+

WO2018133009A1 - 一种富马酸沃诺拉赞组合物及其制备方法 - Google Patents

一种富马酸沃诺拉赞组合物及其制备方法 Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
cyclodextrin
fumarate
injection
substituted
acid
Prior art date
Application number
PCT/CN2017/071723
Other languages
English (en)
French (fr)
Inventor
牟丽秋
赵步文
黄芳芳
Original Assignee
广东东阳光药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广东东阳光药业有限公司 filed Critical 广东东阳光药业有限公司
Priority to PCT/CN2017/071723 priority Critical patent/WO2018133009A1/zh
Publication of WO2018133009A1 publication Critical patent/WO2018133009A1/zh

Links

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及富马酸沃诺拉赞组合物及其制备方法。所述组合物包含富马酸沃诺拉赞、增溶剂、缓冲剂、pH调节剂、溶剂。

Description

一种富马酸沃诺拉赞组合物及其制备方法 技术领域
本发明涉及一种富马酸沃诺拉赞组合物，具体涉及一种安全、稳定的含取代β-环糊精的富马酸沃诺拉赞组合物及其制备方法，属于制药技术领域。
背景技术
富马酸沃诺拉赞(Vonoprazan fumarate)曾用代号TAK-438，是由日本武田公司开发的一种新型胃酸分泌抑制剂，具有速效、强劲、持久的胃酸分泌抑制作用，且在胃壁细胞胃酸分泌的最后一步中，通过抑制K+对H+-K+-ATP酶(质子泵)的结合作用，对胃酸分泌还具有提前终止作用。富马酸沃诺拉赞于2014年在日本首次上市，商品名为Takecab。
富马酸沃诺拉赞的化学名为1-[5-(2-氟苯基)-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基]-N-甲基甲胺富马酸单盐，结构式如下：
Figure PCTCN2017071723-appb-000001
目前富马酸沃诺拉赞的上市剂型为片剂，尚未有其它剂型公开。由于片剂属于口服制剂，对于吞咽困难患者、儿童、老年人用药时，顺应性较差；且对于需要快速起效的急性胃炎、胃溃疡患者，片剂达不到快速起效的临床需求，因此开发新的富马酸沃诺拉赞药物剂型，如注射剂，为更多具备用药需求而难以使用片剂给药或达到疗效的患者提供治疗选择具有重要意义。
富马酸沃诺拉赞为微溶于水的物质，由于其水溶性较差，难以满足注射剂对药物溶解度的需求。因此，对于注射剂型的开发存在着较大挑战。
现有技术CN 201410154778.8公开了沃诺拉赞的新型水溶性有机酸盐和所述水溶性有机酸盐的注射剂及其制备方法，但是这类新型水溶性有机酸盐与已经上市的活性成分富马酸沃诺拉赞相比，其效果并未得到临床实验和药用实践的支持，也未有增加富马酸沃诺拉赞的水溶性的技术手段和效果，且所述注射剂使用100℃蒸汽灭菌30分钟，该方法并非终端灭菌，达不到较优的灭菌效果。因此，通过适当的方法提高富马酸沃诺拉赞水溶性，开发出适于注射用途的富马酸沃诺拉赞组合物和注射剂及其制备方法具有重要意义。
发明内容
发明概述
本发明第一方面提供一种含取代β-环糊精的富马酸沃诺拉赞的组合物，所述取代β-环糊精能够增加富马酸沃诺拉赞在水中溶解度。
本发明第二方面提供了一种由第一方面组合物制备得到的富马酸沃诺拉赞注射剂，该注射剂安全有效，储存稳定性好，给不宜口服的特殊人群带来新的用药选择，满足急性胃炎、胃溃疡患者需要快速起效的临床需求。
本发明第三方面提供一种第二方面所述富马酸沃诺拉赞注射剂的制备方法，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。
