Foam sclerosant composition, and preparation method therefor and use thereof

Abstract

A foam sclerosant composition, and a preparation method therefor and a use thereof. The foam sclerosant composition comprises polidocanol of a single molecular weight and sodium hyaluronate in a volume ratio of 1:0.1-5. A preparation method for polidocanol of a single molecular weight comprises the following steps: reacting polyethyleneglycol of a single molecular weight with 1-halododecane, and carrying out separation and purification, thereby obtaining polidocanol of a single molecular weight. The foam sclerosant has higher foam stability, better drug effects, and smaller toxic and side effects, and can be widely applied to the treatment of vascular related diseases, cystic diseases, tumors, gynecological and obstetrical diseases, inflammations or pains.

Description

A foam hardener composition and its preparation method and application Technical Field

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

[0002] Polidocanol (POL) is a surfactant-based sclerosant with a structure that closely resembles the phospholipid bilayer of cell membranes. It disrupts the cell membrane's surfactant structure by interfering with the surfactant on the cell membrane, leading to endothelial cell lysis and death, and subsequently vascular fibrosis and vascular occlusion. Polidocanol possesses fixed hydrophilic and hydrophobic ends, allowing for directional alignment on the surface of a solution, significantly reducing the solution's surface tension and forming a foam. Therefore, polidocanol is widely used in foam sclerotherapy. Currently, polidocanol is primarily used in sclerotherapy for varicose veins, venous malformations, hemangiomas, internal hemorrhoids, cystic diseases, acne, and tumor ablation. In sclerotherapy, the therapeutic efficacy of foam sclerosants depends on the stability of the foam and the uniformity of bubble size. Generally, smaller average bubble diameters within the foam are associated with more uniform foams, higher drug concentrations, and better foam stability, resulting in improved therapeutic efficacy. Foam stability is typically assessed using metrics such as foam fineness, liquid precipitation time, and half-life. These metrics are influenced by various factors, including the composition of the sclerosant, liquid viscosity, and liquid surface properties.

[0003] Liu Ziyi et al. disclosed a hyaluronic acid-polidocanol composition and studied the effects of hyaluronic acid (HA) on the endothelial cell killing ability, foam stability, blood replacement ability, and viscosity of polidocanol 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 simultaneously, 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 (≤0.4 mL of HA added to 1 mL of POL), the higher the HA dosage added to POL, the better the foam performance (see Liu Ziyi. In vitro study of the effect of hyaluronic acid on the foam properties of polidocanol [D]. Shandong University, 2022.). However, the study used commercially available polidocanol, which is a mixture of different molecular weights and contains many impurities. Its efficacy is affected by polidocanol of different chain lengths and impurities, making it difficult to control during application.

[0004] Polydocanol, also known as ethoxylated hardened alcohol or lauroyl alcohol, is a polymer product derived from the polymerization of lauryl alcohol and multiple ethylene oxides. Currently, polidocanol is primarily produced through the polymerization reaction of lauryl alcohol and ethylene oxide under base-catalyzed conditions. The quality and stability of polidocanol products are significantly affected by factors such as the purity of the starting materials, the catalyst, reaction pressure, temperature, and post-processing. Commercially available lauryl alcohol contains numerous impurities, including decanol and tetradecanol, as well as numerous unknown impurities. The byproducts generated by the introduction of these impurities into the polidocanol polymerization reaction are difficult to separate from the polidocanol, directly impacting the quality of the finished product. Furthermore, in addition to unreacted lauryl alcohol and ethylene oxide, the synthesis of polidocanol also produces numerous byproducts, primarily free polyethylene glycol, diethylene glycol, dioxane, formaldehyde, acetaldehyde, and ethylene glycol. These impurities significantly impact the safety and efficacy of polidocanol.

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

[0006] Patent publication number CN113200821A discloses a method for purifying lauryl alcohol and synthesizing polidocanol. High-purity lauryl alcohol is prepared by vacuum distillation, but the distillation purification requires a pressure of -0.08 MPa and a distillation temperature of 130-150°C. In the process of preparing polidocanol, the lauryl alcohol dehydration temperature is 90-125°C, the vacuum degree is -0.08 MPa, the polymerization temperature is 100-115°C, the polymerization pressure is 0.1-0.8 MPa, 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, which places high demands on equipment and processes.

[0007] Currently, commercially available polidocanol is a mixture of different molecular weights. Polydocanol with different chain lengths has different foaming effects and efficacy, making it difficult to control during application. Therefore, developing and preparing polidocanol with a single molecular weight to effectively control and improve its quality is of great significance for improving the efficacy of polidocanol foam sclerosants and their compositions.

[0008] Summary of the Invention

[0009] 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 polydocanol.

