WO2022228324A1 - 13c美沙西汀颗粒剂及其制备方法和应用 - Google Patents

13c美沙西汀颗粒剂及其制备方法和应用 Download PDF

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WO2022228324A1
WO2022228324A1 PCT/CN2022/088678 CN2022088678W WO2022228324A1 WO 2022228324 A1 WO2022228324 A1 WO 2022228324A1 CN 2022088678 W CN2022088678 W CN 2022088678W WO 2022228324 A1 WO2022228324 A1 WO 2022228324A1
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liver
methacetin
granules
assessment
evaluation
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PCT/CN2022/088678
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English (en)
French (fr)
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龚爱华
白玉杰
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北京华亘安邦科技有限公司
江苏华亘泰来生物科技有限公司
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Priority to EP22794795.9A priority Critical patent/EP4327805A1/en
Priority to US18/288,937 priority patent/US20240207453A1/en
Publication of WO2022228324A1 publication Critical patent/WO2022228324A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—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
    • A61K9/14—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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to 13C methacetin granules and a preparation method and application thereof.
  • the liver is an important metabolic organ in the human body. Although there are many indicators of liver function tests currently used in clinical practice, there are few tests that can quantitatively reflect the liver reserve and compensatory ability in the early stage of liver cirrhosis.
  • the 13C methacetin breath test is a new method for detecting liver reserve function recently. It is found through experiments that the 13C methacetin breath test value can distinguish between cirrhosis and non-cirrhosis, and has a very high clinical value. .
  • 13C methacetin the chemical name is p-acetamidoanisole (methoxy-13C), and its structural formula is shown in formula I:
  • the present invention provides 13C methacetin granules and a preparation method and application thereof.
  • the 13C methacetin granules of the present invention have good stability and uniform particle size, and are favorable for storage and production of subsequent preparations.
  • the preparation method of 13C methacetin granules of the present invention has the advantages of simple operation, good repeatability and high yield.
  • the present invention provides 13C methacetin granules, comprising 13C methacetin, mannitol, a cosolvent and a wetting agent;
  • the cosolvent includes Tween 80, beta cyclodextrin, sodium hydroxide, sodium citrate, phosphoric acid
  • the wetting agent includes water or ethanol.
  • One or both of the aqueous solutions are provided.
  • the weight ratio of the 13C methacetin to the cosolvent is 1:(0.1-100).
  • the weight ratio of the mixture of 13C methacetin, mannitol and the cosolvent to the wetting agent is 100:(1-100).
  • the weight ratio of the mixture of 13C methacetin and the cosolvent to the wetting agent is 100: (1-20);
  • the The wetting agent is an aqueous solution of ethanol, and the volume ratio of ethanol to water in the aqueous solution of ethanol is 1:5-5:1.
  • the weight ratio of the 13C methacetin to the mannitol is 1:(20-60).
  • the present invention also provides a method for preparing the 13C methoxetine granules.
  • the 13C methacetin is pulverized and mixed with mannitol and a cosolvent to obtain a mixture.
  • the mixture is mixed with a wetting agent and then granulated and dried. , to obtain 13C methoxetine granules.
  • the drying temperature is 30-100° C.
  • the drying time is 1-8 h.
  • the drying temperature is 45° C.
  • the drying time is 3 h.
  • the present invention also provides medicines and reagents for the preparation of the 13C methacetin granules or the 13C methacetin granules prepared by the described preparation method for disease diagnosis, liver reserve function evaluation, and liver operation evaluation before and after surgery or application in the kit.
  • the present invention also provides a method for diagnosing a disease, a method for assessing liver reserve function, or a method for assessing before and after liver surgery, using the 13C methacetin granules or the 13C methacetin granules prepared by the preparation method.
  • the diseases include cirrhosis, primary biliary cirrhosis, simple steatosis, stages of chronic liver disease, alcoholic liver disease, degree or stage of liver fibrosis, non-alcoholic fatty liver disease, neonatal cholestasis, biliary atresia, intrahepatic inflammation , one or more of acute liver failure, hepatocellular carcinoma;
  • the evaluation of liver reserve function includes evaluation of liver function in related diseases, evaluation of liver injury from chemotherapy, prediction of death from chronic liver failure, and evaluation of liver detoxification ability.
  • the pre- and post-operative assessment includes one or more of the assessment of regeneration after liver resection, the assessment of the urgency of liver transplantation, the assessment of postoperative liver failure, and the assessment of related pre- and post-operative procedures.
