WO2023227069A1 - Polidocanol à masse moléculaire unique et utilisation associée - Google Patents

Polidocanol à masse moléculaire unique et utilisation associée Download PDF

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WO2023227069A1
WO2023227069A1 PCT/CN2023/096332 CN2023096332W WO2023227069A1 WO 2023227069 A1 WO2023227069 A1 WO 2023227069A1 CN 2023096332 W CN2023096332 W CN 2023096332W WO 2023227069 A1 WO2023227069 A1 WO 2023227069A1
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polydocanol
cysts
polidocanol
molecular weight
single molecular
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PCT/CN2023/096332
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English (en)
Chinese (zh)
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王庆彬
汤家泽
刘彪
于晓朋
郑喜春
李秋芬
王杰
郭军
赵宣
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北京键凯科技股份有限公司
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Publication of WO2023227069A1 publication Critical patent/WO2023227069A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/337—Polymers modified by chemical after-treatment with organic compounds containing other elements
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a preparation method of single molecular weight polidocanol and its application in preparing disease treatment drugs.
  • Polidocanol also known as ethoxyhardened alcohol and lauromacrol, is a polymer product obtained by polymerizing lauryl alcohol and multiple ethylene oxides. At present, polidocanol is mainly produced through the polymerization reaction of lauryl alcohol and ethylene oxide under alkali-catalyzed conditions. The quality and stability of polidocanol products are greatly affected by the purity of starting materials, catalysts, reaction pressure, temperature and post-treatment processes. On the one hand, commercially available lauryl alcohol contains many impurities. In addition to decanol and tetradecanol, there are also many unknown impurities.
  • the by-products generated after these impurities are introduced into the polymerization reaction of polidocanol are difficult to separate from polidocanol, which will directly affect the quality of the finished product of polidocanol.
  • many by-products will be produced during the synthesis of polydocanol.
  • the main by-products are free polyethylene glycol, diethylene glycol, and dioxane. , formaldehyde, acetaldehyde, ethylene glycol, etc.
  • the patent with the publication number CN103922901 discloses a purification method of polidocanol.
  • the high-purity polidocanol refined product is finally obtained through vacuum distillation before adjusting the pH value of the crude product.
  • this invention cannot avoid the risk of by-products generated by impurities (such as n-decanol and n-tetradecanol) brought into lauryl alcohol and ethylene oxide.
  • the patent with publication number CN100335453C discloses a preparation method of polidocanol, which uses NaOH as the catalyst, and adjusts the pH of the crude product to 5-7 with acetic acid to obtain a white or off-white ointment finished product.
  • the finished product prepared by the present invention cannot fully meet pharmaceutical grade quality standards.
  • the patent with publication number CN113200821A discloses a purification method of lauryl alcohol and a synthesis method of polidocanol.
  • High-purity lauryl alcohol is prepared by vacuum distillation, but the distillation purification requirement is -0.08MPa, and the distillation temperature 130 ⁇ 150°C.
  • the dehydration temperature of lauryl alcohol is 90-125°C
  • the vacuum degree is -0.08MPa
  • the polymerization temperature is 100-115°C
  • the polymerization pressure is 0.1-0.8MPa.
  • the degassing temperature is 90-0.08MPa. 120°C. It can be seen that the polymerization reaction is carried out under high temperature and negative pressure conditions, which has high requirements on equipment and technology.
  • the patent with publication number CN113527060A discloses a refining process of lauryl alcohol and a process of preparing lauromanol using the refined product as raw material.
  • This patent uses an organic solvent to refine the raw material of lauryl alcohol through recrystallization. After dissolving the organic solvent and lauryl alcohol, it needs to be cooled to -5°C ⁇ 10°C, stirred and crystallized, recrystallized, filtered and then distilled under reduced pressure (-0.1MPa ⁇ 0.05 MPA), temperature 70 ⁇ 100°C.
  • the polymerization temperature of lauryl alcohol and ethylene oxide is 130 ⁇ 180°C, and the pressure is 0.1 ⁇ 0.5MPa. It can be seen that the preparation of lauryl alcohol and lauronanol has strict requirements on temperature and pressure, as well as high requirements on equipment and technology.
