包衣增重后干燥，得到经第一包衣层和第二包衣层包衣的帕利哌酮包衣片。
h)按第三外保护包衣层处方量称取
Figure PCTCN2015090365-appb-000004
II包衣粉，并均匀分散在适量纯化水中，搅拌均匀形成包衣液。将步骤g)得到的帕利哌酮包衣片置于高效包衣锅中，包保护衣，达到目标包衣增重后干燥，即得帕利哌酮口服控释片。
该实施例的释放曲线见图3，采用FDA推荐的方法，采用桨法，50rpm，释放介质是pH 1.0[NaCl(0.2％w/w)in 0.0825N HCl]，释放介质体积是500ml，在1、2、4、6、8、12、14、18和24小时取样测定释放度。
实施例2：
Figure PCTCN2015090365-appb-000005
Figure PCTCN2015090365-appb-000006
制备工艺：(同实施例1)。
实施例3：
Figure PCTCN2015090365-appb-000007
Figure PCTCN2015090365-appb-000008
制备工艺：(同实施例1)。
实施例4：
Figure PCTCN2015090365-appb-000009
制备工艺：(同实施例1)。
实施例5：
Figure PCTCN2015090365-appb-000010
制备工艺：(同实施例1)。
实施例6：
Figure PCTCN2015090365-appb-000011
Figure PCTCN2015090365-appb-000012
制备工艺如下：
a)将帕利哌酮和聚氧乙烯N80混合，过筛，混合。
b)将硬脂酸镁加入步骤a)得到的帕利哌酮和聚氧乙烯N80的均匀的混合物中并继续混合。
c)将步骤b)得到的均匀的帕利哌酮、聚氧乙烯N80、硬脂酸镁的混合物压片，从而得到帕利哌酮单层片芯。
d)按第一包衣层处方量称取Kollicoat IR、柠檬酸三乙酯和滑石粉，并均匀分散在适量纯化水中形成包衣液。
e)将步骤c)得到的帕利哌酮单层片芯置于高效包衣锅中，使用步骤d)的包衣液包衣，达到目标包衣增重后干燥，得到经第一包衣层包衣的帕利哌酮包衣片。
f)按第二包衣层处方量称取Kollicoat IR、柠檬酸三乙酯和滑石粉，并均匀分散在适量纯化水中，再将分散液加入Kollicoat SR30D中，搅拌均匀形成包衣液。
g)将步骤e)得到的帕利哌酮包衣片置于高效包衣锅中，使用步骤f)的包衣液包衣，达到目标包衣增重后干燥，得到经第一包衣层和第二包衣层包衣的 帕利哌酮包衣片。
h)按第三外保护包衣层处方量称取
Figure PCTCN2015090365-appb-000013
II包衣粉，并均匀分散在适量纯化水中，搅拌均匀形成包衣液。将步骤g)得到的帕利哌酮包衣片置于高效包衣锅中，包保护衣，达到目标包衣增重后干燥，即得帕利哌酮口服控释片。
该实施例的释放曲线见图4，采用FDA推荐的方法，采用桨法，50rpm，释放介质是pH 1.0、pH 4.5和pH 6.8，释放介质体积是500ml，在1、2、4、6、8、12、14、18和24小时取样测定释放度。
实施例7：
Figure PCTCN2015090365-appb-000014
制备工艺同实施例1。
该实施例的释放曲线见图5，采用FDA推荐的方法，采用桨法，50rpm，释放介质是pH 1.0、pH 4.5和pH 6.8介质，释放介质体积是500ml，在1、2、4、6、8、12、14、18和24小时取样测定释放度。
实施例8：
Figure PCTCN2015090365-appb-000015
制备工艺同实施例1。
实施例9
Figure PCTCN2015090365-appb-000016
制备工艺同实施例1。
