WO2023160520A1 - 一种三亚乙基四胺四氢氯化物及其制备方法与组合物 - Google Patents

一种三亚乙基四胺四氢氯化物及其制备方法与组合物 Download PDF

Info

Publication number
WO2023160520A1
WO2023160520A1 PCT/CN2023/077332 CN2023077332W WO2023160520A1 WO 2023160520 A1 WO2023160520 A1 WO 2023160520A1 CN 2023077332 W CN2023077332 W CN 2023077332W WO 2023160520 A1 WO2023160520 A1 WO 2023160520A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparation
teta
triethylenetetraminetetrahydrochloride
solvent
4hcl
Prior art date
Application number
PCT/CN2023/077332
Other languages
English (en)
French (fr)
Inventor
彭成毅
梁明仁
林喻侦
冯台云
Original Assignee
裕捷股份有限公司
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 裕捷股份有限公司 filed Critical 裕捷股份有限公司
Priority to KR1020237039583A priority Critical patent/KR20230172013A/ko
Publication of WO2023160520A1 publication Critical patent/WO2023160520A1/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
    • A61K31/13—Amines
    • A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/84—Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/14—Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This application is about triethylenetetramine tetrahydrochloride, especially the field of synthesis and application of triethylenetetramine tetrahydrochloride.
  • Triethylenetetramine also known as trientine, has a structure of formula 1, which can use the four nitrogen atoms in its structure to chelate copper, helping to excrete excess copper from the body , so it is often used to treat Wilson's disease.
  • triethylenetetramine is mostly used in treatment and research in the form of hydrochloride salt, which can be divided into triethylenetetramine dihydrochloride (TETA 2HCl) and triethylenetetramine tetrahydrochloride ( TETA.4HCl).
  • TETA ⁇ 2HCl Chinese Patent Publication No. CN102924289B discloses a synthesis method of TETA ⁇ 2HCl, however, it also teaches that the stability of TETA ⁇ 2HCl is worse than that of TETA ⁇ 4HCl.
  • TW202002956A discloses a crystalline form of TETA.4HCl Form B and a preparation method thereof.
  • TW202002956A teaches that the crystalline form of TETA ⁇ 4HCl produced by the method described in WO 2006/027705 is Form A; in addition, tablets made of TETA ⁇ 4HCl Form A are stored at 40°C and 75% humidity Discolored chips after six months compared to lozenges made with TETA.4HCl Form B which faded over time There was less tendency to color, which result shows that the TETA.4HCl Form B lozenges have better stability.
  • the method disclosed in TW202002956A is to carry out crystal precipitation at low temperature, and needs to add seed crystals to promote the formation of TETA ⁇ 4HCl form B, the procedure is complicated and inconvenient.
  • the purpose of the present application is to provide a preparation method of triethylenetetraminetetrahydrochloride crystals, which comprises: step 1, adding an antisolvent to a triethylenetetramine at a feed temperature tetraaminetetrahydrochloride aqueous solution, and stirring to precipitate crystals; wherein, the feed temperature is 50° C. to 75° C.; the anti-solvent is an alcohol solvent.
  • the alcoholic solvent comprises methanol (Methanol, MeOH) or ethanol (Ethanol); the alcoholic solvent is preferably methanol.
  • the stirring is carried out under a time condition and a stirring temperature; wherein the time condition is at least 1 hour; the stirring temperature is 5° C. to 25° C., and the stirring temperature is preferably 15 ⁇ 5° C. °C.
  • the first step further includes drying the crystal, so that the weight loss of the crystal is less than 1%.
  • the first step further includes: pre-step 1, mixing a triethylenetetramine dihydrochloride aqueous solution with an acidic solution to form a reaction solution for acidification reaction (Acidification); pre-step 2. Add an alcohol anti-solvent and stir to precipitate the crude product of triethylenetetraminetetrahydrochloride.
  • the alcohol anti-solvent of the pre-step 2 comprises methanol or ethanol;
  • the alcohol solvent is preferably methanol.
  • the stirring in the pre-step 2 is carried out under a temperature condition and a time condition; wherein the temperature condition is 15°C to 35°C, and the temperature condition is preferably 25 ⁇ 5°C; wherein the The time condition is at least 2 hours.
  • the pre-step 2 further comprises drying the crude triethylenetetramine tetrahydrochloride, so that the drying weight loss of the crude triethylenetetramine tetrahydrochloride is ⁇ 10%.
  • Another object of the present application is to provide a triethylenetetraminetetrahydrochloride, wherein the crystals of the triethylenetetraminetetrahydrochloride have XRPD pattern of the peak.
  • Another object of the present application is to provide a pharmaceutical composition comprising triethylenetetraminetetrahydrochloride crystals prepared by the aforementioned preparation method or triethylenetetraminetetrahydrochloride crystals as mentioned above hydrochloride.
  • the pharmaceutical composition may further include a pharmaceutically acceptable carrier.
  • the carrier includes a dissolving agent, diluent, lubricant, binding agent, depolymerizing agent, foaming mixture, dye, sweetener, wetting agent or other non-toxic and Pharmacologically inactive substance.
  • the dissolving agent contains cyclodextrin or modified cyclodextrin; wherein the diluent contains lactose, dextrose, sucrose, cellulose, corn starch or potato starch; wherein the lubricant is contained in Silicon dioxide, talc, stearic acid, magnesium or calcium stearate or polyethylene glycol; wherein the binder comprises starch, tragacanth, gelatin, syrup, acacia, sorbitol, methylcellulose wherein the depolymerizing agent comprises starch, alginic acid, alginate or sodium starch glycolate; wherein the humectant comprises lecithin, polysorbate or lauryl base sulfate.
  • the dosage form of the pharmaceutical composition includes solution, emulsion, suspension, powder, lozenge, pill, tablet or capsule.
  • Another object of the present application is to provide a triethylenetetraminetetrahydrochloride crystal prepared by the aforementioned preparation method or the aforementioned triethylenetetraminetetrahydrochloride for the preparation of prophylaxis Or the use of a pharmaceutical composition for the treatment of Wilson's disease.
  • the present application provides a TETA ⁇ 4HCl whose crystal form is Form N and a preparation method thereof.
  • the TETA ⁇ 4HCl provided by this application has the advantages of simpler preparation and higher yield.
  • the crystal form of TETA 4HCl and its composition provided by the application has excellent stability and moisture absorption resistance, and can improve the shortcomings of TETA 4HCl and tablet storage in the prior art .
  • Fig. 1 is the TETA 4HCl crude product preparation flow chart of the present application
  • Fig. 2 is the TETA 4HCl crystal preparation flowchart of the present application
  • Fig. 3 is the XRPD analysis chart of TETA 4HCl of an embodiment of the present application.