  • the disease includes, but is not limited to, cirrhosis, primary biliary cirrhosis, simple steatosis, staging of chronic liver disease, alcoholic liver disease, degree or stage of liver fibrosis, non-alcoholic fat One or more of liver, neonatal cholestasis, biliary atresia, intrahepatic inflammation, acute liver failure, hepatocellular carcinoma;
  • liver reserve function includes, but is not limited to, one or more of evaluation of liver function in related diseases, evaluation of liver injury from chemotherapy, prediction of death from chronic liver failure, and evaluation of liver detoxification ability;
  • the pre- and post-operative assessment includes, but is not limited to, one or more of the assessment of regeneration after liver resection, the assessment of the urgency of liver transplantation, the assessment of postoperative liver failure, and related pre- and post-operative assessment.
  • the beneficial effects of the present invention include but are not limited to:
  • 13C methacetin granules of the present invention have good stability, which is conducive to storage and the production of subsequent preparations, etc.;
  • the 13C methacetin granules of the present invention have good water solubility, can be quickly dissolved in water during clinical use, and are convenient to take.
  • the 13C methacetin granules of the present invention can be used in the preparation of medicines, reagents or kits for disease diagnosis, liver reserve function assessment, and pre- and post-operative assessment of liver operations, and have good stability.
  • the diseases described in the present invention include liver cirrhosis, primary biliary cirrhosis, simple steatosis, stages of chronic liver disease, alcoholic liver disease, degree or stage of liver fibrosis, non-alcoholic fatty liver disease, neonatal cholestasis, biliary atresia, One or more of intrahepatic inflammation, acute liver failure, hepatocellular carcinoma.
  • the evaluation of liver reserve function in the present invention includes one or more of evaluation of liver function in related diseases, evaluation of liver injury from chemotherapy, prediction of death from chronic liver failure, and evaluation of liver detoxification ability.
  • the pre-operative and post-operative assessments of the present invention include one or more of the assessment of regeneration after liver resection, the assessment of the urgency of liver transplantation, the assessment of postoperative liver failure, and the assessment of related pre- and post-operative assessments.
  • Fig. 1 shows the HPLC spectrogram of the 13C methacetin granules prepared in Example 1;
  • Fig. 2 shows the HPLC spectrogram of the 13C methacetin granules prepared in Example 2;
  • Fig. 3 shows the HPLC spectrogram of the 13C methacetin granules obtained in Example 3;
  • Fig. 4 shows the HPLC spectrogram of the 13C methacetin granules obtained in Example 4;
  • Fig. 5 shows the HPLC spectrogram of the 13C methacetin granules prepared in Example 5;
  • Fig. 6 shows the HPLC spectrogram of the 13C methacetin granules obtained in Example 6;
  • Figure 7 shows the comparison results of the water solubility and stability of the 13C methacetin granules provided by the present invention, powders and other granules.
  • the present invention discloses 13C methoxetine granules, a preparation method and application thereof, and those skilled in the art can learn from the content of this paper and appropriately improve process parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention.
  • the method and application of the present invention have been described through preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the methods and applications described herein without departing from the content, spirit and scope of the present invention. Apply the technology of the present invention.
  • the first object of the present invention is to provide 13C methacetin granules.
  • the second object of the present invention is to provide a preparation method of 13C methacetin granules, which is easy to operate and has a high yield.
  • the third object of the present invention is to provide the application of 13C methacetin granules in the preparation of medicines, reagents or kits for disease diagnosis, liver reserve function assessment, and liver surgery pre- and post-operative assessment.
  • the diseases described in the present invention include liver cirrhosis, primary biliary cirrhosis, simple steatosis, stages of chronic liver disease, alcoholic liver disease, degree or stage of liver fibrosis, non-alcoholic fatty liver disease, neonatal cholestasis, biliary atresia, One or more of intrahepatic inflammation, acute liver failure, hepatocellular carcinoma;
  • the evaluation of liver reserve function in the present invention includes one or more of evaluation of liver function in related diseases, evaluation of liver injury from chemotherapy, prediction of death from chronic liver failure, and evaluation of liver detoxification ability;
  • the pre-operative and post-operative assessments of the present invention include one or more of the assessment of regeneration after liver resection, the assessment of the urgency of liver transplantation, the assessment of postoperative liver failure, and the assessment of related pre- and post-operative assessments.
  • the cosolvent is selected from Tween 80, ⁇ -cyclodextrin, sodium hydroxide, sodium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, polyethylene glycol 6000, polyethylene glycol 4000, polyethylene glycol One or both of alcohol 2000 and polyethylene glycol 1500, the wetting agent is an ethanol aqueous solution, and the volume ratio is 1:5-5:1.
  • the combination of the co-solvent includes polyethylene glycol 4000, or polyethylene glycol 4000 and sodium dihydrogen phosphate, or polyethylene glycol 4000 and disodium hydrogen phosphate.
