Tranexamic acid-hydroxycinnamate conjugate as well as preparation method and application thereof

Abstract

The invention discloses a tranexamic acid-hydroxycinnamate conjugate as well as a preparation method and application thereof, and belongs to the technical field of medicines, a carboxyl terminal of tranexamic acid is connected with a hydroxyl terminal on a 4-position carbon atom of hydroxycinnamate in an ester bond form, and a compound with a brand new molecular structure is constructed. The cationic surfactant has the effect of cationic surface activity. The tranexamic acid-hydroxycinnamic acid ester conjugate has good in-vivo degradability, tranexamic acid, hydroxycinnamic acid or ester thereof are generated through degradation, tranexamic acid can effectively play a fibrinolytic inhibition role, stabilize thrombus and further promote the fibrosis process of blood vessels and hydroxycinnamic acid or ester thereof, inflammatory response caused by sclerotherapy is reduced, and the tranexamic acid-hydroxycinnamic acid ester conjugate can be used for treating sclerotherapy. Side effects accompanied by sclerotherapy are reduced, and the medication safety is improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a tranexamic acid-hydroxycinnamate conjugate or a composition thereof, a preparation method thereof and application thereof in sclerotherapy of venous diseases. BACKGROUND

[0002] Hemangioma, vascular malformation and varicosis are the most common venous diseases in clinic. Hemangioma is a congenital benign tumor originating from the proliferation of vascular endothelial cells. Vascular malformation is a congenital disorder of angiogenesis secondary to accidental mutation of somatic cells. Vascular malformation usually includes high-flow lesions such as arteriovenous malformation and arteriovenous fistula, and low-flow lesions such as venous malformation, lymphatic malformation and capillary malformation, among which venous malformation is the most common in clinic, with an incidence of up to 70% of vascular malformation diseases. Venous malformation usually exists at birth and grows in proportion with the growth of infants and young children, not only causing appearance deformity, but also causing complications such as local pain and / or swelling, thrombosis or phlebitis, and joint pain, and even life-threatening in severe cases (Diagnosis and treatment guidelines for hemangioma and vascular malformation[J].Journal of Tissue Engineering and Regenerative Medicine, 2019, 15(05):277-317.).

[0003] The treatment methods for venous diseases usually include pressure therapy, surgical treatment, sclerotherapy and the like. Pressure therapy is the most conservative treatment method, which promotes local blood circulation, prevents thrombosis and relieves pain by compressing the lesion site. However, since it cannot directly treat the lesion blood vessels, it is usually used as an auxiliary method to relieve discomfort after treatment, accelerate recovery and reduce recurrence. Surgical treatment is an effective method for treating venous malformation, but in general, the lesion is diffuse and has unclear boundaries with normal tissue, so it is difficult to achieve a cure, and therefore surgical treatment is not the first choice, but is used for local control of the lesion area after sclerotherapy or removal of scar tissue (Dompmartin A, Vikkula M, Boon LM. Venous malformation: update on aetiopathogenesis, diagnosis and management [J]. Phlebology, 2010, 255: 224-235.). Sclerotherapy is a treatment method for venous diseases, which injects a liquid or foam sclerosing agent drug directly into the lesion blood vessels to cause damage to abnormal endothelial cells and induce thrombosis, and then induces vascular fibrosis to achieve the purpose of lumen occlusion. At present, sclerotherapy has become a first-line treatment method for venous diseases in clinic, and has better treatment effect, safety and economy.

[0004] Drugs with sclerotherapy effect are called sclerosing agents, which mainly include osmotic sclerosing agents, chemical sclerosing agents and surfactant sclerosing agents (Goldman M, Guex J. Sclerotherapy [M]. Amsterdam: Elsevier, 2017: 173-199.). Among them, osmotic sclerosing agents and chemical sclerosing agents are easy to diffuse and exude after administration, causing severe pain and tissue necrosis, and are rarely used at present. Surfactant sclerosing agents have become the most commonly used sclerosing agents due to their higher treatment safety, and can be prepared into foam preparations due to their surface activity, with longer vascular retention time, wider vascular endothelial contact area and smaller administration dose. Commonly used in clinical practice are polidocanol, sodium tetradecyl sulfate and sodium morrhuate. However, due to the milder effect of surfactant sclerosing agents, they face the problems of high recurrence rate and high revascularization rate. In addition, based on the treatment mechanism, the lesion vascular endothelium is easily damaged by drugs, which can induce the production of active oxygen, which will further enhance and amplify the inflammatory response, leading to the occurrence of other treatment complications. Therefore, it is urgent to develop a more safe, convenient and effective surfactant sclerosing agent and its delivery system.

[0005] Tranexamic acid, also known as antihemophilic factor, has no damage to vascular endothelial cells and no sclerotherapy effect; it is a plasmin inhibitor that can bind to the lysine site of plasminogen, competitively block the conversion of plasminogen to plasmin, and then inhibit the degradation of fibrin, thereby stabilizing the thrombus and achieving the purpose of hemostasis. At the same time, tranexamic acid itself does not induce blood coagulation, but only inhibits the activity of plasminogen and plasmin, protects the thrombus that has been formed, and does not induce the risk of blood coagulation in non-target areas, with high safety (Taeuber I, Weibel S, et al. Association of Intravenous Tranexamic Acid With Thromboembolic Events and Mortality: A Systematic Review, Meta-analysis, and Meta-regression [J]. JAMA surgery, 2021, 156(6): e210884.).

[0006] Patent CN1365665A discloses a synergistic composition containing ascorbate and lysine for use in diseases associated with extracellular matrix degradation, to prevent and treat diseases associated with extracellular matrix degradation, including but not limited to degenerative diseases, particularly atherosclerosis, cancer, infection or other inflammatory diseases. In addition to lysine, proline, hydroxycinnamic acid and its derivatives and vitamins, provitamins and trace elements can also be used. Among them, tranexamic acid is just to take advantage of its property as a plasmin inhibitor; hydroxycinnamate is a well-known antioxidant, which uses its antioxidant properties to block free radical-mediated extracellular matrix degradation-related disease proliferation. SUMMARY

[0007] The present application is to overcome the defects of the existing surfactant sclerosing agent treatment mechanism, poor treatment effect, and many treatment complications, and provides a novel tranexamic acid-hydroxycinnamate ester conjugate. The carboxyl end of tranexamic acid is connected to the hydroxyl end of the 4 carbon atom of hydroxycinnamate ester by an ester bond to construct a novel compound with cationic surface activity. It can be used for sclerotherapy of venous diseases such as hemangioma and vascular malformation. The tranexamic acid-hydroxycinnamate ester conjugate and its self-delivery system provided by the present application have not been reported in the literature.