本发明第四方面还提供了一种富马酸沃诺拉赞输液用溶液及其制备方法。
术语定义
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“终端灭菌法”的具体参数：湿热灭菌，121℃，12min至15min。
在本发明的上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现10％以下的差异或者本领域人员认为的合理的差异，如1％、2％、3％、4％或5％的差异。
发明详述
基于现有技术的不足，本发明经过深入考察和研究，选用取代β-环糊精作为增溶剂与富马酸沃诺拉赞形成包合物，一方面取代β-环糊精增加富马酸沃诺拉赞在水中的溶解性，溶液稳定性好，满足制备成注射剂的溶解度需求；一方面，由该包合物进一步制备得到富马酸沃诺拉赞注射剂，生物利用度高，起效快，安全性好，对特殊人群的用药顺应性好；另一方面使用取代β-环糊精与富马酸沃诺拉赞的组合在注射剂的制备工艺中，溶液稳定性强，能够采用终端灭菌法灭菌，灭菌彻底。
本发明提供一种富马酸沃诺拉赞组合物，含有富马酸沃诺拉赞与增溶剂，其中，所述增溶剂为取代β-环糊精，吐温80，磷脂质，泊洛沙姆或它们的任意组合。所述增溶剂能够增加富马酸沃诺拉赞在水中溶解度。
在一些实施例中所述增溶剂为取代β-环糊精。
一种含有富马酸沃诺拉赞与取代β-环糊精的组合物，其中所述取代β-环糊精为羟丙基-β-环糊精、磺丁基醚-β-环糊精、羟乙基-β-环糊精、甲基-β-环糊精或它们的任意组合。在一些实施例中为羟丙基-β-环糊精；在一些实施例中为磺丁基醚-β-环糊精。
一种富马酸沃诺拉赞组合物，其中，所述组合物为包合物。
一种含有富马酸沃诺拉赞与增溶剂的组合物，其可以制备成富马酸沃诺拉赞液体制剂，所述液体制剂可以是但不限于喷雾剂、混悬剂、溶液剂、注射剂。在一些实施例中，所述液体制剂为注射剂。
本发明提供一种富马酸沃诺拉赞包合物，含有富马酸沃诺拉赞与取代β-环糊精，所述取代β-环糊精能够增加富马酸沃诺拉赞在水中溶解度。
一种含有富马酸沃诺拉赞与取代β-环糊精的包合物，其中所述富马酸沃诺拉赞与取代β-环糊精的重量比例为1:1到1:20。在一些实施例中为1:3；在一些实施例中为1:5；在一些实施例中为1:10。
一种含有富马酸沃诺拉赞与取代β-环糊精的包合物，其中所述取代β-环糊精为羟丙基-β-环糊精、磺丁基醚-β-环糊精、羟乙基-β-环糊精、甲基-β-环糊精或它们的任意组合。在一些实施例中为羟丙基-β-环糊精；在一些实施例中为磺丁基醚-β-环糊精。
一种含有富马酸沃诺拉赞与取代β-环糊精的包合物，其可以制备成富马酸沃诺拉赞液体制剂，所述液体制剂可以是但不限于喷雾剂、混悬剂、溶液剂、注射剂。在一些实施例中，所述液体制剂为注射剂。
本发明提供一种富马酸沃诺拉赞注射剂，包含富马酸沃诺拉赞与取代β-环糊精。
一种富马酸沃诺拉赞注射剂，其中所述取代β-环糊精为羟丙基-β-环糊精、磺丁基醚-β-环糊精、羟乙基-β-环糊精、甲基-β-环糊精或它们的任意组合。在一些实施例中为羟丙基-β-环糊精；在一些实施例中为磺丁基醚-β-环糊精。
一种富马酸沃诺拉赞注射剂，其中，所述注射剂为即用型液体注射剂。
一种富马酸沃诺拉赞注射剂，其中，所述富马酸沃诺拉赞的重量相对于注射剂总体积的比例为0.05％至10％(W/V，g/mL)。在一些实施例中为0.4％。
一种富马酸沃诺拉赞注射剂，其中，所含取代β-环糊精的重量相对于注射剂总体积的比例为0.4％至20％(W/V，g/mL)。在一些实施例中为0.8％；在一些实施例中为1.2％；在一些实施例中为2％。
一种富马酸沃诺拉赞注射剂，其中所述富马酸沃诺拉赞与取代β-环糊精的重量比例为1:1到1:20。在一些实施例中为1:3；在一些实施例中为1:5；在一些实施例中为1:10。
在一些实施方式中，所述一种富马酸沃诺拉赞注射剂，其还包含溶剂、pH调节剂、缓冲剂。其中，所述的溶剂为水。其中，所述pH调节剂包含盐酸、乙酸、氢氧化钠、磷酸氢钠、碳酸钙或氢氧化镁；在一些实施例中，pH调节剂为氢氧化钠。其中，所述缓冲剂为乙酸、一水柠檬酸、琥珀酸、己二酸、酒石酸、抗环血酸、苹果酸、苯甲酸或它们的任意组合；在一些实施例中，所述的缓冲剂为酒石酸；在一些实施例中，所述的缓冲剂为一水柠檬酸。