  • Fig. 4 is the hygroscopicity test result figure of the lozenge of TETA 4HCl of the present application
  • Fig. 5 is the XRPD analysis diagram of TETA 4HCl of an embodiment of the present application.
  • Fig. 6 is the XRPD analysis chart of the comparative example of an embodiment of the present application.
  • Fig. 7 is the stability comparison result of one month's storage of TETA 4HCl of the present application and comparative example
  • Fig. 8 is the stability comparison result of one month's storage of TETA 4HCl of the present application and comparative example
  • Fig. 9 is the comparison result of the stability of TETA 4HCl of the present application and the storage of the comparative example for three months;
  • Fig. 10 is the comparison result of the three-month stability of TETA ⁇ 4HCl of the present application and the comparative example.
  • treating refers to methods of delaying, ameliorating, reducing, or reversing a diagnosable condition and related symptoms caused by the condition in a patient, as well as preventing the condition or any related Symptom approach.
  • pharmaceutically acceptable means that a substance or composition must be compatible with the other ingredients of its pharmaceutical formulation and not exacerbate symptoms in the patient.
  • pharmaceutically acceptable carrier comprises one or more types of ingredients selected from the group consisting of solvents, emulsifying agents, suspending agents, disintegrating agents, binders, excipients, stabilizers, chelating agents, diluents , gelling agent, preservative, lubricant, surfactant, and other similar or suitable carriers for this application.
  • pharmaceutically acceptable excipient includes, but is not limited to, polymers, resins, plasticizers, fillers, lubricants, diluents, binders, disintegrants, solvents, co-solvents, surfactants, At least one of preservatives, sweeteners, flavoring agents, pharmaceutical grade dyes or pigments, and viscosity agents.
  • the term "effective amount” refers to the dose necessary to produce and cause the desired biological response, and is not quantitatively required for therapeutic recovery. Those of ordinary skill in the art to which the present application pertains will appreciate that the effective amount of the pharmaceutical composition may vary depending on factors such as: the desired biological endpoint, the biological activity to be delivered, Active agent, composition of encapsulating matrix, target tissue, etc.
  • pharmaceutical composition refers to a solid or liquid composition in a form, concentration and degree of purity suitable for administration to a patient, which induces a desired physiological change after administration; the pharmaceutical composition is sterile or non-pyrogenic Sexual person (non-pyrogenic).
  • feed refers to the material put into the reaction tank during the production process.
  • IPC in-process control
  • anti-solvent refers to a solvent used to reduce the solubility of a solute.
  • the term "acidification” refers to a reaction in which enough acid is added to a solid or liquid to make it acidic, and the acidity occurs.
  • crystallization or “crystallization” refers to the supersaturation of a solute in a solution to produce crystals.
  • Wash refers to washing the product obtained during the production process with a specific solvent.
  • LOD loss on drying
  • Re-crystallization refers to re-crystallization from solution after re-dissolving a substance or crystal in a solvent.
  • TETA.2HCl is prepared into TETA.4HCl crude product (Crude trientine tetrahydrochloride), and then the TETA.4HCl crude product is prepared into TETA.4HCl provided in this application.
  • the crude product of TETA ⁇ 4HCl is prepared by mixing and dissolving TETA ⁇ 2HCl and pure water, and then adding an acidic solution for acidification reaction (Acidification); then Add anti-solvent and keep stirring to precipitate crystals (Crystallization); then, filter the reaction suspension solution, wash the crystals, and dry the product to obtain the crude product of TETA ⁇ 4HCl.
  • the anti-solvent can be any solvent in which TETA ⁇ 4HCl is substantially insoluble, including but not limited to ethanol or methanol, with methanol being the best; wherein the acidic solution can be any common solution for acidification reaction, preferably hydrochloric acid , more preferably more than 35% hydrochloric acid.
  • the weight ratio of the TETA ⁇ 2HCl to the pure water is 0.5:1-1:1, and the preferred weight ratio is 1:1; the temperature of the acidification reaction is 10°C-40°C , the preferred temperature is 20 ⁇ 10°C; the pH value of the reaction solution of the acidification reaction is ⁇ 2.0; the adding temperature of the anti-solvent is 10°C-40°C, and the preferred temperature is 20 ⁇ 10°C; the anti-solvent and
  • the weight ratio of the TETA ⁇ 2HCl is 2:1 to 6:1, the preferred weight ratio is 4:1; the crystallization temperature is 15°C to 35°C, and the preferred temperature is 25 ⁇ 5°C; the continuous stirring time For at least 2 hours; the product has a loss on drying (LOD) of ⁇ 10%, preferably not more than 5.0% loss on drying.
  • LOD loss on drying
  • the preparation of the TETA ⁇ 4HCl crystal provided in the present application is to mix and dissolve the crude product of TETA ⁇ 4HCl with pure water, then add an anti-solvent and keep stirring to recrystallize (Re-crystallization) to make the crystal precipitation; then, filter the reaction suspension solution, wash the crystals, and dry the product to obtain the TETA ⁇ 4HCl crystal provided by the application.
  • the anti-solvent can be any solvent in which TETA ⁇ 4HCl is substantially insoluble, including but not limited to ethanol or methanol, with methanol being the best.
  • the weight ratio of the TETA ⁇ 4HCl crude product to the pure water is 1:1-1:2, and the preferred weight ratio is 1:1.2;
  • the temperature is 15°C-35°C, preferably 25 ⁇ 5°C;
  • the weight ratio of the TETA ⁇ 4HCl crude product to the anti-solvent is 1:2-1:6, and the preferable weight ratio is 1:4;
  • the feed temperature of the solvent is 50°C to 75°C, preferably 60 ⁇ 5°C;
  • the stirring temperature for the continuous stirring is 5°C to 25°C, preferably 15 ⁇ 5°C 5° C.;
  • the continuous stirring time is at least 1 hour;
  • the weight loss on drying (LOD) of the product is ⁇ 1%, and the weight loss on drying is preferably not more than 0.6%.
  • LOD weight loss on drying
  • the pharmaceutical composition provided by the application can use the technology well known to those with ordinary knowledge in the technical field of the application to combine the active ingredient or composition provided by the application with at least one pharmaceutically acceptable carrier (vehicle) , preparing a dosage form suitable for the composition of the present application.
