WO2023010410A1 - 一种沃替西汀帕莫酸盐冻干粉针剂及其制备方法 - Google Patents

一种沃替西汀帕莫酸盐冻干粉针剂及其制备方法 Download PDF

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WO2023010410A1
WO2023010410A1 PCT/CN2021/110851 CN2021110851W WO2023010410A1 WO 2023010410 A1 WO2023010410 A1 WO 2023010410A1 CN 2021110851 W CN2021110851 W CN 2021110851W WO 2023010410 A1 WO2023010410 A1 WO 2023010410A1
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powder injection
vortioxetine
pamolate
mannitol
drying
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PCT/CN2021/110851
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English (en)
French (fr)
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刘腾飞
方佳磊
王亚南
倪赉一
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浙江华海药业股份有限公司
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Priority to PCT/CN2021/110851 priority Critical patent/WO2023010410A1/zh
Priority to CA3227397A priority patent/CA3227397A1/en
Priority to BR112024002176A priority patent/BR112024002176A2/pt
Priority to AU2021459163A priority patent/AU2021459163A1/en
Priority to EP21952304.0A priority patent/EP4382096A1/en
Priority to CN202180100028.0A priority patent/CN117597111A/zh
Publication of WO2023010410A1 publication Critical patent/WO2023010410A1/zh

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    • 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
    • A61P25/24—Antidepressants
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the invention relates to the field of medical research and development, in particular to a method for manufacturing vortioxetine pamolate suspension and a method for manufacturing vortioxetine pamolate freeze-dried powder injection.
  • Vortioxetine (chemical name 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine) is an antidepressant developed jointly by Takeda and Lundbeck Pharmaceuticals , the structural formula is as follows:
  • Vortioxetine can effectively overcome some of the shortcomings of common antidepressants, such as weight gain, drowsiness and drug sedation and other adverse reactions. Receive and other advantages.
  • common antidepressants such as weight gain, drowsiness and drug sedation and other adverse reactions.
  • Receive and other advantages Currently on the market are all vortioxetine hydrobromide tablets, which have a short duration of efficacy in the body and need to be taken once a day.
  • Vortioxetine pamolate is made into a stable long-acting preparation, and patients can be administered once every two weeks or every four weeks, which can greatly improve the efficiency of drug use and improve the therapeutic effect of the drug for patients , improve patient compliance, and reduce the occurrence of adverse reactions.
  • WO2017167180A1 mentions administering vortioxetine pamolate in the form of a suspension, wherein the pharmaceutical carrier is preferably a viscous injectable carrier, for example, its viscosity is at least 20 cp at 20°C.
  • High viscosity means that it is more difficult to prepare before clinical use, and after preparation, the force of using a syringe to extract is greater, and the requirements for operators are higher.
  • vortex for example, vortex for 2 minutes
  • external equipment such as a vortex machine is required, which increases the difficulty and time of preparation.
  • the object of the present invention is to provide a kind of powder injection of vortioxetine pamoate and preparation method thereof;
  • the object of the present invention is realized by the following technical solutions:
  • the present invention firstly provides a powder injection composition composed of vortioxetine pamolate and pharmaceutical excipients.
  • the mass percentage of the vortioxetine pamolate is 54.0-72.4%.
  • the pharmaceutical excipients include a suspending agent selected from low-molecular suspending agents and high-molecular suspending agents, including glycerin, acacia, agar, and tragacanth gum. , methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, povidone, dextran, carbopol, aluminum monostearate, etc.
  • the suspending agent accounts for 2.3-13.8% (w/w) of the total amount of the powder injection, preferably the suspending agent accounts for 6.9-10.8% (w/w) of the total amount of the powder injection.
  • the preferred suspending agent is sodium carboxymethyl cellulose, more preferably sodium carboxymethyl cellulose with a viscosity of 50-200 cp (4%, w/v).
  • the pharmaceutical excipient further comprises a lyoprotectant selected from sugars, polyalcohols, such as sucrose, trehalose, lactose, xylitol, glucose or mannose alcohol.
  • a lyoprotectant selected from sugars, polyalcohols, such as sucrose, trehalose, lactose, xylitol, glucose or mannose alcohol.