[0010] In a first aspect of the present invention, a foam sclerosant composition is provided, wherein the foam sclerosant 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:

[0011] Where n is an integer, 4≤n≤24;

[0012] Specifically, n is selected from any number of 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 certain 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 polydocanol and 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: 1:4.4, 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 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 a 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 to react;

[0026] A2: After the reaction is complete, 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] Furthermore, 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, 11ethylene glycol, 12ethylene glycol, 13ethylene glycol, tetraethylene glycol, pentadecaethylene glycol, hexadecaethylene glycol, heptaethylene glycol, octaethylene glycol, nonadecaethylene glycol, 21ethylene glycol, 22ethylene glycol, 23ethylene glycol, and 24ethylene glycol, preferably octaethylene glycol, nonaethylene glycol, decaethylene glycol, 11ethylene glycol, 12ethylene glycol, 13ethylene glycol, tetraethylene glycol, and 15ethylene glycol, and more preferably octaethylene glycol, nonaethylene 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, and 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, 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 chromatography, 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] Furthermore, 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 and vascular malformations.

[0052] More preferably, the varicose veins are selected from one or more of lower limb 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 organ cyst is selected from one or more of liver cyst, renal cyst, pararenal pelvic cyst, pancreatic cyst, endometrioma or 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, Kaposiform hemangioendothelioma, reticular hemangioendothelioma, papillary lymphatic hemangioendothelioma, 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 submucosal uterine fibroids and / or cesarean 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, peritendinitis, ankylosing spondylitis, sacroiliitis, gouty arthritis, myofasciitis, tenosynovitis or frozen shoulder;

[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 polydocanol and its foaming preparation of the present invention have better foaming effect and foam maintenance time than the foaming preparations of polydocanol in the prior art because polydocanol with inappropriate PEG chain length is eliminated.

[0067] (3) The foam hardener of the present invention combines a single molecular weight of polydocanol with a certain concentration of sodium hyaluronate. Compared with the foam preparation of the above-mentioned single molecular weight polydocanol and the hyaluronic acid-polydocanol 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 shows the H NMR spectrum of DD-PEG8-OH;

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

[0071] Figure 3 shows the chromatogram of a 1% reference substance of DD-PEG8-OH;

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

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

[0074] FIG6 shows the HPLC chromatogram of DD-PEG9-OH;

[0075] FIG7 shows a chromatogram of a 1% control of DD-PEG9-OH;

[0076] FIG8 shows the mass spectrum of DD-PEG9-OH;

[0077] Figure 9 shows the H NMR spectrum of DD-PEG10-OH;

[0078] FIG10 shows the HPLC chromatogram of DD-PEG10-OH;

[0079] FIG11 shows a chromatogram of a 1% control of DD-PEG10-OH;

[0080] FIG12 shows 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. For example, when the single-chain-length polydocanol of the present invention contains PEG8 (eight ethylene glycol units), it indicates that the single-chain-length polydocanol contains only PEG8, and does not include polydocanol containing other PEGs such as 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, PEG33, PEG34, 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] As used herein, the term "Tessari method," also known as vortex flow technology, refers to the use of two disposable plastic syringes to generate sclerosing foam, one syringe containing a liquid sclerosant solution and the other containing a gas, with the ports of the two syringes connected to a three-way switch at a 90-degree angle. The contents of the two syringes are rapidly pushed back and forth 20 times, and after the first 10 pushes, the channel port is closed as small as possible to generate foam through the turbulent flow.

[0084] As used herein, the term "Tessari / DSS method," also known as the Tessari / dual syringe technique, is based on the basic Tessari method and involves producing foam using two latex-free, disposable plastic syringes, one of which has a rubber plunger, one containing a liquid sclerosant solution, and the other containing a gas. The syringes are connected at 180 degrees to a two-way connector, and the contents of the two syringes are rapidly pushed back and forth five times (applying additional pressure by firmly gripping the plunger of one of the syringes), and then repeated seven times (without additional pressure).

[0085] As used herein, the term "Monfreux method" refers to a method for producing foam using a glass syringe filled with a liquid sclerosant solution. The syringe port is sealed with a rubber or plastic cap. The syringe piston is withdrawn to create negative pressure, which in turn injects air into the syringe through the gap between the syringe barrel and the piston, producing a 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 products are 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 and is expressed as RT, usually in minutes (min).

[0089] As used herein, the term "TLC" refers to thin layer chromatography (TLC), a type of liquid chromatography that typically uses an adsorbent as the stationary phase. Specifically, the stationary phase is spread evenly into a thin layer on a smooth surface such as glass, metal, or plastic. The sample is applied to one end of the thin layer, and the mobile phase flows through the stationary phase by capillary action, spreading the substances being separated.

[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 during which 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 the hardener foam is visible.

[0096] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all commercially available conventional products.

