WO2018133009A1 - Composition de fumarate de vonoprazan et sa méthode de préparation - Google Patents

Composition de fumarate de vonoprazan et sa méthode de préparation Download PDF

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Publication number
WO2018133009A1
WO2018133009A1 PCT/CN2017/071723 CN2017071723W WO2018133009A1 WO 2018133009 A1 WO2018133009 A1 WO 2018133009A1 CN 2017071723 W CN2017071723 W CN 2017071723W WO 2018133009 A1 WO2018133009 A1 WO 2018133009A1
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Prior art keywords
cyclodextrin
fumarate
injection
substituted
acid
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PCT/CN2017/071723
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English (en)
Chinese (zh)
Inventor
牟丽秋
赵步文
黄芳芳
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广东东阳光药业有限公司
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Priority to PCT/CN2017/071723 priority Critical patent/WO2018133009A1/fr
Publication of WO2018133009A1 publication Critical patent/WO2018133009A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • 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
    • 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

Definitions

  • the invention relates to a vonorazanic fumaric acid composition, in particular to a safe and stable vonorazan fumarate composition containing substituted ⁇ -cyclodextrin and a preparation method thereof, and belongs to the technical field of pharmacy.
  • Vonoprazan fumarate formerly known as TAK-438
  • TAK-438 is a novel gastric acid secretion inhibitor developed by Takeda, Japan. It has a fast-acting, strong and long-lasting inhibition of gastric acid secretion, and gastric acid in the stomach wall.
  • K + to H + -K + -ATPase proton pump
  • it also has an early termination effect on gastric acid secretion.
  • Voronafu a fumaric acid, was first launched in Japan in 2014 under the trade name Takecab.
  • vorolazan fumarate 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methyl
  • a single amine salt of fumaric acid the structural formula is as follows:
  • the marketed dosage form of vorolazan fumarate is a tablet, and no other dosage forms have been disclosed. Since the tablets are oral preparations, the compliance is poor for patients with dysphagia, children, and the elderly; and for patients with acute gastritis and gastric ulcers that require rapid onset of action, the tablet does not meet the clinical needs for rapid onset of action. Therefore, the development of a new pharmaceutical formulation of vorolazin fumarate, such as injection, is of great significance for providing more therapeutic options for patients who have difficulty in using tablets or achieving therapeutic effects.
  • Voronazide fumarate is a slightly water-soluble substance, and because of its poor water solubility, it is difficult to meet the demand for injection solubility of the drug. Therefore, there are major challenges in the development of injectable dosage forms.
  • the prior art CN 201410154778.8 discloses a novel water-soluble organic acid salt of Voronazan and an injection of the water-soluble organic acid salt and a preparation method thereof, but the novel water-soluble organic acid salt and the active ingredient already on the market are rich in horses.
  • the acid vorolazan its effect has not been supported by clinical trials and medicinal practices, nor has it increased the water-soluble technical means and effects of vorolazan fumarate, and the injection uses 100 ° C steam. Sterilization for 30 minutes, this method is not terminal sterilization, and does not achieve a superior sterilization effect. Therefore, it has been important to improve the water solubility of vorolazan fumarate by an appropriate method, and to develop a vonolazan fumarate composition and an injection preparation suitable for injection use and a preparation method thereof.
  • a composition comprising a substituted ⁇ -cyclodextrin-containing vorolazan fumarate which is capable of increasing the solubility of vorolazan fumarate in water.
  • a wonorazin fumarate injection prepared by the composition of the first aspect which is safe and effective, has good storage stability, and brings new drug selection to a special group that is not suitable for oral administration. Meet the clinical needs of patients with acute gastritis and gastric ulcer who need rapid onset of action.
  • a third aspect of the present invention provides a method for preparing a fumarazin fumarate injection according to the second aspect, which is simple and easy to perform, can be sterilized by terminal sterilization, has good stability and high safety, and is suitable for the method. Industrial production.
  • the fourth aspect of the present invention also provides a solution of venorazin fumarate infusion solution and a preparation method thereof.
  • the present invention has been intensively investigated and studied, and the substituted ⁇ -cyclodextrin is used as a solubilizing agent to form an inclusion complex with vorolazan fumarate, and on the one hand, the ⁇ -cyclodextrin is substituted to increase fumaric acid.
  • the solubility of vonolazan in water, the stability of the solution is good, and it satisfies the solubility requirement of the preparation into injection; on the one hand, the preparation of vorolazin fumarate is further prepared from the inclusion compound, and the bioavailability is high and the effect is effective.
  • the present invention provides a vorolazan fumarate composition
  • a vorolazan fumarate composition comprising vorolazan fumarate and a solubilizing agent, wherein the solubilizing agent is a substituted ⁇ -cyclodextrin, Tween 80, a phospholipid, a polox Sham or any combination of them.
  • the solubilizer is capable of increasing the solubility of vorolazan fumarate in water.
  • solubilizing agent is a substituted beta-cyclodextrin.
  • a composition comprising vorolazan fumarate and a substituted ⁇ -cyclodextrin, wherein the substituted ⁇ -cyclodextrin is hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrinsperm, hydroxyethyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin or any combination thereof.