实施例8和9的释放曲线见图6，采用FDA推荐的方法，采用桨法，50rpm，释放介质是pH 1.0[NaCl(0.2％w/w)in 0.0825N HCl]，释放介质体积是500ml，在1、2、4、6、8、12、14、18和24小时取样测定释放度。
实施例10：
除了使用硬脂富马酸钠替代硬脂酸镁之外，采用与实施例1相同的方式制备实施例10的帕利哌酮口服控释片。采用FDA推荐的方法，采用桨法，50rpm，释放介质是pH 1.0[NaCl(0.2％w/w)in 0.0825N HCl]，释放介质体积是500ml，在1、2、4、6、8、12、14、18和24小时取样测定实施例10的帕 利哌酮口服控释片的释放度，释放曲线与实施例1的帕利哌酮口服控释片的释放曲线类似。
图1示出了根据现有技术(CN200910199425.9)制得的帕利哌酮双层渗透泵控释片在pH 1.2的释放介质中的释放曲线；图2示出了根据现有技术(CN200910199425.9)制得的帕利哌酮双层渗透泵控释片在pH 1.2、pH 4.5、pH 6.8和水四种不同释放介质中的释放曲线。
将根据本发明实施例1-10制得的帕利哌酮口服控释片的释放曲线与根据现有技术制得的帕利哌酮双层渗透泵控释片的释放曲线进行比较之后，可以看出：根据本发明的帕利哌酮口服控释片在pH 1.0的释放介质中的释放曲线与根据现有技术的帕利哌酮双层渗透泵控释片的释放曲线相似，参见图3和图6(本发明)与图1(现有技术)；根据本发明的帕利哌酮口服控释片在pH 1.0、pH 4.5和pH 6.8的释放介质中的释放曲线与根据现有技术的帕利哌酮双层渗透泵控释片在pH 1.2、pH 4.5和pH 6.8的释放介质中的释放曲线相似，参见图4和图5(本发明)与图2(现有技术)。这表明根据本发明的帕利哌酮口服控释片可以实现与现有技术的帕利哌酮控释片类似的药物释放行为，并且在不同pH值的释放介质中具有基本一致的释放行为。但是，根据本发明的帕利哌酮口服控释片的制备工艺不需要多层压片设备，不需要使用有机溶剂，并且不需要进行激光打孔。因此，与现有技术相比，根据本发明的帕利哌酮口服控释片生产工艺更简单、更环保、更易产业化。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明保护的范围之内。

Claims (15)

  1. 一种帕利哌酮口服控释片，其特征在于该口服控释片包含：
    a)含有帕利哌酮或其药学上可接受的盐或酯的单层片芯；
    b)第一包衣层，其包被在单层片芯上，其中以所述第一包衣层总重量计所述第一层包衣层包含0～61重量％的聚醋酸乙烯酯、22重量％～54重量％的聚乙二醇-聚乙烯醇共聚物、12重量％～40重量％的滑石粉和2重量％～7重量％的柠檬酸三乙酯，其中相对于所述单层片芯的重量所述第一包衣层的重量为5重量％～20重量％；
    c)第二包衣层，其包被在所述第一包衣层上，其中以所述第二包衣层总重量计所述第二包衣层包含60.6重量％～69重量％的聚醋酸乙烯酯、10重量％～18.2重量％的聚乙二醇-聚乙烯醇共聚物、12.9重量％～20重量％的滑石粉和3重量％～7重量％的柠檬酸三乙酯，其中相对于所述单层片芯的重量所述第二包衣层的重量为5重量％～20重量％；
    d)任选地第三外保护包衣层，其包被在所述第二包衣层上，其中所述第三外保护包衣层为胃溶型包衣。
  2. 根据权利要求1所述的帕利哌酮口服控释片，其特征在于单层片芯由帕利哌酮、凝胶骨架高分子材料以及润滑剂组成。
  3. 根据权利要求1或2所述的帕利哌酮口服控释片，其特征在于单层片芯由帕利哌酮、聚氧乙烯、和硬脂酸镁或硬脂富马酸钠组成。