[0008] The inventors creatively found that the conjugate obtained by connecting tranexamic acid and hydroxycinnamate ester by an ester bond has a significant effect on vascular sclerotherapy. The mechanism of action of the tranexamic acid-hydroxycinnamate ester conjugate as a sclerosing agent is: damaging the vascular endothelial cell membrane, causing endothelial cell necrosis, inducing thrombus formation, and at the same time, the ester bond in the molecular structure is rapidly metabolized to release the original drug tranexamic acid, effectively exerting the effect of inhibiting fibrinolysis to further stabilize the thrombus, and ultimately causing the blood vessels to fibrosis, achieving the purpose of sclerotherapy. In addition, the introduction of the hydroxycinnamate structure can reduce the inflammatory response during treatment, thereby reducing the occurrence of complications and improving the safety of treatment. The tranexamic acid-hydroxycinnamate ester conjugate as a sclerosing agent has great potential for sclerotherapy of venous diseases.

[0009] The tranexamic acid-hydroxycinnamate ester conjugate also has excellent foaming properties and can be prepared into a stable foam preparation for administration. Without any other adjuvants, a self-delivery foam system of the drug can be formed, greatly reducing the potential side effects of non-pharmacologically active substances.

[0010] The primary object of the present application is to provide a novel compound structure of tranexamic acid-hydroxycinnamate ester conjugate or a pharmaceutically acceptable salt thereof.

[0011] The tranexamic acid-hydroxycinnamate ester conjugate or a pharmaceutically acceptable salt thereof has the following structure:

[0012]

[0013] wherein R1, R2 are H or OH; R3 is C1-C6 linear or branched alkyl, preferably R3 is C1-C6 linear alkyl; HA represents an acid.

[0014] The pharmaceutically acceptable salt of the tranexamic acid-hydroxycinnamate conjugate refers to an acid salt of the tranexamic acid-hydroxycinnamate conjugate formed by an inorganic acid or an organic acid. The inorganic acid or the organic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, benzenesulfonic acid, oxalic acid, succinic acid, citric acid, tartaric acid.

[0015] The present application provides a pharmaceutical composition comprising the tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof according to the present application and a pharmaceutically acceptable excipient. The tranexamic acid-hydroxycinnamate conjugate includes tranexamic acid-p-coumaric acid methyl ester conjugate, tranexamic acid-p-coumaric acid ethyl ester conjugate, tranexamic acid-p-coumaric acid propyl ester conjugate, tranexamic acid-p-coumaric acid butyl ester conjugate, tranexamic acid-p-coumaric acid pentyl ester conjugate, tranexamic acid-caffeic acid propyl ester conjugate, tranexamic acid-caffeic acid butyl ester conjugate, tranexamic acid-caffeic acid pentyl ester conjugate, tranexamic acid-caffeic acid hexyl ester conjugate, or a combination thereof.

[0016] The present application also provides the use of the tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same as a sclerosing agent in the treatment of venous diseases such as hemangioma, vascular malformation, varicose veins, etc.

[0017] The present application also provides a tranexamic acid-hydroxycinnamate conjugate foam preparation for treating venous diseases. When used, the tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof is dissolved in physiological saline to prepare a solution type injection at a mass fraction of 0.1%-9%, two syringes containing the above solution and air are connected by a three-way valve device, and the liquid-gas ratio is 1:3. The syringe piston is repeatedly pushed and pulled 60 times or more through the three-way valve to mix the liquid and gas until a stable and dense foam is formed.

[0018] The present application also provides a lyophilized injection of a tranexamic acid-hydroxycinnamate conjugate foam preparation for treating venous diseases. When used, the lyophilized foam preparation is dissolved in sterile water for injection or a specific solvent to prepare a foam dosage form by the Tessari method. The mass fraction of the tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof in the solution is 0.1%-9%. Preferably, the mass fraction is 0.8%-5%.

[0019] The specific solvent includes glycerol solution, 1,2-propanediol solution, PEG (molecular weight less than 1000) solution, mass fraction range is 0.1%-50%, preferably mass fraction range is 1%-10%.

[0020] In the above different dosage forms, the tranexamic acid-hydroxycinnamate conjugate used is a single compound of the tranexamic acid-hydroxycinnamate conjugate or a mixture of two or more compounds.

[0021] The application also provides a use of the tranexamic acid-hydroxycinnamate conjugate or the pharmaceutically acceptable salt thereof in the preparation of a foam or a freeze-dried injection as a sclerosing agent in the treatment of venous diseases such as hemangioma, vascular malformation, varicose veins and the like.

[0022] The application also provides a preparation method of the tranexamic acid-hydroxycinnamate conjugate or the pharmaceutically acceptable salt thereof, comprising the following steps:

[0023] Step one: alkyl alcohol is connected to the carboxyl end of hydroxycinnamic acid through Fischer esterification reaction to obtain hydroxycinnamate;

[0024] Step two: acyl chloride of tranexamic acid is connected to the hydroxyl group of the carbon atom at position 4 of the hydroxycinnamate through acylation reaction to obtain the tranexamic acid-hydroxycinnamate conjugate;

[0025] Step three: an acid is added to obtain the pharmaceutically acceptable salt of the tranexamic acid-hydroxycinnamate conjugate.

[0026] In step one, the solvent used for the esterification reaction of hydroxycinnamic acid is the corresponding alkyl alcohol in the reactants. The reaction is carried out under heating for 24h-36h.

[0027] The alkyl alcohol added in step one is alkyl alcohol with carbon chain C1-C6.