  • the ratio of adding cosolvent is 1:0.1 ⁇ 100.
  • the ratio of the 13C methacetin mixed powder to the wetting agent is 100g:(1-100)mL, preferably 100g:(2-20)mL, more preferably 100g : (5 ⁇ 10)mL.
  • the water solubility of the 13C methacetin granules can be improved and the stability of the granules can be improved while ensuring that the 13C methacetin granules are fully dissolved, and at the same time, the amount of the cosolvent is added.
  • the present invention also provides a preparation method of the 13C methacetin granules, comprising the following steps:
  • Crushing of raw and auxiliary materials Use a powder machine to crush and sieve carbon[13C]-methacetin, mannitol and co-solvent respectively, and use a 65-mesh sieve for re-screening and checking.
  • Preparation of ethanol aqueous solution use pharmaceutical grade 95% ethanol and pure water to prepare.
  • the soft material is granulated in a rocking granulator, and the granules of uniform size are placed in a stainless steel container.
  • Drying process put the wet granules into a vacuum drying oven, dry at 45° C. for 3 hours, and sieve the dried granules to obtain the target granules.
  • Mixing and filling Mix the particles in the mixer until the particles are uniform, and complete the filling of the mixed particles.
  • the drying temperature is 30-100°C, preferably 45°C.
  • the drying method includes blast drying and vacuum drying, preferably vacuum drying.
  • the drying temperature can be adjusted and selected according to actual needs, and the drying time can be appropriately shortened or extended according to the type and content of the solvent.
  • the drying time is 1-8 hours.
  • the present invention also provides the application of the above-mentioned 13C methacetin granules in the preparation of medicines, reagents or kits for disease diagnosis, liver reserve function evaluation, and liver operation evaluation before and after surgery.
  • the diseases include cirrhosis, primary biliary cirrhosis, simple steatosis, stages of chronic liver disease, alcoholic liver disease, degree or stage of liver fibrosis, non-alcoholic fatty liver disease, neonatal cholestasis, biliary atresia, intrahepatic inflammation , one or more of acute liver failure, hepatocellular carcinoma;
  • the evaluation of liver reserve function includes one or more of evaluation of liver function in related diseases, evaluation of liver injury from chemotherapy, prediction of death from chronic liver failure, and evaluation of liver detoxification ability;
  • the pre- and post-operative assessment includes one or more of the assessment of regeneration after liver resection, the assessment of the urgency of liver transplantation, the assessment of postoperative liver failure, and the assessment of related pre- and post-operative procedures.
  • the present invention also provides a method for diagnosing a disease, a method for evaluating liver reserve function, or a method for evaluating before and after liver surgery, using the above-mentioned 13C methacetin granules or the 13C methoxetine granules prepared by the above-mentioned preparation method.
  • the diseases include cirrhosis, primary biliary cirrhosis, simple steatosis, stages of chronic liver disease, alcoholic liver disease, degree or stage of liver fibrosis, non-alcoholic fatty liver disease, neonatal cholestasis, biliary atresia, intrahepatic inflammation , one or more of acute liver failure, hepatocellular carcinoma;
  • the evaluation of liver reserve function includes evaluation of liver function in related diseases, evaluation of liver injury from chemotherapy, prediction of death from chronic liver failure, and evaluation of liver detoxification ability. or more;
  • the pre- and post-operative assessment includes one or more of the assessment of regeneration after liver resection, the assessment of the urgency of liver transplantation, the assessment of postoperative liver failure, and the assessment of related pre- and post-operative procedures.
  • the granules of the medicine include powdered granules, capsule granules and the like.
  • the raw materials and reagents used can be purchased from the market.
  • the present embodiment provides the preparation method of 13C methoxetine granules, and the steps are as follows:
  • the present embodiment provides the preparation method of 13C methoxetine granules, comprising the following steps:
  • This example provides a preparation method of 13C methacetin granules, including the following steps: weighing 1 g of 13C methacetin crude product, 60 grams of mannitol, 3 grams of polyethylene glycol 4000, and 1 gram of disodium hydrogen phosphate and crushed according to the steps , mixed, granulated, and dried; 62.5 g of 13C methacetin granules were obtained, the yield was 96.2%, the content was 100.1%, and the purity was 100%.
  • the present embodiment provides the preparation method of 13C methoxetine granules, comprising the following steps:
  • the present embodiment provides the preparation method of 13C methoxetine granules, comprising the following steps:
  • Experimental groups 1-6 13C methacetin granules prepared in Examples 1-6 of the present invention.
  • Control group 1 powder. The excipients and raw materials are weighed according to the prescription ratio, and the powder is prepared after mixing in a mixer for 3 hours.
