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WO2022206090A1 - 一种己酮可可碱注射液及其制备方法 - Google Patents

一种己酮可可碱注射液及其制备方法 Download PDF

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Publication number
WO2022206090A1
WO2022206090A1 PCT/CN2022/070212 CN2022070212W WO2022206090A1 WO 2022206090 A1 WO2022206090 A1 WO 2022206090A1 CN 2022070212 W CN2022070212 W CN 2022070212W WO 2022206090 A1 WO2022206090 A1 WO 2022206090A1
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pentoxifylline
injection
solution
preparation
dissolving
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PCT/CN2022/070212
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English (en)
French (fr)
Inventor
王立江
焦翠欢
王恰茹
李鑫
王晖
赵辉
吴雷
殷合闯
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石家庄四药有限公司
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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
    • A61K31/395—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • 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
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the application relates to the technical field of pharmaceutical preparations, in particular to a pentoxifylline injection and a preparation method thereof.
  • Pentoxifylline chemical name is 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione, molecular formula is C 13 H 18 N 4 O 3 , a methylxanthine derivative, is an alkaloid obtained by re-introducing the hexanone group to the cocoa alkaloid extracted from cocoa beans. It is a white powder or granule, slightly odorous, slightly bitter. Pentoxifylline is easily soluble in chloroform, soluble in water or ethanol, and slightly soluble in ether.
  • Pentoxifylline reduces blood viscosity, thereby improving blood fluidity, promoting microcirculation in ischemic tissues, and increasing oxygen supply to specific organs. Pentoxifylline can also improve the deformability of red blood cells by inhibiting phosphodiesterase and increasing the content of adenosine triphosphate in cells. In addition, pentoxifylline can reduce fibrinogen and inhibit the aggregation of red blood cells and platelets.
  • pentoxifylline injection consists of pentoxifylline, disodium edetate, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection.
  • pentoxifylline injection will have problems such as increased impurities and large pH changes.
  • stabilizers such as taurine and vitamin B6, or unsaturated fatty acids as stabilizers.
  • the composition of the prescription is more complicated.
  • stabilizers will increase the risk of drug safety for patients, and also increase the production process steps and production costs. Therefore, the development of a pentoxifylline injection with a simple prescription and high stability is of great significance for improving the patient's medication safety and reducing production costs.
  • the present application provides a pentoxifylline injection and a preparation method thereof.
  • a preparation method of pentoxifylline injection comprising the steps:
  • Step a adding the osmotic pressure regulator of the recipe amount to the water for injection of 40-60% of the total volume of preparation, stirring and dissolving to obtain a first dissolving solution; adding a pH adjusting agent to the first dissolving solution, adjusting the first dissolving solution The pH is to 6.5-7.5 to obtain the second dissolving solution; then add the pentoxifylline of the recipe amount to the second dissolving solution, stir and dissolve, and obtain the first pentoxifylline medicinal solution;
  • Step b adding water for injection to the first pentoxifylline medicinal solution to prepare the total volume to obtain a second pentoxifylline medicinal solution; adding a pH regulator to the second pentoxifylline medicinal solution, The pH of the second pentoxifylline medicinal solution is adjusted to 6.5-7.5 to obtain the third pentoxifylline medicinal solution; the third pentoxifylline medicinal solution is filtered through a multi-stage polyethersulfone filter element with a decreasing pore size, Filling, sterilization, pentoxifylline injection.
  • the multi-stage polyethersulfone filter element is filtered by a three-stage polyethersulfone filter element, wherein the pore size of the first-stage polyethersulfone filter element is 1.0 ⁇ m, and the pore size of the second-stage polyethersulfone filter element is 1.0 ⁇ m. 0.45 ⁇ m, the pore size of the third-stage polyethersulfone filter element is 0.2 ⁇ m.
  • the osmotic pressure regulator is sodium chloride.
  • the pH adjusting agent in step a and step b is sodium hydroxide solution or hydrochloric acid solution, and the amount of pH adjusting agent added is adjusted according to the required pH value.
  • the concentration of the sodium hydroxide solution or the hydrochloric acid solution is both 0.1 mol/L.
  • the filling is performed in polypropylene ampoules.
  • pentoxifylline injection adopts polypropylene ampoule bottle, which can reduce the introduction of insoluble particles, reduce the pollution of pentoxifylline injection caused by microorganisms, and the polypropylene ampoule bottle is easy to open and not easy to break, which is conducive to product transportation and save.