[0028] In step three, the acid used for the preparation of the tranexamic acid-hydroxycinnamate conjugate or the pharmaceutically acceptable salt thereof is selected from hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, benzenesulfonic acid, oxalic acid, succinic acid, citric acid and tartaric acid.

[0029] In summary, the advantages and positive effects of the present application are as follows: the tranexamic acid-p-coumaric acid ester conjugate is a cationic surfactant drug, has excellent foaming properties, and can be prepared into a foam preparation as a drug self-delivery system; it can effectively damage vascular endothelial cells and cause thrombosis; the tranexamic acid-p-coumaric acid ester conjugate has good in-vivo degradability, and the degradation produces tranexamic acid, p-coumaric acid or its ester, the tranexamic acid can effectively play a fibrinolytic inhibitory effect, stabilize the thrombus, and further promote the fibrosis process of the blood vessels, the p-coumaric acid or its ester helps to reduce the inflammatory reaction caused by the hardening treatment, reduces the side effects accompanying the hardening treatment, and improves the drug safety. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 is a synthesis schematic diagram of the tranexamic acid-p-coumaric acid ester conjugate in the present application;

[0031] Figure 2 is the nuclear magnetic resonance hydrogen spectrum of TA-pCa-1 in the present application;

[0032] Figure 3 is the mass spectrum of TA-pCa-1 in the present application;

[0033] Figure 4 is the nuclear magnetic resonance hydrogen spectrum of TA-pCa-2 in the present application;

[0034] Figure 5 is the mass spectrum of TA-pCa-2 in the present application;

[0035] Figure 6 is the nuclear magnetic resonance hydrogen spectrum of TA-pCa-3 in the present application;

[0036] Figure 7 is the mass spectrum of TA-pCa-3 in the present application;

[0037] Figure 8 is the nuclear magnetic resonance hydrogen spectrum of TA-pCa-4 in the present application;

[0038] Figure 9 is the mass spectrum of TA-pCa-4 in the present application;

[0039] Figure 10 is the nuclear magnetic resonance hydrogen spectrum of TA-pCa-5 in the present application;

[0040] Figure 11 is the mass spectrum of TA-pCa-5 in the present application;

[0041] Figure 12 is a morphological picture of the tranexamic acid-p-coumaric acid ester conjugate foam preparation in the present application;

[0042] Figure 13is the metabolic result of tranexamic acid-p-coumaric acid ester conjugate in plasma in the application;

[0043] Figure 14 is the cytotoxicity result of tranexamic acid-p-coumaric acid ester conjugate on human umbilical vein endothelial cells in the application; wherein A is the short-acting group test result, B is the long-acting group test result, ** p<0.01, *** p<0.001;

[0044] Figure 15 is the calcein release rate of tranexamic acid-p-coumaric acid ester conjugate acting on human umbilical vein endothelial cells in the application, *** p<0.001;

[0045] Figure 16 is the pharmacodynamic result of tranexamic acid-p-coumaric acid ester conjugate injected into the tail vein of mice in the application;

[0046] Figure 17 is the H&E staining result of main organs of mice treated with tranexamic acid-p-coumaric acid ester conjugate in the application;

[0047] Figure 18 is the determination result of coagulation function related indexes of mice treated with tranexamic acid-p-coumaric acid ester conjugate in the application;

[0048] Figure 19 is the synthesis schematic diagram of tranexamic acid-caffeic acid ester conjugate in the application;

[0049] Figure 20 is the nuclear magnetic resonance hydrogen spectrum of TA-CA3 in the application;

[0050] Figure 21 is the mass spectrum of TA-CA3 in the application;

[0051] Figure 22 is the nuclear magnetic resonance hydrogen spectrum of TA-CA4 in the application;

[0052] Figure 23 is the mass spectrum of TA-CA4 in the application;

[0053] Figure 24 is the nuclear magnetic resonance hydrogen spectrum of TA-CA5 in the application;

[0054] Figure 25 is the mass spectrum of TA-CA5 in the application;

[0055] Figure 26 is the nuclear magnetic resonance hydrogen spectrum of TA-CA6 in the application;

[0056] Figure 27 is the mass spectrum of TA-CA6 in the application;

[0057] Figure 28 This is a morphological picture of the tranexamic acid-caffeic acid ester conjugate foam preparation of the present invention;

[0058] Figure 29 It is the metabolic result of the tranexamic acid-caffeate conjugate of the present invention in plasma;

[0059] Figure 30 is the antioxidant capacity determination result of the tranexamic acid-caffeate conjugate of the present invention, *** p < 0.001;

[0060] Figure 31 The results of the cytotoxicity of tranexamic acid-caffeate conjugate to human umbilical vein endothelial cells are shown in Table 1. A is the test result of the 1-hour group, and B is the test result of the 12-hour group. *** p < 0.001;

[0061] Figure 32 is the calcein release rate of the tranexamic acid-caffeate conjugate of the present invention on human umbilical vein endothelial cells, *** p < 0.001;

[0062] Figure 33 This is the pharmacodynamic result of the tranexamic acid-caffeate conjugate injected into the tail vein of mice in the present invention;

[0063] Figure 34 These are the H&E staining results of the main organs of mice treated with tranexamic acid-caffeate conjugate in the present invention;

[0064] Figure 35 These are the results of measuring coagulation function-related indices in mice treated with the tranexamic acid-caffeate conjugate in the present invention. DETAILED DESCRIPTION

[0065] The following embodiments of the present invention are described in further detail with reference to the accompanying drawings and specific implementation methods. The following embodiments or drawings are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0066] Experimental reagents and instruments:

[0067] p-Coumaric acid (p-hydroxycinnamic acid), caffeic acid, anhydrous methanol, anhydrous ethanol, n-propanol, n-butanol, n-pentanol (Shanghai Aldrin Technology Co., Ltd., Shanghai, China); petroleum ether, diethyl ether, dichloromethane (Beijing Mai Rui Da Technology Co., Ltd., Beijing, China); column chromatography silica gel (Qingdao Marine Chemical Plant, Qingdao, China); tranexamic acid chloride (laboratory self-made); 1 mL disposable sterile syringe (Kangdeli Medical Instrument Co., Ltd., Zhejiang, China); disposable medical three-channel rotary valve (Weihai Jierui Medical Products Co., Ltd., Shandong, China); fetal bovine serum, trypsin, penicillin / streptomycin, DMEM medium (Corning, USA); CCK-8 kit, Calcein AM (Biouniverse Biotech Co., Ltd., Shanghai, China); 4% paraformaldehyde tissue fixative, H&E kit (Wuhan Saveer Biological Technology Co., Ltd., Wuhan, China).