一种富马酸沃诺拉赞注射剂，其中，所含缓冲剂的重量相对于注射剂总体积的比例为0.1％至3％(W/V，g/mL)。在一些实施例中为0.4％。
一种富马酸沃诺拉赞注射剂，其中，所述注射剂pH值范围为3.0至9.0，在一些实施例中为4.23。
一种富马酸沃诺拉赞注射剂，其中，所述注射剂pH值范围为3.0至6.0。
一种富马酸沃诺拉赞注射剂，其中，所述注射剂pH值范围为4.0至5.0，在一些实施例中为4.14。
在一些实施方案中，一种富马酸沃诺拉赞注射剂，其包含：
1)富马酸沃诺拉赞0.05％-10％；
2)羟丙基-β-环糊精0.4％-20％；
3)一水柠檬酸0.1％-3％；
4)NaOH适量；
5)纯化水。
在一些实施方案中，一种富马酸沃诺拉赞注射剂，其包含：
1)富马酸沃诺拉赞0.05％-10％；
2)羟丙基-β-环糊精0.4％-20％；
3)酒石酸0.1％-3％；
4)NaOH适量；
5)纯化水。
在一些实施方案中，一种富马酸沃诺拉赞注射剂，其包含：
1)富马酸沃诺拉赞0.05％-10％；
2)磺丁基醚-β-环糊精0.4％-20％；
3)一水柠檬酸0.1％-3％；
4)NaOH适量；
5)纯化水。
在一些实施方案中，一种富马酸沃诺拉赞注射剂，其包含：
1)富马酸沃诺拉赞0.05％-10％；
2)磺丁基醚-β-环糊精0.4％-20％；
3)酒石酸0.1％-3％；
4)NaOH适量；
5)纯化水。
本发明还提供了上述的一种富马酸沃诺拉赞注射剂的制备方法，所述方法包括将缓冲剂、取代β-环糊精溶于纯化水中，使用pH调节剂调节pH至4.0-5.0，加入富马酸沃诺拉赞，搅拌溶解后，加入纯化水定容，测量终溶液pH值，装瓶，加塞，轧盖，终端灭菌。
在一些实施方案中，上述的富马酸沃诺拉赞注射剂可以按照以下方法制备：
1)处方量的缓冲剂溶于处方量50％-90％的纯化水中，形成缓冲溶液；
2)向缓冲溶液中加入处方量的取代β-环糊精，搅拌至完全溶解，使用pH调节剂调节pH至4.5；
3)向体系中加入富马酸沃诺拉赞，搅拌溶解后，加入纯化水定容，并测量终溶液pH值；
4)装瓶，加塞，轧盖，121℃，12min-15min终端灭菌。
另一方面，本发明提供一种富马酸沃诺拉赞输液用溶液。
一种富马酸沃诺拉赞输液用溶液，其中，所述富马酸沃诺拉赞的重量相对于输液剂总体积的比例为0.005％至10％(W/V，g/mL)。在一些实施例中为0.0107％；在一些实施例中为0.053％；在一些实施例中为0.0053％。
一种富马酸沃诺拉赞输液用溶液，包含富马酸沃诺拉赞和缓冲剂，其中，所述缓冲剂为乙酸、一水柠檬酸、琥珀酸、己二酸、酒石酸、抗环血酸、苹果酸、苯甲酸或它们的任意组合。在一些实施例中，所述缓冲剂为酒石酸。
一种富马酸沃诺拉赞输液用溶液，其中，所含缓冲剂的重量相对于输液用溶液总体积的比例为0.001％至3％(W/V，g/mL)。在一些实施例中为0.0053％；在一些实施例中为0.053％。
一种富马酸沃诺拉赞输液用溶液，其还包含等渗调节剂。其中，所述等渗调节剂为氯化钠、葡萄糖、甘露醇、山梨醇、甘油等。在一些实施例中，等渗调节剂为氯化钠；在一些实施例中，等渗调节剂为葡萄糖。其中，调节溶液渗透压至260mosm/L至320mosm/L。
一种富马酸沃诺拉赞输液用溶液，其中，所述输液用溶液pH值范围为3.0至6.0。在一些实施例中为4.5。
本发明还提供了一种富马酸沃诺拉赞输液用溶液的制备方法，所述方法包括将等渗调节剂溶于纯化水中，加入富马酸沃诺拉赞、缓冲剂，搅拌溶解后，使用pH调节剂调节pH至3.0-6.0，加入纯化水定容，测量终溶液pH值。
在一些实施方案中，上述的富马酸沃诺拉赞输液用溶液可以按照以下方法制备：
1)处方量的等渗调节剂溶于处方量50％-90％的纯化水中；
2)加入处方量的缓冲剂，搅拌溶解；
3)向体系中加入富马酸沃诺拉赞，搅拌溶解后，使用pH调节剂调节pH至4.5；
4)加入纯化水定容，并测量终溶液pH值。