  • the lyoprotectant accounts for 4.6-35.0% (w/w) of the total powder injection.
  • the pharmaceutical excipients further include an osmotic pressure regulator, and the osmotic pressure regulator is selected from: sodium chloride, potassium chloride, mannitol, glucose or borax and the like.
  • mannitol is preferably used as an osmotic pressure regulator and a lyoprotectant in the present invention, and it is further preferred to use grade mannitol for injection; the dosage of mannitol is 20.7-32.5% (w/w).
  • the pharmaceutical excipient preferably does not add a wetting agent, such as polysorbate (also known as Tween), poloxamer; the wetting agent acts as a dispersion function in the prescription, which can promote mixing The mixing uniformity of the suspension, but the inventor unexpectedly found that adding a wetting agent such as polysorbate in the prescription of the present invention will cause the prepared suspension to settle faster.
  • a wetting agent such as polysorbate (also known as Tween), poloxamer
  • the preferred formulation of the present invention consists of: vortioxetine pamolate monohydrate, sodium carboxymethylcellulose, mannitol, and water for injection.
  • the preferred formulation specification of the present invention is 140mg-280mg, which is equivalent to about 235.5mg-471.0mg of vortioxetine pamolate monohydrate, wherein the preferred dosage of sodium carboxymethylcellulose is 6.9-10.8% (w/ w), the consumption of mannitol is 20.7-32.5% (w/w).
  • the preferred vortioxetine pamolate powder injection of the present invention has components and contents as follows:
  • the particle size of vortioxetine pamolate is 1-40 ⁇ m (D90); the preferred particle size is 1-20 ⁇ m (D90); the more preferred particle size is 1-10 ⁇ m (D90) .
  • D90 refers to the particle size corresponding to when the cumulative particle size distribution of the sample measured by a laser particle size analyzer reaches 90%.
  • the present invention further provides a preparation method of vortioxetine pamolate powder injection, comprising the following steps:
  • step (3) Secondary mixing: Put the primary mixed solution obtained in step (2) into a homogenizer for homogenization to obtain a suspension with a target particle size of 1-40 ⁇ m (D90), and half-tamp the plug after filling;
  • the target particle size of step (3) is preferably 1-20 ⁇ m (D90), more preferably 1-10 ⁇ m
  • the particle size has a great influence on the properties, needle penetration and bioavailability of the product. If the particle size distribution is wide, or the mixing uniformity is not good, agglomeration and sedimentation will occur, resulting in needle blockage.
  • a homogenizer and a homogenizer are used to adjust the particle size to reach the range of the target particle size.
  • This step provides a kind of method for manufacturing vortioxetine pamolate lyophilized preparation, and this method comprises the following steps:
  • the innovation of the present invention mainly contains:
  • the particles of the powder injection prepared by the invention are evenly dispersed and have a normal appearance, and the broken bottle cuts the solid matter longitudinally, and the internal structure is uniform without atrophy. After adding water for injection, it can be quickly reconstituted (shake gently for ⁇ 30s to obtain a uniformly mixed suspension), and the reconstituted medicinal solution can pass through a needle of 19-22G size, and has good needle penetration.
  • This dosage form not only improves the feasibility of industrialization, but also reduces the difficulties in drug transportation and storage, and provides more effective and convenient treatment methods for clinical psychiatric patients.
  • TSI is the stability index: TSI is an evaluation of the stability of the entire dispersion system, the larger the value, the more unstable it is.
  • Mannitol is injection grade, preferably sodium carboxymethylcellulose with a viscosity of 50-200cp (4%, w/v).
  • the rotation speed is set to 14000rpm, and the raw material drug is slowly added into the diluent under high-speed shear, and mixed for 10 minutes after the sample injection is completed, to obtain an intermediate solution.
  • Freeze-drying the sample is sent into a drying box for freeze-drying, plugged, taken out of the box, and capped to obtain vortioxetine powder injection.
  • Mannitol is injection grade, preferably sodium carboxymethylcellulose with a viscosity of 50-200cp (4%, w/v).
  • the rotation speed is set to 14000rpm, and the raw material drug is slowly added into the diluent under high-speed shear, and mixed for 10 minutes after the sample injection is completed, to obtain an intermediate solution.