  • Control group 2 other granules. 1 g of 13C methacetin crude product and 25 g of mannitol were weighed and crushed according to the steps, mixed, granulated and dried; 25.1 g of 13C methacetin granules were obtained, the yield was 96.5%, the content was 100.4%, and the purity was 99.9%.
  • the solubility of 13C methacetin in water is low, the dissolution rate is slow, and it takes a long time to stir 50mg to 100ml of water, which is inconvenient to take.
  • the powder is easy to agglomerate, and the degradation reaction occurs, which affects the quality of the product; the powder is a mixed powder, and the water solubility of the product is improved after adding auxiliary materials, but it cannot meet the requirements of clinical use, and the dissolution rate is also slow. There is agglomeration during the storage process.
  • Adding excipients helps to improve the stability of the product, and the degraded impurities are less than that of the raw drug powder; the developed granules have been formulated and developed through the preparation process, and the water solubility meets the clinical requirements, and there is no agglomeration during storage. , the degradation is effectively inhibited, and the impurities are very few, far below the standard limit.
  • the granules developed by comparison have better stability and water solubility, and have stable quality and high use value.

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Abstract

涉及药物制剂领域，特别涉及13C美沙西汀颗粒剂及其制备方法和应用。提供了13C美沙西汀颗粒剂，包括13C美沙西汀、甘露醇、助溶剂和润湿剂。所述的13C美沙西汀颗粒剂具有良好的稳定性，有利于储存和后续制剂的生产等；所述的13C美沙西汀颗粒剂水溶性好，在临床使用时能快速溶于水，便于服用。还提供了所述的13C美沙西汀颗粒剂在制备用于疾病的诊断、肝脏储备功能评估、肝脏手术前后评估的药物、试剂或试剂盒中的应用。提供的13C美沙西汀颗粒剂的制备方法，条件温和，操作简单，便于生产控制。

Description

13C美沙西汀颗粒剂及其制备方法和应用
本申请要求于2021年04月30日提交中国专利局、申请号为202110484540.1、发明名称为“13C美沙西汀颗粒剂及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物制剂领域，特别涉及13C美沙西汀颗粒剂及其制备方法和应用。
背景技术
