WO2022063097A1 - 匹莫范色林固体制剂的制备方法 - Google Patents

匹莫范色林固体制剂的制备方法 Download PDF

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WO2022063097A1
WO2022063097A1 PCT/CN2021/119473 CN2021119473W WO2022063097A1 WO 2022063097 A1 WO2022063097 A1 WO 2022063097A1 CN 2021119473 W CN2021119473 W CN 2021119473W WO 2022063097 A1 WO2022063097 A1 WO 2022063097A1
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pimavanserin
particle size
bar
capsules
mixer
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PCT/CN2021/119473
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English (en)
French (fr)
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王少平
杨卫宁
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南京凯旺药业有限公司
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Priority to CN202180065012.0A priority Critical patent/CN116635014A/zh
Priority to US18/027,840 priority patent/US20230346763A1/en
Publication of WO2022063097A1 publication Critical patent/WO2022063097A1/zh

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4833—Encapsulating processes; Filling of capsules
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the invention relates to a preparation method of pimavanserin solid preparation.
  • the method improves the fluidity of pimavanserin powder in the preparation process, can improve the stability of active ingredient content in the solid preparation, and has rapid dissolution Good release and compression formability properties.
  • Pimavanserin is a selective serotonin 2A/2C receptor inverse agonist described in International Patent Application PCT/US2004/001234. Its tartrate salt, i.e. pimavanserin tartrate, was approved by the US FDA on April 29, 2016 For psychiatric disorders (hallucinations and delusions) complicated by Parkinson's disease.
  • Pimavanserin is usually made into solid preparations such as tablets and capsules.
  • solid preparations such as tablets and capsules.
  • Such solid preparations are usually prepared by mixing the active ingredient with appropriate excipients to form granules, and then compressing a certain amount of granules (to make tablets) or filling them into capsules (to make capsules).
  • particle size has a great influence on the fluidity of powder.
  • the particle size is less than 200 ⁇ m, the particles tend to aggregate and show stickiness (see “Pharmaceutics”, edited by Zhang Qiang and Wu Fenglan, 2005 first edition, Peking University Medical Press).
  • the powder fluidity of its active ingredient is very poor, even by increasing the powder particle size, adding lubricants and other common technical means in the field, it is difficult to prepare Due to the uniform content of particles, the content stability of the prepared solid preparation is low, and it is difficult to ensure the accuracy of the dosage in clinical application.
  • the active ingredient in the solid preparation should also have a certain degree of dissolution; and, in the case of tablet preparation, the compressed tablet should also be easy to be compressed and molded And it is not easy to be damaged, which is beneficial to the production and transportation links, and keeps the quality of the medicine stable.
  • Most of the existing solid preparations of pimavanserin tartrate have not reached a satisfactory level in terms of dissolution rate and compression moldability.
  • the field urgently needs a new preparation method of pimavanserin (particularly pimavanserin tartrate) solid preparation, to improve the powder flow of pimavanserin in the preparation process and improve the dissolution rate and compression moldability.
  • the inventor of the present invention has carried out a lot of in-depth research on the solid preparation of pimavanserin, especially pimavanserin tartrate, and unexpectedly found that: contrary to the operation of increasing the particle size of the powder commonly used in the prior art , by further pulverizing the powder of pimavanserin API, its particle size is controlled below 178 ⁇ m (equivalent to 80 mesh sieve), but it can significantly improve the powder fluidity in the granulation process and improve the formulation. content stability, and can improve the compression moldability of the formulation and improve the dissolution rate of the active ingredient, thereby completing the present invention.
  • the present invention relates to a preparation method of pimavanserin solid preparation, which comprises the following steps:
  • the prepared granules are compressed into tablets or filled into capsules.
  • the pimavanserin is pimavanserin tartrate.
  • the pimavanserin is a crystalline form of pimavanserin.
  • the crystalline form is the C crystalline form of pimavanserin as described in the patent international application PCT/US2004/001234.
  • the particle size is represented by D90, preferably by D95, more preferably by D98.
  • pimavanserin crude drug is pulverized to a particle size of 170 ⁇ m or less, 160 ⁇ m or less, or 150 ⁇ m or less.
