Foam hardener composition as well as preparation method and application thereof

Abstract

The invention provides a foam hardener composition as well as a preparation method and application thereof, the foam hardener composition comprises polydocanol with single molecular weight and sodium hyaluronate in a volume ratio of 1: (0.1-5). The preparation method of the polydocanol with the single molecular weight comprises the following steps: reacting polyethylene glycol with the single molecular weight with 1-halogenated dodecane, separating and purifying to obtain the polydocanol with the single molecular weight. The foam hardener disclosed by the invention is higher in foam stability, better in drug effect and smaller in toxic and side effects, and can be widely applied to treatment of vascular related diseases, cystic diseases, tumors, gynecological and obstetrical diseases, inflammations or pains.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a foam hardener composition and a preparation method and application thereof. Background Art

[0002] Polidocanol (POL) is a surfactant-type sclerosant, and its structure is very similar to the cell membrane phospholipid bilayer. It interferes with the surfactant on the cell membrane, destroys the cell membrane structure, causes vascular endothelial cell lysis and death, and then causes vascular fibrosis and vascular occlusion. At the same time, it has fixed hydrophilic and hydrophobic ends, which can be arranged in a directional manner on the surface of the solution, significantly reducing the surface tension of the solution and forming foam, so polidocanol is widely used in foam sclerotherapy. At present, polidocanol is mainly used in sclerotherapy for varicose veins, venous malformations, hemangiomas, internal hemorrhoids, cystic diseases, acne, tumor ablation, etc. In sclerotherapy, the therapeutic efficiency of foam sclerosants depends on the stability of the foam and the uniformity of the bubble size. Generally, the smaller the average bubble diameter in the foam, the more uniform the foam, the higher the drug concentration, the better the foam stability, and the better the therapeutic effect. Usually, the foam stability is evaluated using indicators such as foam fineness, liquid precipitation time and half-life, which are affected by many factors, such as the composition of the sclerosant, liquid viscosity and surface properties of the liquid.

[0003] Liu Ziyi et al. disclosed a hyaluronic acid-polydocanol composition and studied the effect of hyaluronic acid (HA) on the endothelial cell killing ability, foam stability, blood replacement ability and viscosity of polydocanol foam. The results showed that HA can promote endothelial cell proliferation, but 1% POL has a stronger cell killing ability. When both act on endothelial cells at the same time, the cells instantly lyse and die; HA can significantly increase the viscosity of POL foam, thereby improving foam stability and blood replacement ability; within a certain range (HA dosage ≤ 0.4 mL added to 1 mL POL), the more HA dosage added to POL, the better the foam performance (see Liu Ziyi. In vitro study on the effect of hyaluronic acid on the foam performance of polydocanol [D]. Shandong University, 2022.). However, the study used commercially available polydocanol, which is a mixture containing different molecular weights and has many impurities. Its efficacy is affected by polydocanol and impurities of different chain lengths, and it is not easy to control during application.

[0004] Polydocanol, also known as ethoxylated hardened alcohol and polydocanol, is a polymer product obtained by polymerization of lauryl alcohol and multiple ethylene oxides. At present, polydocanol is mainly prepared by polymerization reaction of lauryl alcohol and ethylene oxide under alkaline catalysis. The quality and stability of polydocanol products are greatly affected by the purity of starting materials, catalysts, reaction pressure, temperature and post-treatment process. On the one hand, commercially available lauryl alcohol contains many impurities, and in addition to decanol and tetradecanol, there are many unknown impurities. The by-products generated by the introduction of these impurities into the polymerization reaction of polydocanol are difficult to separate from polydocanol, which will directly affect the quality of the finished polydocanol product. On the other hand, in addition to unreacted lauryl alcohol and ethylene oxide, a large number of by-products will be produced during the synthesis of polydocanol, the main by-products of which are free polyethylene glycol, diethylene glycol, dioxane, formaldehyde, acetaldehyde, ethylene glycol, etc. These impurities have great side effects on the safety and effectiveness of polydocanol.

[0005] Patent publication number CN103922901 discloses a method for purifying polydocanol, which uses a vacuum distillation method before adjusting the pH value of the crude product to finally obtain a high-purity polydocanol refined product. However, this invention cannot avoid the risk of impurities (such as n-decanol and n-tetradecanol) introduced into lauryl alcohol and the formation of by-products with ethylene oxide.

[0006] The patent with publication number CN113200821A discloses a method for purifying lauryl alcohol and a method for synthesizing polidocanol. High-purity lauryl alcohol is prepared by vacuum distillation, but the distillation purification requires -0.08MPa and a distillation temperature of 130-150°C. In the process of preparing polidocanol, 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, and after the polymerization is completed, the degassing temperature is 90-120°C. It can be seen that the polymerization reaction is carried out under high temperature and negative pressure conditions, and the requirements for equipment and process are high.

[0007] At present, the commercially available polidocanol is a mixture of different molecular weights. The foaming effect and efficacy of polidocanol with different chain lengths are different, and it is difficult to control during application. Therefore, the research and development and preparation of polidocanol with a single molecular weight, so as to effectively control and improve the quality of polidocanol, is of great significance for improving the efficacy of polidocanol foam hardeners and their compositions. Summary of the invention

[0008] To solve the above problems, the present invention provides a foam hardener composition, a preparation method and an application thereof, wherein the foam hardener composition is a combination of sodium hyaluronate and single molecular weight polidocanol.