  • the sterilization method is constant temperature sterilization at 121° C. for 12-15 minutes.
  • the application adopts a terminal sterilization process, which greatly improves the sterilization level and sterilization efficiency of the product.
  • step a and step b the temperature of the water for injection is 65-75°C.
  • the application also provides a pentoxifylline injection, which is prepared by the preparation method of the pentoxifylline injection described in any one of the above.
  • the pentoxifylline injection is composed of pentoxifylline, sodium chloride, pH adjuster and water for injection, wherein every 5 mL of pentoxifylline injection contains 95-105 mg of pentoxifylline , sodium chloride 33.25-36.75mg, the pH of pentoxifylline injection is 6.5-7.5.
  • the pH adjuster is sodium hydroxide solution or hydrochloric acid solution.
  • the total volume of preparation mentioned in this application refers to the total volume of the prepared pentoxifylline injection, and the water for injection with 40-60% of the total volume of preparation refers to the amount of water for injection that is pentoxifylline injection. 40-60% of the total volume.
  • the formulation amount mentioned in this application refers to the amount of each component in the formulation of the formulation.
  • the terminal sterilization process mentioned in this application refers to sterilization by moist heat sterilization after the medicine is potted and sealed on the basis of controlling the amount of microbial contamination.
  • the preparation method of pentoxifylline injection provided by the present application, by first adjusting the pH of the system to 6.5-7.5, then adding pentoxifylline to the system, and adjusting again after adding pentoxifylline
  • the pH of the system is 6.5-7.5, (the system in this application refers to the whole formed by the connection and combination of each related part in the reaction, which is the relevant collection of reactants, additives, products, etc.
  • the addition of raw materials, solvents, pH adjusters, etc. and the generation of products significantly improved the stability of pentoxifylline in solution, and cooperated with the third pentoxifylline liquid through the pore size.
  • Multi-stage polyethersulfone filter element filtration reduces the process impurities introduced in the preparation process.
  • the preparation method of pentoxifylline injection provided by the application further improves the stability of the product quality of pentoxifylline injection, significantly reduces the content of impurities in the storage process, and makes the pentoxifylline injection in the long-term storage process.
  • the pH of the alkali injection is stable at 6.5-7.5.
  • the purpose of adding no other auxiliary materials other than sodium chloride to the pentoxifylline injection, and the long-term stability of the product is achieved, and the effect of the auxiliary materials on the pentoxifylline injection is avoided.
  • the adverse effect caused by the drug also avoids the problem of drug safety caused by the auxiliary materials.
  • the application adopts the method of terminal sterilization, and does not use activated carbon in the preparation process, which greatly improves the safety of clinical drug use of the product, reduces the production cost, and has the advantages of Broad application prospects.
  • the application uses multi-stage polyethersulfone filter elements with specific pore size to filter in sequence, which can not only ensure the qualified content of bacteria and endotoxin in the product and reduce the introduction of process impurities, but also further improve the quality stability of the product and reduce the long-term storage process of the product.
  • the content of impurities in the production process and the pH stability of the product are maintained, and activated carbon is not used in the production process, which reduces the pollution to the production clean area, reduces the pressure on environmental protection, and reduces the impurities and insoluble particles that may be introduced by activated carbon, which is conducive to further Improve the effectiveness, safety and stability of product quality.
  • the pentoxifylline injection uses pentoxifylline as the main drug, sodium chloride as the isotonicity regulator, without introducing any auxiliary materials such as stabilizers, which significantly improves the pentoxifylline injection.
  • the total impurity content of Pentoxifylline Injection is ⁇ 0.05%, the impurity content does not increase basically, the pH value of Pentoxifylline Injection is stable, and the color of the solution is always colorless clear solution.
  • the present application achieves the purpose of ensuring product quality stability without adding a stabilizer, the prescription is simpler, the adverse reactions that may occur when the patient is used is reduced, the production cost is also reduced, and it is convenient to use.
  • the realization of industrialized production has high promotion value.