  • the excipients include fillers and lubricants.
  • the filler is microcrystalline cellulose.
  • the lubricant is magnesium stearate.
  • the mass ratio of the pimavanserin bulk drug, filler and lubricant is (20-60):(40-80):(0.1-5), preferably (30- 50):(50-70):(0.2-2), more preferably about 40:59:(0.5-1).
  • the mixing is performed using a mixer.
  • the mixer is a three-dimensional mixer, a V-type mixer, a trough mixer, and a square-cone hopper mixer, more preferably a hopper mixer.
  • the rotating speed of the mixer is about 1-100 rpm, preferably 2-50 rpm, more preferably about 5-20 rpm (for example, about 10 rpm); the mixing time is about 1-60 minutes, preferably 2- 30 minutes, more preferably about 5 to 20 minutes (eg, about 10 minutes).
  • the dry granulation is performed by a dry granulator, and the granulation pressure is about 1-100 bar, preferably 20-80 bar, more preferably 40-60 bar, and particularly preferably about 50 bar.
  • step (3) the following steps (3') are implemented after step (3):
  • a pharmaceutically acceptable excipient such as magnesium stearate
  • the particle size D90 of the prepared particles is 100-1000 ⁇ m, preferably 200-800 ⁇ m, more preferably 300-600 ⁇ m.
  • the solid preparation is in the form of a tablet or capsule, preferably a capsule, characterized in that the capsule shell is preferably selected from gelatin capsules, potato capsules, vegetable (hypromellose) capsules, and sodium alginate capsules , more preferably vegetable (hypromellose) capsules.
  • the method of the invention improves the fluidity of the pimavanserin powder in the preparation process of the solid preparation, can improve the stability of the active ingredient content in the solid preparation, and has the characteristics of rapid dissolution and release and good compression molding. Therefore, the formulation and method of the present invention are not only suitable for operation and control in large-scale industrial production, but also can significantly improve the stability of the administered dose and facilitate the active ingredients to exert their efficacy, thereby benefiting patients.
  • the method of the present invention has no special requirements on the density and particle size of the auxiliary materials, and only needs to use conventional microcrystalline cellulose and magnesium stearate as fillers and lubricants respectively, which greatly reduces the cost of the preparation.
  • the method of the present invention has higher process durability and reproducibility, greatly reduces the requirements for production equipment and process control, has better equipment applicability, and greatly reduces the risk of process parameter control.
  • Figure 1 Dissolution curve of pimavanserin tartrate capsules prepared by the method of the present invention in 0.1 mol/L hydrochloric acid solution.
  • Figure 2 Dissolution curve of pimavanserin tartrate capsules prepared by the method of the present invention in acetic acid-sodium acetate buffer solution at pH 4.5.
  • Figure 3 Dissolution curve of pimavanserin tartrate capsules prepared by the method of the present invention in water.
  • Figure 4 Dissolution curve of pimavanserin tartrate capsules prepared by the method of the present invention in a pH 6.8 phosphate buffer solution.
  • Figure 5 Marketed Drugs Dissolution curve in 0.1mol/L hydrochloric acid solution.
  • the term "about” means a range within 10% of the corresponding numerical value. For example, if the concentration of an ingredient is about 5 mM, it indicates a concentration of 4.5-5.5 mM; if the concentration of an ingredient is in the range of about 5-10 mM, it indicates a concentration range of 4.5-11 mM.
  • active ingredient in the context of this specification refers to pimavanserin, in particular pimavanserin tartrate.
  • particle size as used in the context of this specification generally refers to the particle size at which the cumulative distribution of particles is 90%, ie "D90".
  • the particle diameter is 178 ⁇ m or less
  • the term “particle size” refers to a particle size with 95% cumulative distribution of particles, ie “D95”; more preferably, the term “particle size” refers to a particle size with 98% cumulative distribution of particles, ie "D98”.