[0068] Example 1

[0069] Synthesis of tranexamic acid-p-coumarate conjugate:

[0070] Tranexamic acid-p-coumarate conjugate, abbreviated as TA-pCa-n, wherein pCa-n represents p-coumarate, and n represents the number of carbon atoms in the alkyl alcohol that esterifies with p-coumaric acid. The present application takes n = 1, 2, 3, 4 and 5 as examples, and the synthesis process is as shown in Figure 1 The first step of the reaction is the synthesis of p-coumarate (pCa-n), and the method is as follows: 3.2 g of p-coumaric acid is dissolved in 50 mL of anhydrous methanol, 50 mL of anhydrous ethanol, 50 mL of n-propanol, 50 mL of n-butanol, and 50 mL of n-pentanol, respectively, and 0.405 g of p-toluenesulfonic acid is added as a catalyst. The reaction is carried out at a water bath temperature of 55°C, 60°C, 70°C, 75°C and 80°C, respectively, for 24 h. After the reaction is completed, most of the solvent is first rotary evaporated, and then extracted with diethyl ether and distilled water for several times. Then the organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, and then rotary evaporated to obtain the crude product. Petroleum ether is added to the crude product for slurry, and the solid component is taken out by filtration. This process is repeated three times to obtain the pure product (pCa-1, pCa-2, pCa-3, pCa-4, pCa-5).

[0071] The second step involved the synthesis of tranexamic acid-p-coumarate conjugates (TA-pCa-n). The method was as follows: 1.535 g of tranexamic acid chloride was mixed with 1.015 g of pCa-1, 1.084 g of pCa-2, 1.152 g of pCa-3, 1.288 g of pCa-4, and 1.544 g of pCa-5, respectively, using 30 mL of dichloromethane as the solvent. The mixture was stirred at room temperature for 8 hours, and the organic solvent was then rotary evaporated to obtain the crude product. The crude product was isolated and purified by column chromatography using C18 reverse-phase silica gel as the filler and a methanol / water system as the eluent, using a series of gradient elutions. The receiving solution containing the final product was rotary evaporated to obtain pure TA-pCa-n (TA-pCa-1, TA-pCa-2, TA-pCa-3, TA-pCa-4, and TA-pCa-5).

[0072] The results of H NMR and MS of tranexamic acid-p-coumarate conjugate are as follows Figures 2-11 As shown:

[0073] TA-pCa-1: 1 H NMR (600MHz, DMSO) δ8.23 (s, 2H), 7.81-7.74 (m, 2H), 7.66 (d, J = 16.0Hz,

[0074] 1H),7.21-7.11(m,2H),6.62(d,J=16.0Hz,1H),3.72(s,3H),2.65(p,J=4.2Hz,2H),2.65-2.51(m,1H),2.15-2 .05(m,2H),1.95-1.85(m,2H),1.69-1.59(m,1H),1.43(qd,J=13.0,3.5Hz,2H),1.06(qd,J=13.1,3.4Hz,2H).

[0075] MS (ESI) m / z: [M+H] + calcd for C 18 H 23 NO4 317.38,founded 318.1.

[0076] TA-pCa-2: 1H NMR (600 MHz, DMSO) δ 8.12 (s, 2H), 8.76 (s, 1H), 7.82-7.74 (m, 2H), 7.66 (d, J = 16.0 Hz, 1H), 7.21-7.13 (m, 2H), 6.62 (d, J = 16.1 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.71-2.64 (m, 2H), 2.64-2.52 (m, 1H), 2.16-2.06 (m, 2H), 1.95-1.85 (m, 2H), 1.62 (s, 1H), 1.44 (qd, J = 13.1, 3.4 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.19-1.03 (m, 2H).

[0077] MS (ESI) m / z: [M+H] + calcd for C 19 H 25 NO4 331.18, founded 332.2.

[0078] TA-pCa-3: 1 H NMR (600 MHz, DMSO) δ 8.15 (s, 2H), 7.83-7.75 (m, 2H), 7.66 (d, J = 16.0 Hz,

[0079] 1H), 7.21-7.14 (m, 2H), 6.63 (d, J = 16.0 Hz, 1H), 4.11 (t, J = 6.7 Hz, 2H), 2.66 (d, J = 6.9 Hz, 2H), 2.64-2.52 (m, 1H), 2.11 (dt, J = 13.6, 3.5 Hz, 2H), 1.95-1.77 (m, 2H), 1.66 (h, J = 7.2 Hz, 2H), 1.61 (s, 1H), 1.44 (qd, J = 13.0, 3.4 Hz, 2H), 1.07 (qd, J = 13.0, 3.5 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H).

[0080] MS (ESI) m / z: [M+H] + calcd for C 20 H 27 NO4 345.19, founded 346.2.

[0081] TA-pCa-4: 1 H NMR (600 MHz, DMSO) δ 8.16 (s, 2H), 7.82-7.74 (m, 2H), 7.65 (d, J = 16.0 Hz,

[0082] 1H), 7.21-7.07 (m, 2H), 6.62 (d, J = 16.0 Hz, 1H), 4.15 (t, J = 6.6 Hz, 2H), 2.66 (d, J = 6.9 Hz, 2H), 2.64-2.52 (m, 1H), 2.10 (dt, J = 14.1, 3.6 Hz, 2H), 1.95-1.84 (m, 2H), 1.62 (dq, J = 8.3, 6.7 Hz, 2H), 1.58-1.23 (m, 5H), 1.07 (qd, J = 13.0, 3.4 Hz, 2H), 0.96-0.80 (m, 3H).