[0009] In a first aspect of the present invention, a foam hardener composition is provided, wherein the foam hardener composition comprises polidocanol and sodium hyaluronate, wherein the polidocanol is polidocanol of a single molecular weight, and the monomer molecular structure thereof comprises the following structure:

[0010]

[0011] Wherein, n is an integer, 4≤n≤24;

[0012] Specifically, n is selected from any number among 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24, and each n value corresponds to a polydocanol of a determined molecular weight.

[0013] Preferably, 8≤n≤15;

[0014] More preferably, n is 8, 9 or 10.

[0015] Furthermore, the volume ratio of the single molecular weight polidocanol to sodium hyaluronate is 1:0.1-5 (specifically 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:1.10, 1:1.111, 1:1.12, 1:1.13, 1:1.14, 1:1.15, 1:1.16, 1:1.17, 1:1.18, 1:1.19, 1:1.20, 1:1.21, 1:1.22 1:4.4, 1:4.6, 1:4.8, 1:5); preferably 1:0.5-2; more preferably 1:1.

[0016] Furthermore, the mass concentration of the single molecular weight polydocanol is 0.01-5% (specifically 0.01, 0.025, 0.05, 0.075, 0.1, 0.125, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5%); preferably 0.05-2%; more preferably 1%.

[0017] Furthermore, the mass concentration of the sodium hyaluronate is 0.01-5% (specifically 0.01, 0.025, 0.05, 0.075, 0.1, 0.125, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5%); preferably 0.05-2%; more preferably 0.05-0.25%.

[0018] Furthermore, the foam sclerosing agent composition further comprises pharmaceutically acceptable excipients.

[0019] Furthermore, the pharmaceutically acceptable excipient is selected from one or more of a solubilizer, an antioxidant, an anti-photolysis agent, a pH regulator or an emulsifier.

[0020] Furthermore, the foam sclerosing agent composition is in the form of an injection.

[0021] The second aspect of the present invention provides a method for preparing the foam hardener composition according to the first aspect, the preparation method comprising the following steps:

[0022] (1) Preparation of single molecular weight polydocanol: reacting single molecular weight polyethylene glycol with 1-halododecane, separating and purifying to obtain single molecular weight polydocanol;

[0023] (2) Preparation of the foam hardener composition: dissolve the above-mentioned single molecular weight polydocanol in a solvent, let it stand, add sodium hyaluronate, mix well to obtain a mixed solution, mix the above-mentioned mixed solution with gas to generate foam, and obtain a foam hardener composition.

[0024] Furthermore, in step (1), the method for preparing polydocanol of a single molecular weight comprises the following steps:

[0025] A1: Mix polyethylene glycol of a single molecular weight with a catalyst and an organic solvent, add 1-halododecane dropwise, raise the temperature to a preset temperature, and keep the temperature for reaction;

[0026] A2: After the reaction is completed, the reactants are cooled to room temperature, diluted with water, extracted, separated, and the organic phase is collected;

[0027] A3: Filter, concentrate, dry, separate and purify the organic phase to obtain the single molecular weight polydocanol.

[0028] Further, in step A1, the single molecular weight polyethylene glycol is selected from tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, octaethylene glycol, nonaethylene glycol, decaethylene glycol, elevenethylene glycol, twelveethylene glycol, tridecaethylene glycol, tetradecaethylene glycol, pentaethylene glycol, hexadecaethylene glycol, heptadecaethylene glycol, octaethylene glycol, nonaethylene glycol, twenty-one glycol, twenty-two glycol, twenty-three glycol, and twenty-tetradecaethylene glycol, preferably eighty-one glycol, ninety-one glycol, decaethylene glycol, elevenethylene glycol, twelveethylene glycol, tridecaethylene glycol, fourteenethylene glycol, and pentadecaethylene glycol, and more preferably eighty-one glycol, ninety-one glycol, and decaethylene glycol.

[0029] Furthermore, in step A1, the catalyst is selected from sodium hydroxide, sodium hydride, potassium hydroxide, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, preferably sodium hydroxide and / or sodium hydride.

[0030] Furthermore, in step A1, the organic solvent is selected from one or more of ethanol, methanol, isopropanol, tetrahydrofuran (THF), acetone, acetonitrile, toluene, xylene, n-hexane, cyclohexane, isooctane, n-pentane, petroleum ether, dimethyl sulfoxide (DSMO), N,N-dimethylformamide, dichloromethane (DCM) or diethoxymethane (DEM); preferably one or more of tetrahydrofuran (THF), dimethyl sulfoxide (DSMO), acetonitrile, toluene, N,N-dimethylformamide.

[0031] Furthermore, in step A1, the 1-halododecane includes 1-chlorododecane, 1-bromododecane or 1-iodododecane, preferably 1-bromododecane.

[0032] Furthermore, in step A1, the molar ratio of the single molecular weight polyethylene glycol to the 1-halododecane is 1-15:1 (specifically 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1), preferably 1-10:1.

[0033] Furthermore, in step A1, the molar ratio of the single molecular weight polyethylene glycol to the catalyst is 1-15:1 (specifically 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1), preferably 1-10:1.

[0034] Furthermore, in step A1, the preset temperature is 80-95°C (specifically 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95°C), preferably 80-90°C.