  • API used in the context of this specification refers to the raw material of pimavanserin in unprepared form, including but not limited to amorphous powder and crystalline powder, and the purity meets the requirements of pharmacopoeia or other normative documents, Or meet the general requirements for APIs in the pharmaceutical field. Its sources can be obtained from commercial sources, or can be obtained by researchers themselves through chemical synthesis.
  • the terms “above” and “below” used in the context of this specification are meant to include the present number.
  • the particle size is 178 ⁇ m or less
  • the particle size has the same meaning as “the particle size is less than or equal to 178 ⁇ m”.
  • a specific embodiment of the present invention relates to a preparation method of pimavanserin solid preparation, which comprises the following steps:
  • the mass ratio of the pimavanserin API, microcrystalline cellulose and magnesium stearate is (20-60): (40-80): (0.1-5), preferably (30-50): (50-70):(0.2-2), more preferably about 40:59:(0.5-1);
  • the rotating speed of the mixer is about 1-100 rpm, preferably 2-50 rpm, more preferably about 5-20 rpm (for example about 10 rpm);
  • the mixing time is about 1 to 60 minutes, preferably 2 to 30 minutes, more preferably about 5 to 20 minutes (for example, about 10 minutes);
  • the granulation pressure of the dry granulator is about 1-100 bar, preferably 20-80 bar, more preferably 40-60 bar, particularly preferably about 50 bar;
  • the mass ratio of pimavanserin crude drug and the second part of magnesium stearate is (20-60): ( 0.1-5), preferably (30-50):(0.2-2), more preferably about 40:59:0.5;
  • the prepared granules are compressed into tablets or filled into capsules.
  • the crude drug of pimavanserin tartrate was prepared according to the method described in the patent international application PCT/US2004/001234. Pass the raw drug through an 80-mesh sieve to control its particle size to be less than 178 ⁇ m in D90. Then according to the prescription amount shown in the following table 1, weigh in proportion.
  • Pimavanserin tartrate, microcrystalline cellulose, magnesium stearate that meet the above ratios are added in the hopper mixer, the set rotating speed is 10rpm, and the time is 10 minutes, and the mixer is opened to mix. After the mixing, the mixed powder was added to a dry granulator for dry granulation, and the granulation pressure of the dry granulator was set to 50 bar. After granulation, the granules were filled into No. 3 vegetable capsules, and a total of 5000 capsules were prepared.
  • the raw material of pimavanserin tartrate was passed through an 80-mesh sieve to control its particle size to be less than 178 ⁇ m in D90. Then according to the prescription amount shown in Table 2 below, it is weighed in proportion.
  • Pimavanserin tartrate, microcrystalline cellulose, magnesium stearate (internally added) meeting the above ratios were added to the hopper mixer, the set rotational speed was 10 rpm, and the time was 10 minutes, and the mixer was turned on for mixing. After the mixing, the mixed powder was added to a dry granulator for dry granulation, and the granulation pressure of the dry granulator was set to 50 bar. After granulation, the obtained granules and magnesium stearate (extra) calculated by 0.5mg/capsule were added to the mixer, the set rotation speed was 10rpm, the time was 10 minutes, the mixer was turned on and mixed evenly, then the filling was performed. into No. 3 vegetable capsules.
  • the angle of repose, bulk density and tap density were determined for the capsule particles of Example 2.
  • the measurement method is as follows, and Table 3 shows the results.
  • Angle of repose fix the funnel at a certain height above the graph paper, add materials from the funnel until the bottom of the formed stacking cone just touches the bottom of the funnel, measure the diameter of the cone, and use the ratio of the height of the funnel bottom to the radius of the cone as the tangent value to calculate the angle of repose (parallel measurement three times).
  • Tap Density Fix the graduated cylinder on the stand. Use 10, 500 and 1250 taps and read the corresponding volumes V10, V500 and V1250 to the nearest scale value. When the difference between V500 and V1250 is less than or equal to 2ml, V1250 is the tapped volume VF. When the difference between V500 and V1250 exceeds 2ml, continue to beat 1250 times until the difference between the measured values is less than or equal to 2ml, and the volume read is the final tapped volume VF. Calculation formula: m/VF (measured in parallel three times).
