WO2024027549A1 - 一种含有吡咯类胃酸分泌抑制剂的药物组合物及其制备方法 - Google Patents

一种含有吡咯类胃酸分泌抑制剂的药物组合物及其制备方法 Download PDF

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WO2024027549A1
WO2024027549A1 PCT/CN2023/109519 CN2023109519W WO2024027549A1 WO 2024027549 A1 WO2024027549 A1 WO 2024027549A1 CN 2023109519 W CN2023109519 W CN 2023109519W WO 2024027549 A1 WO2024027549 A1 WO 2024027549A1
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injection
composition according
formula
injection composition
edetate
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French (fr)
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苏梅
韩铖
沈娟
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江苏柯菲平医药股份有限公司
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • the present invention relates to an injection composition and a preparation method thereof, in particular to an injection composition containing an azole gastric acid secretion inhibitor and a preparation method thereof.
  • P-CABs Potassium-competitive acid blockers
  • P-CABs Potassium-competitive acid blockers
  • P-CABs immediately ionize to The ionized form combines to inhibit H + -K + -ATPase. It does not require activation of microcapsules and microtubules concentrated in gastric parietal cells and acid. It can quickly increase the pH value in the stomach. After dissociation, the enzyme activity is restored. For the upper gastrointestinal tract It has a strong inhibitory effect on mucosal damage and is used for gastric ulcer, duodenal ulcer, reflux esophagitis, etc.
  • the chemical name of the compound represented by formula I is 1-[5-(2-fluoro-phenyl)-1- ⁇ [3-(3-methoxypropoxy)phenyl]sulfonyl ⁇ -1H-pyrrole- 3-yl]-N-methylmethylamine is a potassium ion competitive acid blocker (P-CABs). It is useful in the prevention and treatment of gastric acid-related diseases, including (but not limited to) gastrointestinal diseases such as peptic ulcer, Zollinger-Ellison syndrome, gastritis, gastric ulcer, duodenal ulcer, non-steroidal anti- Ulcers caused by inflammatory drugs, Helicobacter pylori infection, gastroesophageal reflux disease, reflux esophagitis, etc.
  • gastrointestinal diseases such as peptic ulcer, Zollinger-Ellison syndrome, gastritis, gastric ulcer, duodenal ulcer, non-steroidal anti- Ulcers caused by inflammatory drugs, Helicobacter pylori infection, gastroesoph
  • Chinese patent CN 108969520A discloses a composition of a crystal form A compound of N-methylformamide hydrochloride.
  • the hydrochloride is formed by combining the compound of formula I with hydrochloric acid.
  • the specific structure is shown in formula II.
  • the oral administration composition composed of the compound represented by formula II is specifically disclosed.
  • the drug has poor compliance and cannot meet the clinical needs for rapid onset of action.
  • injections have the advantages of high bioavailability and rapid onset of action.
  • degradation impurities are easily produced, among which the main known degradation impurities are impurity 1 and impurity 2, whose structures are as follows:
  • the hydrochloride represented by Formula II is a new type of potassium ion competitive acid blocker (P-CABs).
  • P-CABs potassium ion competitive acid blocker
  • a first aspect of the present invention provides an injectable composition, which contains a pharmaceutically acceptable salt of the compound represented by Formula I and a stabilizer, where the stabilizer is edetate salt.
  • the edetate salt is one or more of disodium edetate, calcium sodium edetate, tetrasodium edetate, and dicalcium edetate.
  • the stabilizer is disodium edetate. In some more specific embodiments, the stabilizer is calcium sodium edetate.
  • pharmaceutically acceptable salts of the compound represented by Formula I are fumarate, oxalate, succinate, lactate, methanesulfonate, L-malate, citron Acid, nitrate, hydrobromide, hydrochloride, phosphate, sulfate.
  • the salt of the compound represented by Formula I may be a hydrochloride salt represented by the following Formula II.
  • the injection composition of the present invention contains a pharmaceutically acceptable salt of the compound represented by Formula I and a stabilizer.
  • the weight of the pharmaceutically acceptable salt of the compound represented by Formula I and the stabilizer The ratio is 1:1 ⁇ 20:1.