肝脏是人体重要的代谢器官，目前用于临床的肝功能检查指标虽然很多，但能够在肝硬化早期定量反映肝脏储备和代偿能力的试验却较少。13C美沙西汀呼气试验是近来出现的一种检测肝储备功能的新方法，通过实验发现，13C美沙西汀呼气试验值能够区分肝硬化和非肝硬化，在临床中具有非常高的价值。
其中，13C美沙西汀，化学名为对乙酰氨基苯甲醚(甲氧基-13C)，其结构式如式Ⅰ所示：
Figure PCTCN2022088678-appb-000001
在药物制剂研究中越来越关注产品的剂型，因为药物不同剂型在药物稳定性、服用及吸收过程等方面可能会有不同程度的影响，13C美沙西汀为诊断用，需在体内快速吸收，所以本产品在服用时需尽快溶解在水中服用，为确保13C美沙西汀制剂产品的质量稳定性，以及服用和吸收过程中的安全性和有效性，研发具有优异溶解性和稳定性的13C美沙西汀剂 型具有重要意义。
发明内容
有鉴于此，本发明提供了13C美沙西汀颗粒剂及其制备方法和应用。本发明所述的13C美沙西汀颗粒剂相对于传统的13C美沙西汀，稳定性好，颗粒度均匀，有利于储存以及后续制剂的生产。本发明所述的13C美沙西汀颗粒剂的制备方法，操作简单，重复性好，收率高。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了13C美沙西汀颗粒剂，包括13C美沙西汀、甘露醇、助溶剂和润湿剂；所述助溶剂包括吐温80、β环糊精、氢氧化钠、柠檬酸钠、磷酸氢二钠、磷酸二氢钠、聚乙二醇6000、聚乙二醇4000、聚乙二醇2000、聚乙二醇1500中的一种或多种；所述润湿剂包括水或乙醇的水溶液中的一种或两种。
在本发明的一些具体实施方案中，所述13C美沙西汀与所述助溶剂的重量比为1:(0.1～100)。
在本发明的一些具体实施方案中，以g/mL计，所述13C美沙西汀、甘露醇和所述助溶剂的混合物，与所述润湿剂的重量比为100：(1～100)。
在本发明的一些具体实施方案中，以g/mL计，所述13C美沙西汀和所述助溶剂的混合物，与所述润湿剂的重量比为100：(1～20)；所述润湿剂为乙醇的水溶液，所述乙醇的水溶液中乙醇和水的体积比为1﹕5～5﹕1。
在本发明的一些具体实施方案中，所述13C美沙西汀与所述甘露醇的重量比为1：(20～60)。
本发明还提供了所述的13C美沙西汀颗粒剂的制备方法，取13C美沙西汀粉碎后与甘露醇、助溶剂混合制得混合物，将所述混合物与润湿剂混合后制粒、干燥，制得13C美沙西汀颗粒剂。
在本发明的一些具体实施方案中，所述干燥的温度为30～100℃，所述干燥的时间为1～8h。
在本发明的一些具体实施方案中，所述干燥的温度为45℃，所述干燥的时间为3h。
本发明还提供了所述的13C美沙西汀颗粒剂或所述的制备方法制得的13C美沙西汀颗粒剂在制备用于疾病的诊断、肝脏储备功能评估、肝脏手术前后评估的药物、试剂或试剂盒中的应用。
本发明还提供了疾病的诊断方法、肝脏储备功能评估方法或肝脏手术前后评估方法，施用所述的13C美沙西汀颗粒剂或所述的制备方法制得的13C美沙西汀颗粒剂。所述疾病包括肝硬化、原发胆汁性肝硬化、单纯脂肪变性、慢性肝病分期、酒精性肝病、肝纤维化的程度或分期、非酒精脂肪肝、新生儿胆汁淤积、胆道闭锁、肝内炎症、急性肝衰竭、肝细胞癌中的一种或多种；所述肝脏储备功能评估包括相关疾病肝脏功能评价、化疗肝损伤的评估、预测慢性肝衰死亡、肝解毒能力的评估中的一种或多种；所述手术前后评估包括肝切除后再生的评估、肝移植紧迫性的评估、术后肝衰的评估、相关手术前后评估中的一种或多种。在本发明的一些具体实施方案中，所述疾病包括但不限于肝硬化、原发胆汁性肝硬化、单纯脂肪变性、慢性肝病分期、酒精性肝病、肝纤维化的程度或分期、非酒精脂肪肝、新生儿胆汁淤积、胆道闭锁、肝内炎症、急性肝衰竭、肝细胞癌中的一种或多种；
所述肝脏储备功能评估包括但不限于相关疾病肝脏功能评价、化疗肝损伤的评估、预测慢性肝衰死亡、肝解毒能力的评估中的一种或多种；
所述手术前后评估包括但不限于肝切除后再生的评估、肝移植紧迫性的评估、术后肝衰的评估、相关手术前后评估中的一种或多种。
与现有技术相比，本发明的有益效果包括但不限于：
(1)本发明所述的13C美沙西汀颗粒剂具有良好的稳定性，有利于储存和后续制剂的生产等；
(2)本发明所述的13C美沙西汀颗粒剂的制备方法，条件温和，操作简单，便于生产控制；
(3)本发明所述的13C美沙西汀颗粒剂水溶性好，在临床使用时能快速溶于水，便于服用。
(4)本发明所述的13C美沙西汀颗粒剂可用于制备用于疾病的诊断、肝脏储备功能评估、肝脏手术前后评估的药物、试剂或试剂盒中的应用，其具有良好的稳定性。