  • the substituted ⁇ -cyclodextrin is hydroxypropyl- ⁇ -cyclodextrin; in some embodiments, sulfobutylether- ⁇ -cyclodextrin.
  • a vonorazanic fumaric acid composition wherein the composition is an inclusion compound.
  • a composition comprising vorolazan fumarate and a solubilizing agent which can be prepared as a liquid preparation of vorolazan fumarate, which can be, but not limited to, a spray, a suspension, a solution, an injection .
  • the liquid formulation is an injection.
  • the present invention provides a wornolazan fumarate inclusion complex comprising wortolazan fumarate and a substituted ⁇ -cyclodextrin capable of increasing the fumarate fumarate at Solubility in water.
  • An inclusion complex comprising vorolazan fumarate and a substituted ⁇ -cyclodextrin, wherein the weight ratio of the vorolazan fumarate to the substituted ⁇ -cyclodextrin is 1:1 to 1:20 . In some embodiments it is 1:3; in some embodiments 1:5; in some embodiments 1:10.
  • An inclusion complex comprising vorolazan fumarate and a substituted ⁇ -cyclodextrin, wherein the substituted ⁇ -cyclodextrin is hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -ring Dextrin, hydroxyethyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin or any combination thereof.
  • the substituted ⁇ -cyclodextrin is hydroxypropyl- ⁇ -cyclodextrin; in some embodiments, sulfobutylether- ⁇ -cyclodextrin.
  • An inclusion complex comprising vorolazan fumarate and a substituted ⁇ -cyclodextrin, which can be prepared as a liquid preparation of vorolazan fumarate, which can be, but not limited to, a spray or a suspension. , solution, injection.
  • the liquid formulation is an injection.
  • the present invention provides a vorolazan fumarate injection comprising vonolazan fumarate and substituted ⁇ -cyclodextrin.
  • a vorolazan injection of fumaric acid wherein the substituted ⁇ -cyclodextrin is hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin Refined, methyl- ⁇ -cyclodextrin or any combination thereof.
  • the substituted ⁇ -cyclodextrin is hydroxypropyl- ⁇ -cyclodextrin; in some embodiments, sulfobutylether- ⁇ -cyclodextrin.
  • a vorolazan injection of fumaric acid wherein the injection is a ready-to-use liquid injection.
  • a vorolazan injection of fumaric acid wherein the ratio of the weight of the vorolazan fumarate to the total volume of the injection is 0.05% to 10% (w/v, g/mL). In some embodiments it is 0.4%.
  • a vorolazan injection of fumaric acid wherein the ratio of the weight of the substituted ⁇ -cyclodextrin contained to the total volume of the injection is from 0.4% to 20% (w/v, g/mL). In some embodiments it is 0.8%; in some embodiments 1.2%; in some embodiments 2%.
  • a vorolazin fumarate injection wherein the weight ratio of the vorolazan fumarate to the substituted ⁇ -cyclodextrin is from 1:1 to 1:20. In some embodiments it is 1:3; in some embodiments 1:5; in some embodiments 1:10.
  • the vorolazan fumarate injection further comprises a solvent, a pH adjuster, a buffer.
  • the solvent is water.
  • the pH adjusting agent comprises hydrochloric acid, acetic acid, sodium hydroxide, sodium hydrogen phosphate, calcium carbonate or magnesium hydroxide; in some embodiments, the pH adjusting agent is sodium hydroxide.
  • the buffering agent is acetic acid, citric acid monohydrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, malic acid, benzoic acid or any combination thereof; in some embodiments, the buffering agent Is tartaric acid; in some embodiments, the buffer is citric acid monohydrate.
  • a vorolazan fumarate injection wherein the ratio of the weight of the buffer contained to the total volume of the injection is from 0.1% to 3% (w/v, g/mL). In some embodiments it is 0.4%.
  • a vorolazan injection of fumaric acid wherein the injection has a pH in the range of 3.0 to 9.0, and in some embodiments, 4.23.
  • a vorolazan injection of fumaric acid wherein the injection has a pH in the range of 3.0 to 6.0.
  • a vorolazan fumarate injection wherein the injection has a pH in the range of 4.0 to 5.0, and in some embodiments 4.14.
  • a fumarazin fumarate injection comprising:
  • a fumarazin fumarate injection comprising:
  • a fumarazin fumarate injection comprising:
  • a fumarazin fumarate injection comprising:
  • the present invention also provides a method for preparing the above-mentioned vorolazin fumarate injection, which comprises dissolving a buffer, a substituted ⁇ -cyclodextrin in purified water, and adjusting the pH to 4.0-5.0 using a pH adjuster. Adding fumarate fumarate, stirring and dissolving, adding purified water to volume, measuring the pH value of the final solution, bottling, stoppering, capping, terminal sterilization.
  • the above-described vorolazin fumarate injection can be prepared as follows:
  • the invention provides a solution for the infusion of fumarazin fumarate.
  • a solution of vorolazin fumarate infusion solution wherein the ratio of the weight of the vorolazan fumarate to the total volume of the infusion solution is 0.005% to 10% (w/v, g/mL). In some embodiments it is 0.0107%; in some embodiments 0.053%; in some embodiments 0.0053%.
  • a solution of vorolazin fumarate infusion containing wonolam fumarate and a buffer wherein the buffer is acetic acid, citric acid monohydrate, succinic acid, adipic acid, tartaric acid, anti-ring Blood acid, malic acid, benzoic acid or any combination thereof.
  • the buffer is tartaric acid.
  • a solution of vorolazin fumarate infusion solution wherein the ratio of the weight of the buffer contained to the total volume of the solution for infusion is 0.001% to 3% (W/V, g/mL). In some embodiments 0.0053%; in some embodiments 0.053%.
  • a solution of vorolazan fumarate infusion which further comprises an isotonicity adjusting agent.
  • the isotonicity adjusting agent is sodium chloride, glucose, mannitol, sorbitol, glycerin or the like.
  • the isotonicity adjusting agent is sodium chloride; in some embodiments, the isotonicity adjusting agent is glucose.
  • the solution osmotic pressure was adjusted to 260 mosm / L to 320 mosm / L.