  • the dosage form includes but not limited to solution (Solution), emulsion (Emulsion), suspension (Suspension), powder (Powder), lozenge (Tablet), pill (Pill), tablet (Troche) or capsule (Capsule) and Other dosage forms similar to or suitable for this application.
  • suitable routes of administration for the pharmaceutical composition described in this application include but are not limited to oral administration, injection, mucosal, topical transdermal and other administration routes similar to or applicable to this application; wherein the best route of administration is oral administration .
  • the pharmaceutical composition is an oral dosage form, which can be prepared according to the following process steps: Step 1, take the TETA ⁇ 4HCl crystal provided by this application, grind it or Granulation; step 2, combining the TETA ⁇ 4HCl crystal with a pharmaceutically acceptable carrier as appropriate to form a mixture.
  • step 2 may further include: step 3, compressing the mixture to form a lozenge, and step 4, coating the lozenge with sugar coating or film coating as appropriate.
  • step 4 when the oral dosage form is a capsule or powder, after the second step, it may further include encapsulating the mixture in a capsule.
  • the process steps may further include other basic pharmaceutical steps, which include but not limited to grinding, granulation, sugar coating or film coating.
  • the pharmaceutically acceptable carrier includes but not limited to dissolving agent, diluent, lubricant, Binding agents, depolymerizing agents, effervescent mixtures, dyes, sweeteners, wetting agents or non-toxic and pharmacologically inactive substances for pharmaceutical formulations; wherein the dissolving agent includes but not limited to cyclodextrin or modified Cyclodextrin; wherein the diluent is including but not limited to lactose, dextrose, sucrose, cellulose, corn starch or potato starch; wherein the lubricant is including but not limited to silicon dioxide, talc, stearic acid, hard Magnesium stearate or calcium stearate or polyethylene glycol; Wherein the binding agent is including but not limited to starch, tragacanth, gelatin, syrup, acacia, sorbitol, methylcellulose, carboxymethylcellulose Or polyvinylpyrrolidone; Wherein the depolymerization agent is including
  • the pharmaceutical composition contains at most 85 weight percent (wt%) TETA ⁇ 4HCl, for example, in an embodiment of the present application, the pharmaceutical composition contains 50 weight percent (wt%) TETA ⁇ 4HCl.
  • the pharmaceutical composition is preferably sterile and pyrogen-free.
  • Embodiment 1 the synthesis of TETA ⁇ 4HCl
  • the TETA ⁇ 4HCl crude product obtained in the previous steps and its 1.2 times the weight of pure water are put into the reaction tank and dissolved at 25 ⁇ 5°C; then prepare the TETA ⁇ 4HCl crude product Add 4 times the weight of methanol at the feed temperature of 60 ⁇ 5°C, then lower the temperature of the reaction tank, set the temperature of the reaction tank at 15 ⁇ 5°C, wait for the internal temperature to drop to 15 ⁇ 5°C, and continue to Stir at this temperature for at least 1 hour, carry out re-crystallization (Re-crystallization) to precipitate crystals; then filter the suspended solution in the reaction tank, and wash the crystals twice with methanol that is 2.5 times the weight of the TETA ⁇ 4HCl crude product; Finally, the product is dried to LOD ⁇ 0.6% to obtain the TETA ⁇ 4HCl.
  • Re-crystallization re-crystallization
  • Embodiment two the analysis of the crystal form of TETA ⁇ 4HCl
  • TETA ⁇ 4HCl prepared by the method described in Example 1 was analyzed by X-Ray Powder Diffraction (XRPD). The results are shown in Figure 3.
  • the crystal of TETA 4HCl provided by the present application has XRPD patterns with peaks at 21.9, 24.8, 25.2, 28.0 and 35.6 ⁇ 0.1°2 ⁇ , named Form N (Form N).
  • Embodiment three stability test one
  • the chromatographic purity check was carried out with thin-layer chromatography (TLC) (Chromatographic purity), the TETA 4HCl synthesized in Example 1 was stored at different temperatures (25° C. to 40° C.) and different humidity (60% RH to 75% RH) environments to contain impurities after one month ( impurity).
  • TLC thin-layer chromatography
  • the results are shown in Table 1. No impurities were detected after TETA ⁇ 4HCl was stored for one month at different temperatures and different humidity environments. This result proves that the TETA ⁇ 4HCl provided by this application has good stability.
  • TETA 4HCl prepared by the method described in Example 1 was compressed into lozenges, and the lozenges were stored at 25°C, 60%RH or 40°C, 75%RH under environmental conditions for three months to analyze their content and impurity.
  • the lozenge described in embodiment four is stored in 25 °C, 75%RH environment condition one month, test its hygroscopicity, and with commercially available product trientine hydrochloride sheet ( TETA ⁇ 4HCl form B lozenges) and commercially available TETA ⁇ 2HCl-capsules as comparative examples.
  • TETA ⁇ 4HCl form B lozenges product trientine hydrochloride sheet
  • TETA ⁇ 2HCl-capsules commercially available product trientine hydrochloride sheet
  • TETA ⁇ 2HCl-capsules commercially available TETA ⁇ 2HCl-capsules as comparative examples.
  • the tablet made of the TETA 4HCl crystal of the present application has no obvious moisture absorption and weight gain, while the commercially available TETA 2HCl-capsule moisture absorption and weight gain is more than 75% of the original weight.
  • the result proves that the lozenge made by using the TETA ⁇ 4HCl crystal of the present application has better hygroscopicity resistance.
  • Embodiment six yield analysis and stability comparison
  • TETA ⁇ 4HCl of crystal form N was prepared, and The method disclosed in TW202002956A prepared form B of TETA ⁇ 4HCl as a comparative example.
  • the XRPD analysis results are shown in Figure 5 and Figure 6,
  • Figure 5 is the XRPD pattern of the TETA 4HCl crystal of the present application
  • Figure 6 is the XRPD pattern of the comparative example
  • the XRPD pattern of the comparative example shows that it is the crystal described in the patent publication number TW202002956A Form B.
  • the yield results are shown in Table 3.
  • the TETA 4HCl (form N) prepared according to the preparation method provided by this application has an unexpected high yield (77.1%-86.6%), and the In the preparation procedure, the method has the advantages that TETA ⁇ 4HCl can be obtained without crystallization at low temperature and without using seed crystals.
  • the preparation method provided by the present application not only has the advantage of a simpler preparation procedure, but also can obtain high yields of TETA ⁇ 4HCl.
  • the TETA ⁇ 4HCl synthesized by the preparation method provided in this application belongs to crystal form N, and the TETA ⁇ 4HCl and its composition provided in this application It has excellent stability and moisture absorption resistance, and can improve the stability problems existing in the prior art.