  • the weight ratio of the pharmaceutically acceptable salt of the compound represented by Formula I to the stabilizer can be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1 , 7:1, 8:1, 9:1, 10:1, 15:1 or 20:1, or any range formed by them, such as preferably 5:1 ⁇ 20:1, 5:1 ⁇ 15 :1 or 5:1 ⁇ 10:1 etc.
  • the weight ratio described here is based on the hydrochloride represented by formula II.
  • the compound represented by formula I, or its other salts other than the hydrochloride can be converted to calculate the corresponding weight ratio range.
  • the pH value of the injectable composition of the present invention is a physiologically acceptable pH value, and in some embodiments the pH value of the composition is 3.0 to 4.5. In some embodiments the pH of the composition is between 3.0 and 4.0. In some embodiments, the pH of the composition is 3.5; in some embodiments, the pH of the composition is 4.0; in some embodiments, the pH of the composition is 4.5.
  • the composition of the present invention can be adjusted according to conventional methods in this field.
  • the present invention can add pH adjusters and the like to adjust the pH of the composition.
  • conventional pH adjusters for adjusting the pH of the composition can be added thereto, for example, the pH adjusters are hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, fumaric acid, tartaric acid, One or more of sodium bicarbonate.
  • the pH adjuster is hydrochloric acid.
  • the injectable composition contains the hydrochloride salt of Formula II at a concentration of 1 mg/ml to 20 mg/ml. In some embodiments, the composition contains 1 mg to 10 mg of the hydrochloride salt represented by Formula II per 1 ml of composition. In some embodiments, the composition contains 1 mg to 5 mg of the hydrochloride salt represented by Formula II per 1 ml of composition. In some embodiments, the composition contains 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg of the hydrochloride represented by Formula II per 1 ml of composition. For example, each 1 mL of the composition contains 2.5 mg of the compound represented by Formula II (or any specific value within the scope of the present invention), and 0.125 to 0.5 mg of the stabilizer; or preferably, the stabilizer is 0.25 to 0.5 mg.
  • the injectable composition of a pharmaceutically acceptable salt of the compound of formula I disclosed in the present invention may not necessarily contain other additives other than a stabilizer and a pH adjuster.
  • the injectable composition is composed of a pharmaceutically acceptable salt of the compound of formula I. It consists of a pharmaceutically acceptable salt, a stabilizer, a pH adjuster and water for injection; the concentration of the pharmaceutically acceptable salt active ingredient of the compound described in Formula I is 1 to 20 mg/ml; the pharmaceutically acceptable concentration of the compound described in Formula I is The acceptable weight ratio of salt to edetate is 1:1 to 20:1, preferably 5:1 to 10:1; the pH value is 3.0 to 4.5. The amount of pH adjuster is sufficient to maintain the pH value of the composition.
  • the injection composition of the pharmaceutically acceptable salt of the compound of formula I disclosed in the present invention may also optionally include, but is not limited to, auxiliary materials commonly used in the art, such as osmotic pressure regulators, buffer solutions, etc.
  • the osmotic pressure regulator may be one of sodium chloride and glucose.
  • the total volume ratio of the osmotic pressure regulator to the injection is 0.6% to 1.0% (W/V, g/100mL).
  • the osmotic pressure regulator is sodium chloride.
  • the sodium chloride is used in an amount of 0.6%, 0.7%, 0.8%, 0.9% or 1.0%.
  • the injection composition of the present invention can be prepared into a solution injection.
  • the injection is a large volume injection.
  • the injection is a small volume injection.
  • the present invention also provides a combination including the above-mentioned injection solution and infusion.
  • the infusion may be: electrolyte solution (saline, Ringer's solution, etc.), nutritional infusion (carbohydrate solution (eg, glucose solution, eg, 5% (w/v) glucose solution, etc.)), etc.
  • the composition of the present invention has simple components and safe process. By preparing the pharmaceutically acceptable salt of the compound described in formula I into an injection composition, and by adding a certain amount of stabilizer to control the pH value of the composition, the composition can be ensured.
  • the fewer types and dosages of auxiliary materials in the composition of the present invention the higher the safety to the human body after injection.