  • the present embodiment provides a kind of pentoxifylline injection, and the recipe quantity is as shown in the following table:
  • Step a take 500 mL of water for injection at 70°C, add sodium chloride to the water for injection, stir and dissolve to obtain the first dissolving solution I; add 0.1 mol/L sodium hydroxide solution to the first dissolving solution I to adjust the first dissolving solution The pH of the solution I reaches 7.0 to obtain the second dissolving solution I; adding pentoxifylline to the second dissolving solution I, stirring and dissolving to obtain the first pentoxifylline medicinal solution I;
  • Step b add the remaining water for injection to 1L in the first pentoxifylline medicinal solution I to obtain the second pentoxifylline medicinal solution I; then add 0.1mol/ L sodium hydroxide solution, after adjusting the pH of the second pentoxifylline liquid I to 7.0, the third pentoxifylline liquid I was obtained;
  • the polyethersulfone filter elements of ⁇ m and 0.2 ⁇ m were filtered, and the filtered liquid was filled into polypropylene ampoules, and sterilized at a constant temperature of 121 °C for 12 min to obtain pentoxifylline injection.
  • the present embodiment provides a kind of pentoxifylline injection, and the recipe quantity is as shown in the following table:
  • Step a take 600 mL of water for injection at 65°C, add sodium chloride to the water for injection, stir and dissolve to obtain the first dissolving solution II; add 0.1 mol/L sodium hydroxide solution to the first dissolving solution II to adjust the first dissolving solution The pH of the liquid II reaches 7.5 to obtain the second dissolving liquid II; adding pentoxifylline to the second dissolving liquid II, stirring and dissolving to obtain the first pentoxifylline medicinal liquid II;
  • step b the remaining water for injection is added to the first pentoxifylline medicinal solution II to 1L to obtain the second pentoxifylline medicinal solution II; then 0.1 mol/ L hydrochloric acid solution, after adjusting the pH of the second pentoxifylline liquid II to 6.6, the third pentoxifylline liquid II was obtained; Filter with a 0.2 ⁇ m polyethersulfone filter element, fill the filtered medicinal liquid into polypropylene ampoules, and sterilize at 121°C for 15 min to obtain pentoxifylline injection.
  • the present embodiment provides a kind of pentoxifylline injection, and the recipe quantity is as shown in the following table:
  • Step a take 400 mL of water for injection at 75°C, add sodium chloride to the water for injection, stir and dissolve to obtain the first dissolving solution III; add 0.1 mol/L sodium hydroxide solution to the first dissolving solution III to adjust the first dissolving solution The pH of the liquid III reaches 6.8 to obtain the second dissolving liquid III; adding pentoxifylline to the second dissolving liquid III, stirring and dissolving to obtain the first pentoxifylline medicinal liquid III;
  • step b the remaining water for injection is added to the first pentoxifylline medicinal solution III to 1 L to obtain the second pentoxifylline medicinal solution III; then 0.1 mol/ L sodium hydroxide solution, after adjusting the pH of the second pentoxifylline liquid III to 7.3, the third pentoxifylline liquid III was obtained;
  • the polyethersulfone filter elements of ⁇ m and 0.2 ⁇ m were filtered, and the filtered liquid was filled into polypropylene ampoules, and sterilized at a constant temperature of 121 °C for 12 min to obtain pentoxifylline injection.
  • This comparative example provides a kind of pentoxifylline injection, and the prescription amount is shown in the following table:
  • step a take 500 mL of water for injection at 70°C, add sodium dihydrogen phosphate, disodium edetate and pentoxifylline to the water for injection in turn, and after stirring and dissolving, the first dissolving solution IV is obtained; adding to the first dissolving solution IV 2% disodium hydrogen phosphate solution, adjust the pH of the first dissolving solution IV to 5.0 to obtain the first pentoxifylline liquid IV;
  • step b the remaining water for injection is added to the first pentoxifylline medicinal solution IV to 1L to obtain the second pentoxifylline medicinal solution IV; 0.45 ⁇ m and 0.2 ⁇ m polyethersulfone filter elements were used for filtration, and the filtered liquid was filled into glass ampoules, and sterilized at 121°C for 12 minutes to obtain pentoxifylline injection.
  • This comparative example provides a kind of pentoxifylline injection, and the prescription amount is shown in the following table:
  • Step a take 500 mL of water for injection at 70°C, add sodium chloride and pentoxifylline to the water for injection, stir and dissolve to obtain a first dissolving solution V; add 0.1 mol/L sodium hydroxide solution to the first dissolving solution V, Adjust the pH of the first dissolving solution V to 7.0 to obtain the first pentoxifylline medicinal solution V;
  • Step b adding the remaining water for injection to the first pentoxifylline medicinal solution V to 1L to obtain the second pentoxifylline medicinal solution V; then adding 0.1mol/ L sodium hydroxide solution, after adjusting the pH of the second pentoxifylline liquid V to 7.0, the third pentoxifylline liquid V was obtained;
  • the polyethersulfone filter elements of ⁇ m and 0.2 ⁇ m were filtered, and the filtered liquid was filled into polypropylene ampoules, and sterilized at a constant temperature of 121 °C for 12 min to obtain pentoxifylline injection.