Landscapes

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

Abstract

本申请提供一种三亚乙基四胺四氢氯化物晶体的制备方法，其是包含将一反溶剂在一进料温度下添加至一三亚乙基四胺四氢氯化物水溶液中，并搅拌析出晶体；其中，该进料温度为50℃～75℃；该反溶剂为醇类溶剂。本申请也提供一种新颖的三亚乙基四胺四氢氯化物，其晶体是具有在21.9、24.8、25.2、28.0及35.6±0.1°2θ处具有峰值的XRPD图案，使用本申请的三亚乙基四胺四氢氯化物所制成的组合物具有可稳定存放的优势。

Description

一种三亚乙基四胺四氢氯化物及其制备方法与组合物
相关申请的交叉引用
本申请主张在2022年2月23日在中国提交的中国专利申请No.202210168899.2的优先权，其全部内容通过引用包含于此。
技术领域
本申请是关于三亚乙基四胺四氢氯化物，特别是关于三亚乙基四胺四氢氯化物的合成及其应用的领域。
背景技术
三亚乙基四胺(Trientine，TETA)，又称曲恩汀，具有式一的结构，其可利用其结构中的四个氮原子跟铜螯合，有助于将过多的铜帮助排出体外，因此常被用于治疗威尔森氏症。目前三亚乙基四胺多是以氢氯化物盐形式被用于治疗及研究，其又可分成三亚乙基四胺二氢氯化物(TETA·2HCl)和三亚乙基四胺四氢氯化物(TETA·4HCl)。
中国专利公告号CN102924289B公开了一种TETA·2HCl的合成方法，然而，其也教示TETA·2HCl的稳定度较TETA·4HCl差。TW202002956A公开了一种TETA.4HCl形式B结晶型及其制备方法。TW202002956A教示，使用WO 2006/027705所述的方法所生产出的TETA·4HCl，其结晶型为形式A；此外，以TETA·4HCl形式A所制成的锭剂在40℃及75％湿度下储存六个月之后具有褪色碎片，相较之下，以TETA.4HCl形式B所制成的锭剂随时间推移而发生褪 色的趋势较小，该结果显示TETA·4HCl形式B的锭剂具有较佳的稳定性。然而，TW202002956A所公开的方法是在低温进行晶体析出，且需添加晶种以促进TETA·4HCl形式B的形成，程序较复杂且不便。
据此可知，先前技术中TETA·4HCl的稳定性及制备方法尚有不足之处，有待改善。
发明内容
有鉴于此，本申请的目的即在于提供一种三亚乙基四胺四氢氯化物晶体的制备方法，其是包含：步骤一、将一反溶剂在一进料温度下添加至一三亚乙基四胺四氢氯化物水溶液中，并搅拌析出晶体；其中，该进料温度为50℃～75℃；该反溶剂为醇类溶剂。
为达前述发明目的，其中该醇类溶剂包含甲醇(Methanol，MeOH)或乙醇(Ethanol)；该醇类溶剂较佳为甲醇。
为达前述发明目的，其中，该搅拌是在一时间条件及一搅拌温度下进行；其中该时间条件是至少1小时；该搅拌温度是5℃～25℃，该搅拌温度较佳为15±5℃。
为达前述发明目的，其中该步骤一进一步包含干燥该晶体，使该晶体的干燥减重<1％。
为达前述发明目的，其中，该步骤一前进一步包含：前置步骤一、将一三亚乙基四胺二氢氯化物水溶液与一酸性溶液混合成一反应液进行酸化反应(Acidification)；前置步骤二、加入一醇类反溶剂并搅拌析出三亚乙基四胺四氢氯化物粗产物。
为达前述发明目的，其中该反应液的pH值≤2.0。
为达前述发明目的，其中该前置步骤二的醇类反溶剂包含甲醇、或乙醇； 该醇类溶剂较佳为甲醇。
为达前述发明目的，其中该前置步骤二的搅拌是在一温度条件及一时间条件下进行；其中该温度条件为15℃～35℃，该温度条件较佳为25±5℃；其中该时间条件为至少2小时。
为达前述发明目的，其中该前置步骤二进一步包含干燥该三亚乙基四胺四氢氯化物粗产物，使该三亚乙基四胺四氢氯化物粗产物的干燥减重<10％。
本申请的另一目的在于提供一种三亚乙基四胺四氢氯化物，其中该三亚乙基四胺四氢氯化物的晶体具有在21.9、24.8、25.2、28.0及35.6±0.1°2θ处具有峰值的XRPD图案。
本申请的另一目的在于提供一种医药组合物，其是包含如前所述的制备方法制备而成的三亚乙基四胺四氢氯化物晶体或如前所述的三亚乙基四胺四氢氯化物。
为达前述发明目的，其中该医药组合物可进一步包括一药学上可接受的载剂。
为达前述发明目的，其中该载剂包含溶解剂、稀释剂、润滑剂、结合剂、解聚剂、起泡混合物、染料、甜味剂、湿润剂或其他用于医药调配物的无毒及药理学非活性物质。
为达前述发明目的，其中该溶解剂是包含环糊精或改质环糊精；其中该稀释剂包含乳糖、右旋糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉；其中该润滑剂包含于二氧化硅、滑石、硬脂酸、硬脂酸镁或硬脂酸钙或聚乙二醇；其中该结合剂包含淀粉、黄蓍胶、明胶、糖浆、阿拉伯胶、山梨糖醇、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮；其中该解聚剂包含淀粉、褐藻酸、海藻酸盐或羟基乙酸淀粉钠；其中该湿润剂包含卵磷脂、聚山梨醇酯或月桂 基硫酸盐。
为达前述发明目的，其中该医药组合物的剂型包含溶液、乳剂、悬浮液、粉末、锭剂、丸剂、片剂或胶囊。
本申请的又一目的在于提供一种如前所述的制备方法制备而成的三亚乙基四胺四氢氯化物晶体或如前所述的三亚乙基四胺四氢氯化物用于制备预防或治疗威尔森氏病的医药组合物的用途。
总归来说，本申请是提供一种结晶型为晶型N的TETA·4HCl及其制备方法。本申请所提供的TETA·4HCl具有制备较简易且产量较高的优势。此外，经测试，本申请所提供的结晶型为晶型N的TETA·4HCl及其组合物具有优良的稳定性及抗吸湿性，可改善先前技术所存在的TETA·4HCl及锭剂存放的不足。
附图说明
图1是本申请的TETA·4HCl粗产物制备流程图；
图2是本申请的TETA·4HCl晶体制备流程图；
