WO2016161576A1 - 一种含半胱氨酸盐酸盐的微丸及其制备方法 - Google Patents

一种含半胱氨酸盐酸盐的微丸及其制备方法 Download PDF

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WO2016161576A1
WO2016161576A1 PCT/CN2015/076062 CN2015076062W WO2016161576A1 WO 2016161576 A1 WO2016161576 A1 WO 2016161576A1 CN 2015076062 W CN2015076062 W CN 2015076062W WO 2016161576 A1 WO2016161576 A1 WO 2016161576A1
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cysteine hydrochloride
pellet
preparation
mother
pellets
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PCT/CN2015/076062
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English (en)
French (fr)
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李健
盛晓霞
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杭州领业医药科技有限公司
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Priority to CN201580061217.6A priority Critical patent/CN106999434B/zh
Priority to PCT/CN2015/076062 priority patent/WO2016161576A1/zh
Publication of WO2016161576A1 publication Critical patent/WO2016161576A1/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
    • A61K9/14—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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof

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  • the invention relates to a pellet with cysteine hydrochloride as a main component, and belongs to the technical field of medicine and food.
  • Cysteine hydrochloride (English name: Cysteine Hydrochloride), chemical name is 2-amino-3-mercaptopropionate, its molecular formula is C 3 H 8 NO 2 SCl, molecular weight is 157.62, the chemical formula is as follows :
  • Cysteine hydrochloride is a sulfur-containing amino acid which has an antioxidant action and is mainly used as an antioxidant for injections in pharmaceuticals. Since this product is an amphoteric amino acid, it can form a salt with an acidic drug or a salt with a basic drug, and can be used as a co-solvent and a prodrug carrier. In addition to being used as an antioxidant in the food industry, it is also used as a spice, bread fermentation accelerator, and the like. For some drugs whose solubility decreases with increasing pH, cysteine hydrochloride can be combined with these drugs to form a preparation to promote its dissolution and release, so as to maximize its efficacy. For certain low pH chemically stable drugs, the stability of the quality is guaranteed. At present, cysteine hydrochloride is made into a drug-loaded pill, and as a base pill, it has not been reported in the literature at home and abroad, and no such product has been introduced.
  • An object of the present invention is to provide a pellet having cysteine hydrochloride as a main component.
  • the pellets are not only easy to form, but also fully utilize the original properties of cysteine hydrochloride; for drugs with a decrease in solubility with increasing pH, the dissolution can be improved. At the same time, it can also alleviate the stimulation of contact with the cysteine hydrochloride dust and ensure the use of cysteine hydrochloride pellets.
  • the invention relates to a pellet containing cysteine hydrochloride as a main component, which comprises cysteine hydrochloride and other pharmaceutically acceptable binders, anti-adherents and optionally dilution Agent.
  • the cysteine hydrochloride which is a main component of the pellet of the present invention is cysteine hydrochloride anhydrate, cysteine hydrochloride hydrate or a pharmaceutically acceptable solvate.
  • the binder of the present invention is one of povidone, polyacrylic resin, cellulose, or a mixture of any two thereof.
  • the anti-adhesive agent of the present invention is one of talc, magnesium stearate, and finely divided silica gel or a mixture of any two or more thereof.
  • the diluent according to the present invention is one of microcrystalline cellulose, starch, mannitol, sorbitol or a mixture of any two or more thereof.
  • a preparation method of pellets containing cysteine hydrochloride as a main component comprising the following steps:
  • a part of the slurry prepared in the step (1) is mixed with a suitable amount of cysteine hydrochloride, a diluent or a mixture of cysteine hydrochloride and a diluent by a wet granulator.
  • the wet material is obtained by wet granulation, and the soft material is obtained by passing the soft material through a 16-80 mesh screen to obtain a mother nucleus;