  • the present embodiment provides a kind of pentoxifylline injection, and the recipe quantity is as shown in the following table:
  • Step a take 500 mL of water for injection at 70°C, add sodium chloride to the water for injection, stir and dissolve to obtain the first dissolving solution VI; add 0.1 mol/L hydrochloric acid solution to the first dissolving solution VI to adjust the first dissolving solution VI
  • the pH is to 5.5 to obtain the second dissolving solution VI; add pentoxifylline to the second dissolving solution VI, stir and dissolve to obtain the first pentoxifylline medicinal solution VI;
  • Step b adding the remaining water for injection to the first pentoxifylline medicinal solution VI to 1L to obtain the second pentoxifylline medicinal solution VI; then adding 0.1mol/ L hydrochloric acid solution, after adjusting the pH of the second pentoxifylline liquid VI to 5.5, the third pentoxifylline liquid VI is obtained; Filter with a 0.2 ⁇ m polyethersulfone filter element, fill the filtered medicinal liquid into polypropylene ampoules, and sterilize at 121° C. for 12 min to obtain pentoxifylline injection.
  • pentoxifylline injection products prepared in Examples 1-3 and Comparative Examples 1-3 were investigated by influencing factors and accelerated tests.
  • pentoxifylline injection was subjected to high temperature influence factor test for 0 days, 10 days and 30 days respectively; under the conditions of temperature of 40°C ⁇ 2°C and humidity of 25% ⁇ 5%, Theobromine injection was subjected to accelerated tests for 1 month, 3 months and 6 months respectively, and the results are shown in Table 1-2.
  • the stability of the pentoxifylline injection prepared in Example 1-3 of the present application is higher, in the high temperature influencing factor test and the accelerated 6-month test process.