  • the injection composition of the present invention can achieve better stability and effectiveness by using a smaller amount of stabilizer.
  • the content of impurity 1 and impurity 2 is reduced.
  • the injection composition is safer and has good storage stability, bringing new medication options to special groups who are not suitable for oral administration. It meets the clinical needs of patients with gastrointestinal bleeding and acute peptic ulcer who require rapid onset of action.
  • the second aspect of the present invention provides a method for preparing the above composition, which is simple and easy to implement, can be sterilized by terminal sterilization, has good stability, high safety, and is suitable for industrial production.
  • the present invention adopts the following technical solution: providing a method for preparing the aforementioned pharmaceutically acceptable salt composition containing the compound represented by Formula I, which includes the following steps:
  • the pharmaceutically acceptable salt and stabilizer of the compound of formula I are added to a certain volume of water for injection, dissolved, filled and sealed, and sterilized.
  • the pharmaceutically acceptable salt and stabilizer of the compound represented by Formula I are added to a certain volume of water for injection, dissolved, and the pH is adjusted to 3.0-4.5 with a pH adjuster, filled and sealed, and sterilized by moist heat for 15 minutes. ⁇ 30 minutes.
  • the stabilizer is an edetate salt, for example, one or more of disodium edetate, calcium sodium edetate, tetrasodium edetate, and dicalcium edetate. In some embodiments, the stabilizer is disodium edetate. In some embodiments, the stabilizer is calcium sodium edetate.
  • the pharmaceutically acceptable salt of the compound represented by Formula I is the hydrochloride, and the specific compound is represented by Formula II.
  • the hydrochloride represented by Formula II and calcium sodium edetate or disodium edetate are added to a certain volume of water for injection, dissolved, and the pH is adjusted to 3.0 to 4.5 with a pH adjuster, and the volume is constant; Moist heat sterilization at 121°C for 15 to 30 minutes.
  • the injection prepared by the present invention has a simple process, fewer types and dosages of auxiliary materials, adopts terminal sterilization method for sterilization, does not require the use of activated carbon, reduces production costs, and has high clinical safety.
  • the third aspect of the present invention provides specific uses of the composition.
  • the pharmaceutically acceptable salt of the compound represented by formula I or the compound of formula (II) can be used as a pharmaceutically active ingredient to form a composition, it can be used to treat or prevent peptic ulcers (for example, , gastric ulcer, duodenal ulcer or anastomotic ulcer, etc.), Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (e.g., non-erosive reflux disease) gastroesophageal reflux disease without esophagitis), Barrett's esophagitis, functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by NSAIDs, or after surgery Use in medicines to treat hyperacidity or ulcers caused by stress; or in preparations to inhibit upper gastrointestinal bleeding caused by peptic ulcers
  • the injection composition of the present invention or the injection prepared according to the injection composition has the ability to quickly stop upper gastrointestinal bleeding. Hematologic effects in patients with upper gastrointestinal bleeding who are difficult to administer orally.
  • the impurity detection results are expressed by calculating the peak area (%) of each impurity using the principal component self-control method. See Table 1 for specific examples and investigation results.