本发明提供的富马酸沃诺拉赞组合物能够增加富马酸沃诺拉赞在水中的溶解度，满足制备成注射剂的需求，并可采用终端灭菌法进行灭菌，灭菌彻底，提高注射剂安全性；提供的富马酸沃诺拉赞注射剂，是一种新的剂型，可满足对于急性胃炎、胃溃疡患者需要快速起效的临床需求，并可解决吞咽困难患者的给药难题，安全性高，稳定性好；提供的制备方法简单易行，适于工业化生产。
本发明提供的富马酸沃诺拉赞输液用溶液，制备方法简单易行，适于工业化生产。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
本发明中，min表示分钟，h表示小时，mg表示毫克，g表示克，mL表示毫升，W表示重量，V表示体积。
实施例1：使用羟丙基-β-环糊精(HP-β-CD)增溶富马酸沃诺拉赞。
向烧杯中加入一定体积(约占溶液终体积的75％)的纯化水，加入羟丙基-β-环糊精，用磁力搅拌器进行搅拌溶解；羟丙基-β-环糊精溶解后，加入富马酸沃诺拉赞，搅拌，目测富马酸沃诺拉赞溶解情况，搅拌至富马酸沃诺拉赞完全溶解；加入纯化水定容至20mL。对溶液进行短期稳定性研究(稳定性放置条件为先将样品放置于40℃一定时间，再将样品放置于60℃一定时间)。处方见表1-1。
表1-1
Figure PCTCN2017071723-appb-000002
实施例1结果：搅拌20min后，API完全溶解。短期稳定性研究结果证实，该溶液在40℃放置80h，再将溶液于60℃放置72h，溶液保持稳定。稳定性研究结果见表1-2。
表1-2
Figure PCTCN2017071723-appb-000003
实施例1结论：HP-β-CD与API质量比为10：1时，能有效增溶API；且获得的溶液在40℃放置80小时后继续于60℃放置72小时保持稳定。
实施例2：不同用量的HP-β-CD增溶富马酸沃诺拉赞。
向两个烧杯中分别加入一定体积(约占溶液终体积的75％)的纯化水，分别加入不同用量的HP-β-CD，用磁力搅拌器进行搅拌溶解；HP-β-CD溶解后，加入富马酸沃诺拉赞，搅拌，目测富马酸沃诺拉赞溶解情 况，搅拌至富马酸沃诺拉赞完全溶解；加入纯化水定容至20mL。处方见表2-1，2-2。
表2-1
Figure PCTCN2017071723-appb-000004
表2-2
Figure PCTCN2017071723-appb-000005
实施例2结果：当HP-β-CD用量为240mg，即与API质量比为3：1时，API加入至HP-β-CD溶液中，搅拌60min，API完全溶解；当HP-β-CD用量为400mg，即与API质量比为5：1时，API加入至HP-β-CD溶液中，搅拌20min，API完全溶解。
实施例2结论：HP-β-CD与API比例降至3：1仍能有效增溶API。
实施例3：不同缓冲溶液中HP-β-CD对富马酸沃诺拉赞的增溶作用。
向两个烧杯中分别加入一定体积(约占溶液终体积的75％)的纯化水，再加入处方量的一水柠檬酸或酒石酸，磁力搅拌器搅拌溶解，用2％(w/w)NaOH溶液调节pH至4.5；加入HP-β-CD，磁力搅拌器搅拌溶解；加入富马酸沃诺拉赞，磁力搅拌器搅拌，目测富马酸沃诺拉赞溶解情况，搅拌至富马酸沃诺拉赞完全溶解；用纯化水定容至20mL，并测量pH值。处方见表3-1，3-2。对溶液短期稳定性进行研究(稳定性放置条件为先将样品放置于40℃一定时间，再将样品放置于60℃一定时间)。
表3-1
Figure PCTCN2017071723-appb-000006
表3-2
Figure PCTCN2017071723-appb-000007
实施例3结果：搅拌60min，API完全溶解于溶液中。两个样品终溶液pH值分别为4.22和4.23；初步稳定性研究结果显示，两个溶液在40℃放置24h，再于60℃放置24h，溶液中有关物质含量基本不变。有关物质含量见表3-3，3-4。
实施例3结论：HP-β-CD与API质量比为3：1时，在不同缓冲溶液中能有效增溶API，缓冲剂对溶解速率无明显影响；获得的溶液在40℃放置24h，再于60℃放置24h保持稳定。
表3-3含一水柠檬酸HP-β-CD富马酸沃诺拉赞(3：1)溶液(pH4.22)稳定性数据
Figure PCTCN2017071723-appb-000008
表3-4含酒石酸HP-β-CD富马酸沃诺拉赞(3：1)溶液(pH4.23)稳定性数据