[0083] MS (ESI) m / z: [M+H] + calcd for C 21 H 29 NO4 359.21, founded 360.2.

[0084] TA-pCa-5: 1 H NMR (600 MHz, DMSO) δ 8.21 (s, 2H), 7.82-7.74 (m, 2H), 7.65 (d, J = 16.0 Hz,

[0085] 1H), 7.21-7.07 (m, 2H), 6.62 (d, J = 16.0 Hz, 1H), 4.15 (t, J = 6.6 Hz, 2H), 2.66 (d, J = 6.9 Hz, 2H), 2.64-2.52 (m, 1H), 2.10 (dt, J = 14.1, 3.6 Hz, 2H), 1.95-1.84 (m, 2H), 1.62 (dq, J = 8.3, 6.7 Hz, 2H), 1.58-1.23 (m, 5H), 1.07 (qd, J = 13.0, 3.4 Hz, 2H), 0.96-0.80 (m, 3H).

[0086] MS (ESI) m / z: [M+H] + calcd for C 22 H 31 NO4 373.22, founded 374.2.

[0087] Example 2

[0088] Preparation and characterization of tranexamic acid-p-coumarate conjugate foam sclerosant:

[0089] The preparation method of the foaming agent is as follows: an appropriate amount of TA-pCa-n is weighed and configured into a 1% (w / v) saline solution, two 1 mL disposable syringes are selected, one is filled with 200 μL of the above solution, and the other is filled with 600 μL of air, the two syringes are connected to a three-way valve device in a liquid-air ratio of 1:3, and the syringe piston is repeatedly pushed and pulled at a speed of about 2.5 times per second for 60 times to obtain stable and dense foam. The foam state is shown in Figure 12 The microstructure of the foam is observed using an optical microscope, and TA-pCa-2, TA-pCa-3 and TA-pCa-4 are used as representatives.

[0090] Effect Example 1

[0091] Observation and evaluation of the comparison of the vascular sclerosis treatment effect of TA-pCa-n in mice:

[0092] The physiological saline group, TA-pCa-2, TA-pCa-3 and TA-pCa-4 sclerosing agent foam group are set up, and 6 KM mice are randomly selected from each group. The tail vein is used as the blood vessel model, and 60 μL of physiological saline, 1% TA-pCa-2, 1% TA-pCa-3 and 1% TA-pCa-4 sclerosing agent foam are injected into the tail vein of the mice using an insulin needle. The injection site is selected at the middle part of the left tail vein. Before and after administration, the changes of the tail vein at the injection site are observed under 0.5 W LED yellow light irradiation at 1 day, 4 days, 8 days and 15 days. During the whole process, the mice show normal appearance and good survival state. From the experimental results of the vascular sclerosis treatment in mice, it can be seen that the tranexamic acid-p-coumaric acid ester conjugate TA-pCa-n has very good sclerosis treatment effect, and all the experimental animals show good tolerance, indicating that it has good safety. The experimental results of the comparison of the sclerosis treatment effect are summarized in Table 1.

[0093] Table 1 Comparison of the vascular sclerosis treatment effect of TA-pCa-n in mice

[0094]

[0095] Effect Example 2

[0096] In vitro rat plasma metabolism:

[0097] LC-MS is used to determine the metabolism of TA-pCa-n in rat plasma in vitro: TA-pCa-4 is used as a representative, the physiological saline solution of TA-pCa-4 is mixed with rat plasma and incubated at 37°C, and samples are taken at different time points, 4 times the volume of methanol is added, and the supernatant is analyzed after centrifugation. The results are as follows: Figure 13As shown, TA-pCa-4 was rapidly hydrolyzed by relevant esterases in rat plasma and gradually metabolized to produce tranexamic acid, providing a theoretical basis for the subsequent tranexamic acid to exert fibrinolytic inhibition.

[0098] Effect Example 3

[0099] Cytotoxicity analysis:

[0100] Cytotoxicity of TA-pCa-4 was determined by CCK-8 method using human umbilical vein endothelial cells (HUVEC) as a model: TA-pCa-4 was selected as a representative. Cells were inoculated into 96-well plates at a density of 1×10 4 cells per well, and different concentrations of TA-pCa-4 (10, 25, 50, 75, 100, 150, 200, and 300 μg / mL) were added after adhesion. Short-acting and long-acting groups were set up at the same concentration gradient. The incubation time of the short-acting group with cells was 1 h, and the incubation time of the long-acting group with cells was 12 h. Then, the cell survival rate was determined according to the CCK-8 instruction method. As shown in Figure 14 Figure 14 A is the short-acting group. The cytotoxicity of TA-pCa-4 showed a concentration-dependent effect, and there was obvious cell damage at high concentrations, indicating that TA-pCa-4 can be adsorbed on the cell surface through electrostatic interaction after connecting the tranexamic acid cationic group and quickly kill the cells. Figure 14 B is the long-acting group. The cytotoxicity of the long-acting group showed a good survival rate at a concentration lower than 50 μg / mL, indicating that TA-pCa-4 almost does not damage cells and has high safety under blood dilution to low concentration in blood vessels and in a long acting time.

[0101] Effect Example 4

[0102] Cell damage mechanism investigation:

[0103] The cell damage mechanism of TA-pCa-4 was investigated by Calcein AM release method using human umbilical vein endothelial cells (HUVEC) as a model: TA-pCa-4 was selected as a representative. Cells were inoculated into 24-well plates at a density of 5×10 4 cells per well, Calcein AM was added after adhesion, and incubated at 37℃ for 2 h. Different concentrations of TA-pCa-4 were added after the old culture medium was discarded, and incubated at 37℃ for 30 min. The supernatant was measured for fluorescence intensity at Ex / Em: 494 nm / 517 nm. The blank group was not treated with drugs, and the ethanol-treated group was the positive control. The release rate of Calcein AM was calculated. The higher the release rate, the stronger the damage to the cell membrane. As shown in Figure 15 ​As shown, it is indicated that TA-pCa-4 can kill cells by damaging the cell membrane, and at the same time, due to its cationic surfactant property, it has stronger membrane damage effect.