  • Polidocanol is a surfactant-type hardener whose structure is very similar to the cell membrane phospholipid bilayer. By interfering with the surfactant substances on the cell membrane, it destroys the cell membrane structure, causing the lysis and death of vascular endothelial cells, and then hair Vascular fibrosis and vascular occlusion. It has fixed hydrophilic ends and hydrophobic ends at the same time, which can be oriented and arranged on the surface of the solution, significantly reducing the surface tension of the solution and forming foam. Therefore, polidocanol is widely used in foam sclerosis treatment. At present, polidocanol is mainly used in sclerotherapy for varicose veins, venous malformations, hemangiomas, internal hemorrhoids, cystic diseases, acne, tumor ablation, etc.
  • polidocanol is a mixture of different molecular weights
  • polidocanols with different chain lengths have different foaming effects and medicinal effects, making it difficult to control during the application process. Therefore, it is of great significance to develop and prepare polidocanol with a single molecular weight to effectively control and improve the quality of polidocanol to improve the efficacy of polidocanol.
  • the present invention provides the application of single molecular weight polidocanol in the preparation of disease treatment drugs, and the polidocanol is used as a sclerosing agent and/or hemostatic agent for treatment.
  • the diseases include cystic diseases, vascular related diseases, tumors, obstetric and gynecological diseases, inflammation and/or pain;
  • the vascular related diseases include varicose veins, vascular malformations and/or hemorrhage;
  • the obstetric and gynecological diseases include uterine submucosal fibroids and cesarean scar pregnancy;
  • the cystic disease includes abdominal organ cysts, body surface cysts, lymphoceles, thyroid cysts, bone cysts, digital mucocele and/or pelvic encapsulated effusion;
  • the tumors include benign or malignant solid tumors
  • the inflammation includes infectious inflammation and/or non-infectious inflammation
  • the pain includes chronic pain, acute pain and/or cancer pain.
  • the tumors include: infantile hemangioma, congenital hemangioma, plexiform hemangioma, spindle cell hemangioma, epithelioid hemangioma, pyogenic granuloma, Kaposiform hemangioendothelioma, reticular hemangioma Endothelioma, papillary intralymphatic hemangioendothelioma, composite hemangioendothelioma, Kaposi's sarcoma, angiosarcoma, epithelioid hemangioendothelioma, uterine fibroids and/or abdominal visceral malignancies;
  • the pain includes: muscle and soft tissue pain, bone and joint pain and/or visceral pain;
  • the inflammation includes: tendinitis, tendinitis, tendinosis, peritendinitis, ankylosing spondylitis, sacroiliitis, gouty arthritis, myofasciitis, tenosynovitis and/or frozen shoulder;
  • the varicose veins include: varicose veins of lower limbs, esophageal and gastric varices, varicocele, abdominal wall varicose veins and/or hemorrhoids;
  • the bleeding includes: gastrointestinal bleeding, bladder bleeding, bleeding caused by early, middle or late cancer;
  • the abdominal organ cysts include: liver cysts, renal cysts, parapelvic cysts, pancreatic cysts, endometrium Ectopic cysts and/or ovarian chocolate cysts;
  • the body surface cysts include: skin cysts and/or finger mucous cysts;
  • the abdominal organ malignant tumors include liver cancer.
  • the molecular structure of the single molecular weight polydocanol monomer is:
  • n is an integer, 4 ⁇ n ⁇ 24;
  • n is an integer, 8 ⁇ n ⁇ 15;
  • n is selected from any of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 A numerical value, each value of n corresponds to a polidocanol product of a defined molecular weight.
  • n is 8, 9, 10 or 11.
  • the single molecular weight polydocanol is prepared by the following preparation method: reacting single chain length polyethylene glycol with 1-halododecane, separating and purifying the product to obtain single molecular weight polydocanol. alcohol.
  • single molecular weight means that the compound of the present invention is not a mixture of homologues with different molecular weights. It refers to the average molecular weight of a polymer in which the molecular weight of the compound of the present invention is not a mixture of homologues with different molecular weights.
