WO2020258472A1 - 一种单硝酸异山梨酯缓释片剂及其制备方法 - Google Patents

一种单硝酸异山梨酯缓释片剂及其制备方法 Download PDF

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WO2020258472A1
WO2020258472A1 PCT/CN2019/101622 CN2019101622W WO2020258472A1 WO 2020258472 A1 WO2020258472 A1 WO 2020258472A1 CN 2019101622 W CN2019101622 W CN 2019101622W WO 2020258472 A1 WO2020258472 A1 WO 2020258472A1
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isosorbide mononitrate
sustained
add
corrosive
lubricant
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PCT/CN2019/101622
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English (en)
French (fr)
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秦超
张伟明
陶安进
袁建成
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深圳翰宇药业股份有限公司
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/2009—Inorganic 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the field of medicaments, in particular to an isosorbide mononitrate sustained-release tablet and a preparation method thereof.
  • Isosorbide mononitrate also known as 5-isosorbide mononitrate
  • 5-isosorbide mononitrate is a long-acting nitrate anti-angina and coronary heart disease treatment drug. Its main pharmacological effect is to relax vascular smooth muscle, expand arteries and veins, and expand venous vessels. The role of the main. Isosorbide mononitrate is the main active metabolite in the body of isosorbide dinitrate. Oral absorption is rapid and complete, and there is no liver first-pass metabolism effect. This reduces the difference in blood drug concentration within and between individuals, making the clinical effects of the drug predictable And reproduce. The elimination half-life of isosorbide mononitrate is about 5 hours. It can be used for long-term treatment of coronary heart disease, prevention of angina pectoris, treatment of persistent angina pectoris after myocardial infarction, etc. It is currently one of the best drugs for the prevention and treatment of angina pectoris.
  • the clinical dosage forms of isosorbide mononitrate include ordinary tablets, sustained-release preparations and injections.
  • Ordinary isosorbide mononitrate tablets or capsule preparations due to frequent administration (2 to 3 times a day) and large fluctuations in blood concentration, when the body's blood concentration drops to the lowest level in the middle of the night or early morning, it is easy to Angina pectoris occurs, and frequent administration is prone to drug resistance.
  • sustained-release isosorbide mononitrate preparations are administered once a day during the medication period, the number of medications is reduced, and there is basically no occurrence of drug resistance; at the same time, the sustained-release isosorbide mononitrate preparations have a unique drug release system that conforms to The circadian rhythm of cardiovascular events not only takes effect quickly but also provides long-term protection, which greatly reduces the probability of patients with nocturnal angina and improves patient compliance. For chronic diseases such as coronary heart disease and angina pectoris that require long-term medication, safe and effective isosorbide mononitrate sustained-release tablets are a better medication choice.
  • Isosorbide mononitrate belongs to Class I in the BCS classification, and belongs to high solubility and high permeability drugs. There will be various problems in the process of developing isosorbide mononitrate sustained-release preparations, and the development is relatively difficult.
  • the original reference formulation uses microcrystalline wax as a sustained-release material to prepare matrix tablets, and the tablet core contains microcrystalline wax, magnesium stearate, talc, sodium aluminum silicate and other auxiliary materials.
  • auxiliary materials such as microcrystalline wax and sodium aluminum silicate are rare in the market, which limits their application.
  • One aspect of the present invention provides an isosorbide mononitrate sustained-release tablet, the tablet comprising isosorbide mononitrate, a corrosive matrix material, a binder, a lubricant, and talc; wherein,
  • the corrosive framework material is selected from one or more combinations of carnauba wax, microcrystalline wax, hydrogenated vegetable oil, paraffin wax, stearic acid, stearyl alcohol, and glyceryl behenate ;
  • hydrogenated vegetable oils include hydrogenated castor oil, hydrogenated coconut oil, hydrogenated palm oil, hydrogenated jojoba oil.
  • the binder is selected from hydroxypropyl cellulose (HPC), hypromellose (HPMC), sodium hydroxymethyl cellulose (CMC-Na), ethyl cellulose, povidone , Gelatin, polyethylene glycol, sodium alginate solvent, starch slurry, polyvinyl alcohol or a combination of one or more.
  • the lubricant is selected from magnesium stearate, stearic acid, sodium stearyl fumarate, and polyethylene glycol.
  • the ratio of the corrosive framework material to the talc is 1:0.08-1:0.3.
  • the isosorbide mononitrate sustained-release tablet is prepared by the following steps:
  • Another aspect of the present invention provides a preparation method of isosorbide mononitrate sustained-release tablets, which comprises the following steps:
  • the present invention unexpectedly finds that talc powder can eliminate the softening problem of waxy materials during tableting.
  • the method of adding talc powder reduces the softening problem of waxy matrix tablets, and the prepared tablets have high hardness and good appearance.
  • the release effect is equivalent to RLD.
  • Dosage ratio (%) Isosorbide mononitrate 60 18.6 Hydrogenated vegetable oil 200 61.9 HPC 30 9.3 talcum powder 30 9.3 Magnesium stearate 3 0.9 total 323 100.0
  • the treatment method is the same as in Example 1.
  • Dosage ratio (%) Isosorbide mononitrate 60 18.6 paraffin 200 61.9 HPC 30 9.3 talcum powder 30 9.3 Magnesium stearate 3 0.9 total 323 100.0
  • the treatment method is the same as in Example 1.
  • the treatment method is the same as in Example 1.
  • Dosage ratio (%) Isosorbide mononitrate 60 18.6 Stearyl alcohol 200 61.9 HPC 30 9.3 talcum powder 30 9.3 Magnesium stearate 3 0.9 total 323 100.0
  • the treatment method is the same as in Example 1.
  • Dosage ratio (%) Isosorbide mononitrate 60 18.6 Hydrogenated castor oil 200 61.9 HPC 30 9.3 talcum powder 30 9.3 Magnesium stearate 3 0.9 total 323 100.0
  • the treatment method is the same as in Example 1.
  • the treatment method is the same as in Example 1.
  • Dosage ratio (%) Isosorbide mononitrate 60 18.6 Carnauba wax 110 34.1 Stearyl alcohol 90 27.9 HPC 30 9.3 talcum powder 30 9.3 Magnesium stearate 3 0.9 total 323 100
  • the treatment method is the same as in Example 1.
  • Dosage ratio (%) Isosorbide mononitrate 60 18.6 Carnauba wax 90 27.9 Stearyl alcohol 110 34.1 HPC 30 9.3 talcum powder 30 9.3 Magnesium stearate 3 0.9 total 323 100.0
  • the treatment method is the same as in Example 1.
  • Dosage ratio (%) Isosorbide mononitrate 60 18.6 Carnauba wax 180 55.7 HPC 30 9.3 talcum powder 50 15.5 Magnesium stearate 3 0.9
  • the treatment method is the same as in Example 1.
  • Dosage ratio (%) Isosorbide mononitrate 60 18.6 Carnauba wax 210 65.0 HPC 30 9.3 talcum powder 20 6.2 Magnesium stearate 3 0.9 total 323 100.0
  • the treatment method is the same as in Example 1.
  • Dosage ratio (%) Isosorbide mononitrate 60 18.6 Carnauba wax 230 65.0 HPC 30 9.3 Magnesium stearate 3 0.9 total 323 100.0