  • Test number Angle of repose (°) Bulk density (g/cm 3 ) Tap density (g/cm 3 ) 1 30.2 0.50 0.58 2 31.5 0.49 0.58
  • the granules prepared in Examples 1 and 2 have better fluidity and more reasonable particle size distribution, are suitable for capsule filling, can ensure the stability of the filling dose, and can continuously process material transfer and filling during production. In the process, it can also ensure the stability of the content uniformity of the API, and finally ensure the accuracy of the therapeutic dose.
  • Example 2 10 capsules obtained in Example 2 were randomly selected, numbered 1-10 respectively, and the relative content of the active ingredients in them was measured, and 40 mg was taken as 100%. As shown in Table 5, the distribution of the active ingredient has good uniformity, indicating a stable content.
  • Example 2 The capsules of Example 2 were subjected to dissolution testing:
  • Figure 5 and Table 10 are the commercially available pimavanserin tartrate capsules recorded in the aforementioned FDA review.
  • the dissolution test results of 0.1 mol/L hydrochloric acid solution were used.
  • Table 7 Dissolution profile of pimavanserin tartrate capsules in acetic acid-sodium acetate buffer solution at pH 4.5

Abstract

一种匹莫范色林固体制剂的制备方法，改善了制备过程中匹莫范色林粉体的流动性，可提高固体制剂中活性成分含量的稳定性，并且具有快速溶出释放和压缩成型性良好的特性。

Description

匹莫范色林固体制剂的制备方法 技术领域
本发明涉及一种匹莫范色林固体制剂的制备方法，该方法改善了制备过程中匹莫范色林粉体的流动性，可提高固体制剂中活性成分含量的稳定性，并且具有快速溶出释放和压缩成型性良好的特性。
背景技术
匹莫范色林(Pimavanserin)，结构如下所示，是一种选择性5-羟色胺2A/2C受体反向激动剂，记载于专利国际申请PCT/US2004/001234中。其酒石酸盐，即酒石酸匹莫范色林，于2016年4月29日在美国FDA获得上市批准
Figure PCTCN2021119473-appb-000001
用于帕金森症并发的精神疾病(幻觉和妄想症)。
Figure PCTCN2021119473-appb-000002