  • Freeze-drying the sample is sent into a drying box for freeze-drying, plugged, taken out of the box, and capped to obtain vortioxetine powder injection.
  • Mannitol is injection grade, preferably sodium carboxymethylcellulose with a viscosity of 50-200cp (4%, w/v).
  • the rotation speed is set to 14000rpm, and the raw material drug is slowly added into the diluent under high-speed shear, and mixed for 10 minutes after the sample injection is completed, to obtain an intermediate solution.
  • Freeze-drying the sample is sent into a drying box for freeze-drying, plugged, taken out of the box, and capped to obtain vortioxetine powder injection.
  • Embodiment 4 the influence investigation of sample stability
  • TW80 polysorbate 80
  • TW80 polysorbate 80
  • TW80 product obtained in embodiment 2
  • TURBISCAN Lab stability analyzer
  • Embodiment 5 Investigation on the impact of particle size on sample stability
  • Example 2 the working pressure of the high-pressure homogenizer in step (3) was changed to obtain samples with different particle sizes.
  • the relationship between time and settlement was analyzed by a stability analyzer, and the results are shown in Figure 2.
  • low pressure the working pressure is 100bar, 3 times of circulation treatment, the particle size of the suspension is 35 ⁇ m (D90); medium pressure: the working initial pressure is 100bar, 3 times of circulation treatment, pressurized to 300bar, 2 times of circulation treatment times, the particle size of the suspension is 20 ⁇ m (D90); high pressure: the initial working pressure is 100 bar, and the cycle is processed 3 times, pressurized to 500 bar, and the particle size of the suspension is 10 ⁇ m (D90).
  • the particle size distribution is measured by a laser particle size analyzer, for example by light scattering or laser diffraction techniques.