[0035] Furthermore, in step A1, the insulation reaction time is 12-24 hours (specifically 6, 17, 18, 19, 20, 21, 22, 23, 24 hours), preferably 16-24 hours, and more preferably 16-20 hours.

[0036] Furthermore, in step A2, the extraction operation is repeated 2-6 times (specifically 2, 3, 4, 5, 6 times), preferably 3-5 times, and more preferably 3 or 4 times.

[0037] Furthermore, in step A2, the extraction solvent is selected from one or more of diethyl ether, ethyl acetate, dichloromethane, chloroform, methyl tert-butyl ether or toluene, more preferably ethyl acetate.

[0038] Furthermore, in step A3, the dryer used for drying is Na2SO4 and / or MgSO4.

[0039] Furthermore, in step A3, the separation and purification is carried out by a chromatography method, preferably column chromatography, and the eluent used in the column chromatography is selected from one or more of ethyl acetate, methanol, ethanol, n-hexane, petroleum ether, and dichloromethane.

[0040] Furthermore, in step (2), the solvent is selected from one of ethanol-phosphate buffer, ethanol, and physiological saline.

[0041] In one embodiment of the present invention, the solvent is ethanol-phosphate buffer with a mass concentration of 4%.

[0042] Furthermore, in step (2), the volume ratio of the single molecular weight polidocanol to sodium hyaluronate is 1:0.1-5 (specifically 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1. 5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5); preferably 1:0.5-2; more preferably 1:1.

[0043] Furthermore, in step (2), the mass concentration of the single molecular weight polydocanol is 0.01-5% (specifically 0.01, 0.025, 0.05, 0.075, 0.1, 0.125, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5%); preferably 0.05-2%; more preferably 1%.

[0044] Furthermore, in step (2), the mass concentration of the sodium hyaluronate is 0.01-5% (specifically 0.01, 0.025, 0.05, 0.075, 0.1, 0.125, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5%); preferably 0.05-2%; more preferably 0.05-0.25%.

[0045] Further, in step (2), the volume ratio of the mixed solution to the gas is 1:0.5-5 (such as 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5), preferably 1:3.

[0046] Furthermore, in step (2), the gas includes air, carbon dioxide or oxygen, preferably air.

[0047] Furthermore, in step (2), the method of mixing the mixed solution with gas to generate bubbles includes the Tessari method, the Tessari / DSS method or the Monfreux method.

[0048] In one embodiment of the present invention, the method of mixing the mixed solution with gas to generate bubbles is the Tessari method.

[0049] The third aspect of the present invention provides use of the foam sclerosant composition described in the first aspect or the foam sclerosant composition prepared by the preparation method of the foam sclerosant composition described in the second aspect in preparing a drug for treating a disease.

[0050] Furthermore, the disease is selected from one or more of vascular-related diseases, cystic diseases, tumors, gynecological diseases, inflammation or pain.

[0051] Preferably, the vascular-related disease is selected from one or more of varicose veins or vascular malformations.

[0052] More preferably, the varicose veins are selected from one or more of lower extremity varicose veins, esophageal and gastric varicocele, varicocele, abdominal wall varicose veins or hemorrhoids.

[0053] Preferably, the cystic disease includes one or more of abdominal visceral cysts, body surface cysts, lymphoceles, thyroid cysts, bone cysts, finger mucoceles or pelvic encapsulated effusions.

[0054] More preferably, the abdominal visceral cyst is selected from one or more of a liver cyst, a kidney cyst, a pararenal pelvic cyst, a pancreatic cyst, an endometriosis cyst or an ovarian chocolate cyst.

[0055] More preferably, the body surface cyst includes a skin cyst and / or a finger mucocele;

[0056] Preferably, the tumor comprises a benign or malignant solid tumor.

[0057] More preferably, the tumor is selected from one or more of infantile hemangioma, congenital hemangioma, plexiform hemangioma, spindle cell hemangioma, epithelioid hemangioma, pyogenic granuloma, Kaposi's hemangioendothelioma, reticular hemangioendothelioma, papillary lymphangiogenic endothelioma, complex hemangioendothelioma, Kaposi's sarcoma, angiosarcoma, epithelioid hemangioendothelioma, uterine fibroids or malignant tumors of abdominal organs.

[0058] Even more preferably, the abdominal organ malignant tumor includes liver cancer.

[0059] Preferably, the gynecological diseases include submucous uterine fibroids and / or cesarean section scar pregnancy.

[0060] Preferably, the inflammation includes infectious inflammation and / or non-infectious inflammation.

[0061] More preferably, the inflammation is selected from one or more of tendinitis, tendinitis, tendinosis, tendinitis, ankylosing spondylitis, sacroiliitis, gouty arthritis, myofasciitis, tenosynovitis or scapulohumeral periarthritis;

[0062] Preferably, the pain includes chronic pain, acute pain, and cancer pain.

[0063] More preferably, the pain is selected from one or more of muscle and soft tissue pain, bone and joint pain or visceral pain.

[0064] The beneficial effects of the present invention are as follows:

[0065] (1) The preparation process of polydocanol of the present invention overcomes the defects of the existing process such as the large number of impurities in the lauryl alcohol raw material, the large number of side reaction products, and the high requirements for process conditions (such as pressure, temperature) and equipment. The process is stable, the quality is controllable, and it is suitable for industrial production.