匹莫范色林通常制成片剂和胶囊等固体制剂，例如在美国上市的酒石酸匹莫范色林药品就是以片剂和胶囊的形式存在。此类固体制剂的制备，通常是将活性成分与适当的辅料混合制成颗粒，然后再将一定量的颗粒进行压制(以制成片剂)或者填充于胶囊中(以制成胶囊)。在固体制剂的工业生产中，为了确保所制成的颗粒以及由此制成的片剂或胶囊中活性成分的含量是均匀稳定的，需要在活性成分与辅料混合的过程提高粉体的流动性。
本领域技术人员公知，在固体制剂的制备过程中，粒径对于粉体的流动性有很大的影响。粉体的粒径越大，其休止角一般越小，流动性也就越高。通常，若粒径小于200μm，则粒子易于发生聚集，表现出黏着性(参见《药剂学》，张强、武凤兰主编，2005年第一版，北京大学医学出版社)。然而，由于酒石酸匹莫范色林分子特殊的固有性质，其活性成分的粉体流动性非常差，即使通过增大粉体粒度、添加润滑剂等本领域常用的技术手段，也很难制成含量均一的颗粒，以至于所制成的固体制剂的含量稳定性较低，难以在 临床应用中确保给药剂量的准确性。
除了需要提高粉体流动性之外，为了确保活性成分的吸收，固体制剂中活性成分也应具有一定的溶出度；并且，在制备片剂的情况下，所压制的片剂还应易于压缩成型并且不易破损，从而有利于生产及运输环节，保持药品的质量稳定。大部分现有的酒石酸匹莫范色林固体制剂在溶出度和压缩成型性方面还不能达到令人满意的水平。
综上所述，本领域迫切地需要一种新的匹莫范色林(特别是酒石酸匹莫范色林)的固体制剂的制备方法，以提高制剂过程中匹莫范色林的粉体流动性，并且提高溶出度以及改善压缩成型性。
发明内容
本发明的发明人通过对匹莫范色林、特别是酒石酸匹莫范色林的固体制剂进行大量深入的研究，意外地发现：与现有技术中常用的增大粉体粒径的操作相反，通过将匹莫范色林原料药的粉体进行进一步粉碎，使其粒径控制在178μm(相当于80目筛)以下，反而能够显著地提高制粒过程中的粉体流动性，改善制剂的含量稳定性，并且能够改善制剂的压缩成型性以及提高活性成分的溶出度，由此完成了本发明。
因此，本发明涉及一种匹莫范色林固体制剂的制备方法，其包括以下步骤：
(1)将匹莫范色林原料药粉碎至粒径为178μm以下；
(2)将粉碎后的匹莫范色林原料药与药学上可接受的赋形剂混合；
(3)对混合后的粉末进行干法制粒；
(4)将所制得的颗粒压制成片剂或者填充入胶囊中。
在一个优选的技术方案中，所述匹莫范色林为酒石酸匹莫范色林。在一个优选的技术方案中，所述匹莫范色林为结晶形式的匹莫范色林。在一个更优选的技术方案中，所述结晶形式为如专利国际申请PCT/US2004/001234中记载的匹莫范色林C晶型。
在一个优选的技术方案中，所述粒径以D90、优选以D95、更优选以D98表示。
在一个优选的技术方案中，所述所述步骤(1)中将匹莫范色林原料药粉碎至粒径为170μm以下、160μm以下、或150μm以下。
在一个优选的技术方案中，所述赋形剂包括填充剂和润滑剂。在一个更优选的技术方案中，所述填充剂为微晶纤维素。在一个更优选的技术方案中，所述润滑剂为硬脂酸镁。
在一个更优选的技术方案中，所述匹莫范色林原料药、填充剂和润滑剂的质量比为(20-60)∶(40-80)∶(0.1-5)，优选(30-50)∶(50-70)∶(0.2-2)，更优选约40∶59∶(0.5-1)。
在一个优选的技术方案中，所述混合采用混合机进行。在一个更优选的技术方案中，所述混合机为三维混合机、V型混合机、槽型混合机、方锥料斗式混合机，更优选为料斗混合机。
在一个更优选的技术方案中，所述混合机的转速为约1～100rpm，优选2～50rpm，更优选约5～20rpm(例如约10rpm)；混合时间为约1～60分钟，优选2～30分钟，更优选约5～20分钟(例如约10分钟)。
在一个优选的技术方案中，所述干法制粒采用干法制粒机进行，制粒压力约为1～100bar，优选20～80bar，更优选40～60bar，特别优选制粒压力约为50bar。
在一个优选的技术方案中，在步骤(3)之后实施以下步骤(3’)：
(3’)：将所制得的颗粒与第二份药学上可接受的赋形剂混合，所述第二份药学上可接受的赋形剂包含第二份润滑剂(例如硬脂酸镁)，其中匹莫范色林原料药与所述第二份润滑剂的质量比为(20-60)∶(0.1-5)，优选(30-50)∶(0.2-2)，更优选约40∶59∶0.5。
