Application of ascorbic acid fatty acid ester compound or composition thereof in sclerotherapy

Abstract

The invention discloses application of an ascorbic acid fatty acid ester compound or a composition thereof in sclerotherapy, and belongs to the technical field of medicines.The ascorbic acid fatty acid ester hardener is a non-ionic surfactant medicine, and the anti-sclerotic effect is achieved by effectively damaging vascular endothelial cells, inducing thrombogenesis and promoting vascular fibrosis. Therefore, the angiosclerosis treatment is realized; the ascorbic acid fatty acid ester has excellent foaming property and can be prepared into a stable drug self-delivery system with a vascular replacement function. Compared with a traditional hardening agent, the compound has light inflammatory response and lower tissue toxicity, and a safe and effective new choice is provided for clinical angiosclerosis treatment.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a preparation method of an ascorbic acid fatty acid ester compound or a composition thereof and an application thereof in sclerotherapy. Background Art

[0002] Vascular diseases have long been a major challenge in clinical medicine. Hemangiomas, varicose veins, and vascular malformations, as the most common vascular diseases, have complex pathogenesis and diverse clinical manifestations. From a pathophysiological perspective, the core issue of these diseases lies in abnormal endothelial function. Hemangiomas are mainly manifested by excessive proliferation of endothelial cells; varicose veins are typically characterized by weak venous walls, valve failure, and blood reflux leading to varicose veins; and vascular malformations are more often manifested by developmental defects in vascular structure. These abnormalities not only lead to changes in local tissue hemodynamics but can also cause a range of complications, including pain, functional impairment, and even life-threatening bleeding or embolic events, seriously impacting patients' quality of life. The latest epidemiological research data show that venous malformations are the most common vascular malformation diseases, accounting for more than 70%, and are usually present at birth and increase proportionally with age.

[0003] Modern medicine has developed a variety of intervention methods, including pressure therapy, surgical treatment, sclerotherapy, etc. Pressure therapy, as the most conservative method, mainly improves symptoms by mechanically compressing the lesion site to promote local blood circulation, but it is difficult to achieve a radical cure. Currently, pressure therapy is often used as an auxiliary means to relieve discomfort after treatment. Although surgical treatment can directly remove the lesion, it is difficult to achieve a radical cure because the boundary between the lesion tissue and normal tissue is often unclear. In contrast, sclerotherapy is simple to operate, less invasive, effective, and highly reproducible, and has gradually become the preferred clinical option. Sclerotherapy is an interventional treatment method that directly injects liquid or foam sclerosing drugs into the diseased blood vessels to induce endothelial damage, thrombosis, and ultimately fibrosis. Sclerotherapy is relatively simple to operate, has low requirements on the patient's physical condition, is less invasive, has a fast recovery, can reduce patient pain and reduce the economic burden, so sclerotherapy has now become the first-line treatment method in clinical practice.

[0004] From a pharmaceutical perspective, sclerosants have evolved through several generations. Early osmotic sclerosants, such as hypertonic saline, were rarely used due to their significant non-selective damaging effects upon administration, often causing severe pain and tissue necrosis. Chemical sclerosants, such as sodium morrhuate, carry a significant risk of systemic toxicity. Surfactant sclerosants are currently widely used clinically. These agents offer enhanced safety. Due to their surface activity, they can be formulated as foams, reducing the dosage while increasing drug retention within the blood vessels. However, these agents still present several unresolved technical challenges. First, existing formulations often rely on exogenous stabilizers to maintain foam stability, which not only increases formulation complexity but also introduces safety concerns. Second, based on their mechanism of action, drug damage to the endothelium of affected vessels can easily lead to adverse reactions such as inflammation. More importantly, the long-term efficacy of existing drugs remains unsatisfactory, with a high recurrence rate, closely related to the fact that most of these drugs fail to effectively promote complete vascular fibrosis.

[0005] Ascorbic acid derivatives, a class of compounds with unique biological activities, have shown broad application prospects in the pharmaceutical field in recent years. In particular, ascorbic acid fatty acid esters, by introducing a fatty acid chain at the 6th carbon atom of ascorbic acid, enhance their lipid solubility and stability. While retaining the biological activity of the ascorbic acid nucleus, their esterification significantly improves their physical and chemical properties.

[0006] Ascorbic acid fatty acid ester compounds have the following advantages:

[0007] (1) The molecular structure has both hydrophilic and hydrophobic groups, showing excellent surface activity;

[0008] (2) Good compatibility with biofilm and high safety;

[0009] (3) Good foaming properties, no need to add other exogenous stabilizers to prepare excellent foam;

[0010] (4) By adjusting the length of fatty acid chains, their physical and chemical properties can be controlled, thereby finding suitable compounds for sclerotherapy.