[0104] Effect Example 5

[0105] Evaluation of vascular sclerosis treatment effect in vivo:

[0106] Select 8-10 weeks old, 22g-25g weight Kunming mice, 6 in each group, inject equal volume of normal saline solution and 1% concentration TA-pCa-4 sclerosing agent foam into the tail vein of the mice, 15 days after administration, take photos of the mouse tail shape under 1W white light, and slice the mouse tail administration site, observe the histological changes by H&E staining. As shown in Figure 16 The tail shape of the foam group and the normal saline group is good, and the tail vein of the normal saline group is still clear, while the blood vessels of the foam administration site are not visible, and the H&E staining results show that the blood vessels of the foam administration site have fibrosis and complete occlusion of the lumen. The above pharmacodynamic experiment proves the effectiveness of TA-pCa-n prepared by the method of the application in the sclerotherapy of hemangioma and venous malformation.

[0107] Effect Example 6

[0108] Safety evaluation in vivo:

[0109] Select 8-10 weeks old, 22g-25g weight Kunming mice, 6 in each group, inject equal volume of normal saline solution and 1% concentration TA-pCa-4 sclerosing agent foam into the tail vein of the mice, 15 days after administration, euthanize the mice, collect the heart, liver, spleen, lung, kidney for H&E staining, collect blood and separate plasma for detection of activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT) and fibrinogen (FIB). As shown in Figure 17 The main organs of the mice did not show obvious pathological changes and other abnormalities, and there was no obvious thrombosis. As shown in Figure 18 The coagulation function related indexes of the mice in the foam group were not significantly different from those in the normal saline group, and were within the normal range. The above experimental results show that the tranexamic acid-p-coumarate conjugate sclerosing agent has good biocompatibility and biosafety.

[0110] Example 3

[0111] Synthesis of tranexamic acid-coffee acid ester conjugate:

[0112] Tranexamic acid-coffee acid ester conjugate, abbreviated as TA-CAn, wherein CAn represents coffee acid ester, and n represents the number of carbon atoms in the alkyl alcohol esterified with coffee acid. The synthesis process is shown in Figure 19 The total reaction is divided into two steps. The first step is the synthesis of coffee acid ester (CAn), which is as follows: 10 g of coffee acid is dissolved in 60 mL of n-propanol, n-butanol, n-pentanol and n-hexanol, 0.1 g of p-methylbenzenesulfonic acid is added, and the reaction is carried out at 80°C for 48 h. After the reaction is completed, multiple extractions are carried out using diethyl ether and distilled water, and then the organic phase is washed with 5% NaHCO3 and saturated brine, dried with anhydrous sodium sulfate, and then allowed to stand to obtain the crude product. The crude product is then purified by slurry with petroleum ether, and then filtered to obtain the pure product (CA3, CA4, CA5, CA6).

[0113] The second step is the synthesis of tranexamic acid-coffee acid ester conjugate (TA-CAn), which is as follows: 1.2 g of tranexamic acid chloride is mixed with 1.88 g of CA3, 2.01 g of CA4, 2.12 g of CA5, and 2.24 g of CA6, respectively, using 30 mL of dichloromethane as the solvent, and the reaction is carried out at 30°C for 5 h. The organic solvent is then removed by rotary evaporation to obtain the crude product. The crude product is then separated and purified by column chromatography, using C18 as the filler and a water / methanol system as the eluent. The eluent containing the final product is then rotary evaporated to obtain the pure product (TA-CA3, TA-CA4, TA-CA5, TA-CA6).

[0114] The results of the nuclear magnetic resonance hydrogen spectrum and mass spectrum of the tranexamic acid-coffee acid ester conjugate are shown in Figures 20-27

[0115] TA-CA3: 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.03 (brs, 3H), 7.54 (d, J = 16.0 Hz,

[0116] 1H), 7.47-7.39 (m, 2H), 6.98 (d, J = 8.1 Hz, 1H), 6.44 (d, J = 16.0 Hz, 1H), 4.07 (t, J = 6.7 Hz, 2H), 2.67 (d, J = 6.7 Hz, 2H), 2.54 (tt, J = 121, 3.2 Hz, 1H), 2.16-2.06 (m, 2H), 1.94-1.86 (m, 2H), 1.64 (h, J = 7.1 Hz, 2H), 1.44 (qd, J = 13.3, 3.6 Hz, 2H), 1.07 (qd, J = 13.0, 3.5 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H). ​

[0117] MS (ESI) m / z: [M-H] - calcd for C 20 H 27 NO5 361.19, founded 362.2.

[0118] TA-CA4: 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.09 (br s, 3H), 7.53 (d, J = 15.9 Hz,

[0119] 1H), 7.45 - 7.38 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.43 (d, J = 15.9 Hz, 1H), 4.11 (t, J = 6.6 Hz, 2H), 2.66 (d, J = 6.8 Hz, 2H), 2.53 (tt, J = 12.1, 3.3 Hz, 1H), 2.14 - 2.04 (m, 2H), 1.92 - 1.85 (m, 2H), 1.65 - 1.55 (m, 2H), 1.43 (qd, J = 13.1, 3.0 Hz, 2H), 1.36 (m, 2H), 1.07 (qd, J = 13.1, 3.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 4H).

[0120] MS (ESI) m / z: [M-H] - calcd for C 21 H 29 NO5 375.20, founded 376.3.

[0121] TA-CA5: 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.11 (br s, 3H), 7.52 (d, J = 15.9 Hz,

[0122] 1H), 7.47 - 7.37 (m, 2H), 7.01 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 16.0 Hz, 1H), 4.10 (t, J = 6.6 Hz, 2H), 2.70 - 2.61 (m, 2H), 2.53 (tt, J = 12.0, 3.3 Hz, 1H), 2.13 - 2.06 (m, 2H), 1.92 - 1.85 (m, 2H), 1.66 - 1.55 (m, 2H), 1.43 (qd, J = 13.1, 3.4 Hz, 2H), 1.33 - 1.28 (m, 3H), 1.07 (qd, J = 13.0, 3.4 Hz, 2H), 0.87 (t, J = 7.1 Hz, 3H).