  • the polydocanol with a single chain length of the present invention contains PEG4 (four ethylene glycol units)
  • the polydocanol with a single chain length only contains PEG4, excluding those containing PEG3, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG21, PEG22, PEG23, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, PEG32, Polydocanol of other PEGs such as PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, PEG48, PEG49, PEG50, and PEG51;
  • the polydocanol with a single chain length of the present invention contains PEG5 (five ethylene glycol units), the polydocanol with a single chain length only contains PEG5, excluding those containing PEG3, PEG4, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG21, PEG22, PEG23, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, PEG32, Polydocanol of other PEGs such as PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, PEG48, PEG49, PEG50, and PEG51.
  • the polydocanol with a single chain length of the present invention contains PEG6 (six ethylene glycol units)
  • the polydocanol with a single chain length Alcohol only contains PEG6, excluding alcohol such as PEG3, PEG4, PEG5, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG21, PEG22, PEG23, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, PEG32, PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, PEG48, Polidocanol from other PEGs such as PEG49, PEG50 and PEG51.
  • the polydocanol with a single chain length of the present invention contains PEG7 (seven ethylene glycol units), the polydocanol with a single chain length only contains PEG7, excluding those containing PEG3, PEG4, PEG5, PEG6, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG21, PEG22, PEG23, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, PEG32, Polydocanol of other PEGs such as PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, PEG48, PEG49, PEG50, and PEG51.
  • the polydocanol with a single chain length of the present invention contains PEG8 (eight ethylene glycol units)
  • the polydocanol with a single chain length only contains PEG8, excluding those containing PEG3, PEG4, PEG5, PEG6, PEG7, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG21, PEG22, PEG23, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, PEG32, Polydocanol of other PEGs such as PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, PEG48, PEG49, PEG50, and PEG51.
  • the polydocanol with a single chain length of the present invention contains PEG9 (nine ethylene glycol units)
  • the polydocanol with a single chain length only contains PEG9, excluding those containing PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG10, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG21, PEG22, PEG23, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, PEG32, Polydocanol of other PEGs such as PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, PEG48, PEG49, PEG50, and PEG51.
  • the polydocanol with a single chain length of the present invention contains PEG10 (ten ethylene glycol units), the polydocanol with a single chain length only contains PEG10, excluding those containing PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG21, PEG22, PEG23, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, PEG32, Polydocanol of other PEGs such as PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, PEG48, PEG49, PEG50, and PEG51.
  • the polydocanol with a single chain length of the present invention contains PEG11 (eleven ethylene glycol units)
  • the polydocanol with a single chain length Docanol only contains PEG11, excluding PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG21, PEG22, PEG23, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, PEG32, PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, Polidocanol from other PEGs such as PEG48, PEG49, PEG50 and PEG51.
  • the polydocanol with a single chain length of the present invention contains PEG12 (twelve ethylene glycol units), the polydocanol with a single chain length only contains PEG12, excluding those containing PEG3, PEG4, PEG5, and PEG6.
  • the polydocanol with a single chain length of the present invention contains PEG13 (thirteen ethylene glycol units), the polydocanol with a single chain length only contains PEG13, excluding those containing PEG3, PEG4, PEG5, and PEG6.
  • the polydocanol with a single chain length of the present invention contains PEG14 (fourteen ethylene glycol units), the polydocanol with a single chain length only contains PEG14, excluding those containing PEG3, PEG4, PEG5, and PEG6.
  • the polydocanol with a single chain length of the present invention contains PEG15 (fifteen ethylene glycol units), the polydocanol with a single chain length only contains PEG15, excluding those containing PEG3, PEG4, PEG5, and PEG6.
  • the polydocanol with a single chain length of the present invention contains PEG16 (sixteen ethylene glycol units), the polydocanol with a single chain length only contains PEG16, excluding those containing PEG3, PEG4, PEG5, and PEG6.
  • the polydocanol with a single chain length of the present invention contains PEG17 (seventeen ethylene glycol units), the polydocanol with a single chain length only contains PEG17, excluding those containing PEG3, PEG4, PEG5, and PEG6.
  • the polydocanol with a single chain length of the present invention contains PEG18 (eighteen ethylene glycol units)
  • the polydocanol with a single chain length only contains PEG18, excluding those containing PEG3, PEG4, PEG5, and PEG6.