本发明所述的疾病包括肝硬化、原发胆汁性肝硬化、单纯脂肪变性、慢性肝病分期、酒精性肝病、肝纤维化的程度或分期、非酒精脂肪肝、新生儿胆汁淤积、胆道闭锁、肝内炎症、急性肝衰竭、肝细胞癌中的一种或多种。
本发明中所述肝脏储备功能评估包括相关疾病肝脏功能评价、化疗肝损伤的评估、预测慢性肝衰死亡、肝解毒能力的评估中的一种或多种。
本发明所述手术前后评估包括肝切除后再生的评估、肝移植紧迫性的评估、术后肝衰的评估、相关手术前后评估中的一种或多种。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示实施例1制得的13C美沙西汀颗粒的HPLC谱图；
图2示实施例2制得的13C美沙西汀颗粒的HPLC谱图；
图3示实施例3制得的13C美沙西汀颗粒的HPLC谱图；
图4示实施例4制得的13C美沙西汀颗粒的HPLC谱图；
图5示实施例5制得的13C美沙西汀颗粒的HPLC谱图；
图6示实施例6制得的13C美沙西汀颗粒的HPLC谱图；
图7示本发明提供的13C美沙西汀颗粒与散剂、其他颗粒剂的水溶性、稳定性的比较结果。
具体实施方式
本发明公开了13C美沙西汀颗粒剂及其制备方法和应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述， 相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明的第一目的在于提供13C美沙西汀颗粒剂。
本发明的第二目的在于提供13C美沙西汀颗粒剂的制备方法，所述制备方法操作简便，收率高。
本发明的第三目的在于提供13C美沙西汀颗粒剂在制备用于疾病的诊断、肝脏储备功能评估、肝脏手术前后评估的药物、试剂或试剂盒中的应用。
本发明所述的疾病包括肝硬化、原发胆汁性肝硬化、单纯脂肪变性、慢性肝病分期、酒精性肝病、肝纤维化的程度或分期、非酒精脂肪肝、新生儿胆汁淤积、胆道闭锁、肝内炎症、急性肝衰竭、肝细胞癌中的一种或多种；
本发明中所述肝脏储备功能评估包括相关疾病肝脏功能评价、化疗肝损伤的评估、预测慢性肝衰死亡、肝解毒能力的评估中的一种或多种；
本发明所述手术前后评估包括肝切除后再生的评估、肝移植紧迫性的评估、术后肝衰的评估、相关手术前后评估中的一种或多种。
其中，所述助溶剂选自吐温80、β环糊精、氢氧化钠、柠檬酸钠、磷酸氢二钠、磷酸二氢钠、聚乙二醇6000、聚乙二醇4000、聚乙二醇2000、聚乙二醇1500中的一种或两种，所述润湿剂为乙醇水溶液，体积比为1﹕5-5﹕1。
在本发明一优选实施方式中，所述助溶剂的组合方式包括聚乙二醇4000，或聚乙二醇4000和磷酸二氢钠，或聚乙二醇4000和磷酸氢二钠。加入助溶剂的比例为1:0.1～100。
在本发明一优选实施方式中，所述13C美沙西汀混合粉与所述润湿剂的比例为100g﹕(1～100)mL，优选为100g﹕(2～20)mL，更优选为100g﹕(5～10)mL。
采用上述辅料用量比，能够在保证13C美沙西汀颗粒充分溶解的同时，配合加入助溶剂的量，促进13C美沙西汀颗粒剂的水溶性，提高颗粒的稳定性。
本发明还提供了一种所述13C美沙西汀颗粒剂的制备方法，包括如下步骤：
1原辅料粉碎：使用粉粹机分别对碳[13C]-美沙西汀、甘露醇、助溶剂进行粉碎过筛，并使用65目筛进行复筛复核。
2配料混合：将原料药碳[13C]-美沙西汀、辅料按比例分别称重。原辅料加入至混合机混合。
3制粒工序：
配制乙醇水溶液：使用药用级95％乙醇加纯水配制。
将混合粉投入湿法混合制粒机中，按比例将润湿剂加入混合物中，同时开启搅拌、制成软材。
将软材置于摇摆式颗粒机中制粒，大小均匀的颗粒置入不锈钢容器中。
4干燥工序：将湿颗粒放入减压干燥烘箱中，在45℃干燥3小时，将烘干后颗粒进行筛分得目标颗粒。
5总混灌装：将颗粒在混合机中混至颗粒均匀一致，将总混后的颗粒灌装完成。
在本发明一优选实施方式中，所述干燥的温度为30～100℃，优选为45℃。进一步的，所述干燥的方式包括鼓风干燥、真空干燥，优选为真空烘干。
如在不同实施方式中，所述干燥的温度可根据实际需求进行调整选择，干燥的时间可根据溶剂种类和含量进行适当的缩短或延长。
在本发明一优选实施方式中，所述干燥的时间为1～8h。
本发明还提供了上述13C美沙西汀颗粒剂在制备用于疾病的诊断、肝脏储备功能评估、肝脏手术前后评估的药物、试剂或试剂盒中的应用。