Figure PCTCN2017071723-appb-000009
实施例4：不同缓冲溶液中HP-β-CD对富马酸沃诺拉赞的增溶作用。
向四个烧杯中分别加入一定体积(约占溶液终体积的75％)的纯化水，分别加入不同用量的HP-β-CD或酒石酸或一水柠檬酸，用磁力搅拌器进行搅拌溶解；酒石酸或一水柠檬酸溶解后用2％(w/w)NaOH调节pH值至4.5；HP-β-CD溶解后，加入富马酸沃诺拉赞，搅拌，目测富马酸沃诺拉赞溶解情况，搅拌至富马酸沃诺拉赞完全溶解；加入纯化水定容至20mL，并测量终溶液pH值。处方见表4-1和4-2。
表4-1
Figure PCTCN2017071723-appb-000010
表4-2
Figure PCTCN2017071723-appb-000011
实施例5：磺丁基醚-β-环糊精(SBE-β-CD)增溶富马酸沃诺拉赞
向两个烧杯中分别加入一定体积(约占溶液终体积的75％)的纯化水，分别加入不同用量的SBE-β-CD，用磁力搅拌器进行搅拌溶解；SBE-β-CD溶解后，加入富马酸沃诺拉赞，搅拌，目测富马酸沃诺拉赞溶解情况，搅拌至富马酸沃诺拉赞完全溶解；加入纯化水定容至20mL。处方见表5-1，5-2。
表5-1
Figure PCTCN2017071723-appb-000012
表5-2
Figure PCTCN2017071723-appb-000013
实施例5结果：当SBE-β-CD用量为240mg，即与API质量比为3：1时，API加入至SBE-β-CD溶液 中，搅拌60min，API完全溶解；当SBE-β-CD用量为400mg，即与API质量比为5：1时，API加入至SBE-β-CD溶液中，搅拌20min，API完全溶解。
实施例5结论：当SBE-β-CD与API质量比为3：1及以上时，能有效增溶API。
实施例6：不同缓冲溶液中SBE-β-CD对富马酸沃诺拉赞的增溶作用。
向两个烧杯中分别加入一定体积(约占溶液终体积的75％)的纯化水，再加入处方量的一水柠檬酸或酒石酸，磁力搅拌器搅拌溶解，用2％(w/w)NaOH溶液调节pH至4.5；加入SBE-β-CD，磁力搅拌器搅拌溶解；加入富马酸沃诺拉赞，磁力搅拌器搅拌，目测富马酸沃诺拉赞溶解情况，搅拌至富马酸沃诺拉赞完全溶解；用纯化水定容至20mL，并测量pH值。处方见表6-1，6-2。对溶液短期稳定性进行研究(稳定性放置条件为先将样品放置于40℃一定时间，再将样品放置于60℃一定时间)。
表6-1
Figure PCTCN2017071723-appb-000014
表6-2
Figure PCTCN2017071723-appb-000015
实施例6结果：搅拌60min，API完全溶解于溶液中。两个样品终溶液pH值分别为4.14(一水柠檬酸)和4.21(酒石酸)；初步稳定性研究结果显示，两个溶液在40℃放置24h，再于60℃放置24h，溶液中有关物质含量基本不变。有关物质含量见表6-3，6-4。
实施例6结论：SEB-β-CD与API质量比为3：1时，在不同缓冲溶液中能有效增溶API，且对溶解速率无明显影响；获得的溶液在40℃放置24h，再于60℃放置24h保持稳定。
表6-3含一水柠檬酸SBE-β-CD富马酸沃诺拉赞溶液(pH4.14)稳定性数据
Figure PCTCN2017071723-appb-000016
表6-4含酒石酸SBE-β-CD富马酸沃诺拉赞溶液(pH4.21)稳定性数据
Figure PCTCN2017071723-appb-000017
实施例7：SBE-β-CD富马酸沃诺拉赞溶液对灭菌条件的稳定性。
向四个烧杯中加入一定体积(约占溶液终体积的75％)的纯化水，分别加入不同用量的SBE-β-CD或酒石酸或一水柠檬酸，用磁力搅拌器进行搅拌溶解；酒石酸或一水柠檬酸溶解后用2％(w/w)NaOH调节pH值至4.5；SBE-β-CD溶解后，加入富马酸沃诺拉赞，搅拌，目测富马酸沃诺拉赞溶解情况，搅拌至富马酸沃诺拉赞完全溶解；加入纯化水定容至目标终体积，并测量终溶液pH值。高压蒸汽灭菌锅进行灭菌，灭菌条件为121℃，12min。处方见表7-1至7-5。
表7-1(01号)
Figure PCTCN2017071723-appb-000018