图3是本申请一实施例的TETA·4HCl的XRPD分析图；
图4是本申请的TETA·4HCl的锭剂的吸湿性测试结果图；
图5是本申请一实施例的TETA·4HCl的XRPD分析图；
图6是本申请一实施例的比较例的XRPD分析图；
图7是本申请的TETA·4HCl与比较例的存放一个月的稳定性比较结果；
图8是本申请的TETA·4HCl与比较例的存放一个月的稳定性比较结果；
图9是本申请的TETA·4HCl与比较例的存放三个月的稳定性比较结果；
图10是本申请的TETA·4HCl与比较例的存放三个月的稳定性比较结果。
具体实施方式
本说明书中所述的所有技术性及科学术语，除非另外有所定义，皆为该所属领域具有通常技艺者可共同了解的意义。
本说明书及申请专利范围中所述的单数用语“一”、“一个”、“该”，除非另有说明，皆可指涉多于一个对象。
本说明书使用的“或”、“以及”、“和”，除非另有说明，皆指涉“或/和”。此外，用语“包含”、“包括”皆非有所限制的开放式连接词。前述段落仅为是系统性的指涉而不应解释为对发明主体的限制。
术语“治疗”、“用于治疗”以及其类用语是指称推迟、改善、减少、或逆转患者所罹患的可诊断病症以及该病症造成的相关症状的方法以及预防该病症或任何其所属的相关症状的方法。
术语“药学上可接受”是指称物质或组合物必须与其药学上调配物的其他成分兼容，且不加剧患者的症状。
术语“药学上可接受的载剂”包含一种或多种选自于下列的成分类型：溶剂、乳化剂、悬浮剂、分解剂、黏结剂、赋形剂、稳定剂、螯合剂、稀释剂、胶凝剂、防腐剂、润滑剂、表面活性剂、及其他类似或适用于本申请的载剂。
术语“药学上可接受的赋形剂”包括但不限于，聚合物、树脂、增塑剂、填料、润滑剂、稀释剂、黏合剂、崩解剂、溶剂、共一溶剂、界面活性剂、防腐剂、甜味剂、调味剂、药学级的染料或颜料、及黏度剂至少一种。
术语“有效量”是指称产生、造成预期的生物体反应所必须的剂量，且非以治疗痊愈所需为定量。本申请所属技术领域具通常知识者可理解，医药组合物的有效量可视诸如下列等因素而变化：期望生物终点、拟递送生物活 性剂、囊封基质(encapsulating matrix)的组成、目标组织等等。
术语“医药组合物”是指称一固体或液体组成物，其形式、浓度和纯度程度适合投予给患者，在投予之后，其可诱发所欲生理变化；医药组成物为无菌或非发热性者(non-pyrogenic)。
术语“进料(Feed)”是指在生产过程中将物质投入反应槽内。
术语“制程中管制(In-process control，IPC)”是指于生产过程中，所为的监测及制程调整。
术语“反溶剂(anti-solvent)”是指用于降低溶质的溶解度的溶剂。
术语“酸化反应(Acidification)”是指在固体或液体中加入足够的酸，使其呈现酸性，并因该酸性而发生的反应。
术语“晶体析出”或“结晶”(crystallization)是指溶液中的溶质呈现过饱合状态而产生晶体。
术语“洗晶(Wash)”是指以特定溶剂淋洗生产过程中所得产物。
术语“干燥减重(loss on drying，LOD)”是指产物经干燥至恒重后所减失的重量。
术语“再结晶(Re-crystallization)”是指将物质或晶体再次溶于溶剂后，重新从溶液中结晶。
本申请所提供的制备方法可视情况，先将TETA·2HCl制备成TETA·4HCl粗产物(Crude trientine tetrahydrochloride)，再将TETA·4HCl粗产物制备成本申请所提供的TETA·4HCl。
TETA·4HCl粗产物(Crude trientine tetrahydrochloride)的制备：
举例来说，在本申请的一实施例中，TETA·4HCl粗产物的制备是将TETA·2HCl与纯水混合溶解后，加入酸性溶液进行酸化反应(Acidification)；接着 加入反溶剂并持续搅拌以使晶体析出(Crystallization)；然后，过滤反应悬浮溶液，并进行洗晶、干燥产物后，即可得到TETA·4HCl粗产物。
其中该反溶剂可以是TETA·4HCl基本不溶于其中的任何溶剂，包括但不限于乙醇或甲醇，以甲醇为最佳；其中该酸性溶液可以是任何常见用于酸化反应的溶液，较佳为盐酸，更佳为35％以上的盐酸。
其中，为得到较好的制备效果，该TETA·2HCl与该纯水的重量比例为0.5：1～1：1，较佳重量比例为1：1；该酸化反应的温度为10℃～40℃，较佳温度为20±10℃；该酸化反应的反应液的pH值为≤2.0；该加入反溶剂的加入温度为10℃～40℃，较佳温度为20±10℃；该反溶剂与该TETA·2HCl的重量比例2：1～6：1，较佳重量比例为4：1；该晶体析出的温度为15℃～35℃，较佳温度为25±5℃；该持续搅拌的时间为至少2小时；该产物的干燥减重(LOD)<10％，较佳干燥减重为不要超过5.0％。
TETA·4HCl晶体(trientine tetrahydrochloride)的制备：
在本申请的一实施例中，本申请所提供的TETA·4HCl晶体的制备是将TETA·4HCl粗产物与纯水混合溶解后，加入反溶剂并持续搅拌以再结晶(Re-crystallization)使晶体析出；然后，过滤反应悬浮溶液，并进行洗晶、干燥产物后，即可得到本申请所提供的TETA·4HCl晶体。
其中该反溶剂可以是TETA·4HCl基本不溶于其中的任何溶剂，包括但不限于乙醇或甲醇，以甲醇为最佳。
其中，为得到较好的制备效果，该TETA·4HCl粗产物与该纯水的重量比例为1：1～1：2，较佳重量比例为1：1.2；该产物与该纯水混合溶解的温度为15℃～35℃，较佳温度为25±5℃；该TETA·4HCl粗产物与该反溶剂的重量比例为1：2～1：6，较佳重量比例为1：4；该反溶剂的进料温度为50℃～75℃，较佳温度为60±5℃；该持续搅拌的搅拌温度为5℃～25℃，较佳温度为15± 5℃；该持续搅拌的时间为至少1小时；该产物的干燥减重(LOD)<1％，较佳干燥减重为不要超过0.6％。