  • the polydocanol with a single chain length of the present invention contains PEG19 (nineteen ethylene glycol units), the polydocanol with a single chain length only contains PEG19, excluding those containing PEG3, PEG4, PEG5, and PEG6.
  • the polydocanol with a single chain length of the present invention contains PEG20 (twenty ethylene glycol units), the polydocanol with a single chain length only contains PEG20, excluding those containing PEG3, PEG4, PEG5, and PEG6.
  • the polydocanol with a single chain length of the present invention contains PEG21 (twenty-one ethylene glycol units), the polydocanol with a single chain length only contains PEG21, excluding PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG22, PEG23, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, Polydocanol of other PEGs such as PEG32, PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, PEG48, PEG49, PEG50, and PEG51.
  • the polydocanol with a single chain length of the present invention contains PEG22 (twenty-two ethylene glycol units), the polydocanol with a single chain length only contains PEG22, excluding those containing PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG21, PEG23, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, Polydocanol of other PEGs such as PEG32, PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, PEG48, PEG49, PEG50, and PEG51
  • the polydocanol with a single chain length of the present invention contains PEG23 (twenty-three ethylene glycol units), the polydocanol with a single chain length only contains PEG23, excluding those containing PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG21, PEG22, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, Polydocanol of other PEGs such as PEG32, PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, PEG48, PEG49, PEG50, and PEG51
  • the polydocanol with a single chain length of the present invention contains PEG24 (twenty-four ethylene glycol units), the polydocanol with a single chain length only contains PEG24, excluding those containing PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17, PEG18, PEG19, PEG20, PEG21, PEG22, PEG23, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, PEG32, PEG33, PEG34, PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, Polidocanol from other PEGs such as PEG47, PEG48, PEG49, PEG50 and PEG51.
  • preparation method of the present invention includes the following steps:
  • S1 Mix single molecular weight polyethylene glycol with catalyst and organic solvent, add 1-halododecane dropwise, raise the temperature to the preset temperature, and keep the reaction warm;
  • the catalyst is one or more of sodium hydroxide, sodium hydride, potassium hydroxide, potassium hydride, potassium tert-butoxide or sodium tert-butoxide, preferably sodium hydroxide or sodium hydride.
  • the organic solvent is selected from: ethanol, methanol, isopropyl alcohol, tetrahydrofuran (THF), acetone, acetonitrile, toluene, xylene, n-hexane, cyclohexane, isooctane, n-pentane, petroleum ether, At least one of dimethyl sulfoxide (DSMO), N,N-dimethylformamide, dichloromethane (DCM), and diethoxymethane (DEM). More preferably, it is at least one selected from tetrahydrofuran (THF), dimethyl sulfoxide (DSMO), acetonitrile, toluene, and N,N-dimethylformamide.
  • the 1-halododecane is 1-chlorododecane, 1-bromododecane or 1-iodododecane, preferably 1-bromododecane.
  • the preset temperature is 80°C to 95°C, such as 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C, 89°C, 90°C, 91°C. , 92°C, 93°C, 94°C, 95°C, preferably 80 to 90°C.
  • the time of the insulation reaction is 12 to 24 hours, preferably 16 to 24 hours, for example, the time of the insulation reaction is 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours;
  • the insulation reaction time is 16 to 20 hours.
  • the molar ratio of the single molecular weight polyethylene glycol to the 1-halododecane is 2 to 15:1, more preferably 2 to 10:1, such as 2:1, 3: 1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1.
  • the extraction operation is repeated 2 to 6 times, more preferably 3 to 5 times, more preferably 3 or 4 times;
  • the extraction solvent is one or a combination of one or more of diethyl ether, ethyl acetate, dichloromethane, chloroform, methyl tert-butyl ether, and toluene. More preferably, the extraction solvent is Ethyl acetate;
  • the organic phase is a mixture of organic phases obtained by the above repeated extraction
  • the desiccant used for drying is one or more of Na 2 SO 4 or MgSO 4 .