  4. 根据权利要求1至3中任一项所述的帕利哌酮口服控释片，其特征在于单层片芯由相对于单层片芯总重量的0.75重量％～6.7重量％的帕利哌酮、92重量％～99重量％的聚氧乙烯、和0.5重量％～2重量％的硬脂酸镁或硬脂富马酸钠组成。
  5. 根据权利要求1至4中任一项所述的帕利哌酮口服控释片，其特征在于单层片芯中的帕利哌酮的用量为1mg至12mg。
  6. 根据权利要求3所述的帕利哌酮口服控释片，其特征在于单层片芯所 用的聚氧乙烯分子量为100000到1000000。
  7. 根据权利要求3或6所述的帕利哌酮口服控释片，其特征在于单层片芯所用的聚氧乙烯中含有相对于聚氧乙烯总重量的0～3重量％的二氧化硅。
  8. 根据权利要求3所述的帕利哌酮口服控释片，其特征在于单层片芯是通过包括以下步骤的方法制备的：
    a)将帕利哌酮和聚氧乙烯混合，过筛，混合；
    b)将硬脂酸镁或硬脂富马酸钠加入步骤a)得到的帕利哌酮和聚氧乙烯的均匀的混合物中并继续混合；
    c)将步骤b)得到的均匀的帕利哌酮、聚氧乙烯、硬脂酸镁或硬脂富马酸钠的混合物压片，从而得到帕利哌酮单层片芯。
  9. 一种根据权利要求1-8中任一项所述的帕利哌酮口服控释片的制备方法，该制备方法包括：
    a)将包含帕利哌酮或其药学上可接受的盐或酯的物质直接压片以制备单层片芯；
    b)用第一包衣层包被该单层片芯，其中以所述第一包衣层总重量计所述第一包衣层包含0～61重量％的聚醋酸乙烯酯、22重量％～54重量％的聚乙二醇-聚乙烯醇共聚物、12重量％～40重量％的滑石粉和2重量％～7重量％的柠檬酸三乙酯，其中相对于单层片芯的重量所述第一包衣层的重量为5重量％～20重量％；
    c)用第二包衣层包被步骤b)得到的包衣片，其中以所述第二包衣层总重量计所述第二包衣层包含60.6重量％～69重量％的聚醋酸乙烯酯、10重量％～18.2重量％的聚乙二醇-聚乙烯醇共聚物、12.9重量％～20重量％的滑石粉和3重量％～7重量％的柠檬酸三乙酯，其中相对于单层片芯的重量所述第二包衣层的重量为5重量％～20重量％；
    d)任选地用第三外保护包衣层包被步骤c)得到的包衣片，由此制成帕利哌酮口服控释片，其中所述第三外保护包衣层为胃溶型包衣。
  10. 根据权利要求9所述的帕利哌酮口服控释片的制备方法，其特征在于所述第一包衣层、第二包衣层和第三外保护包衣层均以包衣聚合物的水分散体的形式涂覆。
  11. 根据权利要求9或10所述的帕利哌酮口服控释片的制备方法，其特征在于单层片芯由帕利哌酮、凝胶骨架高分子材料以及润滑剂组成。
  12. 根据权利要求9至11中任一项所述的帕利哌酮口服控释片的制备方法，其特征在于单层片芯由帕利哌酮、聚氧乙烯、和硬脂酸镁或硬脂富马酸钠组成。
  13. 根据权利要求9至12中任一项所述的帕利哌酮口服控释片的制备方法，其特征在于单层片芯由相对于单层片芯总重量的0.75重量％～6.7重量％的帕利哌酮、92重量％～99重量％的聚氧乙烯、和0.5重量％～2重量％的硬脂酸镁或硬脂富马酸钠组成。
  14. 根据权利要求9至13中任一项所述的帕利哌酮口服控释片的制备方法，其特征在于单层片芯中的帕利哌酮的用量为1.5mg至12mg。
  15. 根据权利要求12所述的帕利哌酮口服控释片的制备方法，其特征在于单层片芯所用的聚氧乙烯分子量为100000到1000000。
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CN107412180B (zh) * 2017-06-17 2020-05-26 江西医学高等专科学校 一种帕利哌酮包芯片及其制备方法
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