[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 (2.2 g, 55 mmol) was added to a 500 ml single-necked flask containing DMSO (200 ml) at room temperature and stirred for 30 min. Octaethylene glycol (20 g, 54.1 mmol) was then slowly added under nitrogen and stirred at room temperature for 2 hrs. 1-Bromododecane (13.5 g, 54.1 mmol) was slowly added to the reaction flask under nitrogen, and the reaction mixture was heated to 90°C and stirred for 18 hrs. The reaction mixture was cooled to room temperature, water (400 ml) was added, and the mixture was extracted with EtOAc (100 ml) three times. The organic phases were combined and washed with saturated NaCl solution (100 ml). The organic phases were dried over anhydrous Na2SO4, filtered, concentrated, and dissolved in DCM. The sample was separated in a normal phase with a gradient of DCM:MeOH = 0-3%. The product spot was confirmed by TLC. The product fractions were combined and concentrated to give 2.1 g of a light yellow solid in a 7.2% yield.

[0100] The NMR results are shown in Figure 1. 1H 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-reference method was used to determine the product content of 98.62%. The specific results are shown in Table 1. The chromatographic results are shown in Figure 2. Figure 3 is a chromatogram of a 1% reference substance of DD-PEG8-OH. The mass spectrum results are shown in Figure 4, MS (ESI+): m / z+H=539.5.

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

[0103] 1.2 Synthesis, purification and characterization of DD-PEG9-OH

[0104] NaH (484 mg, 12.1 mmol) was added to a 500 ml single-necked flask containing DMSO (200 ml) at room temperature and stirred for 30 minutes. Nonaethylene glycol (20 g, 48.3 mmol) was then slowly added under nitrogen and stirred at room temperature for 2 hours. 1-Bromododecane (3.02 g, 12.1 mmol) was then slowly added to the reaction flask under nitrogen, and the reaction mixture was heated to 90°C and stirred for 18 hours. The reaction mixture was cooled to room temperature, water (400 ml) was added, and the mixture was extracted with ethyl acetate (100 ml) three times. The organic phases were combined and washed with saturated sodium chloride solution (100 ml), dried over anhydrous Na2SO4, filtered, concentrated to dryness, and dissolved in DCM. Separation was performed in the normal phase using a DCM / MeOH gradient (0-3%). The product was confirmed by TLC. The product fractions were combined and concentrated to yield 1.36 g of a light yellow solid in a 19.3% yield.

[0105] The NMR results are shown in Figure 5. 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).

[0106] The specific results of the chromatogram of DD-PEG9-OH are shown in Table 2, the chromatogram is shown in Figure 6, Figure 7 is the chromatogram of the 1% reference substance of DD-PEG9-OH, and the mass spectrum results are shown in Figure 8, MS (ESI+): m / z+H=582.8.

[0107] Table 2 Chromatographic results of DD-PEG9-OH

[0108] 1.3 Chemical synthesis, purification and characterization of DD-PEG10-OH

[0109] HO-PEG10-OH (18 g, 40 mmol, 2 eq) was added to THF (144 mL, 8 V). NaH (60%, 1.2 g, 1.5 eq) was added with stirring and allowed to react for 20 min. 1-Bromododecane (5 g, 20 mmol, 1 eq) was dissolved in THF (10 mL) and added dropwise. After completion of the addition, the system was heated to 80°C and allowed to react overnight. The reaction was monitored by TLC. Saturated NH4Cl solution was added to adjust the pH to <7. The salts were filtered, and the THF was dried by spin drying. Water (100 mL) was added for dilution, and the mixture was extracted with DCM (3 x 100 mL). The organic phases were separated, dried over anhydrous Na2SO4, filtered, concentrated, and eluted with column chromatography using MeOH:DCM = 1:10 to afford 14 g of a pale yellow solid in a yield of 55.8%.

[0110] The NMR results are shown in Figure 9. 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).

[0111] The specific results of the chromatogram of DD-PEG10-OH are shown in Table 3, the chromatogram is shown in Figure 10, Figure 11 is the chromatogram of the 1% reference substance of DD-PEG10-OH, and the mass spectrum results are shown in Figure 12, MS (ESI+): m / z+H=628.1.

[0112] Table 3 Chromatogram results of DD-PEG10-OH

[0113] Example 2 Differences in foam stability of single molecular weight polydocanol with different chain lengths

[0114] 2.1 Experimental methods

[0115] Weigh the single molecular weight polidocanol samples (DD-PEG8-OH, DD-PEG9-OH, and DD-PEG10-OH prepared in Example 1) and the reference substance (polidocanol in a mixture state containing different molecular weights, purchased from Siegfried Hameln GmbH, Germany, batch number OK13103) separately, 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 pipe, and quickly push the syringe until foam is formed 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. Record the following parameters, namely, foam emptying time, foam half-life, and foam coalescence time.