[0066] (2) The single molecular weight polidocanol and its foaming preparation of the present invention have better foaming effect and foam maintenance time than the polidocanol foaming preparations in the prior art because the polidocanol with inappropriate PEG chain length is eliminated.

[0067] (3) The foam hardener of the present invention combines a single molecular weight of polidocanol with a certain concentration of sodium hyaluronate. Compared with the foam preparation of the above-mentioned single molecular weight polidocanol and the hyaluronic acid-polidocanol hardener composition in the prior art, its foam stability is higher, the efficacy is better, and the toxic side effects are smaller.

[0068] (4) The single molecular weight polydocanol and its foamed preparation, as well as the foam sclerosant composition of the present invention can be widely used in the treatment of vascular-related diseases, cystic diseases, tumors, gynecological diseases, inflammation or pain. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 Shown is the H NMR spectrum of DD-PEG8-OH;

[0070] Figure 2 Shown is the HPLC chromatogram of DD-PEG8-OH;

[0071] Figure 3 Shown is the chromatogram of 1% control of DD-PEG8-OH;

[0072] Figure 4 Shown is the mass spectrum of DD-PEG8-OH;

[0073] Figure 5 Shown is the H NMR spectrum of DD-PEG9-OH;

[0074] Figure 6 Shown is the HPLC chromatogram of DD-PEG9-OH;

[0075] Figure 7 Shown is the chromatogram of 1% control of DD-PEG9-OH;

[0076] Figure 8 Shown is the mass spectrum of DD-PEG9-OH;

[0077] Fig. 9Shown is the H NMR spectrum of DD-PEG10-OH;

[0078] Fig.10 Shown is the HPLC chromatogram of DD-PEG10-OH;

[0079] Fig.11 Shown is the chromatogram of the 1% control of DD-PEG10-OH;

[0080] Fig.12 Shown is the mass spectrum of DD-PEG10-OH. DETAILED DESCRIPTION

[0081] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0082] In the present invention, the term "single molecular weight" means that the compound of the present invention has a single chain length and a precise chemical structure, and is not a mixture of homologues with different molecular weights, indicating that the molecular weight of the compound of the present invention is not the average molecular weight of a high molecular weight polymer formed by a mixture of homologues with different molecular weights. PEG35, PEG36, PEG37, PEG38, PEG39, PEG40, PEG41, PEG42, PEG43, PEG44, PEG45, PEG46, PEG47, PEG48, PEG49, PEG50, and PEG51. By the same token, we can understand the situations when "single-chain-length polydocanol contains PEG9" and "single-chain-length polydocanol contains PEG10".

[0083] In the present invention, the term "Tessari method", also known as vortex technology, refers to the use of two disposable plastic syringes to produce hardening foam, one syringe containing a liquid hardener solution and the other syringe containing a gas, the ports of the two syringes are connected to a three-way switch at 90 degrees, the contents of the two syringes are pushed back and forth quickly 20 times, and after the first 10 pushes are completed, the channel port is closed as small as possible to produce foam through the turbulence thus formed.

[0084] In the present invention, the term "Tessari / DSS method", also known as Tessari / dual syringe set technology, is based on the basic Tessari method, using two latex-free disposable plastic syringes to generate foam, one of which has a rubber piston, one syringe containing a liquid hardener solution, and the other syringe containing gas, the ports of the two syringes are connected to a two-way connector at 180 degrees, and the contents of the two syringes are quickly pushed back and forth 5 times (additional pressure is generated by squeezing the piston of one of the syringes), and then the pushing action is repeated 7 times (without additional pressure).

[0085] In the present invention, the term "Monfreux method" refers to a method of generating foam using a glass syringe containing a liquid hardener solution. The syringe port is closed with a rubber cap or a plastic cap, and the syringe piston is retracted to generate negative pressure, and air is injected into the syringe through the gap between the syringe barrel and the piston, generating liquid foam containing large bubbles.

[0086] In the present invention, the term "loading" refers to the operation of adding the product to be separated onto the chromatography column.

[0087] In the present invention, "forward separation" means that the product is separated by column chromatography in which the stationary phase is polar and the mobile phase is a solvent with a polarity lower than that of the stationary phase.

[0088] In the present invention, the term "retention time" refers to the time from the start of injection of the separated sample component to the appearance of the maximum concentration of the component, that is, the time from the start of injection to the appearance of the apex of the chromatographic peak of a component, which is called the retention time of this component, expressed as RT, and usually measured in minutes (min).

[0089] In the present invention, the term "TLC" refers to thin layer chromatography (Thin Layer Chromatography, TLC) which usually refers to a liquid chromatography method with an adsorbent as the stationary phase. That is, the stationary phase is evenly spread into a thin layer on a smooth surface such as glass, metal or plastic, and the sample is applied to one end of the thin layer. The mobile phase flows through the stationary phase by capillary action to expand the separated substances.

[0090] In the present invention, the term "eq" means "Equivlent", which means molar equivalent.

[0091] In the present invention, the term "HO-PEG10-OH" refers to decaethylene glycol.

[0092] In the present invention, the term "DD-PEG8-OH" refers to polidocanol containing PEG8 (eight ethylene glycol units), which is also referred to as "P8" in the present invention. The same applies to "DD-PEG9-OH" and "DD-PEG10-OH".

[0093] In the present invention, the term "foam drainage time (FDT)" refers to the time when liquid begins to precipitate, that is, the length of time that the hardener liquid is visible.