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Abstract

一种含有吡咯类胃酸分泌抑制剂的药物组合物及其制备方法，其包含由式I表示的化合物的药学可接受的盐及稳定剂。同时，还提供了该组合物的制备方法，该方法简单经济，适合工业化大生产。目前临床上暂无该化合物的注射用组合物。

Description

一种含有吡咯类胃酸分泌抑制剂的药物组合物及其制备方法 技术领域
本发明涉及一种注射用组合物及其制备方法，具体涉及一种含有吡咯类胃酸分泌抑制剂的注射用组合物及其制备方法。
背景技术
质子泵抑制剂通过抑制胃酸分泌以治疗消化性溃疡、反流性食管炎和卓艾综合症等在临床上得到广泛应用。钾竞争性的酸阻滞剂(P-CABs)是一种新型抑酸药物，可逆性竞争抑制胃壁细胞上质子泵中钾离子结合位点，在酸性环境下，P-CABs立刻离子化，以离子化形式结合抑制H+-K+-ATP酶，不需要集中于胃壁细胞的微囊和微管及酸的激活，能迅速升高胃内pH值，离解后酶活性恢复，对于上消化道的粘膜损伤，具有强效的抑制作用，用于胃溃疡、十二指肠溃疡、反流性食管炎等。
目前临床上暂无注射液形式的质子泵抑制剂，主要为口服固体制剂或者冻干粉针剂。口服固体制剂的质子泵抑制剂，如片剂，对于需快速起效的消化道出血、急性消化性溃疡，以及无法口服的患者顺应性较差，达不到快速起效的临床需求。注射用冻干粉针剂虽然可解决上述问题，但其制剂中所涉及的辅料较多，包材成本更高；因其原料稳定性问题，无法采用具有最高无菌保证水平的最终灭菌工艺，其制备工艺及生产成本均较高；且其存储条件也更为苛刻，需要低温保存。
式I所示的化合物化学名称为1-[5-(2-氟-苯基)-1-{[3-(3-甲氧基丙氧基)苯基]磺酰基}-1H-吡咯-3-基]-N-甲基甲胺，是一种钾离子竞争性酸阻滞剂(P-CABs)。具有用于预防和治疗胃酸相关性疾病，所述疾病包括(但不限于)胃肠道疾病例如消化性溃疡、卓-艾综合症、胃炎、胃溃疡、十二指肠溃疡、非甾体抗炎药引起的溃疡、幽门螺旋杆菌感染、胃食管反流疾病、反流性食管炎等。
中国专利CN 108969520A公开了一种N-甲基甲酰胺盐酸盐的A晶型化合物的组合物，将式I化合物与盐酸结合而形成的盐酸盐，具体结构如式II所示。并具体公开了式II所示化合物组成的口服给药组合物。对于需快速起效的消化道出血、急性消化性溃疡，以及无法口服的患者顺应性较差，达不到快速起效的临床需求。注射剂相比片剂，具有生物利用度高、起效迅速等优点。
由式II表示的盐酸盐在制备和贮藏期间，容易产生相应的降解杂质，其中主要已知降解杂质为杂质1和杂质2，其结构分别如下：
式II表示的盐酸盐作为一种新型的钾离子竞争性酸阻滞剂(P-CABs)，目前临床上暂无注射液形式的质子泵抑制剂，要将其研制成注射液，既需要解决溶解性问题，又尽可能减少辅料种类及用量，以降低因辅料造成的制剂对人体的不良反应，提高其安全性；同时需要控制生产及存放过程中的相关杂质含量，提高该组合物的制剂稳定性。
发明内容
本发明第一方面提供一种注射用组合物，其包含由式I所示的化合物的药学上可接受的盐和稳定剂，所述稳定剂为依地酸盐。
在一些实施方案中，所述依地酸盐为依地酸二钠、依地酸钙钠、依地酸四钠、依地酸二钙中的一种或多种。在一些更具体的实施例中，所述稳定剂为依地酸二钠。在一些更具体的实施例中，所述稳定剂为依地酸钙钠。
在一些实施方案中，式I表示的化合物的药学上可接受的盐为富马酸盐、草酸盐、丁二酸盐、乳酸盐、甲磺酸盐、L-苹果酸盐、枸橼酸盐、硝酸盐、氢溴酸盐、盐酸盐、磷酸盐、硫酸盐。在一些具体的实施例中，，由式I表示的化合物的盐可以是由以下式II所示的盐酸盐。
在一些实施方案中，本发明的注射液组合物包含由式I所示的化合物的药学上可接受的盐和稳定剂，式I所示的化合物的药学上可接受的盐与稳定剂的重量比为1:1～20:1。在一些实施方案中，式I所示的化合物的药学上可接受的盐与稳定剂的重量比可以为1:1、2:1、3:1、4:1、5:1、6:1、7:1、8:1、9:1、10:1、15:1或20:1，或者他们所形成的任意的范围，例如优选的5:1～20:1、5:1～15:1或者5:1～10:1等。此处所述的重量比是以式II所示的盐酸盐计，式I所示化合物，或者其除了盐酸盐以外的其他盐，可以经过换算计算相应重量比范围。