[0116] 2.2 Experimental Results

[0117] 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.

[0118] When 1% P8, P9, and P10 solutions were fully mixed with air at a volume ratio of 1:3, they all formed uniform foam. The foam emptying time, foam half-life, and foam coalescence time are shown in Table 4. The following conclusions were drawn:

[0119] (1) The foam emptying time of samples P8 and P9 was 3 s, which was shorter than that of the control (5 s). The foam emptying time of sample P10 was 8 s, which was slightly longer than that of the control (5 s).

[0120] (2) The foam half-life of sample P8 was 170s, slightly longer than that of the control (167s). The foam half-life of samples P9 and P10 was 149s and 158s, respectively, both shorter than that of the control (167s).

[0121] (3) The foam coagulation time of samples P8, P9 and P10 were 13 min, 19 min and 20 min, respectively, which were all shorter than that of the control (22 min).

[0122] Table 4 Parameters of P8, P9, P10 and reference

[0123] Example 3 Effect of Sodium Hyaluronate on the Foam Stability of Single Molecular Weight Polydocanol

[0124] 3.1 Experimental methods

[0125] 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 at 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 coalescence time.

[0126] 3.2 Experimental Results

[0127] As shown in Table 5, the addition of sodium hyaluronate to a 1% P9 solution can significantly prolong the foam half-life of P9. Within the concentration range of 0.025% to 0.25%, the foam half-life is positively correlated with the concentration of sodium hyaluronate.

[0128] Table 5 Parameters of P9 and different concentrations of sodium hyaluronate

[0129] Example 4 Evaluation of the Effect of Adding Hyaluronic Acid on the Venous Vascular Sclerosis Effect of Single Molecular Weight Polydocanol

[0130] 4.1 Experimental methods

[0131] The rabbit marginal auricular vein was used as an experimental model to compare the effects 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 a 0.5% chlorhexidine alcohol solution. (2) Polydocanol with sodium hyaluronate was foamed using the Tessari method, that is, two 10 mL syringes were connected with a three-way pipe and rapidly injected at a certain gas-liquid ratio until foam formed. (3) The marginal auricular 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. The puncture site was then taped. (4) The sclerosis of the marginal auricular vein was observed 3, 7, 14, and 21 days after administration.

[0132] 4.2 Experimental Results

[0133] 4.2.1. Results after 14 days of administration into the rabbit ear vein

[0134] In this example, 14 days after different types of polidocanol were injected into the ear veins of some rabbits, some blood vessels became blocked. This was apparent by the darker and lighter colors in some sections of the veins, and blood flow in some uninjected vessels increased. All rabbit ear vessels were scored, with 1 being considered effective and 0 being considered ineffective.

[0135] The calculation rule for the effectiveness is: Effectiveness = rabbit ear score / total number of rabbit ears * 100% (calculated based on the number of rabbit ears)

[0136] As shown in 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 were higher than the positive control group; the P9 (1%) supplemented with sodium hyaluronate (0.05%) group (prepared in Example 3) had an effective rate of 100%, which was higher than both the positive control group and the 1% P9 group. This suggests that adding 0.05% sodium hyaluronate to the 1% P9 sample can enhance the vascular sclerosis effect in vivo.

[0137] Table 6 Effectiveness of venous sclerosis 14 days after injection of different types of polidocanol into rabbit ear vein

[0138] 4.2.2. Results after 21 days of administration into the rabbit ear vein

[0139] After 21 days of injection of different types of polidocanol into the ear veins of some rabbits, some blood vessels in the ears were completely blocked. This was evident by the color of some blood vessels becoming lighter or disappearing, while blood flow in uninjected vessels increased.

[0140] All rabbit ear vessels were scored, with valid scores being 1 and invalid scores being 0. The calculation rules are described in 4.2.1.

[0141] 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%, both higher than the positive control group. The P9 (1%) group supplemented with sodium hyaluronate (0.05%) (prepared in Example 3) and the P9 (0.5%) group supplemented with sodium hyaluronate (0.05%) (prepared in Example 3) both had effective rates of 100%, both higher than the positive control group. This suggests that the addition of 0.05% sodium hyaluronate to the 1% P9 sample can enhance the vascular sclerosis effect in vivo.

[0142] The efficacy rates for both the P9 (1%) plus sodium hyaluronate (0.05%) group and the P9 (0.5%) plus sodium hyaluronate (0.05%) group were 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 may help reduce the dosage of P9 samples in clinical use, thereby reducing toxic reactions and increasing product safety.

[0143] Table 7 Effectiveness of venous sclerosis 21 days after injection of different types of polidocanol into rabbit ear vein

[0144] 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 above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to 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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