  • the properties, pH value, and content of the medium product are basically unchanged between batches, and the content of related substances is low, and the impurities are basically not increased, which proves that the pentoxifylline injection prepared in the embodiment of the application has better stability and safety, Thus, it is more beneficial to improve the safety of clinical application.

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Abstract

一种己酮可可碱注射液，其制备方法为：将处方量的渗透压调节剂加入配制总体积量40-60%的注射用水中，搅拌溶解，调节pH至6.5-7.5，然后加入处方量的己酮可可碱，搅拌溶解，补加注射用水至配制总量，调节pH至6.5-7.5，经过孔径依次减小的多级聚醚砜滤芯过滤，灌装，灭菌，得己酮可可碱注射液。所述己酮可可碱注射液在不加入稳定剂的情况下保持稳定，处方简单，在6个月的加速试验过程中，杂质含量基本不增加，总杂质含量≤0.05%，pH值稳定，始终为无色澄明溶液。

Description

一种己酮可可碱注射液及其制备方法
本专利申请要求于2021年4月2日提交的中国专利申请No.CN202110362113.6的优先权。在先申请的公开内容通过整体引用并入本申请。
技术领域
本申请涉及药物制剂技术领域，尤其涉及一种己酮可可碱注射液及其制备方法。
 背景技术
己酮可可碱，化学名为3,7-二氢-3,7-二甲基-1-(5-氧代己基)-1H-嘌呤-2,6-二酮，分子式为C 13H 18N 4O 3，是一种甲基黄嘌呤类衍生物，是从可可豆中提取的可可豆碱上再引入己酮基而得到的一种生物碱，为白色粉末或颗粒，微臭、微苦。己酮可可碱在三氯甲烷中易溶，在水中或乙醇中能溶解，在乙醚中微溶。己酮可可碱可降低血液粘稠度，从而改善血液流动性，促进缺血组织的微循环，增加特殊器官的氧气供应。己酮可可碱还可通过抑制磷酸二酯酶，升高细胞内三磷酸腺苷的含量，从而改善红细胞的变形能力。除此之外，己酮可可碱还能降低纤维蛋白原，抑制红细胞及血小板的聚集。
但是，现有己酮可可碱注射液的处方组成为己酮可可碱、依地酸二钠、磷酸二氢钠、磷酸氢二钠和注射用水。在长期放置过程中，己酮可可碱注射液会出现杂质增加，pH变化较大的问题。为了提高己酮可可碱注射液的稳定性，一般需要在己酮可可碱注射液中加入稳定剂，如牛磺酸和维生素B6，或不饱和脂肪酸等作为稳定剂，己酮可可碱注射液的处方组成较为复杂。稳定剂的加入会增加患者用药安全性的风险，也会增加生产工艺步骤和生产成本。因此，研发一种处方组成简单且稳定性高的己酮可可碱注射液，对提高患者的用药安全及降低生产成本具有十分重要的意义。
 技术问题
针对现有的己酮可可碱注射液存在的长期存储过程杂质增多、pH值变化较大以及含有较多辅料的问题，本申请提供一种己酮可可碱注射液及其制备方法。
 技术解决方案
为解决上述技术问题，本申请提供的技术方案是：
一种己酮可可碱注射液的制备方法，包括如下步骤：
步骤a，将处方量的渗透压调节剂加入配制总体积量40-60%的注射用水中，搅拌溶解，得第一溶解液；向第一溶解液中加入pH调节剂，调节第一溶解液的pH至6.5-7.5，得第二溶解液；然后向第二溶解液中加入处方量的己酮可可碱，搅拌溶解，得第一己酮可可碱药液；
步骤b，向所述第一己酮可可碱药液中补加注射用水至配制总体积量，得第二己酮可可碱药液；向第二己酮可可碱药液中加入pH调节剂，调节第二己酮可可碱药液的pH至6.5-7.5，得第三己酮可可碱药液；所述第三己酮可可碱药液经过孔径依次减小的多级聚醚砜滤芯过滤、灌装、灭菌，得己酮可可碱注射液。
在其中一些实施例中，所述多级聚醚砜滤芯过滤为三级聚醚砜滤芯过滤，其中，第一级聚醚砜滤芯的孔径为1.0μm，第二级聚醚砜滤芯的孔径为0.45μm，第三级聚醚砜滤芯的孔径为0.2μm。
在其中一些实施例中，所述渗透压调节剂为氯化钠。
在其中一些实施例中，步骤a和步骤b中所述pH调节剂为氢氧化钠溶液或盐酸溶液，pH调节剂的加入量根据所需pH值进行调节。