  • a laser particle size analyzer for example by light scattering or laser diffraction techniques.
  • the powder is loaded into a laser diffraction spectrometer, for example via a dispersing unit. The test method is described in detail as follows:
  • Dispersion medium refractive index 1.33

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Abstract

提供一种沃替西汀帕莫酸盐冻干粉针剂及其制备方法。制备得到的粉针剂产品通针性和稳定性良好，非常适用于产业化。

Description

一种沃替西汀帕莫酸盐冻干粉针剂及其制备方法 技术领域
本发明涉及医药研发领域，具体涉及制造沃替西汀帕莫酸盐混悬液的方法，以及一种制造沃替西汀帕莫酸盐冻干粉针剂的方法。
背景技术
沃替西汀(vortioxetine，化学名称为1-[2-(2,4-二甲基苯基硫烷基)苯基]哌嗪)，是由武田公司和灵北制药合作研发的抗抑郁药，结构式如下所示：
Figure PCTCN2021110851-appb-000001
沃替西汀能有效克服常见抗抑郁药中存在的一些缺点，如体重增加、困倦及药物镇静作用等不良发应，具有多作用靶点、不良反应率低、复发率低和持续治疗安全耐受等优点。目前上市的都是氢溴酸沃替西汀片，在体内发挥药效的持续时间较短，需要每日服用一次。
WO2017167180A1首次将沃替西汀和帕莫酸按一定比例制成盐，延长了沃替西汀在体内的滞留时间，实现了沃替西汀在体内的缓慢释放。将沃替西汀帕莫酸盐制成稳定的长效制剂，患者可实现每两周，或每四周给药一次，这对患者来说，可大大提高药物的使用效率，提高药物的治疗效果，提高患者的依从性，减少不良反应的发生。
WO2017167180A1提到将沃替西汀帕莫酸盐以混悬液形式给药，其中药用载体优选黏性可注射载体，例如其黏度在20℃时为至少20cp。高黏度意味着临床使用前配制难度较大，且配制后使用注射器抽取的力度较大，对操作人员的要求较高。另外，配制时需要涡旋(如涡旋2min)，则要借助涡旋机等外部设备，增加了配制难度和配制时间。对于混悬液的配液方式，即使最终能够制备得到均匀混合的混悬液，但操作过程复杂，比较耗时费力，而且仍 具有API成细小聚团难以分散的风险。
发明内容
本发明的目的在于提供一种沃替西汀帕莫酸盐的粉针剂及其制备方法；本发明的目的通过以下技术方案实现：
本发明首先提供了一种沃替西汀帕莫酸盐和药用辅料组成的粉针剂组合物。
在本发明的一些实施方式中，基于组合物的总质量，所述沃替西汀帕莫酸盐的质量百分比为54.0-72.4％。
在本发明的一些实施方式中，所述药用辅料包含助悬剂，所述助悬剂选自低分子助悬剂和高分子助悬剂，包括甘油、阿拉伯胶、琼脂、西黄耆胶、甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚维酮、葡聚糖、卡波普、单硬脂酸铝等。助悬剂占粉针剂总量的2.3-13.8％(w/w)，优选助悬剂占粉针剂总量的6.9-10.8％(w/w)。优选助悬剂为羧甲基纤维素钠，进一步优选为黏度为50-200cp(4％，w/v)的羧甲基纤维素钠。
在本发明的一些实施方式中，所述药用辅料还包含冻干保护剂，所述冻干保护剂选自糖类、多元醇，例如蔗糖、海藻糖、乳糖、木糖醇、葡萄糖或甘露醇。优选地，冻干保护剂占粉针剂总量的4.6-35.0％(w/w)。
在本发明的一些实施方式中，所述药用辅料还包含渗透压调节剂，所述渗透压调节剂选自：氯化钠、氯化钾、甘露醇、葡萄糖或硼砂等。
在本发明的一些实施方式中，本发明中优选甘露醇为渗透压调节剂和冻干保护剂，进一步优选使用注射用级别甘露醇；甘露醇的用量为20.7-32.5％(w/w)。
在本发明的一些实施方式中，所述药用辅料优选不添加润湿剂，例如聚山梨酯(又称吐温)、泊洛沙姆；润湿剂在处方中作为分散功能，可以促进混悬液的混合均一性，但发明人意外发现本发明的处方中添加了聚山梨酯等润湿剂将导致配制的混悬液沉降较快。
本发明优选的处方组成为：沃替西汀帕莫酸盐一水合物、羧甲基纤维素钠、甘露醇、注射用水。