本申请提供的医药组合物是可利用本申请所属技术领域中具有通常知识者所详知的技术，将本案所提供的有效成分或组合物，与至少一药学上可接受的载剂(vehicle)，制备一适用本申请组合物的剂型。其中该剂型包含但不限于溶液(Solution)、乳剂(Emulsion)、悬浮液(Suspension)、粉末(Powder)、锭剂(Tablet)、丸剂(Pill)、片剂(Troche)或胶囊(Capsule)以及其他类似或适用本申请的剂型。
此外，本申请所述医药组合物适合的给药途径是包含但不限于口服、注射、黏膜、外用经皮以及其他类似或适用本申请的给药途径；其中最佳给药途径为口服给药。
本申请所属技术领域中具有通常知识者可依现有的技术，将本申请所提供的TETA·4HCl与至少一药学上可接受的载剂，制备成一适用的剂型。举例来说，在本申请的一实施例中，医药组合物为口服剂型，可依以下制程步骤制备而成：步骤一、取一本申请所提供的TETA·4HCl晶体，视情况将其研磨或粒化；步骤二、视情况将该TETA·4HCl晶体与药学上可接受的载剂组合形成一混合物。
其中当该口服剂型为锭剂时，该步骤二后可进一步包含：步骤三、压缩该混合物以形成一锭剂，以及步骤四、视情况对该锭剂包糖衣或包薄膜衣。其中当该口服剂型为胶囊或粉末时，该步骤二后可进一步包含将该混合物封装于胶囊中。其中该制程步骤更可进一步包含其他制药基本步骤，其是包含但不限于研磨、粒化、包糖衣或包薄膜衣。
其中该药学上可接受的载剂是包含但不限于溶解剂、稀释剂、润滑剂、 结合剂、解聚剂、起泡混合物、染料、甜味剂、湿润剂或用于医药调配物的无毒及药理学非活性物质；其中该溶解剂是包含但不限于环糊精或改质环糊精；其中该稀释剂是包含但不限于乳糖、右旋糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉；其中该润滑剂是包含但不限于二氧化硅、滑石、硬脂酸、硬脂酸镁或硬脂酸钙或聚乙二醇；其中该结合剂是包含但不限于淀粉、黄蓍胶、明胶、糖浆、阿拉伯胶、山梨糖醇、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮；其中该解聚剂是包含但不限于淀粉、褐藻酸、海藻酸盐或羟基乙酸淀粉钠；其中该湿润剂是包含但不限于卵磷脂、聚山梨醇酯或月桂基硫酸盐。
其中该医药组合物包含至多85重量百分浓度(wt％)的TETA·4HCl，例如在本申请的一实施例中，医药组合物含有50重量百分浓度(wt％)的TETA·4HCl。其中该医药组合物较佳为无菌及无热原质。
本申请所使用的材料，除有特别指明者，皆为市售易于取得的材料。
本申请的新颖技术特征，包含特定特征，是揭示于申请专利范围，针对本申请的技术特征，较佳的理解兹配合说明书、依据本申请原理的实施例、和附图将本申请较佳的实施例详细说明。
本申请是以下面的实施例予以示范阐明，但本申请不受下述实施例所限制。
实施例一、TETA·4HCl的合成
TETA·4HCl粗产物(Crude trientine tetrahydrochloride)的制备：
如图1的流程所示，将10kg的三亚乙基四胺二氢氯化物(Trientine Dihydrochloride，TETA·2HCl)及10kg的纯水(Purified water，PW)投入反应槽中，使其于25±5℃下溶解；将反应槽的温度设定在15±5℃，接着在温度20±10℃内将9.45～9.9公斤的35％以上的盐酸(Hydrochloric acid)加入反应槽 中并以20±10℃的温度进行酸化反应(Acidification)，并将反应液的pH值控制在≤2.0；然后，将反应槽的温度设定在15±5℃，并将40公斤的甲醇(Methanol，MeOH)在内温为20±10℃的范围内加入，进行晶体析出(Crystallization)；接着，将反应槽的温度控制在25±5℃并搅拌至少2小时；然后，过滤反应槽内悬浮溶液，并以每次25公斤的甲醇进行两次洗晶；最后将产物干燥至干燥减重(LOD)<5％，即可得到该TETA·4HCl粗产物。
TETA·4HCl(trientine tetrahydrochloride)的制备：
如图2的流程所示，将前述步骤所得的TETA·4HCl粗产物及其1.2倍重的纯水投入反应槽中，使其于25±5℃下溶解；接着准备该TETA·4HCl粗产物的4倍重的甲醇在温度60±5℃的进料温度加入，接着将反应槽进行降温，设定反应槽的温度在15±5℃，等内温降至15±5℃的后，持续在此温度下搅拌至少1小时，进行再结晶(Re-crystallization)使晶体析出；接着过滤反应槽内悬浮溶液，并以每次为该TETA·4HCl粗产物2.5倍重的甲醇进行两次洗晶；最后将产物干燥至LOD<0.6％，即可得到该TETA·4HCl。
实施例二、TETA·4HCl的晶体形式的分析
以X光粉末绕射(X-Ray Powder Diffraction，XRPD)分析实施例一所述方法制备而得的TETA·4HCl。结果如图3所示，本申请所提供的TETA·4HCl的晶体具有在21.9、24.8、25.2、28.0及35.6±0.1°2θ处具有峰值的XRPD图案，命名为晶型N(Form N)。
实施例三、稳定性测试一
依据美国药典(United States Pharmacopeia，USP)所公开的方法，以薄层层析(Thin-layer chromatography，TLC)进行层析法纯度检查 (Chromatographic purity)，分析实施例一所合成的TETA·4HCl在不同温度(25℃～40℃)及不同湿度(60％RH～75％RH)环境下存放一个月后所含的不纯物(impurity)。结果如表一所示，TETA·4HCl在不同温度及不同湿度环境下存放一个月后未验出含有不纯物，该结果证实本申请所提供的TETA·4HCl具有良好的稳定性。
表一