进一步优选的，所述氢氧化钠溶液或盐酸溶液的浓度均为0.1mol/L。
在其中一些实施例中，所述灌装采用聚丙烯安瓿进行灌装。
本申请中己酮可可碱注射液采用聚丙烯安瓿瓶，可以减少不溶性微粒的引入，降低微生物对己酮可可碱注射液造成的污染，且聚丙烯安瓿瓶开启方便，不易破碎，有利于产品运输和保存。
在其中一些实施例中，所述灭菌的方式为121℃恒温灭菌12-15min。
本申请采用终端灭菌工艺，大大提高了产品的无菌水平和灭菌效率。
在其中一些实施例中，步骤a和步骤b中，所述注射用水的温度为65-75℃。
本申请还提供一种己酮可可碱注射液，由上述任一项所述的己酮可可碱注射液的制备方法制备得到。
在其中一些实施例中，所述己酮可可碱注射液由己酮可可碱、氯化钠、pH调节剂和注射用水组成，其中每5mL己酮可可碱注射液中含有己酮可可碱95-105mg，氯化钠33.25-36.75mg，己酮可可碱注射液的pH为6.5-7.5。
在其中一些实施例中，所述pH调节剂为氢氧化钠溶液或盐酸溶液。
本申请中所述配制总体积量是指配制的己酮可可碱注射液的总体积量，所述配制总体积量40-60%的注射用水是指注射用水的量是己酮可可碱注射液的总体积量的40-60%。
本申请中所述处方量是指制剂处方中各组分的量。
本申请中所述终端灭菌工艺（terminal sterilization process）是指在控制微生物污染量的基础上，在药品灌封后，通过湿热灭菌方式除菌。
 有益效果
相对于现有技术，本申请提供的己酮可可碱注射液的制备方法，通过先调节体系的pH至6.5-7.5后再向体系中加入己酮可可碱，且加入己酮可可碱后再次调整体系pH为6.5-7.5的工艺，（本申请中的体系是指反应中各个有联系的部分联系组合而成的整体，是反应中的反应物、加入物、生成物等有关集合，是随着原料、溶剂、pH调节剂等的加入以及产物的生成而变化的），显著提高了己酮可可碱在溶液中的稳定性，并配合将第三己酮可可碱药液经孔径依次减小的多级聚醚砜滤芯过滤，减少了制备过程中引入的工艺杂质。同时，本申请提供的己酮可可碱注射液的制备方法，还进一步提高了己酮可可碱注射液产品质量的稳定性，显著降低了存储过程中杂质的含量，使长期存储过程中己酮可可碱注射液的pH稳定在6.5-7.5。本申请通过严格控制制备工艺及参数，实现了在己酮可可碱注射液中除氯化钠之外不加入其他辅料，且产品长期稳定性良好的目的，避免了辅料对己酮可可碱注射液造成的不利影响，也避免了辅料带来的用药安全问题，同时本申请采用终端灭菌的方法，在制备过程中不采用活性炭，大大提高了产品临床用药的安全性，降低了生产成本，具有广阔的应用前景。
本申请采用特定孔径的多级聚醚砜滤芯依次过滤，不但能够保证产品细菌、内毒素含量合格，减少工艺杂质的引入，同时，还能进一步提高产品的质量稳定性，降低产品在长期存储过程中的杂质的含量，并维持产品pH稳定，且在生产过程中不采用活性炭，降低了对生产洁净区的污染，减轻了环保压力，也降低了活性炭可能引入的杂质和不溶性微粒，有利于进一步提高产品质量的有效性、安全性和稳定性。
本申请提供的己酮可可碱注射液，以己酮可可碱为主药，以氯化钠为等渗调节剂，在不引入任何稳定剂等辅料的前提下，显著提高了己酮可可碱注射液的稳定性，加速6个月试验过程中，己酮可可碱注射液的总杂质含量≤0.05%，杂质含量基本不增加，己酮可可碱注射液的pH值稳定，溶液颜色始终为无色澄明溶液。与现有技术相比，本申请实现了在不加入稳定剂的情况下保证产品质量稳定性的目的，处方更加简单，降低了患者使用时可能产生的不良反应，同时还降低了生产成本，便于实现工业化生产，具有较高的推广价值。
本申请的实施方式
为了使本申请的目的、技术方案及优点更加清楚明白，以下结合实施例，对本申请进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本申请，并不用于限定本申请。
为了更好的说明本申请，下面通过实施例做进一步的举例说明。
实施例1
本实施例提供一种己酮可可碱注射液，处方量如下表所示：
己酮可可碱              20g
氯化钠                     7g
pH调节剂适量
注射用水至1L。
上述己酮可可碱注射液的制备方法如下：
步骤a，取70℃注射用水500mL，向注射用水中加入氯化钠，搅拌溶解，得第一溶解液Ⅰ；向第一溶解液Ⅰ中加入0.1mol/L氢氧化钠溶液，调节第一溶解液Ⅰ的pH至7.0，得第二溶解液Ⅰ；向第二溶解液Ⅰ中加入己酮可可碱，搅拌溶解，得第一己酮可可碱药液Ⅰ；