表7-2(02号)
Figure PCTCN2017071723-appb-000019
表7-3(03号)
Figure PCTCN2017071723-appb-000020
表7-4(04号)
Figure PCTCN2017071723-appb-000021
表7-5(05号)
Figure PCTCN2017071723-appb-000022
实施例7结果：低浓度样品和高浓度样品灭菌前后溶液均为澄清透明，无色溶液。灭菌后溶液中有关物质含量略有增长；SBE-β-CD用量及缓冲剂种类对溶液中有关物质含量无明显影响。有关物质含量见表7-5。
表7-6
Figure PCTCN2017071723-appb-000023
Figure PCTCN2017071723-appb-000024
实施例7结论：5个处方样品溶液在121℃灭菌12min后基本保持稳定。
实施例8：SBE-β-CD富马酸沃诺拉赞溶液长期稳定性研究
向两个烧杯中分别加入一定体积(约占溶液终体积的75％)的纯化水，分别加入处方量的SBE-β-CD，用磁力搅拌器进行搅拌溶解；02中加入酒石酸搅拌溶解；加入富马酸沃诺拉赞，搅拌，目测富马酸沃诺拉赞溶解情况，搅拌至富马酸沃诺拉赞完全溶解；用2％(w/w)NaOH溶液将样品溶液01、02调节pH值至4.5；加入纯化水定容至60mL，并测量终溶液pH值。高压蒸汽灭菌锅进行灭菌，灭菌条件为121℃，15min。灭菌后样品放置于40℃条件下，分别于1,3,6个月检测样品有关物质变化情况。处方见表8-1，8-2。
表8-1(01号)
Figure PCTCN2017071723-appb-000025
表8-2(02号)
Figure PCTCN2017071723-appb-000026
实施例8实验结果：
表8-3
Figure PCTCN2017071723-appb-000027
Figure PCTCN2017071723-appb-000028
两样品于40℃条件放置6个月，杂质含量仅轻微增长。
实施例8结论：SBE-β-CD富马酸沃诺拉赞溶液长期稳定性良好。
实施例9：富马酸沃诺拉赞输液用溶液制备
向两个烧杯中分别加入一定体积(约占溶液终体积的75％)的纯化水，分别加入处方量的氯化钠或葡萄糖，用磁力搅拌器进行搅拌溶解；加入处方量酒石酸搅拌溶解；加入富马酸沃诺拉赞，搅拌，目测富马酸沃诺拉赞溶解情况，搅拌至富马酸沃诺拉赞完全溶解；用2％(w/w)NaOH溶液将样品溶液调节pH值至4.5；加入纯化水定容至目标终体积，并测量终溶液pH值。
表9-1(01号)
Figure PCTCN2017071723-appb-000029
表9-2(02号)
Figure PCTCN2017071723-appb-000030
表9-3(03号)
Figure PCTCN2017071723-appb-000031
表9-4(04号)
Figure PCTCN2017071723-appb-000032
Figure PCTCN2017071723-appb-000033
实施例9实验结果：四个样品中的富马酸沃诺拉赞搅拌半个小时后溶解，获得的溶液澄清透明，无色；溶液可湿热灭菌或过滤除菌。
由上述结果可以看出，实施例1-实施例7分别使用取代-β-环糊精制备富马酸沃诺拉赞组合物或注射剂，在稳定性实验中，单杂和总杂含量基本不变，在影响因素实验中，单杂和总杂仅有轻微增加，变化趋势不明显，即使经过高压蒸汽灭菌，灭菌前后单杂和总杂的含量变化也较小，符合注射剂的杂质含量控制标准。从稳定性实验结果分析得出，本发明的富马酸沃诺拉赞组合物或注射剂具有好的溶解性和溶液稳定性。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、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内。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“一些实施方式”、“一些实施方案”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (14)