*未验出：低于定量极限(Below Quantification Limit，BQL)。
实施例四、稳定性测试二
将实施例一所述方法制备而得的TETA·4HCl压缩制成锭剂，将该锭剂存放于25℃、60％RH或40℃、75％RH环境条件下三个月后分析其含量和不纯物。
结果如表二所示，该锭剂存放三个月后，TETA·4HCl无明显降解情形，且所有不纯物皆与起始测定结果相同并低于分析的定量极限(Quantification  Limit)。
表二

*未验出：低于定量极限(Below Quantification Limit，BQL)。
实施例五、吸湿性测试
将实施例四所述锭剂存放于25℃、75％RH环境条件一个月后，测试其吸湿性，并以市售产品盐酸曲恩汀片(TETA·4HCl形式B锭剂)及市售TETA·2HCl-胶囊作为比较例。结果如图4所示，使用本申请的TETA·4HCl晶体制成的锭剂无明显吸湿增重情形，而市售TETA·2HCl-胶囊吸湿增重则是达原重量的75％以上，所述结果证实使用本申请的TETA·4HCl晶体制成的锭剂具有较佳的抗吸湿性。
实施例六、产率分析及稳定性比较
依实施例一所述的制备方法制备晶型N的TETA·4HCl，并以 TW202002956A所公开的方法制备形式B的TETA·4HCl作为比较例。
XRPD分析结果如图5及图6所示，图5为本申请的TETA·4HCl晶体的XRPD图，图6为比较例的XRPD图，比较例的XRPD图显示其为专利公开号TW202002956A所述的形式B。产率结果如表三所示，依本申请所提供的制备方法制备而成的TETA·4HCl(晶型N)具有无法预期的较高产率(77.1％～86.6％)，且本申请所提供的方法在制备程序上具有不需要在低温下进行晶体析出及不需要使用晶种即可获得TETA·4HCl的优势。
表三
此外，将本申请的TETA·4HCl与比较例存放在不同温度(25℃～40℃)及不同湿度(60％RH～75％RH)一个月或三个月后，依据美国药典所公开的方法，以薄层层析进行层析法纯度检查。稳定性比较结果如图7～图10所示，本申请的TETA·4HCl与比较例具有相似的稳定性。
总结上述结果可知，本申请所提供的制备方法不但具有制备程序较简易的优势，且可获得高产量的TETA·4HCl。此外以本申请所提供的制备方法所合成出的TETA·4HCl是属于晶型N，本申请所提供的TETA·4HCl与其组合物 具有优良的稳定性及抗吸湿性，可改善先前技术所存在的稳定性问题。
于本说明书较佳实施例揭示的内容，本申请所属领域具有通常知识者可明显得知前述实施例仅为例示；具本申请所属技术领域通常知识者可藉由诸多变换、替换而实施，而不与本申请的技术特征有所差异。依据说明书实施例，本申请可有多种变换仍无碍于实施。本说明书提供的请求项界定本申请的范围，该范围涵盖前述方法与结构及与其相等的发明。
上述多项功效，实属充分符合新颖性及创造性的法定专利要件，于是依法提出申请，恳请贵局核准本件发明专利申请案，以励发明。

Claims (15)

  1. 一种三亚乙基四胺四氢氯化物晶体的制备方法，包含：
    步骤一、将一反溶剂在一进料温度下添加至一三亚乙基四胺四氢氯化物水溶液中，并搅拌析出晶体；
    其中，所述进料温度为50℃～75℃；所述反溶剂为醇类溶剂。
  2. 如权利要求1所述的制备方法，其中，所述搅拌是在一时间条件及一搅拌温度下进行；其中，所述时间条件是至少1小时，所述搅拌温度是5℃～25℃。
  3. 如权利要求1或2所述的制备方法，其中，所述反溶剂为甲醇。
  4. 如权利要求3所述的制备方法，其中，所述步骤一进一步包含干燥所述晶体，使所述晶体的干燥减重<1％。
  5. 如权利要求1或2所述的制备方法，其中，所述步骤一前进一步包含：
    前置步骤一、将一三亚乙基四胺二氢氯化物水溶液与一酸性溶液混合成一反应液进行酸化反应；
    前置步骤二、加入一醇类反溶剂并搅拌析出三亚乙基四胺四氢氯化物粗产物。
  6. 如权利要求5所述的制备方法，其中，所述反应液的pH值≤2.0。
  7. 如权利要求5所述的制备方法，其中，所述前置步骤二的醇类反溶剂为甲醇。
  8. 如权利要求5所述的制备方法，其中，所述前置步骤二的搅拌是在一温度条件及一时间条件下进行；其中所述温度条件为15℃～35℃，所述时间条件为至少2小时。
  9. 如权利要求5所述的制备方法，其中，所述前置步骤二进一步包含干燥所述三亚乙基四胺四氢氯化物粗产物，使所述三亚乙基四胺四氢氯化物粗 产物的干燥减重<10％。
  10. 一种三亚乙基四胺四氢氯化物，其中，所述三亚乙基四胺四氢氯化物的晶体具有在21.9、24.8、25.2、28.0及35.6±0.1°2θ处具有峰值的XRPD图案。
  11. 一种医药组合物，包含如权利要求1至9中任一项所述的制备方法制备而成的三亚乙基四胺四氢氯化物晶体或如权利要求10所述的三亚乙基四胺四氢氯化物。
  12. 如权利要求11所述的医药组合物，其中，所述医药组合物可进一步包括一药学上可接受的载剂。
  13. 如权利要求12所述的医药组合物，其中，所述载剂包含溶解剂、稀释剂、润滑剂、结合剂、解聚剂、起泡混合物、染料、甜味剂、湿润剂或其他用于医药调配物的无毒及药理学非活性物质。
  14. 如权利要求11所述的医药组合物，其中，所述医药组合物的剂型包含溶液、乳剂、悬浮液、粉末、锭剂、丸剂、片剂或胶囊。
  15. 一种如权利要求1至9中任一项所述的制备方法制备而成的三亚乙基四胺四氢氯化物晶体或如权利要求10所述的三亚乙基四胺四氢氯化物用于制备预防或治疗威尔森氏病的医药组合物的用途。
PCT/CN2023/077332 2022-02-23 2023-02-21 一种三亚乙基四胺四氢氯化物及其制备方法与组合物 WO2023160520A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020237039583A KR20230172013A (ko) 2022-02-23 2023-02-21 트리엔틴 테트라하이드로클로라이드 및 이의 제조 방법 및 이의 조성물

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210168899.2A CN116675607A (zh) 2022-02-23 2022-02-23 一种三亚乙基四胺四氢氯化物及其制备方法与组合物
CN202210168899.2 2022-02-23