  • the mother core is put into a centrifugal granulation coating machine, the rotation speed is adjusted to rotate the mother core, and the remaining suspension is sprayed on the mother core, and after drying, the cysteine hydrochloride pellets are obtained.
  • the cysteine hydrochloride pellets prepared by the above preparation method can obtain pellets of different particle diameters by preparing the mother nucleus of different particle diameters or adjusting the amount of the suspension.
  • the pellet diameter is preferably 0.2 to 1.2 mm.
  • Cysteine hydrochloride has antioxidant properties, and cysteine hydrochloride pellets can be used as a drug carrier to protect the drug from oxidation.
  • Cysteine hydrochloride is strong in hydrochloric acid.
  • the cysteine hydrochloride pellets of the present invention can improve the solubility of these drugs and thereby improve their dissolution. degree.
  • the cysteine hydrochloride pellet of the present invention uses ethanol as a suspension solvent, is easy to volatilize, can prepare low-moisture pellets, and can be prepared into a pellet preparation for some moisture-sensitive drugs.
  • the cysteine hydrochloride pellet of the present invention can alleviate the stimulation of the contact person by the cysteine hydrochloride dust and ensure the use effect of the cysteine hydrochloride pellet.
  • cysteine hydrochloride pellets of the present invention can ensure the stability of their quality.
  • High performance liquid phase analysis (HPLC) data was taken from Agilent 1260.
  • a C 18 column was used, 2.7 ⁇ m ⁇ 150 mm ⁇ 4.6 mm, column temperature 40 ° C, wavelength 225 nm, flow rate 1.0 mL / min, injection volume 10 ⁇ L.
  • Buffer 1.5g disodium hydrogen phosphate dissolved in 900mL water, adjusted to pH value of 3.1 ⁇ 0.1 with phosphoric acid, and then made up to 1000mL;
  • the gradient is as follows:
  • the various reagents or starting materials used in the examples are commercially available unless otherwise specified.
  • the particle size of the microcrystalline cellulose pellets, the starch pellets, and the sucrose pellets is 600 to 800 ⁇ m.
  • Dabigatran etexilate mesylate is a pH-dependent drug whose solubility decreases with increasing pH, so the cysteine hydrochloride pellets prepared in the present invention (Example 1) are commercially available. Microcrystalline cellulose pellets, starch pellets and sucrose pellets are used as the pellet core, and the outer layer is sprayed with the galactosyl methanesulfonate active material layer (the preparation method of the active material layer is referred to the patent document CN100528157C), and the ratio is obtained after drying. The dissolution rate of dabigatran etexilate mesylate pellets prepared in the four different pellet cores was compared with the addition of the group ester mesylate pellets. The results are shown in Table 1.
  • the experimental method is as follows: the cysteine hydrochloride pellets prepared in the first embodiment of the invention, the commercially available microcrystalline cellulose pellets, the commercially available starch pellets and the commercially available sucrose pellets are prepared as pellet cores, respectively. 6 parts of each of the genomic group of pellets (containing 150 mg of dabigatran etexilate), and under the dissolution apparatus, check by 100 rpm, basket method, medium water 900 ml dissolution method, press 0, 5, 10, 15, 30 min. Samples were taken for sampling, each time 10 ml, 0.45 ⁇ m polyethersulfone membrane was filtered through 4.0 ml, and the filtrate was taken for analysis under high performance liquid chromatography. The results are shown in Table 1.
  • the dabigatran etexilate mesylate pellets prepared by using the cysteine hydrochloride pellets of the present invention as pellet cores have faster dissolution rates than the other three pellet cores of dabigatran etexilate.
  • the mesylate salt pellets can reach 95% or more within 15 minutes, indicating that the main drug is completely dissolved, and the dabigatran etexilate mesylate pellets prepared by the other three pellet cores cannot be completely dissolved.
  • the dabigatran etexilate mesylate pellet prepared by using the cysteine hydrochloride of the present invention as a pellet core can reach the therapeutic concentration in a short time, and the onset is rapid, while the other three
  • the dabigatran etexilate mesylate pellet prepared by the pellet core cannot achieve this effect.

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Abstract

一种以半胱氨酸盐酸盐为主要成分的微丸，其包含半胱氨酸盐酸盐及其它药学上可接受的粘合剂、抗粘剂及任选的稀释剂，所制备的半胱氨酸盐酸盐微丸，对于溶解度随pH值升高而降低的药物来说，具有提高其溶出度等优点。