所述疾病包括肝硬化、原发胆汁性肝硬化、单纯脂肪变性、慢性肝病分期、酒精性肝病、肝纤维化的程度或分期、非酒精脂肪肝、新生儿胆汁淤积、胆道闭锁、肝内炎症、急性肝衰竭、肝细胞癌中的一种或多种；
所述肝脏储备功能评估包括相关疾病肝脏功能评价、化疗肝损伤的评估、预测慢性肝衰死亡、肝解毒能力的评估中的一种或多种；
所述手术前后评估包括肝切除后再生的评估、肝移植紧迫性的评估、术后肝衰的评估、相关手术前后评估中的一种或多种。
本发明还提供了疾病的诊断方法、肝脏储备功能评估方法或肝脏手术前后评估方法，施用上述的13C美沙西汀颗粒剂或上述的制备方法制得的13C美沙西汀颗粒剂。所述疾病包括肝硬化、原发胆汁性肝硬化、单纯脂肪变性、慢性肝病分期、酒精性肝病、肝纤维化的程度或分期、非酒精脂肪肝、新生儿胆汁淤积、胆道闭锁、肝内炎症、急性肝衰竭、肝细胞癌中的一种或多种；所述肝脏储备功能评估包括相关疾病肝脏功能评价、化疗肝损伤的评估、预测慢性肝衰死亡、肝解毒能力的评估中的一种或多种；所述手术前后评估包括肝切除后再生的评估、肝移植紧迫性的评估、术后肝衰的评估、相关手术前后评估中的一种或多种。
在本发明一优选实施方式中，所述药物的颗粒剂包括冲服颗粒、胶囊颗粒等。
本发明提供的13C美沙西汀颗粒剂及其制备方法和应用中，所用原料及试剂均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1
本实施例提供了13C美沙西汀颗粒剂的制备方法，步骤如下：
称取13C美沙西汀粗品1g，20克甘露醇，5克聚乙二醇4000，按步骤粉碎，混合，制粒，干燥；得到25.1g的13C美沙西汀颗粒，收率为96.5％，含量为100.4％，纯度为99.9％。
实施例2
本实施例提供了13C美沙西汀颗粒剂的制备方法，包括如下步骤：
称取13C美沙西汀粗品1g，50克甘露醇，5克聚乙二醇4000，磷酸二氢钠0.5克按步骤粉碎，混合，制粒，干燥；得到53.3g的13C美沙西汀颗粒，收率为94.3％，含量为99.8％，纯度为99.9％。
实施例3
本实施例提供了13C美沙西汀颗粒剂的制备方法，包括如下步骤：称取13C美沙西汀粗品1g，60克甘露醇，3克聚乙二醇4000，磷酸氢二钠1克按步骤粉碎，混合，制粒，干燥；得到62.5g的13C美沙西汀颗粒，收率为96.2％，含量为100.1％，纯度为100％。
实施例4
本实施例提供了13C美沙西汀颗粒剂的制备方法，包括如下步骤：
称取13C美沙西汀粗品1g，50克甘露醇，3克聚乙二醇2000，磷酸氢二钠2克按步骤粉碎，混合，制粒，干燥；得到53.1g的13C美沙西汀颗粒，收率为96.2％，含量为99.8％，纯度为100％。
实施例5
本实施例提供了13C美沙西汀颗粒剂的制备方法，包括如下步骤：
称取13C美沙西汀粗品1g，50克甘露醇，3克吐温80、1克柠檬酸钠按步骤粉碎，混合，制粒，干燥；得到52.8g的13C美沙西汀颗粒，收率为96.0％，含量为99.5％，纯度为99.9％。
实施例6
称取13C美沙西汀粗品1g，30克甘露醇，3克β环糊精、1克磷酸氢二钠按步骤粉碎，混合，制粒，干燥；得到32.7g的13C美沙西汀颗粒，收率为93.4％，含量为99.8％，纯度为100％。
效果例1
本发明实施例1～6制备得到的13C美沙西汀颗粒剂的长期稳定性试验(25±2℃/60％±5％RH)，结果如表1～表6所示：
表1 实施例1制备得到的13C美沙西汀颗粒剂的稳定性检测结果
Figure PCTCN2022088678-appb-000002
表2 实施例2制备得到的13C美沙西汀颗粒剂的稳定性检测结果
Figure PCTCN2022088678-appb-000003
表3 实施例3制备得到的13C美沙西汀颗粒剂的稳定性检测结果
Figure PCTCN2022088678-appb-000004
表4 实施例4制备得到的13C美沙西汀颗粒剂的稳定性检测结果
Figure PCTCN2022088678-appb-000005
表5 实施例5制备得到的13C美沙西汀颗粒剂的稳定性检测结果
Figure PCTCN2022088678-appb-000006
表6 实施例6制备得到的13C美沙西汀颗粒剂的稳定性检测结果
Figure PCTCN2022088678-appb-000007
效果例2
实验组1～6：本发明实施例1～6制得的13C美沙西汀颗粒剂；
对照组1：散剂。将各辅料和原料药按照处方比例称重，在混合机混合3小时混合均匀后制得散剂粉。