Publications (1)

Publication Number Publication Date
WO2023160520A1 true WO2023160520A1 (zh) 2023-08-31

Family

ID=87764742

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/077332 WO2023160520A1 (zh) 2022-02-23 2023-02-21 一种三亚乙基四胺四氢氯化物及其制备方法与组合物

Country Status (3)

Country Link
KR (1) KR20230172013A (zh)
CN (1) CN116675607A (zh)
WO (1) WO2023160520A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CS197093B1 (cs) * 1978-06-16 1980-04-30 Ivo Kuhr Způsob přípravy čistého dihydrochloridu triethylentetraminu
WO2006027705A2 (en) * 2004-07-19 2006-03-16 Protemix Corporation Limited Synthesis of triethylenetetramines
CN111479798A (zh) * 2018-05-04 2020-07-31 Gmp奥奋有限公司 三亚乙基四胺四盐酸盐的晶形及其医药用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CS197093B1 (cs) * 1978-06-16 1980-04-30 Ivo Kuhr Způsob přípravy čistého dihydrochloridu triethylentetraminu
WO2006027705A2 (en) * 2004-07-19 2006-03-16 Protemix Corporation Limited Synthesis of triethylenetetramines
CN111479798A (zh) * 2018-05-04 2020-07-31 Gmp奥奋有限公司 三亚乙基四胺四盐酸盐的晶形及其医药用途

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ALLEN, K. G. D.; TWEDT, D. C.; HUNSAKER, H. A.: "Tetramine cupruretic agents: a comparison in dogs", AMERICAN JOURNAL OF VETERINARY RESEARCH, AMERICAN VETERINARY MEDICINE ASSOCIATION, US, vol. 48, no. 1, 1 January 1987 (1987-01-01), US , pages 28 - 30, XP009508978, ISSN: 0002-9645 *
BASELT, RANDALL C.; SUNDERMAN, F. WILLIAM, JR.; MITCHELL, JOHN; HORAK, EVA: "Comparisons of antidotal efficacy of sodium diethyldithiocarbamate, D-penicillamine and triethylenetetramine upon acute toxicity of nickel carbonyl in rats", RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY., PJD PUBLICATIONS LTD., WESTBURY, NY., US, vol. 18, no. 4, 1 December 1977 (1977-12-01), US , pages 677 - 88, XP009508982, ISSN: 0034-5164 *
BERNAL IVAN, CETRULLO JAMES: "The Phenomenon of Conglomerate Crystallization. XII. Spontaneous Resolution in Coordination Compounds. IX. The Structure of Racemic [cis+Rh(trien)(NOz)2]CI", INORGANICA CHIMICA ACTA, vol. 144, no. 2, 1 January 1988 (1988-01-01), pages 227 - 232, XP093085769 *
BRUCE L. MAY, SUZANNA D. KEAN, CHRISTOPHER J. EASTON, STEPHEN F. LINCOLN: "Preparation and characterization of 6A-polyamine-mono-substituted β-cyclodextrins", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, ROYAL SOCIETY OF CHEMISTRY, CAMBRIDGE, UK, vol. 1, no. 21, 1 January 1997 (1997-01-01), Cambridge, UK , pages 3157 - 3160, XP055278917, ISSN: 0300-922X, DOI: 10.1039/a704467d *
D. H. PEACOCK: "322. Polyamines. Part II. The preparation of ββ′-diaminodiethylamine and NN′-bis-(β-aminoethyl)ethylenediamine", JOURNAL OF THE CHEMICAL SOCIETY, 1 January 1936 (1936-01-01), pages 1518 - 1520, XP055519217, ISSN: 0368-1769, DOI: 10.1039/JR9360001518 *

Also Published As

Publication number Publication date
CN116675607A (zh) 2023-09-01
KR20230172013A (ko) 2023-12-21

Similar Documents

Publication Publication Date Title
JP2023122634A (ja) トリエチレンテトラミン四塩酸塩、その製造方法及び組成物
US10537555B2 (en) Complex of angiotensin receptor antagonist and neutral endopeptidase inhibitor
CN112142679B (zh) 一种吉非替尼与香草酸共晶甲醇溶剂合物及其制备方法
US20080234323A1 (en) Amorphous and Three Crystalline Forms of Rimonabant Hydrochloride
JP2017526699A (ja) （６ｓ）−５−メチルテトラヒドロ葉酸又はその塩の組成物及びその調製と応用
US10556863B1 (en) Crystalline form of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide, preparation method therefor and use thereof
US10696629B2 (en) Crystalline form of dextral oxiracetam, preparation method therefor and use thereof
WO2008061456A1 (fr) Composé folacine-metformine et sa production
WO2021227146A1 (zh) N-[8-(2-羟基苯甲酰基)氨基]辛酸一钾晶型化合物、制备方法及用途
WO2010060387A1 (zh) 硝克柳胺化合物五种晶型、其制法和其药物组合物与用途
WO2023160520A1 (zh) 一种三亚乙基四胺四氢氯化物及其制备方法与组合物
AU2016269359B2 (en) Sodium salt of uric acid transporter inhibitor and crystalline form thereof
CN101993417B (zh) 磷酸二甲啡烷的稳定晶型
CN102746227B (zh) 一种磷酸二甲啡烷晶型ⅱ及制备方法和药物组合物
JP5795693B2 (ja) 晶癖を有する結晶及び該結晶を有効成分として含有する医薬組成物
CN110372635B (zh) 氢溴酸沃替西汀α晶型的制备方法
WO2020052627A1 (zh) 取代的吡咯并嘧啶类cdk抑制剂的盐及其结晶和用途
US10155740B2 (en) Crystal forms of immunomodulatory drug pomalidomide and co-crystal with gentisic acid
CN115073368B (zh) 一种米力农-5-磺基水杨酸晶型
CN112094312B (zh) 环维黄杨星d二盐酸盐的晶型a
CN113402390B (zh) 一种阿司匹林药物共晶体及其制备方法和应用
US20040038985A1 (en) Crystal forms of 1- [6-chloro-5-(trifluoromethly) -2-pyridinyl] piperazine hydrochloride
US9663507B1 (en) Crystallisation of thiamine hydrochloride
BR102023002771A2 (pt) Tetrahidroclorito de trientina e um método de preparação e sua composição farmacêutica
CN115572292A (zh) 小檗碱丁二酸盐晶型及其制备方法和其组合物与应用

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: 23759145

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 20237039583

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020237039583

Country of ref document: KR