[0094] In the present invention, the term "foam half-life (FHT)" refers to the time it takes for half of the foam volume to disappear, that is, the time it takes for the foam emptying rate to be 50%.

[0095] In the present invention, the term "foam coalescence time (FCT)" refers to the time required for the foam to completely disappear, that is, the length of time that the hardener foam is visible.

[0096] The embodiments of the present invention will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. If no specific conditions are specified in the examples, the conditions are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be obtained commercially.

[0097] Example 1 Synthesis of single molecular weight polydocanol with different chain lengths

[0098] 1.1 Synthesis, purification and characterization of DD-PEG8-OH

[0099] NaH (2.2g, 55mmol) was added to a 500ml single-mouth bottle containing DMSO (200ml) at room temperature, stirred for 30mins, and then octaethylene glycol (20g, 54.1mmol) was slowly added under nitrogen protection, and stirred at room temperature for 2hrs. 1-Bromododecane (13.5g, 54.1mmol) was slowly added to the reaction bottle under nitrogen protection, and then the reaction was heated to 90°C and stirred for 18hrs. The reaction was cooled to room temperature, water (400ml) was added, and extracted with EtOAc (100ml) for 3 times. After the organic phases were combined, saturated NaCl solution (100ml) was added to wash, and the organic phases were dried with anhydrous Na2SO4, filtered, concentrated, dissolved in DCM, and sampled, separated in the forward direction, with a separation gradient of DCM: MeOH = 0-3%, and the product point was determined by TLC spot plate. The product fractions were combined and concentrated to obtain 2.1g of light yellow solid with a yield of 7.2%.

[0100] The results of NMR are as follows Figure 1 As shown, 1 H NMR (300MHz, CDCl3) δ: 0.87-0.90 (3H, t), 1.25 (18H, s), 1.52-1.59 (2H, t), 2.68 (1H, s), 3.42-3.46 (2H, t), 3.55-3.72 (29H, m).

[0101] The main component self-comparison method was used to measure the product content to be 98.62%. The specific results are shown in Table 1. The chromatographic results are shown in Figure 2 As shown, Figure 3 This is the chromatogram of the 1% reference substance of DD-PEG8-OH. The mass spectrum results are as follows Figure 4 As shown, MS (ESI+): m / z+H=539.5.

[0102] Table 1 Chromatographic results of DD-PEG8-OH

[0103]

[0104] 1.2 Synthesis, purification and characterization of DD-PEG9-OH

[0105] NaH (484 mg, 12.1 mmol) was added to a 500 ml single-mouth bottle containing DMSO (200 ml) at room temperature, stirred for 30 mins, and then nonaglycone (20 g, 48.3 mmol) was slowly added under nitrogen protection, and stirred at room temperature for 2 hrs. 1-Bromododecane (3.02 g, 12.1 mmol) was slowly added to the reaction bottle under nitrogen protection, and then the reaction was heated to 90 ° C and stirred for 18 hrs. The reaction was cooled to room temperature, water (400 ml) was added, and extracted with ethyl acetate (100 ml), extracted 3 times in total, and the organic phases were combined and washed with saturated sodium chloride solution (100 ml), and the organic phases were dried with anhydrous Na2SO4, filtered, concentrated to dryness, dissolved in DCM, and sampled, separated in the forward direction, and separated with a gradient of DCM / MeOH (0-3%). The product point was determined by TLC spot plate, and the product fractions were combined and concentrated to obtain 1.36 g of light yellow solid, with a yield of 19.3%.

[0106] The results of NMR are as follows Figure 5 As shown, 1 H NMR (300MHz, CDCl3) δ: 0.87-0.91 (3H, t), 1.27 (18H, s), 1.56-1.60 (2H, t), 2.53-2.57 (1H, t), 3.43-3.47 (2H, t), 3.56-3.76 (36H, m).

[0107] Chromatographic results of DD-PEG9-OH The specific results are shown in Table 2, and the chromatogram is shown in Figure 6 As shown, Figure 7 This is the chromatogram of the 1% reference substance of DD-PEG9-OH. The mass spectrum results are as follows Figure 8 As shown, MS (ESI+): m / z+H=582.8.

[0108] Table 2 Chromatographic results of DD-PEG9-OH

[0109]

[0110]

[0111] 1.3 Chemical synthesis, purification and characterization of DD-PEG10-OH

[0112] HO-PEG10-OH (18 g, 40 mmol, 2 eq) was added to THF (144 mL, 8 V), and NaH (60%, 1.2 g, 1.5 eq) was added under stirring to react for 20 min. 1-Bromododecane (5 g, 20 mmol, 1 eq) was dissolved in THF (10 mL) and added dropwise to the system. After the addition was completed, the system was heated to 80° C. and reacted overnight. After the reaction of the raw materials was completed by TLC monitoring, a saturated NH4Cl solution was added to adjust the pH of the system to <7, the salt was filtered and the THF was dried by spin drying, water (100 ml) was added to dilute, and DCM (3*100 ml) was extracted, separated, the organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated to dryness, and column chromatography was performed with MeOH:DCM=1:10 to elute 14 g of a light yellow solid with a yield of 55.8%.

[0113] The results of NMR are as follows Fig. 9 As shown, 1 H NMR (300MHz, CDCl3) δ: 5.544 (1H, t), 3.518-3.366 (40H, m), 1.477-1.455 (2H, t), 1.249 (18H, s), 0.863 (3H, t).