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Abstract

一种单硝酸异山梨酯缓释片剂及其制备方法，所述片剂由单硝酸异山梨酯、溶蚀性骨架材料、粘合剂、润滑剂以及滑石粉制成，各组分的质量份数：单硝酸异山梨酯15-20、溶蚀性骨架材料60-65、粘合剂8-11、润滑剂0.5-1.5、滑石粉5-20。通过加入滑石粉，减轻蜡质骨架片的软化问题，制得的片硬度高，外观好，释放效果与RLD相当。

Description

一种单硝酸异山梨酯缓释片剂及其制备方法 技术领域
本发明涉及药剂领域，具体涉及一种单硝酸异山梨酯缓释片剂及其制备方法。
背景技术
单硝酸异山梨酯，又称5-单硝酸异山梨酯，为长效硝酸酯类抗心绞痛和冠心病治疗药物，主要的药理作用是舒张血管平滑肌，扩张动脉和静脉血管，并以扩张静脉血管的作用为主。单硝酸异山梨酯是硝酸异山梨酯体内主要活性代谢产物，口服吸收迅速完全，无肝脏首过代谢效应，这就减少了个体内和个体间的血药浓度的差异，使得药物临床作用可以预见和重现。单硝酸异山梨酯的消除半衰期约为5小时，可用于冠心病的长期治疗、心绞痛的预防、心肌梗死后持续心绞痛的治疗等，是目前防治心绞痛最好的药物之一。
目前，单硝酸异山梨酯临床使用剂型有普通片剂、缓释制剂和注射剂。普通单硝酸异山梨酯片剂或胶囊制剂，由于给药次数频繁(需日服2～3次)、血药浓度波动较大，在深夜或凌晨时机体血药浓度降至最低水平时，易发生心绞痛，且频繁给药易产生耐药性。而单硝酸异山梨酯缓释制剂在服药期间，每日给药一次，减小了服药次数，基本无耐药性的发生；同时单硝酸异山梨酯缓释制剂具有的独特药物释放系统，符合心血管事件发生的昼夜节律，不仅快速起效且能长效保护，从而大大降低了患者夜间心绞痛的发生概率，提高了患者依从性。对于需要长期用药的冠心病和心绞痛这类慢性疾病，安全有效的单硝酸异山梨酯缓释片是较好的用药选择。
单硝酸异山梨酯属于BCS分类中的I类，属于高溶解性和高渗透性药物，在开发单硝酸异山梨酯缓释制剂的过程中会存在各种问题，开发难度比较大。
原研参比制剂以微晶蜡作为缓释材料制备骨架片，片芯包含微晶蜡、硬脂酸镁、滑石粉、硅酸铝钠等多种辅料。但微晶蜡和硅酸铝钠等辅料在市场上都少见，限制了其应用。
除原研参比制剂外，其余厂家以氢化植物油、山嵛酸甘油酯、巴西棕榈蜡等其它蜡质缓释材料制备骨架片。但经过试验发现，蜡质类材料因为熔点低，在压片过程中容易发生软化的问题。压片时若转速稍高，产热量大，更易发生该问题。
发明内容
本发明一个方面提供了一种单硝酸异山梨酯缓释片剂，所述片剂包括单硝酸异山梨酯、溶蚀性骨架材料、粘合剂、润滑剂以及滑石粉；其中，
类型 用量，质量份计
单硝酸异山梨酯 15-20
溶蚀性骨架材料 60-65
粘合剂 8-11
润滑剂 0.5-1.5
滑石粉 5-20
在本发明的技术方案中，溶蚀性骨架材料选自巴西棕榈蜡、微晶蜡、氢化植物油、石蜡、硬脂酸、十八醇、山嵛酸甘油酯中的一种或几种的组合物；其中氢化植物油包括氢化蓖麻油、氢化椰子油、氢化棕榈油、氢化霍霍巴油。
在本发明的技术方案中，粘合剂选自羟丙纤维素(HPC)、羟丙甲纤维素(HPMC)、羟甲基纤维素钠(CMC-Na)、乙基纤维素、聚维酮、明胶、聚乙二醇、海藻酸钠溶剂、淀粉浆、聚乙烯醇中的一种或多种的组合。
在本发明的技术方案中，润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、聚乙二醇。
在本发明的技术方案中，溶蚀性骨架材料与滑石粉的比例为1:0.08-1:0.3。
在本发明的技术方案中，单硝酸异山梨酯缓释片剂通过以下步骤制得：
1)称取处方量的单硝酸异山梨酯，粉碎过筛；
2)加入溶蚀性骨架材料、粘合剂、滑石粉，预混合，加入95％乙醇制粒，干燥，整粒；
3)加入润滑剂，混合，压片。
本发明另一方面提供了单硝酸异山梨酯缓释片剂的制备方法，其包括以下步骤：
1)称取处方量的单硝酸异山梨酯，粉碎过筛；
2)加入溶蚀性骨架材料、粘合剂、滑石粉，预混合，加入95％乙醇制粒，干燥，整粒；
3)加入润滑剂，混合，压片。
有益效果
本发明意外地发现滑石粉可以消除蜡质材料压片时的软化问题，通过加入滑石粉的方法，减轻蜡质骨架片的软化问题，制得的片硬度高，外观好。释放效果与RLD相当。
具体实施方式
实施例1。
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