  • the separation and purification is carried out by chromatography, preferably column chromatography, and the column
  • the eluent used in chromatography is selected from one or more of ethyl acetate, methanol, ethanol, n-hexane, petroleum ether or dichloromethane.
  • the present invention also provides a preparation of polidocanol, including the aforementioned single molecular weight polidocanol or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients;
  • the pharmaceutically acceptable salt is obtained by adding a pharmaceutically acceptable acid, and the pharmaceutically acceptable acid includes hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid or lactic acid;
  • the preparation also includes active substances and clean gas;
  • the preparation is an injection.
  • the injection is a stock solution or a foaming preparation.
  • the injection is a foaming preparation.
  • the invention also provides a polidocanol foam preparation for use in the preparation and treatment of cystic diseases, varicose veins, vascular malformations, gastrointestinal bleeding, cesarean scar pregnancy, and benign or malignant solid tumors.
  • the present invention also provides the use of single molecular weight polidocanol in the preparation of disease treatment drugs, and the polidocanol is used as a sclerosing agent and/or hemostatic agent for treatment.
  • the diseases include cystic diseases, vascular related diseases, tumors, obstetric and gynecological diseases, inflammation and/or pain.
  • the vascular related diseases include varicose veins, vascular malformations and/or hemorrhage.
  • the obstetric and gynecological diseases include uterine submucosal fibroids and cesarean scar pregnancy.
  • the cystic disease includes abdominal organ cysts, body surface cysts, lymphoceles, thyroid cysts, bone cysts, digital mucocele and/or pelvic encapsulated effusion.
  • the tumors include benign or malignant solid tumors.
  • the inflammation includes infectious inflammation and/or non-infectious inflammation.
  • the pain includes chronic pain, acute pain, and cancer pain.
  • the tumors include: infantile hemangioma, congenital hemangioma, plexiform hemangioma, spindle cell hemangioma, epithelioid hemangioma, pyogenic granuloma, Kaposiform hemangioendothelioma, reticular hemangioendothelioma, Papillary intralymphatic hemangioendothelioma, combined hemangioendothelioma, Kaposi's sarcoma, angiosarcoma, epithelioid hemangioendothelioma, uterine fibroids, and/or abdominal visceral malignancies.
  • the pain includes muscle and soft tissue pain, bone and joint pain, and/or visceral pain.
  • the inflammation includes tendonitis, tendonitis, tendinosis, peritendinitis, spondylitis, sacroiliitis, gouty arthritis, myofasciitis, tenosynovitis and/or frozen shoulder.
  • the tumors include: infantile hemangioma, congenital hemangioma, plexiform hemangioma, spindle cell hemangioma, epithelioid hemangioma, pyogenic granuloma, Kaposiform hemangioendothelioma, reticular hemangioendothelioma, Papillary intralymphatic hemangioendothelioma, combined hemangioendothelioma, Kaposi's sarcoma, angiosarcoma, epithelioid hemangioendothelioma, uterine fibroids, abdominal viscera malignant tumors.
  • the varicose veins include: varicose veins of the lower limbs, esophageal and gastric varices, varicocele, abdominal wall varicose veins and/or hemorrhoids.
  • the bleeding includes: gastrointestinal bleeding, bladder bleeding, and bleeding caused by early, middle or late cancer.
  • the abdominal organ cysts include: liver cysts, renal cysts, pararenal pelvic cysts, pancreatic cysts, endometriosis cysts and/or ovarian chocolate cysts.
  • the body surface cysts include: skin cysts and finger mucous cysts.
  • the abdominal organ malignant tumors include liver cancer.
  • the present invention uses single molecular weight polidocanol to prepare drugs for cystic diseases, varicose veins, vascular malformations, gastrointestinal bleeding, cesarean scar pregnancy, and benign or malignant solid tumors. Compared with the prior art, this invention has The invented single molecular weight polidocanol has better efficacy and fewer toxic and side effects.
  • the preparation process of polidocanol of the present invention overcomes the defects of the existing process that the raw material of lauryl alcohol has many impurities, many side reaction products, and high process conditions (such as pressure, temperature) and equipment requirements.
  • the process is stable, the quality is controllable, and it is suitable for Industrial production.