[0123] MS (ESI) m / z: [M-H]- - calcd for C 22 H 31 NO5 389.22, founded 390.2.

[0124] TA-CA6: 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.05 (brs, 4H), 7.53 (d, J = 15.9 Hz,

[0125] 1H), 7.45 - 7.39 (m, 2H), 6.99 (d, J = 8.2 Hz, 1H), 6.44 (d, J = 15.9 Hz, 1H), 4.10 (t, J = 6.6 Hz, 2H), 2.66 (d, J = 6.7 Hz, 2H), 2.59 - 2.51 (m, 1H), 2.14 - 2.05 (m, 2H), 1.92 - 1.85 (m, 2H), 1.67 - 1.55 (m, 2H), 1.44 (qd, J = 13.1, 3.4 Hz, 2H), 1.07 (qd, J = 13.0, 3.4 Hz, 2H), 0.86 (t, J = 6.8 Hz, 3H).

[0126] MS (ESI) m / z: [M-H]- - calcd for C 23 H 33 NO5 403.24, founded 404.3.

[0127] Example 4

[0128] Preparation and characterization of tranexamic acid-coffee acid ester conjugate foam sclerosant:

[0129] The preparation method of the foam is as follows: an appropriate amount of TA-CAn is weighed and configured into a 5% (w / v) physiological saline solution, two 1 mL disposable syringes are selected, one is filled with 200 μL of the above solution, and the other is filled with 600 μL of air, the two syringes are connected to a three-way valve device in a liquid-air ratio of 1:3, and the piston of the syringe is repeatedly pushed and pulled at a speed of about 2 times per second for 40 times, to obtain stable and dense foam. The foam state is as shown in Figure 28 TA-CA3, TA-CA4 and TA-CA5 are taken as representatives, and the microstructure of the foam is observed using an optical microscope.

[0130] Effect Example 7

[0131] Comparison and observation evaluation of the vascular sclerosis treatment effect of TA-CAn in mice:

[0132] The physiological saline group, TA-CA3, TA-CA4 and TA-CA5 sclerosing agent foam group were set up, and 6 KM mice were randomly selected from each group. The tail vein was used as the blood vessel model, and 20 μL of physiological saline, 5% TA-CA3, 5% TA-CA4 and 5% TA-CA5 sclerosing agent foam were injected by insulin needle. The injection site was selected at the middle part of the left tail vein. Before and after administration, the changes of the tail vein at the injection site were observed under 0.5 W LED yellow light irradiation at 1 day, 6 days, 9 days and 20 days. During the whole process, the mouse tail appeared normal, and the mouse survival state was good. It can be seen from the results of the vascular sclerosis treatment experiment in mice that the tranexamic acid-coffee acid ester conjugate TA-CAn has very good sclerosis treatment effect, and all experimental animals show good tolerance, indicating that it has good safety. The results of the comparison observation of sclerosis treatment effect are summarized in Table 2.

[0133] Table 2 Comparison observation results of TA-CAn mouse in vivo vascular sclerosis treatment effect

[0134]

[0135] Effect Example 8

[0136] In vitro rat plasma metabolism:

[0137] LC-MS was used to determine the metabolism of TA-CA5 in rat plasma in vitro: TA-CA5 was selected as a representative, and the physiological saline solution of TA-CA5 was mixed with rat plasma and incubated at 37°C. Samples were taken at different time points, and 4 times the volume of methanol was added. After centrifugation, the supernatant was sampled and analyzed. As shown in Figure 29 , TA-CA5 was rapidly hydrolyzed under the action of related esterases in rat plasma and gradually metabolized to produce tranexamic acid, providing a theoretical basis for the subsequent tranexamic acid to play a fibrinolytic inhibition role.

[0138] Effect Example 9

[0139] Antioxidant capacity determination:

[0140] Prussian blue method was used to determine the reducing capacity of TA-CA5: TA-CA5 was selected as a representative, and CA5 and caffeic acid (Caffeic acid, CA) were used as controls. Potassium ferricyanide solution was mixed with different concentrations of caffeic acid, CA5 and TA-CA5 sample solution, and an appropriate amount of phosphate buffer was added. Incubate at 50°C for 20 min, then add trichloroacetic acid and ferric chloride in turn, and measure the absorbance at 700 nm after standing for 10 min. The stronger the reducing capacity of the sample, the higher the absorbance. As shown in Figure 30As shown, the absorbance of the three compound treatment groups showed a concentration-dependent manner, and as the concentration increased, there was no significant difference in the absorbance between the CA5 treatment group and the caffeic acid treatment group, and the TA-CA5 treatment group showed a slight decrease but still maintained a high level, indicating that TA-CA5 still had strong reducing ability and could efficiently play an antioxidant role.

[0141] Effect Example 10

[0142] Cytotoxicity analysis:

[0143] Using human umbilical vein endothelial cells (HUVEC) as a model, the cytotoxicity of TA-CA5 was determined by CCK-8 method: cells were seeded into 96-well plates at a density of 1 x 10 4 cells per well, and after adhering, different concentrations of TA-CA5 were added, and different incubation times were set for the experiment, one group for 1 h and the other group for 12 h, and then the cell survival rate was determined according to the CCK-8 instruction method. As shown in Figure 31 Figure 31 A is the 1 h group, and the cytotoxicity of TA-CA5 shows a concentration-dependent manner, with obvious cell damage at high concentrations, indicating that TA-CA5 can be adsorbed on the cell surface through electrostatic interaction after connecting the tranexamic acid cationic group and quickly kill the cells. Figure 31 B is the 12 h group, and the cytotoxicity of low concentration does not increase significantly with time, indicating that low concentration of TA-CA5 almost does not damage the cells and has high safety in a longer action time.