在一些实施方案中，本发明注射用组合物pH值为生理学上可接受的pH值，在一些实施方案中所述组合物pH值为3.0～4.5。在一些实施方案中所述组合物pH值为3.0～4.0。在一些实施例中，所述组合物的pH为3.5；在一些实施例中，所述组合物的pH为4.0；在一些实施例中，所述组合物的pH为4.5。本发明所述组合物可以按照本领域的常规方法进行调整即可。
在一些实施方案中，本发明可以添加pH调节剂等来调节组合物pH。其中，在制备注射液组合物时，可以向其中加入用于调节组合物pH的常规pH调节剂，例如所述pH调节剂为盐酸、氢氧化钠、柠檬酸、磷酸、富马酸、酒石酸、碳酸氢钠中的一种或多种。在一些具体的实施例中，所述pH调节剂为盐酸。
本公开的注射液组合物中所含的活性成分的量根据目标患者的使用条件、靶向治疗程度等而变化。在一些实施方案中，所述注射用组合物含有式II表示的盐酸盐浓度为1mg/ml至20mg/ml。在一些实施方案中，所述每1ml组合物含有式II表示的盐酸盐1mg至10mg。在一些实施方案中，所述每1ml组合物含有式II表示的盐酸盐1mg至5mg。在一些实施方案中，所述每1ml组合物含有式II表示的盐酸盐1mg，2mg，2.5mg，3mg，3.5mg，4mg，4.5mg，5mg。例如，每1mL组合物含有式II所示的化合物2.5mg(或者本发明范围内的任意具体数值)，稳定剂0.125～0.5mg；或者稳定剂优选为0.25～0.5mg。
本发明公开的式I的化合物的药学上可接受的盐的注射用组合物，可以不必包含稳定剂和pH调节剂以外的其他添加剂，例如所述注射组合物由式I所示的化合物的药学上可接受的盐、稳定剂、pH调节剂和注射用水组成；其中式I所述的化合物的药学上可接受的盐活性成分浓度为1～20mg/ml；式I所述的化合物的药学上可接受的盐与依地酸盐的重量比为1:1～20:1，优选为5:1～10:1；pH值为3.0～4.5。pH调节剂的量能够维持组合物pH值即可。
本发明公开的式I的化合物的药学上可接受的盐的注射用组合物，也可以可选地包括，但不限于，本领域中常规使用的辅料，例如渗透压调节剂、缓冲溶液等。所述渗透压调节剂可以为氯化钠、葡萄糖中的一种。所述渗透压调节剂与注射剂总体积比例，为0.6％～1.0％(W/V，g/100mL)。在一些实施方案中，所述渗透压调节剂为氯化钠。在一些实施方案中，所述氯化钠的用量为0.6％，0.7％，0.8％，0.9％或1.0％。
本发明注射用组合物可以制备成溶液型注射剂。在一些实施方案中，所述注射剂为大容量注射液。在一些实施方案中，所述注射剂为小容量注射剂。
本发明还提供了包括上述注射溶液与输液组合。所述输液可以是：电解质溶液(盐水、林格氏溶液等等)、营养输液(碳水化合物溶液(例如，葡萄糖溶液，例如5％(w/v)葡萄糖溶液等等))，等等。本发明组合物组分简单，工艺安全，通过将式I所述化合物的药学上可接受的盐，制备成注射用组合物，通过加入一定量的稳定剂，控制组合物pH值，可以保证组合物良好的物理化学稳定性，杂质含量易控制且增长较少，满足注射剂质量和溶解度要求，不需要加入额外的助溶剂或增溶剂等辅料，提高了组合物制剂的安全性。
本发明组合物辅料的种类及用量越少，注射后对人体的安全性越高，本发明的注射液组合物可以通过较少用量的稳定剂即可让组合物达到较好的稳定性，有效减少了杂质1和杂质2的含量。
该注射液组合物安全性更高，储存稳定性好，给不宜口服的特殊人群带来新的用药选择， 满足消化道出血、急性消化性溃疡患者需要快速起效的临床需求。
本发明第二方面提供一种上述组合物的制备方法，该方法简单易行，可采用终端灭菌法灭菌，稳定性好，安全性高，适于工业化生产。
为实现本发明的第二个目的，本发明采用以下的技术方案：提供一种前述的含式I所示的化合物的药学上可接受的盐组合物的制备方法，包括如下步骤：