Description

一种含半胱氨酸盐酸盐的微丸及其制备方法 技术领域
本发明涉及一种以半胱氨酸盐酸盐作为主要成分的微丸，属于医药食品技术领域。
背景技术
半胱氨酸盐酸盐(英文名称为Cysteine Hydrochloride)，化学名为2-氨基-3-巯基丙酸盐酸盐，其分子式为C3H8NO2SCl，分子量为157.62，化学式如下所示：
Figure PCTCN2015076062-appb-000001
半胱氨酸盐酸盐为含硫基的氨基酸，具有抗氧化作用，在药剂中主要用作注射剂的抗氧剂。由于本品属于两性氨基酸，既可与酸性药物成盐，也可与碱性药物成盐，可作助溶剂和前体药物载体剂。在食品工业中除作抗氧剂外，还用作香料、面包发酵促进剂等。对一些溶解度随pH升高而降低的药物，半胱氨酸盐酸盐可以与这些药物组合成制剂，促进其溶解释放，使其发挥最大的药效。对于某些低pH值化学稳定的药物，可保证其质量的稳定性。目前，将半胱氨酸盐酸盐制成载药丸心，并作为基丸，在国内外尚未有文献报道，也无该产品问世。
发明内容
本发明的目的在于提供一种以半胱氨酸盐酸盐作为主要成分的微丸。该微丸不仅容易成型，且能充分发挥半胱氨酸盐酸盐原有的性质；对于溶解度随pH值升高而降低的药物来说，能提高其溶出度。同时，还能减轻半胱氨酸盐酸盐粉尘对接触人员的刺激，并确保半胱氨酸盐酸盐微丸的使用效果。
本发明所述的一种以半胱氨酸盐酸盐为主要成分的微丸，其包含半胱氨酸盐酸盐及其它药学上可接受的粘合剂、抗粘剂及任选的稀释剂。本发明微丸的主要成分半胱氨酸盐酸盐为半胱氨酸盐酸盐无水物、半胱氨酸盐酸盐水合物或药学上可接受的溶剂化物。
本发明所述的粘合剂为聚维酮、聚丙烯酸树脂、纤维素类中的一种或其任意两种的混合物。
本发明所述的抗粘剂为滑石粉、硬脂酸镁、微粉硅胶中的一种或其任意两种及以上的混合物。
本发明所述的稀释剂为微晶纤维素、淀粉、甘露醇、山梨醇中的一种或其任意两种及以上的混合物。
一种以半胱氨酸盐酸盐作为主要成分的微丸的制备方法，包括如下步骤：
(1)混悬液的制备：将粘合剂溶于无水乙醇中，再分别加入半胱氨酸盐酸盐与抗粘剂，分散均匀，过100目筛网，即得；
(2)母核的制备：利用湿法制粒机将步骤(1)制得的部分浆液与适量半胱氨酸盐酸盐、稀释剂或半胱氨酸盐酸盐与稀释剂的混合物混合，经湿法制粒，制得软材，将软材过16～80目筛网制得母核；
(3)将母核投入离心造粒包衣机中，调节转速使母核旋转，将剩余混悬液喷于母核上，干燥后即得半胱氨酸盐酸盐微丸。
上述制备方法制备得到的半胱氨酸盐酸盐微丸可通过制备不同粒径的母核或调节混悬液的用量来获得不同粒径的微丸。微丸粒径优选为0.2～1.2mm。
根据上述制备方法制成的半胱氨酸盐酸盐微丸的优点如下：
1、半胱氨酸盐酸盐具有抗氧化性，以半胱氨酸盐酸盐微丸作为药物载体可保护药物不易被氧化。
2、半胱氨酸盐酸盐酸性较强，对于溶解度随pH值升高而降低的药物来说，本发明的半胱氨酸盐酸盐微丸可提高这些药物的溶解度，进而提高其溶出度。
3、本发明的半胱氨酸盐酸盐微丸采用乙醇为混悬液溶剂，易于挥发，可制备低水分微丸，进而对于某些对水分敏感的药物亦可制备成微丸制剂。
4、本发明的半胱氨酸盐酸盐微丸能减轻半胱氨酸盐酸盐粉尘对接触人员的刺激，并确保半胱氨酸盐酸盐微丸的使用效果。
5、对于某些低pH值化学稳定的药物，本发明的半胱氨酸盐酸盐微丸可保证其质量的稳定性。
具体实施方式
通过下述实施例将有助于进一步理解本发明，但是不用于限制本发明。除非另有说明，所述的百分比通常为重量％。
采集数据所用的仪器及方法：
高效液相分析(HPLC)数据采自于Agilent 1260。采用C18色谱柱，2.7μm×150mm×4.6mm，柱温40℃，波长225nm，流速1.0mL/min，进样量10μL。
缓冲液：1.5g磷酸氢二钠溶于900mL水中，用磷酸调节pH值至3.1±0.1，再定容至1000mL；
流动相A：缓冲溶液-甲醇-乙腈＝75:20:5；
流动相B：缓冲溶液-甲醇-乙腈(15:60:25)；
梯度如下表：
时间(min) A(％) B(％)
0 75 25
1.6 75 25
3 65 35
6 55 45
11 20 80
11.02 75 25
16 75 25
除非特殊注明，实施例均在室温下操作。
实施例中所用的各种试剂或原料如无特别说明均为市售购买。微晶纤维素微丸、淀粉微丸、蔗糖微丸的粒径为600～800μm。
实施例1
处方组成：
物料名称 质量(g) 组成百分比(％)
半胱氨酸盐酸盐(母核) 370 61.7
半胱氨酸盐酸盐(混悬液) 200 33.3
聚维酮 25 41.7
滑石粉 5 8.3
合计 600 100％
制备方法：
(1)混悬液的制备：将粘合剂聚维酮溶于无水乙醇中，再分别加入半胱氨酸盐酸盐与滑石粉，分散均匀，过100目筛网，即得；
(2)母核的制备：利用湿法制粒机将步骤(1)制得的混悬液量的15％与适量半胱氨酸盐酸盐混合，经湿法制粒，制得软材，将上软材过30目筛网制得 母核；