在一个优选的技术方案中，所制备的颗粒粒度D90为100～1000μm，优选200～800μm，更优选300～600μm。
在一个优选的技术方案中，所述固体制剂为片剂或胶囊剂形式，优选胶囊剂，特征在于胶囊壳优选自明胶胶囊、土豆胶囊、植物(羟丙甲纤维素)胶囊、海藻酸钠胶囊，更优选植物(羟丙甲纤维素)胶囊。
本发明的方法改善了固体制剂制备过程中的匹莫范色林粉体的流动性，可提高固体制剂中活性成分含量的稳定性，并且具有快速溶出释放和压缩成型性良好的特性。因此，本发明的制剂和方法不但适于大规模工业生产中的操作和控制，而且能够显著提高给药剂量的稳定性并且利于活性成分发挥药效，由此使患者受益。特别是，本发明的方法对辅料的密度和粒度没有特殊要求，只需要分别将常规的微晶纤维素和硬脂酸镁作为填充剂和润滑剂即可， 大大地降低了制剂的成本。另外，本发明的方法的工艺耐用性和重现性更高，大大降低了对生产设备和工艺控制的要求，具有更好的设备适用性，也大大降低了工艺参数控制的风险。
附图说明
图1：按本发明的方法制备的酒石酸匹莫范色林胶囊在0.1mol/L盐酸溶液中的溶出曲线。
图2：按本发明的方法制备的酒石酸匹莫范色林胶囊在pH4.5乙酸-乙酸钠缓冲溶液中的溶出曲线。
图3：按本发明的方法制备的酒石酸匹莫范色林胶囊在水中的溶出曲线。
图4：按本发明的方法制备的酒石酸匹莫范色林胶囊在pH6.8磷酸盐缓冲溶液中的溶出曲线。
图5：上市药品
Figure PCTCN2021119473-appb-000003
在0.1mol/L盐酸溶液中的溶出曲线。
具体实施方式
本说明书上下文中所用的术语“约”表示在相应数值上下浮动10％的范围。例如，若某种成分的浓度为约5mM，表明其浓度为4.5-5.5mM；若某种成分的浓度范围为约5-10mM，表明其浓度范围为4.5-11mM。
除非特别指出，否则本说明书上下文中的“活性成分”指匹莫范色林，特别是酒石酸匹莫范色林。
本说明书上下文所用的术语“粒径”一般是指颗粒累积分布为90％的粒径，即“D90”。例如，本说明书上下文所述“粒径为178μm以下”一般指“D90为178μm以下”。优选地，术语“粒径”指颗粒累积分布为95％的粒径，即“D95”；更优选地，术语“粒径”指颗粒累积分布为98％的粒径，即“D98”。
本说明书上下文所用的术语“原料药”是指未制成制剂形式的匹莫范色林原料物质，其形式包括但不限于无定形粉末和晶体粉末，纯度满足药典或其它规范性文件的要求，或者满足制药领域对于原料药的一般要求。其来源可为通过市售获得，也可由研究者自行通过化学合成获得。
本说明书上下文所用的术语“以上”、“以下”表示包含本数。例如，“粒径为178μm以下”与“粒径小于或等于178μm”含义相同。
本发明的一个具体实施方式涉及一种匹莫范色林固体制剂的制备方法， 其包括以下步骤：
(1)将酒石酸匹莫范色林原料药粉碎至D90(优选D95，更优选D98)为178μm以下(例如，将酒石酸匹莫范色林原料药通过80目筛)；
(2)利用料斗混合机将粉碎后的酒石酸匹莫范色林原料药与药学上可接受的赋形剂混合，所述药学上可接受的赋形剂包含微晶纤维素和硬脂酸镁，且所述匹莫范色林原料药、微晶纤维素和硬脂酸镁的质量比为(20-60)∶(40-80)∶(0.1-5)，优选(30-50)∶(50-70)∶(0.2-2)，更优选约40∶59∶(0.5-1)；所述混合机的转速为约1～100rpm，优选2～50rpm，更优选约5～20rpm(例如约10rpm)；混合时间为约1～60分钟，优选2～30分钟，更优选约5～20分钟(例如约10分钟)；
(3)用干法制粒机对混合后的粉末进行干法制粒，所述干法制粒机的制粒压力约为1～100bar，优选20～80bar，更优选40～60bar，特别优选约50bar；
(3’)任选将所制得的颗粒与第二份硬脂酸镁混合，匹莫范色林原料药与所述第二份硬脂酸镁的质量比为(20-60)∶(0.1-5)，优选(30-50)∶(0.2-2)，更优选约40∶59∶0.5；
(4)将所制得的颗粒压制成片剂或者填充入胶囊中。