步骤b，向第一己酮可可碱药液Ⅰ中补加剩余的注射用水至1L，得第二己酮可可碱药液Ⅰ；然后向第二己酮可可碱药液Ⅰ中加入0.1mol/L氢氧化钠溶液，调节第二己酮可可碱药液Ⅰ的pH至7.0后，得第三己酮可可碱药液Ⅰ；第三己酮可可碱药液Ⅰ依次通过孔径为1.0μm、0.45μm和0.2μm的聚醚砜滤芯过滤，将过滤后的药液灌装聚丙烯安瓿，121℃恒温灭菌12min，得己酮可可碱注射液。
实施例2
本实施例提供一种己酮可可碱注射液，处方量如下表所示：
己酮可可碱              19g
氯化钠                    6.65g
pH调节剂适量
注射用水至1L。
上述己酮可可碱注射液的制备方法如下：
步骤a，取65℃注射用水600mL，向注射用水中加入氯化钠，搅拌溶解，得第一溶解液Ⅱ；向第一溶解液Ⅱ中加入0.1mol/L氢氧化钠溶液，调节第一溶解液Ⅱ的pH至7.5，得第二溶解液Ⅱ；向第二溶解液Ⅱ中加入己酮可可碱，搅拌溶解，得第一己酮可可碱药液Ⅱ；
步骤b，向第一己酮可可碱药液Ⅱ中补加剩余的注射用水至1L，得第二己酮可可碱药液Ⅱ；然后向第二己酮可可碱药液Ⅱ中加入0.1mol/L盐酸溶液，调节第二己酮可可碱药液Ⅱ的pH至6.6后，得第三己酮可可碱药液Ⅱ；第三己酮可可碱药液Ⅱ依次通过孔径为1.0μm、0.45μm和0.2μm的聚醚砜滤芯过滤，将过滤后的药液灌装聚丙烯安瓿，121℃恒温灭菌15min，得己酮可可碱注射液。
实施例3
本实施例提供一种己酮可可碱注射液，处方量如下表所示：
己酮可可碱              21g
氯化钠                    7.35g
pH调节剂适量
注射用水至1L。
上述己酮可可碱注射液的制备方法如下：
步骤a，取75℃注射用水400mL，向注射用水中加入氯化钠，搅拌溶解，得第一溶解液Ⅲ；向第一溶解液Ⅲ中加入0.1mol/L氢氧化钠溶液，调节第一溶解液Ⅲ的pH至6.8，得第二溶解液Ⅲ；向第二溶解液Ⅲ中加入己酮可可碱，搅拌溶解，得第一己酮可可碱药液Ⅲ；
步骤b，向第一己酮可可碱药液Ⅲ中补加剩余的注射用水至1L，得第二己酮可可碱药液Ⅲ；然后向第二己酮可可碱药液Ⅲ中加入0.1mol/L氢氧化钠溶液，调节第二己酮可可碱药液Ⅲ的pH至7.3后，得第三己酮可可碱药液Ⅲ；第三己酮可可碱药液Ⅲ依次通过孔径为1.0μm、0.45μm和0.2μm的聚醚砜滤芯过滤，将过滤后的药液灌装聚丙烯安瓿，121℃恒温灭菌12min，得己酮可可碱注射液。
对比例1
本对比例提供一种己酮可可碱注射液，处方量如下表所示：
己酮可可碱              20g
磷酸二氢钠              1g
依地酸二钠             10mg
2%磷酸氢二钠溶液适量
注射用水至1L。
上述己酮可可碱注射液的制备方法如下：
步骤a，取70℃注射用水500mL，向注射用水中依次加入磷酸二氢钠、依地酸二钠和己酮可可碱，搅拌溶解后，得第一溶解液Ⅳ；向第一溶解液Ⅳ中加入2%磷酸氢二钠溶液，调节第一溶解液Ⅳ的pH至5.0，得第一己酮可可碱药液Ⅳ；
步骤b，向第一己酮可可碱药液Ⅳ中补加剩余的注射用水至1L，得第二己酮可可碱药液Ⅳ；第二己酮可可碱药液Ⅳ依次通过孔径为1.0μm、0.45μm和0.2μm的聚醚砜滤芯过滤，将过滤后的药液灌装玻璃安瓿，121℃恒温灭菌12min，得己酮可可碱注射液。
对比例2
本对比例提供一种己酮可可碱注射液，处方量如下表所示：
己酮可可碱              20g
氯化钠                    7g
pH调节剂适量
注射用水至1L。
上述己酮可可碱注射液的制备方法如下：
步骤a，取70℃注射用水500mL，向注射用水中加入氯化钠和己酮可可碱，搅拌溶解，得第一溶解液Ⅴ；向第一溶解液Ⅴ中加入0.1mol/L氢氧化钠溶液，调节第一溶解液Ⅴ的pH至7.0，得第一己酮可可碱药液Ⅴ；
步骤b，向第一己酮可可碱药液Ⅴ中补加剩余的注射用水至1L，得第二己酮可可碱药液Ⅴ；然后向第二己酮可可碱药液Ⅴ中加入0.1mol/L氢氧化钠溶液，调节第二己酮可可碱药液Ⅴ的pH至7.0后，得第三己酮可可碱药液Ⅴ；第三己酮可可碱药液Ⅴ依次通过孔径为1.0μm、0.45μm和0.2μm的聚醚砜滤芯过滤，将过滤后的药液灌装聚丙烯安瓿，121℃恒温灭菌12min，得己酮可可碱注射液。
对比例3
本实施例提供一种己酮可可碱注射液，处方量如下表所示：
己酮可可碱              20g