(3)将母核投入离心造粒包衣机中，调节转速使母核旋转，将剩余混悬液喷于母核上，干燥后即得粒径为600～800μm、半胱氨酸盐酸盐质量分数为95％的成品微丸。
实施例2
处方组成：
物料名称 质量(g) 组成百分比(％)
甘露醇 323 53.8
半胱氨酸盐酸盐(混悬液) 240 40.0
聚丙烯酸树脂 30 5.0
滑石粉 7 1.2
合计 600 100％
制备方法：
(1)混悬液的制备：将粘合剂聚丙烯酸树脂溶于无水乙醇中，再分别加入半胱氨酸盐酸盐、滑石粉，分散均匀，过100目筛网，即得；
(2)母核的制备：利用湿法制粒机将步骤(1)制得的混悬液量的18％与甘露醇混合，经湿法制粒，制得软材，将软材过80目筛网制得母核；
(3)将母核投入离心造粒包衣机中，调节转速使母核旋转，将剩余混悬液喷于母核上，干燥后即得粒径为200～400μm、半胱氨酸盐酸盐质量分数为40％的成品微丸。
实施例3
处方组成：
物料名称 质量(g) 组成百分比(％)
半胱氨酸盐酸盐(母核) 150 25
微晶纤维素 104 17.3
半胱氨酸盐酸盐(混悬液) 300 50
聚丙烯酸树脂 37 6.2
微粉硅胶 9 1.5
合计 600 100
制备方法：
(1)混悬液的制备：将粘合剂聚丙烯酸树脂溶于无水乙醇中，再分别加入半胱氨酸盐酸盐与微粉硅胶，分散均匀，过100目筛网，即得；
(2)母核的制备：利用湿法制粒机将步骤(1)制得的混悬液量的20％与半胱氨酸盐酸盐和微晶纤维素混合，经湿法制粒，制得软材，将软材过16目筛网制母核；
(3)将母核投入离心造粒包衣机中，调节转速使母核旋转，将剩余混悬液喷于母核上，干燥后即得粒径为1000～1200μm、半胱氨酸盐酸盐质量分数为75％的成品微丸。
实施例4
处方组成：
物料名称 质量(g) 组成百分比(％)
半胱氨酸盐酸盐(母核) 150 25
淀粉 104 17.3
半胱氨酸盐酸盐(混悬液) 300 50
聚维酮 18 3.0
聚丙烯酸树脂 18 3.0
硬脂酸镁 10 1.7
合计 600 100
制备方法：
(1)混悬液的制备：将粘合剂聚丙烯酸树脂与聚维酮溶于无水乙醇中，再分别加入半胱氨酸盐酸盐与硬脂酸镁，分散均匀，过100目筛网，即得；
(2)母核的制备：利用湿法制粒机将步骤(1)制得的混悬液量的13％与适量半胱氨酸盐酸盐和淀粉混合，经湿法制粒，制得软材，将软材过30目筛网制得母核；
(3)将母核投入离心造粒包衣机中，调节转速使母核旋转，将剩余混悬液喷于母核上，干燥后即得粒径为600～800μm、半胱氨酸盐酸盐质量分数为75％的成品微丸。
实施例5
处方组成：
物料名称 质量(g) 组成百分比(％)
半胱氨酸盐酸盐(母核) 370 61.7
半胱氨酸盐酸盐(混悬液) 200 33.3
乙基纤维素 25 41.7
滑石粉 5 8.3
合计 600 100％
制备方法：
(1)混悬液的制备：将粘合剂乙基纤维素溶于无水乙醇中，再分别加入半胱氨酸盐酸盐与滑石粉，分散均匀，过100目筛网，即得；
(2)母核的制备：利用湿法制粒机将步骤(1)制得的浆液量的15％与适量半胱氨酸盐酸盐混合，经湿法制粒，制得软材，将上软材过30目筛网制得母核；
(3)将母核投入离心造粒包衣机中，调节转速使母核旋转，将剩余混悬液喷于母核上，干燥后即得粒径为600～800μm、半胱氨酸盐酸盐质量分数为95％的成品微丸。
对比例1
达比加群酯甲磺酸盐为pH依赖性药物，其溶解度随pH的增大而降低，故将本发明制备的半胱氨酸盐酸盐微丸(实施例1)与市售常见的微晶纤维素微丸、淀粉微丸及蔗糖微丸作为丸芯，外层喷达比加群酯甲磺酸盐活性物质层(活性物质层制备方法参考专利文献CN100528157C)，干燥后获得达比加群酯甲磺酸盐微丸，对比这四种不同丸芯制备得到的达比加群酯甲磺酸盐微丸在水中的溶出度，结果见表1。
实验方法如下：分别取以本发明实施例1制备的半胱氨酸盐酸盐微丸、市售微晶纤维素微丸、市售淀粉微丸与市售蔗糖微丸为丸芯制备的达比加群酯微丸各6份(每份含达比加群酯150mg)，至溶出仪下，按100rpm、篮法、介质水900ml溶出方法进行检查，按0、5、10、15、30min取样点进行取样，每次取10ml，0.45μm的聚醚砜滤膜滤过4.0ml，取续滤液，至高效液相色谱下分析，结果见表1。
表1介质水中的溶出值结果对比
Figure PCTCN2015076062-appb-000002
从表1结果可知，采用本发明半胱氨酸盐酸盐微丸为丸芯制备的达比加群酯甲磺酸盐微丸溶出度均快于其它三种丸芯的达比加群酯甲磺酸盐微丸，且15min内即可达到95％以上，表明主药完全溶出，而其它三种丸芯制备的达比加群酯甲磺酸盐微丸均不能完全溶出。考虑体内体外的相关性，以本发明半胱氨酸盐酸盐为丸芯制备的达比加群酯甲磺酸盐微丸在较短时间即可达到治疗浓度，起效迅速，而其它三种丸芯制备的达比加群酯甲磺酸盐微丸不能达到此效果。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。