本发明的更具体的实施方式将通过以下实施例进行例示性解释说明，但应认识到所述实施例并非意在限制本发明的范围。
实施例1：胶囊制备工艺1
按专利国际申请PCT/US2004/001234中记载的方法制备酒石酸匹莫范色林原料药。将原料药通过80目筛，以将其粒径控制于D90为178μm以下。然后按照以下下表1所示的处方量按比例称取。
表1：制备工艺1的处方量
处方 用量(mg/粒胶囊) 作用
酒石酸匹莫范色林 40 活性成分
微晶纤维素 59 填充剂
硬脂酸镁 1 润滑剂
将满足上述比例的酒石酸匹莫范色林、微晶纤维素、硬脂酸镁加入到料 斗混合机中，设定转速为10rpm、时间为10分钟，开启混合机进行混合。混合结束后，将上述混合粉末加入到干法制粒机进行干法制粒，设置干法制粒机制粒压力为50bar。制粒后，将颗粒填充入3号植物胶囊，共制备5000粒胶囊。
实施例2：胶囊制备工艺2
将酒石酸匹莫范色林原料药通过80目筛，以将其粒径控制于D90为178μm以下。然后按照下表2所示的处方量按比例称取。
表2：制备工艺2的处方量
处方 用量(mg/粒胶囊) 作用
酒石酸匹莫范色林 40 活性成分
微晶纤维素 59 填充剂
硬脂酸镁(内加) 0.5 润滑剂
硬脂酸镁(外加) 0.5 润滑剂
将满足上述比例的酒石酸匹莫范色林、微晶纤维素、硬脂酸镁(内加)加入到料斗混合机中，设定转速为10rpm、时间为10分钟，开启混合机进行混合。混合结束后，将上述混合粉末加入到干法制粒机进行干法制粒，设置干法制粒机制粒压力为50bar。制粒后，将制得的颗粒以及按0.5mg/粒胶囊计的硬脂酸镁(外加)加入到混合机中，设定转速为10rpm、时间为10分钟，开启混合机混合均匀后，填充入3号植物胶囊。
实施例3：颗粒流动性和粒径分布评价
对实施例2的胶囊颗粒测定休止角、松密度和振实密度。测定方法如下，结果如表3所示。
休止角：将漏斗固定于坐标纸上方一定高度，从漏斗加入物料直到形成的堆积圆锥底部与漏斗底部刚好接触，测定圆锥直径，以漏斗底高度与圆锥半径比作为正切值计算休止角(平行测定三次)。
松密度：在干燥的250ml量筒(可读至2mL)中加入约100g没压实的待测物，称量精确至0.1％，仔细刮平样品，不要压紧，读出初体积V0，即最近的刻度值，堆积密度(g/ml)，计算公式：m/V0(平行测定三次)。
振实密度：将量筒固定在支架上。使用10、500和1250次拍打，并读取相应的体积V10、V500和V1250至最近刻度值。当V500和V1250相差小于或等于2ml时，V1250是振实体积VF。当V500和V1250相差超过2ml时，继续拍打1250次，直至测量值间差异小于或等于2ml，所读取的体积即为最终振实体积VF。计算公式：m/VF(平行测定三次)。
表3：胶囊颗粒流动性测量结果
试验编号 休止角(°) 松密度(g/cm 3) 振实密度(g/cm 3)
1 30.2 0.50 0.58
2 31.5 0.49 0.58
此外，为了对所制备的胶囊颗粒的粒径分布进行评价，用不同的筛对其进行筛分，其结果如表4所示：
表4：胶囊颗粒的粒径分布
  孔径(μm) 占比(重量％)
20目 850 0.24
30目 600 56.5
45目 355 27.1
60目 250 11.3
以上表明，实施例1和2制得的颗粒流动性较好，粒径分布也更为合理，适合于胶囊充填，可确保充填剂量的稳定性，而且在生产中的物料转移、充填的持续加工过程中，也可确保原料药含量均匀性的稳定性，最终确保治疗剂量的准确性。
实施例4：含量均匀度评价
随机取实施例2中获得的胶囊10粒，编号分别为1-10，对其中活性成分的含量相对值进行测定，以40mg作为100％。如表5所示，活性成分的分布具有良好均匀性，表明含量稳定。
表5：
Figure PCTCN2021119473-appb-000004
Figure PCTCN2021119473-appb-000005
实施例5：溶出度评价
对实施例2的胶囊进行溶出度测定：