  • the single molecular weight polydocanol and its foaming preparation of the present invention eliminate the polydocanol with inappropriate PEG chain length in the original drug, thereby obtaining the single molecular weight polydocanol with better foaming effect than the original drug.
  • Alcohol, foaming effect and foam maintenance time are superior to the foaming preparations of polidocanol in the prior art.
  • Figure 1 shows the hydrogen nuclear magnetic spectrum of DD-PEG4-OH
  • Figure 2 shows the HPLC chromatogram of DD-PEG4-OH
  • Figure 3 shows the chromatogram of 1% reference substance of DD-PEG4-OH
  • Figure 4 shows the mass spectrum of DD-PEG4-OH
  • Figure 5 shows the hydrogen nuclear magnetic spectrum of DD-PEG8-OH
  • Figure 6 shows the HPLC chromatogram of DD-PEG8-OH
  • Figure 7 shows the chromatogram of 1% reference substance of DD-PEG8-OH
  • Figure 8 shows the mass spectrum of DD-PEG8-OH
  • Figure 9 shows the hydrogen nuclear magnetic spectrum of DD-PEG9-OH
  • Figure 10 shows the HPLC chromatogram of DD-PEG9-OH
  • Figure 11 shows the chromatogram of 1% reference substance of DD-PEG9-OH
  • Figure 12 shows the mass spectrum of DD-PEG9-OH
  • Figure 13 shows the TIC chart of DD-PEG9-OH
  • Figure 14 shows the hydrogen nuclear magnetic spectrum of DD-PEG10-OH
  • Figure 15 shows the HPLC chromatogram of DD-PEG10-OH
  • Figure 16 shows the chromatogram of 1% reference substance of DD-PEG10-OH
  • Figure 17 shows the mass spectrum of DD-PEG10-OH
  • Figure 18 shows the hydrogen nuclear magnetic spectrum of DD-PEG11-OH
  • Figure 19 shows the HPLC chromatogram of DD-PEG11-OH
  • Figure 20 shows the chromatogram of 1% reference substance of DD-PEG11-OH
  • Figure 21 shows the mass spectrum of DD-PEG11-OH
  • Figure 22 shows the hydrogen nuclear magnetic spectrum of DD-PEG12-OH
  • Figure 23 shows the HPLC chromatogram of DD-PEG12-OH
  • Figure 24 shows the chromatogram of 1% reference substance of DD-PEG12-OH
  • Figure 25 shows the TIC chart of DD-PEG12-OH
  • Figure 26 shows the mass spectrum of DD-PEG12-OH
  • Figure 27 shows the hydrogen nuclear magnetic spectrum of DD-PEG24-OH
  • Figure 28 shows the HPLC chromatogram of DD-PEG24-OH
  • Figure 29 shows the chromatogram of 1% reference substance of DD-PEG24-OH
  • Figure 30 shows the mass spectrum of DD-PEG24-OH
  • Figure 31 shows the foam emptying time (s) of the sample of Example 3.
  • Figure 32 shows the foam half-life (s) of the sample of Example 3.
  • Figure 33 shows the foam coalescence time (m) of the sample of Example 3.
  • Figure 34 shows images of vein appearance 14 days after injection of different types of polidocanol into the ear margin veins of rabbits in Example 4;
  • Figure 35 shows the 14-day venous sclerosis effective rate after injecting different types of polidocanol into the ear margin veins of rabbits in Example 4;
  • Figure 36 shows images of vein appearance 21 days after injection of different types of polidocanol into rabbit ear margin veins in Example 4.
  • Figure 37 shows the 21-day venous sclerosis effective rate after injecting different types of polidocanol into the ear margin veins of rabbits in Example 4;
  • Figure 38 shows the pathological changes of the marginal ear vein of rabbits after 14 days of administration in Example 4.
  • the term "sclerotherapy” refers to the injection of sclerosant to turn blood vessels into fibrous cords, which are eventually absorbed by surrounding tissues, or to use sclerosis to destroy cells in the lesions, causing them to dehydrate, coagulate, and denature, thereby producing sterility. Inflammation promotes cyst wall collapse, adhesion, and fibrosis until closure, thereby reducing or eliminating corresponding clinical symptoms.