对照组2：其他颗粒剂。称取13C美沙西汀粗品1g，25g甘露醇按步骤粉碎，混合，制粒，干燥；得到25.1g的13C美沙西汀颗粒，收率为96.5％，含量为100.4％，纯度为99.9％。
比较结果见表7。
表7 水溶性及稳定性对比
Figure PCTCN2022088678-appb-000008
Figure PCTCN2022088678-appb-000009
因13C美沙西汀在水中的溶解度较低，溶解速度较慢，50mg溶解到100ml水中需要搅拌较长时间，在服用时不方便。在储存过程中粉末易结块，且发生降解反应，影响产品质量；散剂为混合粉，添加辅料后对产品的水溶性有提高，但是还不能满足临床使用的要求，溶解速度也较慢，粉末在储存过程有结块，加入辅料有助于提高产品的稳定性，降解的杂质较原料药粉末减少；研制的颗粒经过处方改造及制剂工艺开发，水溶性达到临床要求，贮存时也没有结块，降解得到有效抑制，杂质很少，远低于标准限度。经对比研制的颗粒剂具有更好的稳定性和水溶性，质量稳定使用价值高。
以上对本发明所提供的13C美沙西汀颗粒剂及其制备方法和应用进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (12)

13C美沙西汀颗粒剂，其特征在于，包括13C美沙西汀、甘露醇、助溶剂和润湿剂；
所述助溶剂包括吐温80、β环糊精、氢氧化钠、柠檬酸钠、磷酸氢二钠、磷酸二氢钠、聚乙二醇6000、聚乙二醇4000、聚乙二醇2000、聚乙二醇1500中的一种或多种；
所述润湿剂包括水或乙醇的水溶液中的一种或两种。
如权利要求1所述的13C美沙西汀颗粒剂，其特征在于，所述13C美沙西汀与所述助溶剂的重量比为1:(0.1～100)。
如权利要求1或2所述的13C美沙西汀颗粒剂，其特征在于，以g/mL计，所述13C美沙西汀、甘露醇和所述助溶剂的混合物，与所述润湿剂的重量比为100：(1～100)。
如权利要求3所述的13C美沙西汀颗粒剂，其特征在于，以g/mL计，所述13C美沙西汀和所述助溶剂的混合物，与所述润湿剂的重量比为100：(1～20)；所述润湿剂为乙醇的水溶液，所述乙醇的水溶液中乙醇和水的体积比为1﹕5～5﹕1。
如权利要求1至4任一项所述的13C美沙西汀颗粒剂，其特征在于，所述13C美沙西汀与所述甘露醇的重量比为1：(20～60)。
如权利要求1至5任一项所述的13C美沙西汀颗粒剂的制备方法，其特征在于，取13C美沙西汀粉碎后与甘露醇、助溶剂混合制得混合物，将所述混合物与润湿剂混合后制粒、干燥，制得13C美沙西汀颗粒剂。
如权利要求6所述的制备方法，其特征在于，所述干燥的温度为30～100℃，所述干燥的时间为1～8h。
如权利要求7所述的制备方法，其特征在于，所述干燥的温度为45℃，所述干燥的时间为3h。
如权利要求1至5任一项所述的13C美沙西汀颗粒剂或如权利要求6至8任一项所述的制备方法制得的13C美沙西汀颗粒剂在制备疾病的诊断、肝脏储备功能评估、肝脏手术前后评估的药物、试剂或试剂盒中 的应用。
如权利要求9所述的应用，其特征在于，所述疾病包括肝硬化、原发胆汁性肝硬化、单纯脂肪变性、慢性肝病分期、酒精性肝病、肝纤维化的程度或分期、非酒精脂肪肝、新生儿胆汁淤积、胆道闭锁、肝内炎症、急性肝衰竭、肝细胞癌中的一种或多种；
所述肝脏储备功能评估包括相关疾病肝脏功能评价、化疗肝损伤的评估、预测慢性肝衰死亡、肝解毒能力的评估中的一种或多种；
所述手术前后评估包括肝切除后再生的评估、肝移植紧迫性的评估、术后肝衰的评估、相关手术前后评估中的一种或多种。
疾病的诊断方法、肝脏储备功能评估方法或肝脏手术前后评估方法，其特征在于，施用如权利要求1至5任一项所述的13C美沙西汀颗粒剂或如权利要求6至8任一项所述的制备方法制得的13C美沙西汀颗粒剂。
如权利要求11所述的疾病的诊断方法、肝脏储备功能评估的方法或肝脏手术前后评估的方法，其特征在于，所述疾病包括但不限于肝硬化、原发胆汁性肝硬化、单纯脂肪变性、慢性肝病分期、酒精性肝病、肝纤维化的程度或分期、非酒精脂肪肝、新生儿胆汁淤积、胆道闭锁、肝内炎症、急性肝衰竭、肝细胞癌中的一种或多种；
所述肝脏储备功能评估包括但不限于相关疾病肝脏功能评价、化疗肝损伤的评估、预测慢性肝衰死亡、肝解毒能力的评估中的一种或多种；
所述手术前后评估包括但不限于肝切除后再生的评估、肝移植紧迫性的评估、术后肝衰的评估、相关手术前后评估中的一种或多种。
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