  1. 一种组合物，包含富马酸沃诺拉赞和增溶剂，其中，所述增溶剂为取代β-环糊精、吐温80、磷脂质、泊洛沙姆或它们的任意组合。
  2. 根据权利要求1所述的组合物，其中，所述取代β-环糊精为羟丙基-β-环糊精、磺丁基醚-β-环糊精、羟乙基-β-环糊精、甲基-β-环糊精或它们的任意组合。
  3. 一种富马酸沃诺拉赞包合物，含有富马酸沃诺拉赞与取代β-环糊精，其中，所述取代β-环糊精为羟丙基-β-环糊精、磺丁基醚-β-环糊精、羟乙基-β-环糊精、甲基-β-环糊精或它们的任意组合。
  4. 根据权利要求3所述的包合物，其被进一步制备成富马酸沃诺拉赞液体制剂。
  5. 一种富马酸沃诺拉赞注射剂，其包含富马酸沃诺拉赞和取代β-环糊精，其中，所述取代β-环糊精为羟丙基-β-环糊精、磺丁基醚-β-环糊精、羟乙基-β-环糊精、甲基-β-环糊精或它们的任意组合。
  6. 根据权利要求5所述的注射剂，其中，所述注射剂为即用型液体注射剂。
  7. 根据权利要求5所述的注射剂，其中，所述富马酸沃诺拉赞的重量相对于注射剂总体积的比例为0.05％至10％。
  8. 根据权利要求5所述的注射剂，其中，所述取代β-环糊精的重量相对于注射剂总体积的比例为0.4％至20％。
  9. 根据权利要求5所述的注射剂，其中，富马酸沃诺拉赞与所述取代β-环糊精的重量比例为1:1到1:20。
  10. 根据权利要求5-9任一所述的注射剂，其进一步包含pH调节剂、缓冲剂和溶剂，其中，所述pH调节剂为盐酸、乙酸、氢氧化钠、磷酸氢钠、碳酸钙或氢氧化镁，所述缓冲剂为乙酸、一水柠檬酸、琥珀酸、己二酸、酒石酸、抗环血酸、苹果酸、苯甲酸或它们的任意组合。
  11. 根据权利要求5所述的注射剂，其pH值为3.0至9.0。
  12. 根据权利要求10所述的注射剂，其中，所述缓冲剂的重量相对于注射剂的总体积的比例为0.1％至3％。
  13. 根据权利要求5所述的注射剂，包含磺丁基醚-β-环糊精、一水柠檬酸、氢氧化钠和纯化水，或者包含羟丙基-β-环糊精、一水柠檬酸、氢氧化钠和纯化水。
  14. 一种制备权利要求5-13任一项所述注射剂的方法，其包括：
    1)向容器中加入一定体积的纯化水，再加入处方量的缓冲剂，搅拌溶解；
    2)用pH调节剂调节pH至4.0至5.0；
    3)加入取代β-环糊精，搅拌溶解；
    4)加入富马酸沃诺拉赞，搅拌至富马酸沃诺拉赞完全溶解；
    5)用纯化水定容；
    6)将5)中的溶液进行灭菌，灭菌条件为121℃，12～15min。
PCT/CN2017/071723 2017-01-19 2017-01-19 一种富马酸沃诺拉赞组合物及其制备方法 WO2018133009A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/071723 WO2018133009A1 (zh) 2017-01-19 2017-01-19 一种富马酸沃诺拉赞组合物及其制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/071723 WO2018133009A1 (zh) 2017-01-19 2017-01-19 一种富马酸沃诺拉赞组合物及其制备方法