将式I所式的化合物的药学上可接受的盐和稳定剂加入一定体积的注射用水中，溶解，灌装封口，灭菌即得。
进一步地，将式I所示的化合物的药学上可接受的盐和稳定剂加入一定体积的注射用水中，溶解，用pH调节剂调pH至3.0～4.5，灌装封口，湿热灭菌15分钟～30分钟。
所述稳定剂为依地酸盐，例如为依地酸二钠、依地酸钙钠、依地酸四钠、依地酸二钙中的一种或多种。在一些实施方案中，稳定剂为依地酸二钠。在一些实施方案中，稳定剂为依地酸钙钠。
在一些实施方案中，式I所示化合物的药学上可接受的盐为盐酸盐，具体化合物如式II所示。
在一些实施方案中，式II所示的盐酸盐和依地酸钙钠或依地酸二钠加入一定体积的注射用水中，溶解，用pH调节剂调pH至3.0～4.5，定容；121℃湿热灭菌15分钟～30分钟。
在一些实施方案中，根据生产批用量取80～90％的注射用水，加入式II表示的盐酸盐和依地酸钙钠或依地酸二钠，搅拌使之溶解；用1mol/L盐酸调节pH至3.0～4.5范围内，补加注射用水至全量；过滤，充入氮气，灌装封口，121℃湿热灭菌15分钟。
通过本发明制备出注射液，工艺简单，辅料种类及用量较少，采用终端灭菌法进行灭菌，无需使用活性炭，生产成本降低，临床安全性较高。
本发明第三方面提供该组合物的具体用途，式I所示化合物的药学上可接受的盐或式(II)化合物作为药学活性成分组成组合物时，可用于治疗或预防消化性溃疡(例如，胃溃疡、十二指肠溃疡或吻合口溃疡等)、卓-艾综合症、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病(例如，非糜烂性的反流性疾病或无食管炎的胃食管反流疾病)、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡的药物中的用途；或者在制备抑制用于消化性溃疡、急性应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血。
本发明注射用组合物或按照注射用组合物制备所得的注射剂对上胃肠道出血具有快速止 血效果，对于难以口服给药的上胃肠道出血的患者。
具体实施方式
以下的实施例便于更好地理解本发明，但并不限定本发明。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。
实施例1～实施例6
称取式II所示的化合物、稳定剂，将其溶解于90％处方量注射用水中，用盐酸调节溶液pH后，加注射用水补齐。将溶液灌装到2ml，灌封前后充入氮气；组合物在121℃/15min条件下进行灭菌，即得。考察不同实施例样品的性状及杂质的变化，杂质的变化通过HPLC进行检测，用于检测杂质含量的分析方法如下所示：
用十八烷基硅烷键合硅胶为填充剂的色谱柱,检测器为UV，检测波长为230nm；流动相为0.01mol/L磷酸氢二钾缓冲液-乙腈。
杂质检测结果以主成分自身对照法计算各杂质的峰面积(％)表示，具体实施例及考察结果见表1。
表1

如表1中所示，不同稳定剂的组合物0天及高温60℃条件10天后，样品性状均未发生变化，杂质变化均较小。组合物在放置光照5000Lx条件10天后，未加稳定剂的组合物性状由无色澄明液体变为淡黄色混悬液，有关物质显著增长；组合物中加入稳定剂后，组合物的稳定性有不同程度的改善，选用本发明所述的依地酸二钠、依地酸钙钠作为稳定剂的注射液组合物稳定性显著增加，且性状较好，特别是杂质1和2的增长明显减少。
实施例7～实施例16
称取式II所示的化合物、依地酸二钠或依地酸钙钠，将其溶解于90％处方量注射用水中，用盐酸调节溶液pH后，加注射用水补齐。将溶液灌装到2ml安瓿瓶中，灌封前后充入氮气；样品在121℃/15min条件下进行灭菌，即得。将组合物置于高温60℃及光照5000Lx条件下进行稳定性考察，确认注射液的性状及杂质的变化。结果见表2-表3。
表2

表3