本发明优选的制剂规格为140mg-280mg，相当于约235.5mg-471.0mg的沃替西汀帕莫酸盐一水合物，其中优选羧甲基纤维素钠的用量为6.9-10.8％(w/w)，甘露醇的用量为20.7-32.5％(w/w)。
本发明优选沃替西汀帕莫酸盐粉针剂，其组分和含量如下所示：
成分 含量百分比(w/w)
沃替西汀帕莫酸盐一水合物 56.7-72.4％
羧甲基纤维素钠 6.9-10.8％
甘露醇 20.7-32.5％
本发明的一些实施方式中沃替西汀帕莫酸盐的粒径为1-40μm(D90)；优选的粒径为1-20μm(D90)；更进一步优选粒径为1-10μm(D90)。
D90是指使用激光粒度仪测量的样品的累计粒度分布数达到90％时所对应的粒径。
本发明还进一步提供了一种沃替西汀帕莫酸盐粉针剂的制备方法，包括以下步骤：
(1)稀释液的制备：将注射用水加热，搅拌条件下，加入处方量的辅料，搅拌至完全溶解，过滤备用；
(2)一次混合：称量处方量的沃替西汀帕莫酸盐一水合物粉末，搅拌条件下缓慢投入步骤(1)稀释液中，高速剪切分散；
(3)二次混合：将步骤(2)中所得到的一次混合液投入均质机中进行匀化，得到目标粒径为1-40μm(D90)的悬浮液，灌装后半压塞；
(4)冻干：将步骤(3)灌装后的样品装入干燥箱，在设置完成的冻干参数条件下进行冻干，压塞。
步骤(3)的目标粒径优选为1-20μm(D90)，进一步优选为1-10μm
(D90)。
粒径对于产品的性状、通针性和生物利用度有很大的影响，粒径分布较宽，或者混合均一性不佳，会出现结块和沉降，导致针头堵塞问题。本发明的制备过程中用到匀浆机和均质机来调整粒径大小达到目标粒径的范围。
该步骤提供一种制造沃替西汀帕莫酸盐冻干制剂的方法，该方法包括以下步骤：
(1)将灌装完毕的沃替西汀帕莫酸盐混悬液冷冻至-40℃；
(2)在低于约0℃的温度、适当的真空度下进行一次干燥；
(3)在高于约0℃的温度下进行二次干燥。
本发明的创新点主要有：
1、通过优化产品剂型和处方，降低产品的絮凝效应，保证混悬液静置时不发生明显沉降行为；
2、通过摸索研究，确定匀浆和高压均质工艺，制得粒径合适且混悬均匀的混悬液；
3、基于关键冻干参数，分别优化预冻、一次干燥和二次干燥工艺，最终成功制备了外观、水分等理化性质合格的粉针剂。
本发明制备的粉针剂颗粒分散均匀，外观正常，破瓶纵向切开固形物，内部结构均一，无萎缩现象。加入注射用水后能迅速复溶(轻轻晃摇＜30s，便能得到混合均匀的混悬液)，复溶后的药液能够通过19～22G大小的针头，具有良好的通针性。该剂型的开发不仅提高了产业化的可行性，还减少了药物运输和存储中的困难，为临床精神类患者提供了更有效、使用更加方便的治疗手段。
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，本领域普通技术人员来讲还可以根据这些附图获得其他的附图。
图1：样品稳定性的影响考察。
图2：粒径对样品稳定性的影响考察。
纵坐标TSI为稳定性指数：TSI是对整个分散体系稳定性的一个评价，其数值越大，就越不稳定。
具体实施方式
下面结合实施例进一步详细描述本发明，以便本领域的技术人员能够更清楚地理解和实施本发明。但本发明并不限于以下实施例，对本发明所作的任何不背离本发明精神和范围的变更、修改和等同替换，均落在本发明的范围之内。
实施例1
成分 用量 功能
沃替西汀帕莫酸盐一水合物 94.2g 活性成分
羧甲基纤维素钠 9g 助悬剂
甘露醇 27g 渗透压调节剂、冻干保护剂
聚山梨酯80 1.2g 润湿剂
注射用水 1000mL 溶剂
备注：甘露醇为注射剂级别，优选黏度为50-200cp(4％，w/v)的羧甲基纤维素钠。
工艺步骤：
(1)取80％注射用水，在50℃条件下水浴，在360rpm转速下依次加入甘露醇、羧甲基纤维素钠、聚山梨酯80，搅拌至完全溶解，冷却至室温后定重，使用0.22μm微孔滤膜过滤，获得稀释液。
(2)使用匀浆机，转速设置为14000rpm，在高速剪切下向稀释液中缓慢投入原料药，投样结束后混合10分钟，得到中间体溶液。
(3)使用高压均质机，设置出液流量，投入中间体溶液，缓慢加压至100bar，循环3次，再缓慢加压至500bar，循环2次，得到粒径10μm(D90)的混悬液。灌装，半压塞。
(4)冻干：将样品送入干燥箱中进行冻干，压塞，出箱，轧盖，得到沃替西汀粉针剂。
实施例2
成分 用量 功能