Claims (6)

  1. 一种以半胱氨酸盐酸盐为主要成分的微丸，其特征在于，所述微丸包含半胱氨酸盐酸盐及其它药学上可接受的粘合剂、抗粘剂及任选的稀释剂。
  2. 根据权利要求1所述的微丸，其特征在于，所述主要成分半胱氨酸盐酸盐为半胱氨酸盐酸盐无水物、半胱氨酸盐酸盐水合物或药学上可接受的溶剂化物。
  3. 根据权利要求1～2中任一项所述的微丸，其特征在于，所述粘合剂为聚维酮、聚丙烯酸树脂、纤维素类中的一种或其任意两种及以上的混合物。
  4. 根据权利要求1～2中任一项所述的微丸，其特征在于，所述抗粘剂为滑石粉、硬脂酸镁、微粉硅胶中的一种或其任意两种及以上的混合物。
  5. 根据权利要求1～2中任一项所述的微丸，其特征在于，所述稀释剂为微晶纤维素、淀粉、甘露醇、山梨醇中的一种或其任意两种及以上的混合物。
  6. 根据权利要求1～5中任一项所述的微丸，其制备方法包括如下步骤：
    (1)混悬液的制备：将粘合剂溶于无水乙醇中，再分别加入半胱氨酸盐酸盐与抗粘剂，分散均匀，过100目筛网，即得；
    (2)母核的制备：利用湿法制粒机将步骤(1)制得的部分浆液与适量半胱氨酸盐酸盐、稀释剂或半胱氨酸盐酸盐与稀释剂的混合物混合，经湿法制粒，制得软材，将软材过16～80目筛网制得母核；
    (3)将母核投入离心造粒包衣机中，调节转速使母核旋转，将剩余混悬液喷于母核上，干燥后即得半胱氨酸盐酸盐微丸。
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