如表2和表3所示，当稳定剂与式II所示的化合物的质量比为0.02时，组合物的稳定性稍差，且样品在高温及光照条件下杂质显著增加，光照条件下组合物颜色由无色变为淡黄色；当稳定剂与式II所示的化合物的质量比在本发明所述的0.05～1.0范围内时，注射液组合物在高温及光照条件下稳定性较好，且性状无显著变化。
实施例17～实施例21
称取式II所示的化合物、依地酸二钠或依地酸钙钠，将其溶解于90％处方量注射用水中，用盐酸调节溶液pH后，加注射用水补齐。将溶液灌装到2ml安瓿瓶中，灌封前后充入氮气；样品在121℃/15min条件下进行灭菌，即得。将组合物置于高温60℃及光照5000Lx条件下进行稳定性考察，确认注射液的性状及杂质的变化。结果见表4。
表4

上述表中结果证实了pH对注射液组合物稳定性的影响。结合实施例17～实施例21，当注射液组合物的pH为2.0时，较低的pH使式II所示的化合物的溶解度降低，组合物中有晶体析出；当注射液组合物的pH为5.0时，组合物的稳定性变差，且在放置高温及光照条件后，杂质显著增加，光照条件下溶液颜色由无色变为淡黄色；当注射液组合物的pH在本发明所述的3.0～4.5范围内时，组合物稳定性较好，且性状无显著变化。
实施例22～实施例27
称取式II所示的化合物、依地酸二钠或依地酸钙钠，将其溶解于90％处方量注射用水中，用盐酸或磷酸调节溶液pH后，加注射用水补齐。将溶液灌装到2ml棕色安瓿瓶中，灌封前后充入氮气；组合物在121℃/15min条件下进行灭菌，即得。结果见表5。
表5
如表5中所示，注射液组合物中式II所示的化合物浓度为25mg/ml时，样品在制备过程中有晶体析出，难以满足该组合物的溶解，并且在制备及存放过程中可能发生沉淀或可能产生杂质。注射液组合物中式II所示的化合物浓度为1mg/ml或更低时，需要大剂量的可注射液溶液以达到足够的治疗效果，增加了使用过程中的难度；而在本发明所述的式II所示的化合物浓度为1mg/ml～20mg/ml范围时，有效克服了上述问题。
上面已经详细描述了本专利的部分组成，但对于本领域技术人员显而易见的是，阐述这种详细描述仅是为了说明示例性实施方式，而不应理解为限制本专利的范围。因此，本公开的实质范围由所附权利要求及其同等方案限定。

Claims (20)

  1. 一种注射用组合物，包含由式I所示的化合物的药学上可接受的盐和稳定剂，其中所述稳定剂为依地酸盐，
  2. 根据权利要求1所述的注射用组合物，其特征在于，所述药学上可接受的盐选自：富马酸盐、草酸盐、丁二酸盐、乳酸盐、甲磺酸盐、L-苹果酸盐、枸橼酸盐、硝酸盐、氢溴酸盐、盐酸盐、磷酸盐、硫酸盐中的一种。
  3. 根据权利要求1所述的注射用组合物，其特征在于，所述式I所述化合物的药学上可接受的盐为盐酸盐，具体化合物如下式II所示，
  4. 根据权利要求1所述的注射用组合物，其特征在于，所述依地酸盐为依地酸二钠、依地酸钙钠、依地酸四钠、依地酸二钙中的一种或多种；优选为依地酸二钠或依地酸钙钠中的一种或多种。
  5. 根据权利要求1-4之一所述的注射用组合物，其特征在于，所述式I所述的化合物的药学上可接受的盐活性成分浓度为1–20mg/mL。
  6. 根据权利要求1-4之一所述的注射用组合物，其特征在于，所述式I所述的化合物的药学上可接受的盐与依地酸盐的重量比为1:1～20:1，优选为5:1～10:1。
  7. 根据权利要求1-4之一所述的注射用组合物，其特征在于，所述注射用组合物pH值为3.0～4.5。
  8. 根据权利要求1所述的注射用组合物，其特征在于，所述注射组合物还包含pH调节剂，所述pH调节剂为盐酸、氢氧化钠、柠檬酸、磷酸、富马酸、酒石酸、碳酸氢钠中的一种或 多种，优选为盐酸。
  9. 根据权利要求1所述的注射用组合物，其特征在于，所述注射组合物由式I所示的化合物的药学上可接受的盐、稳定剂、pH调节剂和注射用水组成；其中式I所述的化合物的药学上可接受的盐活性成分浓度为1–20mg/ml；式I所述的化合物的药学上可接受的盐与依地酸盐的重量比为1:1～20:1，优选为5:1～10:1；pH值为3.0～4.5。