[0114] Chromatographic results of DD-PEG10-OH The specific results are shown in Table 3 and the chromatogram is shown in Fig.10 As shown, Fig.11 This is the chromatogram of the 1% reference substance of DD-PEG10-OH. The mass spectrum results are as follows Fig.12 As shown, MS (ESI+): m / z+H=628.1.

[0115] Table 3 Chromatographic results of DD-PEG10-OH

[0116]

[0117]

[0118] Example 2 Differences in foam stability of single molecular weight polidocanol with different chain lengths

[0119] 2.1 Experimental methods

[0120] Weigh the single molecular weight polidocanol samples (DD-PEG8-OH, DD-PEG9-OH, DD-PEG10-OH prepared in Example 1) and the reference substance (containing polidocanol in a mixture state with different molecular weights, purchased from SiegfriedHameln GmbH, Germany, batch number OK13103) respectively, and prepare a 1% solution with 4% ethanol PBS. Use the Tessari method to foam the polidocanol, that is, connect two 2.5mL syringes with a three-way tube, and quickly push them to form foam at a gas-liquid ratio of 3:1. Collect all the foam into one syringe, adjust the volume to 2ml, and observe the foam state while standing, and record the following parameters, namely, foam emptying time, foam half-life, and foam coalescence time.

[0121] 2.2 Experimental Results

[0122] P8 represents a single molecular weight polydocanol of DD-PEG8-OH, P9 represents a single molecular weight polydocanol of DD-PEG9-OH, and P10 represents a single molecular weight polydocanol of DD-PEG10-OH.

[0123] After the 1% concentration of P8, P9 and P10 solutions were fully mixed with air at a volume ratio of 1:3, uniform foams were formed. The foam emptying time, foam half-life and foam coalescence time are shown in Table 4. The following conclusions were obtained:

[0124] (1) The foam emptying time of samples P8 and P9 was 3 s, which was shorter than that of the control sample (5 s). The foam emptying time of sample P10 was 8 s, which was slightly longer than that of the control sample (5 s).

[0125] (2) The foam half-life of sample P8 was 170 s, slightly longer than that of the reference sample (167 s). The foam half-life of samples P9 and P10 was 149 s and 158 s, respectively, both shorter than that of the reference sample (167 s).

[0126] (3) The foam coagulation time of samples P8, P9 and P10 were 13 min, 19 min and 20 min, respectively, which were shorter than that of the control sample (22 min).

[0127] Table 4 Parameters of P8, P9, P10 and reference substances

[0128] Sample concentration Foam emptying time Bubble Half-Life Foam coagulation time P8(1％) 3s 170s 13m P9(1％) 3s 149s 19m P10(1％) 8s 158s 20m Reference substance (1%) 5s 167s 22min

[0129] Example 3 Effect of Sodium Hyaluronate on the Foam Stability of Single Molecular Weight Polydocanol

[0130] 3.1 Experimental methods

[0131] The experimental steps are as follows: (1) Weigh a single molecular weight polidocanol sample (DD-PEG9-OH prepared in Example 1), dissolve it in a 4% ethanol PBS solution, prepare a 2% solution, and let it stand until the foam disappears. (2) Prepare a 0.5% sodium hyaluronate solution, and then dilute it to concentrations of 0.25%, 0.1% and 0.05% respectively. (3) Mix the 2% single molecular weight polidocanol solution with sodium hyaluronate solutions of different concentration gradients in a volume ratio of 1:1. The P9 concentration in the solution is 1%, and the concentrations of the sodium hyaluronate solutions are 0.25%, 0.125%, 0.05% and 0.025% respectively. (4) Use a 2.5 ml syringe to draw 0.5 ml of the mixed solution and another syringe to draw 1.5 ml of air. Connect them to a three-way pipe and then draw 40 times until a uniform foam is formed. Collect all the foam into one syringe and adjust the volume to 2 ml. Let it stand and observe the foam state. Record the following parameters, namely, foam emptying time, foam half-life, and foam aggregation time.

[0132] 3.2 Experimental Results

[0133] As shown in Table 5, adding sodium hyaluronate to 1% P9 solution can significantly prolong the foam half-life of P9. In the concentration range of 0.025% to 0.25%, the foam half-life is positively correlated with the concentration of sodium hyaluronate.

[0134] Table 5 Parameters of P9 and different concentrations of sodium hyaluronate

[0135] Sample concentration Foam emptying time Bubble Half-Life Foam coagulation time P9(1％) 3s 149s 19min P9 (1%) + sodium hyaluronate (0.25%) 60s 684s 35min P9 (1%) + sodium hyaluronate (0.125%) 90s 596s 38min P9 (1%) + sodium hyaluronate (0.05%) 74s 495s 38min P9 (1%) + sodium hyaluronate (0.025%) 47s 312s 22min Reference substance (1%) 5s 167s 22min

[0136] Example 4 Evaluation of the effect of adding hyaluronic acid on the venous vascular sclerosis effect of single molecular weight polidocanol

[0137] 4.1 Experimental methods

[0138] The rabbit marginal auricular vein was used as an experimental model to compare the effect of adding different concentrations of sodium hyaluronate on the sclerotic effect of polidocanol. The specific methods are as follows: (1) Rabbits were anesthetized with xylazine (2-5 mg / kg, intramuscular injection). The ears were then shaved and disinfected with 0.5% chlorhexidine alcohol solution. (2) The polidocanol with sodium hyaluronate added was foamed using the Tessari method, that is, two 10 mL syringes were connected with a three-way pipe, and a certain gas-liquid ratio was used to quickly push until foam was formed. (3) The marginal vein was punctured with a disposable syringe, and the sclerosant was slowly injected with a maximum volume of 0.25 ml. In all groups, manual pressure was applied to the puncture site and along the entire extension of the vein for 90 seconds. Then tape was applied to the puncture site. (4) The sclerosis of the marginal auricular vein was observed 3, 7, 14, and 21 days after administration.