巴西棕榈蜡 200 61.9
HPC 30 9.3
滑石粉 30 9.3
硬脂酸镁 3 0.9
合计 323 100.0
制备方法：
1、称取处方量的单硝酸异山梨酯，采用气流喷射筛网过筛；
2、加入巴西棕榈蜡、HPC、滑石粉，混合；
3、加入硬脂酸镁，混合，压片。
实施例2。
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
氢化植物油 200 61.9
HPC 30 9.3
滑石粉 30 9.3
硬脂酸镁 3 0.9
合计 323 100.0
处理方法同实施例1。
实施例3。
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
石蜡 200 61.9
HPC 30 9.3
滑石粉 30 9.3
硬脂酸镁 3 0.9
合计 323 100.0
处理方法同实施例1。
实施例4。
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
硬脂酸 200 61.9
HPC 30 9.3
滑石粉 30 9.3
硬脂酸镁 3 0.9
合计 323 100.0
处理方法同实施例1。
实施例5。
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
十八醇 200 61.9
HPC 30 9.3
滑石粉 30 9.3
硬脂酸镁 3 0.9
合计 323 100.0
处理方法同实施例1。
实施例6。
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
氢化蓖麻油 200 61.9
HPC 30 9.3
滑石粉 30 9.3
硬脂酸镁 3 0.9
合计 323 100.0
处理方法同实施例1。
实施例7。
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
巴西棕榈蜡 200 61.9
HPC 30 9.3
滑石粉 30 9.3
硬脂酸镁 3 0.9
合计 323 100.0
处理方法同实施例1。
实施例8。
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
巴西棕榈蜡 110 34.1
十八醇 90 27.9
HPC 30 9.3
滑石粉 30 9.3
硬脂酸镁 3 0.9
合计 323 100
处理方法同实施例1。
实施例9。
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
巴西棕榈蜡 90 27.9
十八醇 110 34.1
HPC 30 9.3
滑石粉 30 9.3
硬脂酸镁 3 0.9
合计 323 100.0
处理方法同实施例1。
实施例10
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
巴西棕榈蜡 180 55.7
HPC 30 9.3
滑石粉 50 15.5
硬脂酸镁 3 0.9
合计 323 100.0
处理方法同实施例1。
实施例11
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
巴西棕榈蜡 210 65.0
HPC 30 9.3
滑石粉 20 6.2
硬脂酸镁 3 0.9
合计 323 100.0
处理方法同实施例1。
对比实施例1
  用量(mg) 用量比例(％)
单硝酸异山梨酯 60 18.6
巴西棕榈蜡 230 65.0
HPC 30 9.3
硬脂酸镁 3 0.9
合计 323 100.0
制备方法：
1、称取处方量的单硝酸异山梨酯，采用气流喷射筛网过筛；
2、加入巴西棕榈蜡、HPC、混合；
3、加入硬脂酸镁，混合，压片。
各处方的片剂硬度检测见下表
  压片开始时 压片3h后
对比实施例1 80N 65N
实施例1 94N 88N
实施例2 96N 90N
实施例10 99N 91N
实施例11 91N 87N
各处方的片剂加速1个月后硬度检测见下表
Figure PCTCN2019101622-appb-000001
各处方的片剂溶出度检测见下表
Figure PCTCN2019101622-appb-000002
通过实验结果可知，通过添加滑石粉可以大幅提高压片过程中和保存过程中片剂的硬度，且得到的样品的溶出度和原研药厂溶出度比较，拟合度高。