[0011] Ascorbic acid fatty acid esters are widely used in food, cosmetics, and other fields, but their use in the treatment of vascular diseases, particularly as sclerosing agents, has yet to be systematically studied. Based on this background, the present invention, through in-depth research and extensive experiments, has for the first time discovered that ascorbic acid fatty acid esters with a specific structure possess unique advantages as nonionic surfactants in the treatment of vascular sclerotherapy. This discovery not only overcomes the shortcomings of existing sclerosing agents, providing an innovative solution for sclerotherapy, but also opens up new research directions for the treatment of vascular diseases. Summary of the Invention

[0012] To overcome the problems of limited sclerosing agent types, unstable therapeutic effects, and significant side effects in the field of vascular sclerotherapy, the present invention innovatively provides a new ascorbic acid fatty acid ester compound and its use as a foam sclerosing agent. Ascorbic acid fatty acid ester is abbreviated as ascorbic acid ester. Its structure is an ester bond in which a fatty chain is introduced into the C6 hydroxyl group of the ascorbic acid molecule. The obtained ascorbic acid ester is prepared by the Tessari method (Tessari L, Cavezzi A, Frullini A. Preliminary experience with a new sclerosing foam in the treatment of varicose veins [J]. Dermatologic surgery: official publication for American Society for Dermatologic Surgery [et al], 2001, 27 (1): 58-60.) to prepare a stable ascorbic acid ester foam sclerosing agent with vascular replacement function for sclerotherapy of hemangiomas, varicose veins, and venous malformations.

[0013] The ascorbic acid ester studied in this study cleverly combines a pharmacologically active group (ascorbic acid) with a hydrophobic carrier (a fatty acid chain) in its molecular structure. Without the addition of any surfactants, foam stabilizers, or other pharmaceutical excipients, it can be formulated into a stable drug delivery system with vascular replacement capabilities. This innovation not only fundamentally addresses the allergic reactions and other issues associated with traditional sclerosants due to their reliance on other excipients, but also significantly reduces the side effects associated with non-pharmacologically active substances, providing a safer, more efficient, and more economical option for clinical application.

[0014] The primary purpose of the present invention is to provide an ascorbic acid fatty acid ester compound, referred to as ascorbic acid ester. The ascorbic acid ester has the following structure:

[0015]

[0016] n=1-10, preferably n=3-8.

[0017] The ascorbic acid ester of the present invention introduces a fatty chain into the C6 hydroxyl group of the ascorbic acid molecule via an ester bond, wherein the fatty acid chain is a straight-chain alkyl with a carbon chain length of C4-C9.

[0018] Preferably, the fatty acid chain of the ascorbic acid ester is a straight chain alkyl group with a carbon chain length of C6-C8.

[0019] The present invention provides a pharmaceutical composition comprising the ascorbic acid ester or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Preferably, the ascorbic acid fatty acid ester is amyl ascorbate, hexyl ascorbate, heptyl ascorbate, octyl ascorbate, nonyl ascorbate, decyl ascorbate, or a combination thereof.

[0020] The present invention also provides use of the ascorbic acid ester or its pharmaceutically acceptable salt or the pharmaceutical composition as a sclerosing agent in sclerotherapy.

[0021] The present invention also provides use of the ascorbic acid ester or its pharmaceutically acceptable salt or the pharmaceutical composition in preparing drugs for treating hemangiomas, varicose veins and vascular malformations.

[0022] The pharmaceutically acceptable excipients of the present invention include but are not limited to foam stabilizers (foam stabilizers), isotonic regulators, pH buffers, antioxidants, local anesthetics, and surfactants, wherein the foam stabilizer is one or a mixture of any proportion of two or more of glycerol (Gly), polyethylene glycol (PEG), ethanol (EtOH), and 1,2-propylene glycol (PG).

[0023] An ascorbic acid ester foam preparation for sclerotherapy. During the sclerotherapy process, ascorbic acid ester is dissolved in normal saline, and two medical syringes containing the ascorbic acid ester solution and air, respectively, are connected through a medical three-way valve. The syringe pistons are repeatedly pushed and pulled 40 times at a liquid-to-gas ratio of 1:3 to fully mix the solution and gas between the two syringes, thereby obtaining a uniform and stable foam.

[0024] The mass volume concentration (w / v) of ascorbic acid ester in the prepared ascorbic acid ester solution is 0.1%-10%, preferably 1%-4%.

[0025] The invention relates to a freeze-dried injection of an ascorbic acid ester foam preparation for sclerotherapy. 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.

[0026] The mass volume concentration (w / v) of ascorbic acid ester in the prepared ascorbic acid ester solution is 0.1%-10%, preferably 1%-4%.

[0027] The specific solvents of the present invention include glycerol solution and 1,2-propylene glycol solution, and their mass volume concentration (w / v) is 0.1%-55%, preferably 5%-40%.

[0028] In the above different dosage forms, the ascorbic acid ester is a single compound of ascorbic acid ester or a mixture of multiple different compounds in any proportion. Different compounds refer to ascorbic acid esters containing fatty acid chain structures of different lengths.

[0029] The present invention also provides application of a foam hardener prepared from ascorbic acid fatty acid ester in hardening therapy.

[0030] The mass volume concentration (w / v) of the foam hardener prepared from ascorbic acid ester of the present invention is in the range of 0.1% to 10%, preferably in the range of 1% to 4%.