[0139] 4.2 Experimental Results

[0140] 4.2.1. Results after 14 days of administration via the rabbit ear vein

[0141] In this example, after 14 days of injection of different types of polidocanol into the ear vein of some rabbits, some blood vessels were blocked. From the appearance, the color was darker in some places and lighter in others, and the blood flow of some uninjected blood vessels increased. All rabbit ear blood vessels were scored, with 1 being effective and 0 being ineffective.

[0142] The calculation rule of effective rate is: effective rate = score of rabbit ears / total number of rabbit ears * 100% (calculated by number of rabbit ears)

[0143] As can be seen from Table 6, 14 days after administration, the positive control group (1% polidocanol, i.e., the control substance described in Example 2) had an effective rate of 83.33%, and the 1% P9 group (prepared in Example 2) had an effective rate of 91.67%, which was higher than the positive control group; the P9 (1%) group with sodium hyaluronate (0.05%) (prepared in Example 3) had an effective rate of 100%, which was higher than the positive control group and the 1% P9 group. This indicates that adding 0.05% sodium hyaluronate to the 1% P9 sample can enhance the vascular sclerosis effect in vivo.

[0144] Table 6 Effectiveness of venous sclerosis in rabbits 14 days after injection of different types of polidocanol into the ear vein

[0145] Group D14 effective rate (%) Negative control (4% ethanol PBS solution) 0.00 Positive Control 83.33 P9(1％) 91.67 P9 (1%) + sodium hyaluronate (0.05%) 100.00 P9 (0.5%) + sodium hyaluronate (0.05%) 83.33 P9 (0.25%) + sodium hyaluronate (0.05%) 66.00

[0146] 4.2.2. Results after 21 days of administration via the rabbit ear vein

[0147] After 21 days of injection of different types of polidocanol into the ear veins of some rabbits, some blood vessels in the rabbit ears were completely blocked. From the appearance, some blood vessels became lighter or gradually disappeared, and the blood flow of the uninjected blood vessels increased.

[0148] All rabbit ear vessels were scored, with valid being recorded as 1 and invalid being recorded as 0. The calculation rules are shown in 4.2.1.

[0149] The results in Table 7 show that 21 days after administration, the positive control group (1% polidocanol, i.e., the control substance described in Example 2) had an effective rate of 75%, and the 1% P9 group (prepared in Example 2) had an effective rate of 83.33%, which was higher than the positive control group; the P9 (1%) group with sodium hyaluronate (0.05%) (prepared in Example 3) and the P9 (0.5%) group with sodium hyaluronate (0.05%) (prepared in Example 3) had an effective rate of 100%, which was higher than the positive control group. This indicates that the addition of 0.05% sodium hyaluronate to the 1% P9 sample can enhance the vascular sclerosis effect in vivo.

[0150] The effective rates of the P9 (1%) group with sodium hyaluronate (0.05%) and the P9 (0.5%) group with sodium hyaluronate (0.05%) were both 100%. This suggests that adding sodium hyaluronate (0.05%) to a low-concentration P9 sample (0.5%) can achieve the same vascular sclerosis effect as a high-concentration P9 sample (1%), which is helpful to reduce the dosage of the P9 sample in clinical use, thereby reducing toxic reactions and increasing product safety.

[0151] Table 7 Effectiveness of venous sclerosis in rabbits after injection of different types of polidocanol into the ear vein 21 days later

[0152] Group D21 effective rate (%) Negative control (4% ethanol PBS solution) 0.00 Positive Control 75.00 P9(1％) 83.33 P9 (1%) + sodium hyaluronate (0.05%) 100.00 P9 (0.5%) + sodium hyaluronate (0.05%) 100.00 P9 (0.25%) + sodium hyaluronate (0.05%) 83.00

[0153] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. However, these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A foam hardener composition, characterized in that: The foam hardener composition comprises polidocanol and sodium hyaluronate, wherein the polidocanol is a polidocanol of a single molecular weight, and its monomer molecular structure comprises the following structure: Wherein, n is an integer, 4≤n≤24; preferably, 8≤n≤15; more preferably, n is 8, 9, or 10.

2. The foam hardener composition according to claim 1, characterized in that The volume ratio of the single molecular weight polydocanol and sodium hyaluronate is 1:0.1-5; preferably 1:0.5-2; more preferably 1:

1.

3. The foam hardener composition according to claim 1, characterized in that The mass concentration of the single molecular weight polydocanol is 0.01-5%, preferably 0.05-2%, and more preferably 1%.

4. The foam hardener composition according to claim 1, characterized in that: The mass concentration of the sodium hyaluronate is 0.01-5%, preferably 0.05-2%, and more preferably 0.05-0.25%.