[0144] Effect Example 11

[0145] Cell damage mechanism investigation:

[0146] Using human umbilical vein endothelial cells (HUVEC) as a model, the cell damage mechanism of TA-CA5 was investigated by calcein release method: cells were seeded into 24-well plates at a density of 5 x 10 4 cells per well, and after adhering, Calcein AM was added, incubated at 37℃ for 2 h, and then the old culture medium was discarded and 50 μg / mL, 100 μg / mL, and 150 μg / mL of TA-CA5 were added, incubated at 37℃ for 30 min, and the supernatant was measured for fluorescence intensity at Ex / Em: 494 nm / 517 nm. The blank group was not treated with drugs, and the ethanol-treated group was the positive control. The calcein release rate was calculated, and the higher the release rate, the stronger the damage to the cell membrane. As shown in Figure 32 , the calcein release rate of 150 μg / mL TA-CA5 was significantly higher than that of 50 μg / mL and 100 μg / mL, indicating that high concentration of TA-CA5 can kill cells by damaging the cell membrane, and due to its cationic surfactant properties, it has strong membrane damage effect.​

[0147] Example 12

[0148] Evaluation of the effect of in vivo vascular sclerosis treatment:

[0149] Select 8-10 weeks old, weight 22g-25g Kunming mice, 6 in each group, respectively, inject equal volume of physiological saline solution and 5% concentration of TA-CA5 sclerosing agent foam into the tail vein of the mice, 20 days after administration, take photos of the mouse tail shape under 1W white light, and slice the mouse tail administration site, observe the histological changes by H&E staining. As shown in Figure 33 , the tail shape of the foam group and the physiological saline group remains good, the physiological saline group still has a clear tail vein, and the blood vessels of the administration site of the foam group disappear, and the H&E staining results show that the blood vessels of the administration site of the foam group have fibrosis and the lumen is completely occluded. The above pharmacodynamic experiment proves the effectiveness of TA-CAn prepared by the method of the application in the sclerotherapy of hemangioma and venous malformation.

[0150] Example 13

[0151] Evaluation of in vivo safety:

[0152] Select 8-10 weeks old, weight 22g-25g Kunming mice, 6 in each group, respectively, inject equal volume of physiological saline solution and 5% concentration of TA-CA5 sclerosing agent foam into the tail vein of the mice, 20 days after administration, euthanize the mice, collect the heart, liver, spleen, lung, kidney for H&E staining, collect blood and separate plasma for detection of activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT) and fibrinogen (FIB). As shown in Figure 34 , the main organs of the mice did not show obvious pathological changes and other abnormalities, and there was no obvious thrombosis. As shown in Figure 35 , the coagulation function related indexes of the mice in the foam group had no significant difference with those in the physiological saline group, and were within the normal range. The above experimental results show that the tranexamic acid-coffee acid ester conjugate sclerosing agent has good biocompatibility and biological safety.

[0153] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof, characterized in that: The structure is as follows: Wherein, R1 and R2 are H or OH; R3 is a C1-C6 straight chain or branched alkyl group; and HA represents an acid.

2. The tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salt of the tranexamic acid-hydroxycinnamate conjugate refers to an acid salt formed by the tranexamic acid-hydroxycinnamate conjugate and an inorganic acid or an organic acid, wherein the inorganic acid or the organic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, benzenesulfonic acid, oxalic acid, succinic acid, citric acid, and tartaric acid.

3. A method for preparing the tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The steps include: Step 1: alkyl alcohol is connected to the carboxyl end of hydroxycinnamic acid through Fischer esterification reaction to obtain hydroxycinnamate; Step 2: connecting tranexamic acid chloride to the hydroxyl group of the 4-carbon atom of hydroxycinnamate through an acylation reaction to obtain a tranexamic acid-hydroxycinnamate conjugate; Step 3: Add acid to obtain a pharmaceutically acceptable salt of the tranexamic acid-hydroxycinnamate conjugate.

4. A pharmaceutical composition, characterized in that The invention comprises the tranexamic acid-hydroxycinnamate conjugate according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

5. The pharmaceutical composition according to claim 4, characterized in that The tranexamic acid-hydroxycinnamate conjugate includes tranexamic acid-methyl p-coumarate conjugate, tranexamic acid-ethyl p-coumarate conjugate, tranexamic acid-propyl p-coumarate conjugate, tranexamic acid-butyl p-coumarate conjugate, tranexamic acid-pentyl p-coumarate conjugate, tranexamic acid-propyl caffeate conjugate, tranexamic acid-butyl caffeate conjugate, tranexamic acid-pentyl caffeate conjugate, tranexamic acid-hexyl caffeate conjugate or a combination thereof.

6. Use of the tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof according to claim 1 or 2, or the pharmaceutical composition according to claim 4 or 5, in the preparation of a sclerosing agent.

7. Use of the tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof according to claim 1 or 2, or the pharmaceutical composition according to claim 4 or 5, in the preparation of a medicament for treating hemangiomas, varicose veins and vascular malformations.

8. A tranexamic acid-hydroxycinnamate conjugate foam preparation for treating venous diseases, characterized in that: The foam is prepared using the tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof according to claim 1 or 2. When used, the tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof is dissolved in physiological saline to prepare a solution. Two syringes containing the solution and air, respectively, are connected by a three-way valve device. The syringe pistons are repeatedly pushed and pulled through the three-way valve to mix gas and liquid to form a stable and dense foam. The mass fraction of the tranexamic acid-hydroxycinnamate conjugate or a pharmaceutically acceptable salt thereof in the solution is 0.1%-9%.

9. A freeze-dried injection of the tranexamic acid-hydroxycinnamate conjugate foam preparation for treating venous diseases according to claim 8, characterized in that: When used, the freeze-dried foam preparation is dissolved in sterile water for injection or a specific solvent and prepared into a foam dosage form for administration by the Tessari method; the specific solvents include glycerol solution, 1,2-propylene glycol solution, and PEG solution; the mass fraction of the tranexamic acid-hydroxycinnamate conjugate or its pharmaceutically acceptable salt in the solution is 0.1%-9%.

10. Use of the tranexamic acid-hydroxycinnamate conjugate foam preparation for treating venous diseases according to claim 8 or the lyophilized injection of the tranexamic acid-hydroxycinnamate conjugate foam preparation for treating venous diseases according to claim 9 in the preparation of a medicament for treating hemangioma, varicose veins, and vascular malformation.

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