  • a solution of inofazan fumarate infusion solution wherein the infusion solution has a pH in the range of 3.0 to 6.0. In some embodiments it is 4.5.
  • the invention also provides a preparation method of a solution of vorolazin fumarate infusion, which comprises dissolving an isotonic regulator in purified water, adding vorolazan fumarate, a buffering agent, and stirring and dissolving. Adjust the pH to 3.0-6.0 with a pH adjuster, add purified water to volume, and measure the pH of the final solution.
  • the above-described solution of vorolazin fumarate infusion can be prepared as follows:
  • the wovonazin fumaric acid composition provided by the invention can increase the solubility of wortolazan fumarate in water, meet the requirement for preparation into an injection, and can be sterilized by terminal sterilization method, and the sterilization is thorough and improved.
  • Injectables safety the provided Norfolk fumarate injection is a new dosage form that meets the clinical need for rapid onset of action in patients with acute gastritis and gastric ulcer, and can solve the problem of drug delivery in patients with dysphagia.
  • High safety and good stability; the preparation method is simple and easy to implement, and is suitable for industrial production.
  • the invention provides a solution for the infusion solution of fumarate fumarate, which is simple and easy to manufacture, and is suitable for industrial production.
  • reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
  • min minute
  • h hour
  • mg milligram
  • g gram
  • mL milliliter
  • W weight
  • V volume
  • Example 1 Solubilization of vorolazan fumarate using hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD).
  • Example 1 After stirring for 20 min, the API was completely dissolved. The results of the short-term stability study confirmed that the solution was allowed to stand at 40 ° C for 80 h, and the solution was allowed to stand at 60 ° C for 72 h, and the solution remained stable. The stability study results are shown in Table 1-2.
  • Example 1 Conclusion: When the HP- ⁇ -CD to API mass ratio was 10:1, the API was effectively solubilized; and the obtained solution was allowed to stand at 40 ° C for 80 hours and then kept at 60 ° C for 72 hours to remain stable.
  • Example 2 Different amounts of HP- ⁇ -CD solubilized vorolazan fumarate.
  • Example 2 Conclusion: The HP- ⁇ -CD to API ratio reduced to 3:1 still effectively solubilized the API.
  • Example 3 Solubilization of vonolazan fumarate by HP- ⁇ -CD in different buffer solutions.
  • Example 3 Results After stirring for 60 min, the API was completely dissolved in the solution.
  • the pH values of the final solutions of the two samples were 4.22 and 4.23, respectively.
  • the preliminary stability study showed that the two solutions were placed at 40 ° C for 24 h and then at 60 ° C for 24 h.
  • the content of the relevant substances in the solution was basically unchanged.
  • the relevant substances are shown in Table 3-3, 3-4.
  • Example 3 When the mass ratio of HP- ⁇ -CD to API is 3:1, the API can be effectively solubilized in different buffer solutions, and the buffer has no significant effect on the dissolution rate; the obtained solution is placed at 40 ° C for 24 h, and then It was kept stable at 60 ° C for 24 h.
  • Example 4 Solubilization of HP- ⁇ -CD to vorolazan fumarate in different buffer solutions.
  • Example 5 Conclusion: When the SBE- ⁇ -CD to API mass ratio is 3:1 and above, the API can be effectively solubilized.
  • Example 6 Solubilization of SBE- ⁇ -CD to vorolazan fumarate in different buffer solutions.
  • Example 6 Results: After stirring for 60 min, the API was completely dissolved in the solution.
  • the pH values of the final solutions of the two samples were 4.14 (citric acid monohydrate) and 4.21 (tartaric acid) respectively.
  • the preliminary stability study showed that the two solutions were placed at 40 ° C for 24 h and then at 60 ° C for 24 h. Basically unchanged.
  • the relevant substances are shown in Table 6-3, 6-4.
  • Example 6 When the mass ratio of SEB- ⁇ -CD to API is 3:1, the API can be effectively solubilized in different buffer solutions, and the dissolution rate is not affected; the obtained solution is placed at 40 ° C for 24 h, and then Stable at 60 ° C for 24 h.
  • Example 7 Stability of SBE-[beta]-CD fumarazin fumarate solution to sterilization conditions.
  • Example 7 Results: Both the low concentration sample and the high concentration sample were clear and transparent before and after sterilization, and the colorless solution was obtained. After sterilization, the content of related substances in the solution increased slightly; the amount of SBE- ⁇ -CD and the type of buffer had no significant effect on the content of related substances in the solution. The relevant substances are shown in Table 7-5.
  • Example 7 Conclusion: The five prescription sample solutions remained substantially stable after 12 minutes of sterilization at 121 °C.
  • the two samples were allowed to stand at 40 ° C for 6 months, and the impurity content increased only slightly.
  • Example 9 Preparation of a solution of vorolazin fumarate infusion solution
  • Example 9 Experimental results: The vanoramine fumarate in the four samples was dissolved after stirring for half an hour, and the obtained solution was clear and transparent, colorless; the solution was sterilized by moist heat sterilization or filtration.
  • Example 1 - Example 7 respectively used a substituted- ⁇ -cyclodextrin to prepare a vorolazin fumarate composition or an injection, and in the stability test, the single impurity and the total impurity content are substantially not In the influencing factors experiment, the single and total impurities only increased slightly, and the change trend was not obvious. Even after autoclaving, the content of single and total impurities before and after sterilization was small, which was consistent with the impurity content of the injection. Control standards. From the analysis of the results of the stability test, it was found that the fumarazin fumarate composition or the injection of the present invention has good solubility and solution stability.