  10. 根据权利要求3所述的注射用组合物，其特征在于，所述注射用组合物为每1mL组合物含有式II所示的化合物2.5mg，稳定剂0.125～0.5mg；其中稳定剂优选为0.25～0.5mg。
  11. 根据权利要求1-4之一所述的注射用组合物，其特征在于，所述注射用组合物制备成溶液型注射剂。
  12. 根据权利要求11所述的注射用组合物，其特征在于，所述溶液型注射剂为小容量输液或大容量输液。
  13. 根据权利要求1-4之一所述的注射用组合物，其特征在于，所述注射用组合物还包括渗透压调节剂。
  14. 根据权利要求13所述的注射用组合物，其特征在于，所述渗透压调节剂为氯化钠、葡萄糖中的一种。
  15. 根据权利要求13所述的注射用组合物，其特征在于，渗透压调节剂为氯化钠，所述渗透压调节剂的重量与注射液总体积比例，所述渗透压调节剂用量为0.6％～1.0％；优选为0.6％，0.7％，0.8％或0.9％。
  16. 一种权利要求1-15任一项所述的注射用组合物的制备方法，其特征在于，式I所述的化合物的药学上可接受的盐和依地酸盐加入一定体积的注射用水中，溶解，灭菌即得。
  17. 根据权利要求16所述的注射用组合物的制备方法，其特征在于，
    式I所述的化合物的药学上可接受的盐和依地酸盐加入一定体积的注射用水中，溶解；用pH调节剂调pH至3.0～4.5；加入注射用水定容；湿热灭菌15min～30min。
  18. 根据权利要求16或17所述的注射用组合物的制备方法，其特征在于，取处方量80％～90％的注射用水，加入I所述的化合物的药学上可接受的盐和依地酸盐，搅拌使之溶解；用1mol/L盐酸调节pH至3.0～4.0范围内，补加注射用水至全量；过滤，充入氮气，灌装封口，121℃湿热灭菌15min～30min。
  19. 权利要求1-15之一所述的注射用组合物在制备用于治疗或预防消化性溃疡、卓-艾综合症、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能 性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡的药物中的用途；或者在制备抑制用于消化性溃疡、急性应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血药物中的用途。
  20. 根据权利要求19所述的用途，其特征在于，所述的消化性溃疡包括胃溃疡、十二指肠溃疡或吻合口溃疡；所述的症状性胃食管反流疾病包括非糜烂性的反流性疾病或无食管炎的胃食管反流疾病。
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CHEN SONGFENG, LIU DELIANG, CHEN HONGHUI, LIAO AIJUN, LI FANGFANG, LIU CHENGXIA, LI XING, LI SHENGBAO, ZHANG YAN, WANG YANG, XIA M: "The Efficacy and Safety of Keverprazan, a Novel Potassium-Competitive Acid Blocker, in Treating Erosive Oesophagitis: a Phase III, Randomised, Double-Blind Multicentre Study", ALIMENTARY PHARMACOLOGY & THERAPEUTICS, BLACKWELL SCIENTIFIC PUBLICATIONS LTD., CAMBRIDGE., GB, vol. 55, no. 12, 1 June 2022 (2022-06-01), GB , pages 1524 - 1533, XP093135059, ISSN: 0269-2813, DOI: 10.1111/apt.16959 *

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