氯化钠                    7g
pH调节剂适量
注射用水至1L。
上述己酮可可碱注射液的制备方法如下：
步骤a，取70℃注射用水500mL，向注射用水中加入氯化钠，搅拌溶解，得第一溶解液Ⅵ；向第一溶解液Ⅵ中加入0.1mol/L盐酸溶液，调节第一溶解液Ⅵ的pH至5.5，得第二溶解液Ⅵ；向第二溶解液Ⅵ中加入己酮可可碱，搅拌溶解，得第一己酮可可碱药液Ⅵ；
步骤b，向第一己酮可可碱药液Ⅵ中补加剩余的注射用水至1L，得第二己酮可可碱药液Ⅵ；然后向第二己酮可可碱药液Ⅵ中加入0.1mol/L盐酸溶液，调节第二己酮可可碱药液Ⅵ的pH至5.5后，得第三己酮可可碱药液Ⅵ；第三己酮可可碱药液Ⅵ依次通过孔径为1.0μm、0.45μm和0.2μm的聚醚砜滤芯过滤，将过滤后的药液灌装聚丙烯安瓿，121℃恒温灭菌12min，得己酮可可碱注射液。
稳定性
参照药物稳定性指导原则，对实施例1-3以及对比例1-3制备的己酮可可碱注射液产品进行影响因素试验和加速试验考察。在温度60℃条件下，对己酮可可碱注射液分别进行0天、10天、30天的高温影响因素试验；在温度40℃±2℃、湿度25%±5%条件下，对己酮可可碱注射液分别进行1月、3月、6月的加速试验，结果如表1-2所示。
表1 高温影响因素试验结果
Figure dest_path_image001
Figure dest_path_image002
表2 加速试验结果
Figure dest_path_image003
Figure dest_path_image004
由上述试验数据可以看出，与对比例1-3相比，本申请实施例1-3制备的己酮可可碱注射液的稳定性更高，在高温影响因素试验以及加速6个月试验过程中产品批次间性状、pH值、含量基本不变，且有关物质含量低，杂质基本不增加，这证明本申请实施例制备的己酮可可碱注射液具有更好的稳定性和安全性，从而更有利于提高临床应用的安全性。
以上所述仅为本申请的较佳实施例而已，并不用以限制本申请，凡在本申请的精神和原则之内所作的任何修改、等同替换或改进等，均应包含在本申请的保护范围之内。

Claims (10)

  1. 一种己酮可可碱注射液的制备方法，其特征在于，包括如下步骤：
    步骤a，将处方量的渗透压调节剂加入配制总体积量40-60%的注射用水中，搅拌溶解，得第一溶解液；向所述第一溶解液中加入pH调节剂，调节所述第一溶解液的pH至6.5-7.5，得第二溶解液；然后向所述第二溶解液中加入处方量的己酮可可碱，搅拌溶解，得第一己酮可可碱药液；
    步骤b，向所述第一己酮可可碱药液中补加注射用水至配制总体积量，得第二己酮可可碱药液；向所述第二己酮可可碱药液中加入pH调节剂，调节所述第二己酮可可碱药液的pH至6.5-7.5，得第三己酮可可碱药液；所述第三己酮可可碱药液经过孔径依次减小的多级聚醚砜滤芯过滤、灌装、灭菌，得己酮可可碱注射液。
  2. 如权利要求1所述的己酮可可碱注射液的制备方法，其特征在于，所述多级聚醚砜滤芯过滤为三级聚醚砜滤芯过滤，其中，第一级聚醚砜滤芯的孔径为1.0μm，第二级聚醚砜滤芯的孔径为0.45μm，第三级聚醚砜滤芯的孔径为0.2μm。
  3. 如权利要求1所述的己酮可可碱注射液的制备方法，其特征在于，所述渗透压调节剂为氯化钠。
  4. 如权利要求1所述的己酮可可碱注射液的制备方法，其特征在于，步骤a和步骤b中，所述pH调节剂为氢氧化钠溶液或盐酸溶液。
  5. 如权利要求1所述的己酮可可碱注射液的制备方法，其特征在于，所述灌装采用聚丙烯安瓿进行灌装。
  6. 如权利要求1所述的己酮可可碱注射液的制备方法，其特征在于，所述灭菌的方式为121℃恒温灭菌12-15min。
  7. 如权利要求1所述的己酮可可碱注射液的制备方法，其特征在于，步骤a和步骤b中，所述注射用水的温度为65-75℃。
  8. 一种己酮可可碱注射液，其特征在于，由权利要求1-7任一项所述的己酮可可碱注射液的制备方法制备得到。
  9. 如权利要求8所述的己酮可可碱注射液，其特征在于，所述己酮可可碱注射液由己酮可可碱、氯化钠、pH调节剂和注射用水组成，其中每5mL己酮可可碱注射液中含有己酮可可碱95-105mg，氯化钠33.25-36.75mg，己酮可可碱注射液的pH为6.5-7.5。
  10. 如权利要求9所述的己酮可可碱注射液，其特征在于，所述pH调节剂为氢氧化钠溶液或盐酸溶液。
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