沃替西汀帕莫酸盐一水合物 94.2g 活性成分
羧甲基纤维素钠 9g 助悬剂
甘露醇 27g 渗透压调节剂、冻干保护剂
注射用水 1000mL 溶剂
备注：甘露醇为注射剂级别，优选黏度为50-200cp(4％，w/v)的羧甲基纤维素钠。
工艺步骤：
(1)取80％注射用水，在50℃条件下水浴，在360rpm转速下依次加入甘露醇、羧甲基纤维素钠，搅拌至完全溶解，冷却至室温后定重，使用0.22μm微孔滤膜过滤，获得稀释液。
(2)使用匀浆机，转速设置为14000rpm，在高速剪切下向稀释液中缓慢投入原料药，投样结束后混合10分钟，得到中间体溶液。
(3)使用高压均质机，设置出液流量，投入中间体溶液，缓慢加压至100bar，循环3次，再缓慢加压至500bar，循环2次，得到粒径10μm(D90)的混悬液。灌装，半压塞。
(4)冻干：将样品送入干燥箱中进行冻干，压塞，出箱，轧盖，得到沃替西汀粉针剂。
实施例3
成分 用量 功能
沃替西汀帕莫酸盐一水合物 42.3g 活性成分
羧甲基纤维素钠 9g 助悬剂
甘露醇 27g 渗透压调节剂、冻干保护剂
注射用水 1000mL 溶剂
备注：甘露醇为注射剂级别，优选黏度为50-200cp(4％，w/v)的羧甲基纤维素钠。
工艺步骤：
(1)取80％注射用水，在50℃条件下水浴，在360rpm转速下依次加入甘露醇、羧甲基纤维素钠，搅拌至完全溶解，冷却至室温后定重，使用0.22μm微孔滤膜过滤，获得稀释液。
(2)使用匀浆机，转速设置为14000rpm，在高速剪切下向稀释液中缓慢投入原料药，投样结束后混合10分钟，得到中间体溶液。
(3)使用高压均质机，设置出液流量，投入中间体溶液，缓慢加压至100bar，循环3次，再缓慢加压至500bar，循环2次，得到粒径10μm(D90)的混悬液。灌装，半压塞。
(4)冻干：将样品送入干燥箱中进行冻干，压塞，出箱，轧盖，得到沃替西汀粉针剂。
实施例4：样品稳定性的影响考察
将实施例1得到的产品(含聚山梨酯80，简称TW80)和实施例2得到的产品(不含TW80)通过稳定性分析仪(型号：TURBISCAN Lab)分析时间与沉降的关系，结果如图1所示。
实验结果表明不含有聚山梨酯80的体系，原料药颗粒沉降速度慢。而随着聚山梨酯80的引入，原料药颗粒沉降速度快，分层现象明显。表明两种不同体系的混悬液的性质具有较大差异，且不添加聚山梨酯80的药液优于添加了聚山梨酯80的药液。
实施例5：粒径对样品稳定性的影响考察
参考实施例2，改变步骤(3)的高压均质机工作压力，获得不同粒径的样品。通过稳定性分析仪分析时间与沉降的关系，结果如图2所示。
在图2中，低压力：工作压力为100bar，循环处理3次，混悬液粒径为35μm(D90)；中压力：工作初压力100bar，循环处理3次，加压至300bar，循环处理2次，混悬液粒径为20μm(D90)；高压力：工作初压力100bar，循环处理3次，加压至500bar，循环处理2次，混悬液粒径为10μm(D90)。
实验结果表明，高压匀质机的工作压力越高，所得原料药颗粒的粒径较小，沉降速度更慢，稳定性越好。
测试实施例
由激光粒度仪测量粒度分布，例如通过光散射或激光衍射技术进行粒度分布测量。为了测定粒度，例如通过分散单元将粉末装入激光衍射分光仪中。测试方法详细描述如下：
设备：Mastersizer激光粒度仪
产品折光系数：1.59
吸收系数：0.1
分散介质折光系数：1.33
分析模式：通用型
测量时间：10s
遮光度：10-20％
按照上述参数设置仪器。取一支样品，用1-3ml水复溶制备成混悬液，然后加入纯化水稀释至原溶液体积的10-50倍。取适量处理好的样品加入进样池中，加样时应注意搅拌均匀并且边搅拌边加样，待循环稳定1min后，循环测定3次，取平均值。
以上所述仅为本发明的较佳实施例，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. 一种沃替西汀帕莫酸盐粉针剂，其特征在于是由沃替西汀帕莫酸盐和药用辅料组成的组合物。
  2. 根据权利要求1所述的粉针剂，其特征在于所述药用辅料包括助悬剂；优选地，助悬剂选自甘油、阿拉伯胶、琼脂、西黄耆胶、甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚维酮、葡聚糖、卡波普或单硬脂酸铝；进一步优选地，助悬剂为羧甲基纤维素钠。