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Abstract

La présente invention concerne une composition de fumarate de vonoprazan et sa méthode de préparation. La composition comprend du fumarate de vonoprazan, un agent de solubilisation, un tampon, un agent de régulation du pH et un solvant.
PCT/CN2017/071723 2017-01-19 2017-01-19 Composition de fumarate de vonoprazan et sa méthode de préparation WO2018133009A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115364065A (zh) * 2022-08-23 2022-11-22 宁波高新区美诺华医药创新研究院有限公司 富马酸伏诺拉生片

Citations (3)

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Publication number Priority date Publication date Assignee Title
CN106031710A (zh) * 2015-03-16 2016-10-19 南京优科制药有限公司 一种富马酸氟呐普拉赞的注射剂及其制备方法
CN106551898A (zh) * 2015-09-21 2017-04-05 广东东阳光药业有限公司 一种富马酸沃诺拉赞组合物及其制备方法
CN106924179A (zh) * 2015-12-29 2017-07-07 成都康弘药业集团股份有限公司 一种含有富马酸沃诺拉赞的液体制剂及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106031710A (zh) * 2015-03-16 2016-10-19 南京优科制药有限公司 一种富马酸氟呐普拉赞的注射剂及其制备方法
CN106551898A (zh) * 2015-09-21 2017-04-05 广东东阳光药业有限公司 一种富马酸沃诺拉赞组合物及其制备方法
CN106924179A (zh) * 2015-12-29 2017-07-07 成都康弘药业集团股份有限公司 一种含有富马酸沃诺拉赞的液体制剂及其制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115364065A (zh) * 2022-08-23 2022-11-22 宁波高新区美诺华医药创新研究院有限公司 富马酸伏诺拉生片
CN115364065B (zh) * 2022-08-23 2024-03-15 宁波高新区美诺华医药创新研究院有限公司 富马酸伏诺拉生片

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