5. The foam hardener composition according to claim 1, characterized in that: The foam sclerosing agent composition further comprises a pharmaceutically acceptable auxiliary material.

6. The foam hardener composition according to claim 5, characterized in that: The pharmaceutically acceptable excipient is selected from one or more of a solubilizer, an antioxidant, an anti-photolysis agent, a pH regulator, and an emulsifier; And / or, the foam sclerosant composition is in the form of an injection.

7. A method for preparing the foam hardener composition according to claim 1, characterized in that: The preparation method comprises the following steps: (1) Preparation of single molecular weight polydocanol: reacting single molecular weight polyethylene glycol with 1-halododecane, separating and purifying to obtain single molecular weight polydocanol; (2) Preparation of the foam hardener composition: dissolve the above-mentioned single molecular weight polydocanol in a solvent, let it stand, add sodium hyaluronate, mix well to obtain a mixed solution, mix the above-mentioned mixed solution with gas to generate foam, and obtain a foam hardener composition.

8. The preparation method according to claim 7, characterized in that: In step (1), the method for preparing polydocanol of a single molecular weight comprises the following steps: A1: Mix polyethylene glycol of a single molecular weight with a catalyst and an organic solvent, add 1-halododecane dropwise, raise the temperature to a preset temperature, and keep the temperature for reaction; A2: After the reaction is completed, the reactants are cooled to room temperature, diluted with water, extracted, separated, and the organic phase is collected; A3: filtering, concentrating, drying, separating and purifying the organic phase to obtain the single molecular weight polidocanol; and / or, in step A1, the polyethylene glycol of single molecular weight is selected from tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, octaethylene glycol, nonaethylene glycol, decaethylene glycol, 11ethylene glycol, dodecaethylene glycol, 13ethylene glycol, tetradecaethylene glycol, 15ethylene glycol, 16ethylene glycol, 17ethylene glycol, 18ethylene glycol, 19ethylene glycol, 21ethylene glycol, 22ethylene glycol, 23ethylene glycol, and 24ethylene glycol, preferably octaethylene glycol, nonaethylene glycol, decaethylene glycol, 11ethylene glycol, dodecaethylene glycol, 13ethylene glycol, tetradecaethylene glycol, and 15ethylene glycol, and more preferably octaethylene glycol, nonaethylene glycol, and decaethylene glycol; And / or, in step A1, the 1-halododecane includes 1-chlorododecane, 1-bromododecane or 1-iodododecane, preferably 1-bromododecane; And / or, in step A1, the molar ratio of the polyethylene glycol with a single molecular weight to the 1-halododecane is 1-15:1, preferably 1-10:

1.

9. The preparation method according to claim 7, characterized in that: In step (2), the solvent is selected from one of ethanol-phosphate buffer, ethanol, and physiological saline; And / or, the volume ratio of the single molecular weight polidocanol to sodium hyaluronate is 1:0.1-5; preferably 1:0.5-2; more preferably 1:1; And / or, the mass concentration of the single molecular weight polidocanol is 0.01-5%; preferably 0.05-2%; more preferably 1%; And / or, the mass concentration of the sodium hyaluronate is 0.01-5%; preferably 0.05-2%; more preferably 0.05-0.25% And / or, the volume ratio of the mixed solution to the gas is 1:0.5-5; preferably 1:3; and / or, the gas comprises air, carbon dioxide or oxygen, preferably air; And / or, the method of mixing the mixed solution with gas to generate bubbles includes the Tessari method, the Tessari / DSS method or the Monfreux method.

10. Use of the foam hardener composition according to any one of claims 1 to 6 or the foam hardener composition prepared by the preparation method according to any one of claims 7 to 9 in preparing a drug for treating a disease; Preferably, the disease is selected from one or more of vascular-related diseases, cystic diseases, tumors, gynecological diseases, inflammation or pain; Preferably, the vascular-related disease is selected from one or more of varicose veins or vascular malformations; More preferably, the varicose veins are selected from one or more of lower extremity varicose veins, esophageal and gastric varicose veins, varicocele, abdominal wall varicose veins or hemorrhoids; Preferably, the cystic disease includes one or more of abdominal visceral cysts, body surface cysts, lymphoceles, thyroid cysts, bone cysts, finger mucoceles or pelvic encapsulated effusions; More preferably, the abdominal visceral cyst is selected from one or more of liver cyst, kidney cyst, pararenal pelvic cyst, pancreatic cyst, endometriosis cyst or ovarian chocolate cyst; More preferably, the body surface cyst includes a skin cyst and / or a finger mucocele; Preferably, the tumor comprises a benign or malignant solid tumor; More preferably, the tumor is selected from one or more of 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 or abdominal visceral malignant tumors; More preferably, the abdominal organ malignant tumor includes liver cancer; Preferably, the gynecological diseases include submucosal uterine fibroids and / or cesarean scar pregnancy; Preferably, the inflammation includes infectious inflammation and / or non-infectious inflammation; More preferably, the inflammation is selected from one or more of tendinitis, tendinitis, tendinosis, tendinitis, ankylosing spondylitis, sacroiliitis, gouty arthritis, myofasciitis, tenosynovitis or scapulohumeral periarthritis; Preferably, the pain includes chronic pain, acute pain, and cancer pain; More preferably, the pain is selected from one or more of muscle and soft tissue pain, bone and joint pain or visceral pain.

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