  • the term "loading" refers to the operation of adding the product to be separated onto the chromatography column.
  • forward separation refers to the use of column chromatography to separate products in the present invention, in which the stationary phase is polar and the mobile phase is a solvent with less polarity than the stationary phase.
  • the term "retention time” refers to the time elapsed by the separated sample component from the beginning of the injection to the time when the maximum concentration value of the component appears, that is, from the beginning of the injection to the time when the apex of the chromatographic peak of a certain component appears.
  • the time is called the retention time of this component, expressed as RT, and is often measured in minutes (min) as the time unit.
  • Tessari method also known as vortex technology, refers to the production of foam sheets using two disposable plastic syringes, one containing a liquid hardener solution and the other containing air.
  • the port is connected to a three-way valve, and the contents of the two syringes are quickly pushed back and forth multiple times, creating foam through the turbulence created.
  • HO-PEG24-OH refers to tetraethylene glycol
  • DD-PEG4-OH refers to polidocanol containing 4 PEGs
  • DD-PEG8-OH refers to polidocanol containing 4 PEGs
  • DD-PEG9-OH refers to polidocanol containing 4 PEGs
  • DD-PEG10-OH refers to polidocanol containing 4 PEGs
  • DD-PEG11-OH refers to polidocanol containing 4 PEGs
  • DD-PEG12-OH refers to polidocanol containing 4 PEGs
  • the terms "10V” and “8V” refer to THF (170mL, 8V).
  • a certain solid material is 1g
  • 10V solvent refers to 10ml of solvent.
  • the raw material tetraethylene glycol is directly used as the solvent.
  • PEG with other molecular weights, such as PEG8 or above must be added with a solvent because it is a solid.
  • THF (170 mL, 8V) in the embodiment of the present invention refers to the mass volume ratio of THF to solute. The mass of HO-PEG24-OH Volume ratio.
  • TLC thin layer chromatography
  • TLC Thin Layer Chromatography
  • the organic phases were combined and washed with saturated sodium chloride solution (100 ml).
  • the organic phase was dried with anhydrous Na 2 SO 4 , filter, concentrate to dryness, dissolve dichloromethane and load the sample, forward separation, the separation gradient is: dichloromethane: methanol (0% ⁇ 4%), TLC spot plate determines the product point, the product fractions are combined and concentrated to obtain 1.64g white Solid, yield 25.1%.
  • HUVEC Human Umbilical Vein Endothelial Cells
  • HUVEC human umbilical vein endothelial cells
  • HUVEC human umbilical vein endothelial cells
  • DPBS phosphate buffer saline
  • Test sample dilution Take polidocanol (purchased from Siegfried Hameln GmbH, Germany, batch number OK13103) and prepared in Example 1: DD-PEG4-OH, DD-PEG8-OH, DD-PEG9-OH, DD-PEG10-OH, DD-PEG11-OH, DD-PEG24-OH, and PBS solution (containing ethanol with a mass concentration of 4%) were used to prepare test sample mother solutions of appropriate concentrations.
  • the diluted concentrations of the test samples in each group are equal.
  • HUVEC human umbilical vein endothelial cells
  • Foam drainage time is the length of time the hardener liquid is visible.
  • Foam half-life is the time it takes for the foam emptying rate to reach 50%
  • FCT Foam coalescence time
  • P4 represents the single molecular weight polydocanol of DD-PEG4-OH
  • P8 represents the single molecular weight polydocanol of DD-PEG8-OH
  • P9 represents the single molecular weight polydocanol of DD-PEG9-OH.
  • the polidocanol in this embodiment is a mixture of polidocanols containing different molecular weights and not a single molecular weight.
  • Foam drainage time is the length of time the hardener liquid is visible.
  • the results are shown in Figure 31.
  • the abscissa is the sample of each molecular weight, and the ordinate is the time when the liquid appears (unit s).
  • the P4 sample that is, DD-PEG4-OH
  • the P4 sample is difficult to form foam. After other samples form uniform foam, Liquid will precipitate within 3 to 8 seconds, and the precipitation time of P10 sample is relatively slow.