Publications (1)

Publication Number Publication Date
WO2018133009A1 true WO2018133009A1 (zh) 2018-07-26

Family

ID=62907557

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/071723 WO2018133009A1 (zh) 2017-01-19 2017-01-19 一种富马酸沃诺拉赞组合物及其制备方法

Country Status (1)

Country Link
WO (1) WO2018133009A1 (zh)

Cited By (3)

* 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
US20220387476A1 (en) * 2019-12-18 2022-12-08 Daewoong Pharmaceutical Co., Ltd. Liquid Pharmaceutical Composition of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine
CN118566356A (zh) * 2024-04-23 2024-08-30 瓴川医药科技(山东)有限公司 富马酸伏诺拉生中基因毒性杂质n-亚硝基-伏诺拉生的检测方法

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

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 (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220387476A1 (en) * 2019-12-18 2022-12-08 Daewoong Pharmaceutical Co., Ltd. Liquid Pharmaceutical Composition of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine
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
CN118566356A (zh) * 2024-04-23 2024-08-30 瓴川医药科技(山东)有限公司 富马酸伏诺拉生中基因毒性杂质n-亚硝基-伏诺拉生的检测方法

Similar Documents

Publication Publication Date Title
CA2567075C (en) Pharmaceutical suspension composition
KR101420315B1 (ko) 약학적 액제 조성물
WO2018133009A1 (zh) 一种富马酸沃诺拉赞组合物及其制备方法
CN116327959A (zh) 一种美洛昔康组合物、制剂及其制备方法与应用
CN103622907B (zh) 一种布洛芬脂肪乳注射液及其制备方法
CN102784382B (zh) 一种阿加曲班药物组合物及其制备方法和应用
CN106551898B (zh) 一种富马酸沃诺拉赞组合物及其制备方法
CN106943346B (zh) 甲地高辛液体制剂、其制备方法及其用途
CA3157999A1 (en) Injectable compositions of ursodeoxycholic acid
WO2024027549A1 (zh) 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
CN103142509B (zh) 一种注射用硼替佐米药物组合物
CN107157926B (zh) 一种多西他赛注射剂的制备方法
JP4475405B2 (ja) 医薬組成物
TWI857310B (zh) 酮咯酸胺丁三醇的液體組合物、其製備方法及應用
CN103432067A (zh) 酮洛芬溶液及其制备方法
CN110538155B (zh) 一种注射用兰索拉唑冻干剂及其制备方法
WO2004096229A1 (ja) 溶液医薬組成物
WO2014007239A1 (ja) アムホテリシンｂ含有組成物
JPH07316065A (ja) Ｆｒ９０１４６９物質製剤
CN116098861A (zh) 一种米力农注射液及其制备方法
CN117462488A (zh) 含有右旋布洛芬的改善了稳定性的注射用制剂及包含其的注射用药物容器
CN1823775A (zh) 一种稳定的帕洛诺司琼注射液及其制备方法
RU2545902C1 (ru) Фармацевтическая композиция в виде лиофилизата с комплексообразующим агентом для приготовления раствора для парентерального применения и способ ее получения
CN115645363A (zh) 一种布美他尼注射液及其制备方法
CN116139079A (zh) 稳定的奥沙利铂水溶液及其制备方法和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17892949

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17892949

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载