采用篮法，以100rpm的速率在900ml溶出介质中进行实验，所述溶出介质分别为0.1mol/L盐酸溶液、pH4.5乙酸-乙酸钠缓冲溶液、水和pH6.8磷酸盐缓冲溶液，按照FDA综述(NDA210793产品质量综述)所述的方法对每种溶出介质平行进行六次实验。在实验开始后5、10、15、20、30、45分钟时分别测定溶出度，结果分别见于图1-图5和表6-表10中。
作为对比，图5和表10为前述FDA综述记载的市售的酒石酸匹莫范色林胶囊
Figure PCTCN2021119473-appb-000006
的溶出度测定结果，所用的溶出介质为0.1mol/L盐酸溶液。
表6：酒石酸匹莫范色林胶囊在0.1mol/L盐酸溶液中的溶出曲线
Figure PCTCN2021119473-appb-000007
表7：酒石酸匹莫范色林胶囊在pH4.5乙酸-乙酸钠缓冲溶液中的溶出曲线
Figure PCTCN2021119473-appb-000008
表8：酒石酸匹莫范色林胶囊在水中的溶出曲线
Figure PCTCN2021119473-appb-000009
表9：酒石酸匹莫范色林胶囊在pH6.8磷酸盐缓冲溶液中的溶出曲线
Figure PCTCN2021119473-appb-000010
Figure PCTCN2021119473-appb-000011
表10：
Figure PCTCN2021119473-appb-000012
在0.1mol/L盐酸溶液中的溶出曲线(文献数据)
Figure PCTCN2021119473-appb-000013
N/A：未测定
实验结果表明，在所测定的各种溶出介质中，本发明的方法所制备的制剂都在5分钟时即实现了几乎完全的溶出；而根据前述文献的记载，在0.1mol/L盐酸溶液中，市售的酒石酸匹莫范色林胶囊
Figure PCTCN2021119473-appb-000014
直到30分钟时都未能实现90％以上的溶出。这表明本发明的方法制备的固体制剂在溶出度方面相比于市售的原研药品取得了显著的改善。
Figure PCTCN2021119473-appb-000015
Figure PCTCN2021119473-appb-000016
Figure PCTCN2021119473-appb-000017

Claims (10)

  1. 一种匹莫范色林固体制剂的制备方法，其包括以下步骤：
    (1)将匹莫范色林原料药粉碎至粒径为178μm以下；
    (2)将粉碎后的匹莫范色林原料药与药学上可接受的赋形剂混合；
    (3)对混合后的粉末进行干法制粒；
    (4)将所制得的颗粒压制成片剂或者填充入胶囊中。
  2. 如权利要求1所述的方法，其中匹莫范色林为酒石酸匹莫范色林。
  3. 如前述任一项权利要求所述的方法，其中所述粒径以D90、优选以D95、更优选以D98表示。
  4. 如前述任一项权利要求所述的方法，其中所述步骤(1)中将匹莫范色林原料药粉碎至粒径为170μm以下、160μm以下、或150μm以下。
  5. 如前述任一项权利要求所述的方法，其中所述赋形剂包括填充剂(例如微晶纤维素)和润滑剂(例如硬脂酸镁)。
  6. 如权利要求5所述的方法，其中所述匹莫范色林原料药、填充剂和润滑剂的质量比为(20-60)∶(40-80)∶(0.1-5)，优选(30-50)∶(50-70)∶(0.2-2)，更优选约40∶59∶1。
  7. 如前述任一项权利要求所述的方法，其中所述混合采用混合机(例如料斗混合机)进行。
  8. 如权利要求7所述的方法，其中混合机的转速为约1～100rpm，混合时间为约1～60分钟。
  9. 如前述任一项权利要求所述的方法，其中所述干法制粒采用干法制粒机进行，制粒压力约为1～100bar，优选20～80bar，更优选40～60bar，特别优选约为50bar。
  10. 如前述任一项权利要求所述的方法，其中在步骤(3)之后实施以下步骤(3’)：
    (3’)将所制得的颗粒与第二份药学上可接受的赋形剂混合，所述第二份药学上可接受的赋形剂包含第二份润滑剂(例如硬脂酸镁)。
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