  3. 根据权利要求2所述的粉针剂，所述助悬剂占粉针剂总量的2.3-13.8％(w/w)，进一步优选为6.9-10.8％(w/w)。
  4. 根据权利要求1所述的粉针剂，所述药用辅料还包含冻干保护剂，所述冻干保护剂选自蔗糖、海藻糖、乳糖、木糖醇、葡萄糖或甘露醇；优选为甘露醇。
  5. 根据权利要求4所述的粉针剂，所述冻干保护剂占粉针剂总量的4.6-35.0％(w/w)，进一步优选为20.7-32.5％(w/w)。
  6. 根据权利要求1所述的粉针剂，所述药用辅料还包含渗透压调节剂，所述渗透压调节剂选自氯化钠、氯化钾、甘露醇、葡萄糖或硼砂，优选为甘露醇。
  7. 根据权利要求1所述的粉针剂，所述药用辅料包含优选作为冻干保护剂和渗透压调节剂的甘露醇，其占粉针剂总量20.7-32.5％(w/w)。
  8. 根据权利要求1所述的粉针剂，基于粉针剂的总质量，所述沃替西汀帕莫酸盐的质量百分比为54.0-72.4％。
  9. 根据权利要求1所述的粉针剂，其包括约235.5-471.0mg的沃替西汀帕莫酸盐一水合物，其中羧甲基纤维素钠的用量为6.9-10.8％(w/w)，甘露醇的用量为20.7-32.5％(w/w)。
  10. 根据权利要求1所述的粉针剂，所述药用辅料不包括润湿剂。
  11. 根据权利要求1所述的粉针剂，所述药用辅料不包括吐温。
  12. 根据权利要求1所述的粉针剂，其中沃替西汀帕莫酸盐的粒径为1-40μm(D90)；优选的粒径为1-20μm(D90)；更进一步优选粒径为1-10μm(D90)。
  13. 一种沃替西汀帕莫酸盐粉针剂的制备方法，包括以下步骤：
    (1)稀释液的制备：将注射用水加热，搅拌条件下，加入处方量的辅料，搅拌至完全溶解，过滤备用；
    (2)一次混合：称量处方量的沃替西汀帕莫酸盐一水合物粉末，搅拌条件下缓慢投入步骤(1)稀释液中，高速剪切分散；
    (3)二次混合：将步骤(2)中所得到的一次混合液投入均质机中进行匀化，得到目标粒径为1-40μm(D90)的悬浮液，灌装后半压塞；
    (4)冻干：将步骤(3)灌装后的样品装入干燥箱，在设置完成的冻干参数条件下进行冻干，压塞。
  14. 根据权利要求13所述的制备方法，优选的粒径为1-20μm(D90)；更进一步优选粒径为1-10μm(D90)。
  15. 根据权利要求13所述的制备方法，其中步骤(4)冻干过程包括以下步骤：
    (1)将灌装完毕的沃替西汀帕莫酸盐混悬液冷冻至-40℃；
    (2)在低于约0℃的温度、适当的真空度下进行一次干燥；
    (3)在高于约0℃的温度下进行二次干燥。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106491604A (zh) * 2015-09-07 2017-03-15 常州方楠医药技术有限公司 一种无定型沃替西汀或其盐与药用辅料的组合物及其制备方法
WO2017167180A1 (zh) 2016-03-29 2017-10-05 上海华汇拓医药科技有限公司 沃替西汀的帕莫酸盐及其晶型
WO2018086534A1 (zh) * 2016-11-09 2018-05-17 广东东阳光药业有限公司 氢溴酸沃替西汀长效注射制剂
WO2018153315A1 (zh) * 2017-02-23 2018-08-30 上海华汇拓医药科技有限公司 一种多奈哌齐半帕莫酸盐的粉针剂、包含其的组合物及它们的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106491604A (zh) * 2015-09-07 2017-03-15 常州方楠医药技术有限公司 一种无定型沃替西汀或其盐与药用辅料的组合物及其制备方法
WO2017167180A1 (zh) 2016-03-29 2017-10-05 上海华汇拓医药科技有限公司 沃替西汀的帕莫酸盐及其晶型
WO2018086534A1 (zh) * 2016-11-09 2018-05-17 广东东阳光药业有限公司 氢溴酸沃替西汀长效注射制剂
WO2018153315A1 (zh) * 2017-02-23 2018-08-30 上海华汇拓医药科技有限公司 一种多奈哌齐半帕莫酸盐的粉针剂、包含其的组合物及它们的制备方法

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