Claims (7)

  1. 一种单硝酸异山梨酯缓释片剂，所述片剂由单硝酸异山梨酯、溶蚀性骨架材料、粘合剂、润滑剂以及滑石粉制成；其中，
    类型 质量份数 单硝酸异山梨酯 15-20 溶蚀性骨架材料 60-65 粘合剂 8-11 润滑剂 0.5-1.5 滑石粉 5-20
    。
  2. 根据权利要求1所述的单硝酸异山梨酯缓释片剂，溶蚀性骨架材料选自巴西棕榈蜡、微晶蜡、氢化植物油、石蜡、硬脂酸、十八醇、山嵛酸甘油酯中的一种或几种的组合物；其中氢化植物油包括氢化蓖麻油、氢化椰子油、氢化棕榈油、氢化霍霍巴油。
  3. 根据权利要求1或2所述的单硝酸异山梨酯缓释片剂，粘合剂选自羟丙纤维素(HPC)、羟丙甲纤维素(HPMC)、羟甲基纤维素钠(CMC-Na)、乙基纤维素、聚维酮、明胶、聚乙二醇、海藻酸钠溶剂、淀粉浆、聚乙烯醇中的一种或多种的组合。
  4. 根据权利要求1-3任一项所述的单硝酸异山梨酯缓释片剂，润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、聚乙二醇。
  5. 根据权利要求1-4任一项所述的单硝酸异山梨酯缓释片剂，溶蚀性骨架材料与滑石粉的比例为1:0.08-1:0.3。
  6. 根据权利要求1-5任一项所述的单硝酸异山梨酯缓释片剂，其通过以下步骤制得：
    1)称取处方量的单硝酸异山梨酯，粉碎过筛；
    2)加入溶蚀性骨架材料、粘合剂、滑石粉，预混合，加入95％乙醇制粒，干燥，整粒；
    3)加入润滑剂，混合，压片。
  7. 据权利要求1-6任一项所述的单硝酸异山梨酯缓释片剂的制备方法，其包括以下步骤：
    1)称取处方量的单硝酸异山梨酯，粉碎过筛；
    2)加入溶蚀性骨架材料、粘合剂、滑石粉，预混合，加入95％乙醇制粒，干燥，整粒；
    3)加入润滑剂，混合，压片。
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