  • Foam half-life time is the time it takes for the foam emptying rate to be 50%. As shown in Figure 32, it is difficult for the P4 sample to form foam, and even if a small amount of foam is formed, it will disappear in a very short time. Other samples can form uniform foam after 20 pumps, among which the foam half-life of P8 to P24 is more than 120s.
  • FCT Foam coalescence time
  • Example 4 In vivo experiments to evaluate the venous sclerosis effect of single molecular weight polidocanol with different chain lengths
  • Photographs of rabbit ear blood vessels were collected before administration, 7 days, 14 days and 21 days after administration to observe phenomena such as vascular hardening and blockage.
  • Figure 34 shows the appearance of the veins of some rabbits 14 days after intravenous injection of different types of polidocanol into the ear margins of some rabbits in this example (p8 group, P9 low-dose group, positive control low-dose group). After 14 days of administration, some Blood vessels are blocked. From the appearance, the color is darker and lighter, and the blood flow of some uninjected blood vessels becomes larger. All rabbit ear blood vessels were scored, valid as 1 and invalid as 0.
  • the effective rates of venous sclerosis 14 days after intravenous injection of different types of polidocanol into the rabbit ear margin are shown in Table 10 and Figure 35. From Table 10 and Figure 35, it can be seen that the P8 group, P10 group, P1 group, P9 high-dose group and P9 The effective rates in the low-dose group were all above 83.33%, not lower than the positive control low-dose group.
  • Figure 36 shows the appearance of veins 21 days after intravenous injection of different types of polidocanol into some rabbit ear margins in this example (p8 group, p9 low group, positive control low group). After 21 days of administration, some blood vessels in the rabbit ear Completely blocked. From the appearance, the color of some blood vessels becomes lighter or gradually disappears, and the blood flow of uninjected blood vessels increases.
  • Table 11 and Figure 37 show that the effective rates of P8 group, P10 group, P11 group, P9 high-dose group and P9 low-dose group are all higher than the positive control low-dose group, but the overall venous sclerosis effective rate in Table 11 is lower than Table 10 and Figure 35, this is because after polidocanol destroys the vascular endothelium, fibrosis will gradually occur in the blood vessels. On the 21st day, some blood vessels will gradually become blocked until they are blocked, and some blood vessels will open again.
  • Venous pathological section results 14 days after intravenous injection of different types of polidocanol into rabbit ear margins
  • the pathological changes under venoscopy in each group were scored from aspects such as inflammatory response, vascular proliferation, vascular lumen stenosis, and fibrosis to evaluate the degree of pathological damage to the blood vessels. Score is 10 points.
  • Table 12 Mean table of rabbit ear vascular pathological scores in each group
  • P8, P9 low-dose groups, P9 high-dose groups, P10, P11 and the positive control group (polidocanol group) high- and low-dose groups all have pathological changes in blood vessels.
  • the specific description is as follows: Under low magnification, the blood vessels The tissue structure of each layer of the wall is unclear and the blood vessel lumen is occluded. Under high magnification, a large number of fibroblast proliferations can be seen in the lumen, and red blood cells are scattered among local fibroblasts; new capillaries and macrophages that phagocytose hemosiderin can be seen locally.
  • the above results show that the single molecular weight polidocanol of the present invention can effectively fibrosis the vascular endothelium and further seal the vascular lumen.

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Abstract

La présente invention se rapporte à l'utilisation de polidocanol à masse moléculaire unique dans la préparation d'un médicament pour traiter une maladie. Le polidocanol peut servir d'agent de durcissement et/ou d'agent hémostatique pour le traitement. Le polidocanol à masse moléculaire unique est préparé par le procédé de préparation suivant consistant : à faire réagir du polyéthylène glycol à masse moléculaire unique avec du 1-halododécane, et à effectuer une séparation et une purification pour obtenir le polidocanol à masse moléculaire unique. Le propolidocanol de la présente invention est produit par un procédé stable, est de qualité contrôlable, présente une bonne efficacité, et provoque peu d'effets toxiques et secondaires.
PCT/CN2023/096332 2022-05-25 2023-05-25 Polidocanol à masse moléculaire unique et utilisation associée WO2023227069A1 (fr)

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