[0031] The present invention also provides a method for preparing ascorbic acid ester, comprising the following steps:

[0032] Step 1: Add the solvent and ascorbic acid to the reaction system under stirring in an ice bath;

[0033] Step 2: Slowly add n-alkyl acyl chloride dropwise under stirring in an ice bath. After the addition is complete, heat to 25°C and continue the reaction.

[0034] Step 3: After the reaction is completed, extract, wash, and dry to obtain a crude product;

[0035] Step 4: Separate and purify the crude product to obtain ascorbic acid ester.

[0036] In step 1, N,N-dimethylacetamide and dichloromethane are used as a mixed solvent, ice-bathed for 30-40 minutes, ascorbic acid is added, and stirred until the solution system is clear.

[0037] In step 2, the carbon chain length of the alkyl group in the n-alkyl acyl chloride is C4-C9.

[0038] In step 4, the crude product is purified by column chromatography. The chromatography column is filled with silica gel, and the eluent is a petroleum ether / ethyl acetate system with the addition of 1% glacial acetic acid. The target compound is not easy to elute, so 1% glacial acetic acid is added to the eluent to enhance the elution ability.

[0039] Positive effects of the present invention:

[0040] The ascorbic acid fatty acid ester sclerosant disclosed in this invention is a nonionic surfactant with excellent foam stability. It can be formulated into a stable self-delivery drug system with vascular replacement function. Compared with traditional sclerosants, it has a milder inflammatory response and lower tissue toxicity, providing a safe and effective new option for the clinical treatment of vascular sclerotherapy.

[0041] 2. The ascorbic acid ester disclosed in the present invention breaks through the limitations of traditional sclerosing agents, is significantly innovative, provides more options for the treatment of vascular sclerotherapy, and fills the gap in the field of ascorbic acid ester foam sclerosing agents.

[0042] 3. Ascorbic acid ester foam sclerosant significantly reduces fluid usage and is safer than liquid sclerosant injections. It effectively damages vascular endothelial cells, promotes thrombosis, and induces vascular fibrosis and closure, thereby achieving vascular sclerotherapy. It is suitable for sclerotherapy of hemangiomas, varicose veins, and venous malformations, with a high success rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 Schematic diagram of the synthesis of the ascorbyl ester hardener of the present invention;

[0044] Figure 2 is the hydrogen nuclear magnetic resonance spectrum of AA5 in the present invention;

[0045] Figure 3 is the mass spectrum of AA5 in the present invention;

[0046] Figure 4 is the hydrogen nuclear magnetic resonance spectrum of AA6 in the present invention;

[0047] Figure 5 is the mass spectrum of AA6 in the present invention;

[0048] Figure 6 is the hydrogen nuclear magnetic resonance spectrum of AA7 of the present invention;

[0049] Figure 7 is the mass spectrum of AA7 in the present invention;

[0050] Figure 8 is the hydrogen nuclear magnetic resonance spectrum of AA8 in the present invention;

[0051] Figure 9 is the mass spectrum of AA8 in the present invention;

[0052] Figure 10 is the hydrogen nuclear magnetic resonance spectrum of AA9 in the present invention;

[0053] Figure 11 is the mass spectrum of AA9 in the present invention;

[0054] Figure 12 is the hydrogen nuclear magnetic resonance spectrum of AA10 in the present invention;

[0055] Figure 13 is the mass spectrum of AA10 in the present invention;

[0056] Figure 14 is the measurement result of the critical micelle concentration of ascorbic acid ester in the present invention;

[0057] Figure 15 is the result of the ascorbate π-A isotherm measurement in the present invention;

[0058] Figure 16 is a curve showing the change of static elasticity of the ascorbic acid ester monomolecular film with surface pressure in the present invention;

[0059] Figure 17 This is a morphological diagram of the ascorbic acid ester foam preparation of the present invention;

[0060] Figure 18 is the particle size measurement result of the ascorbic acid ester foam preparation in the present invention;

[0061] Figure 19 is the result of measuring the water bleeding time of the ascorbic acid ester foam preparation of the present invention;

[0062] Figure 20 is the half-life measurement result of the ascorbic acid ester foam preparation of the present invention;

[0063] Figure 21 The results of the hemolysis test of ascorbic acid ester in the present invention are shown in FIG. 1 , wherein (a) the results of the hemolysis test at different concentrations are shown, and (b) the results of the hemolysis rate determination at different concentrations are shown. *** p < 0.001;

[0064] Figure 22 These are the morphological images and pseudo-color images of laser speckle blood flow imaging of mice before tail vein injection and 6 hours, 2 days, 5 days, 10 days, 15 days, and 20 days after injection of normal saline (NS) and ascorbic acid ester (Foam) in the present invention; (a) is the morphological image, and (b) is the pseudo-color image of laser speckle blood flow imaging;

[0065] Figure 23 The H&E staining results of the rats in the present invention were obtained by tail vein injection of normal saline (NS) and ascorbic acid ester (Foam) for 20 days;

[0066] Figure 24 These are the H&E staining results of the main organs (heart, liver, spleen, lung, and kidney) of mice injected with normal saline (NS) and ascorbic acid ester (Foam) for 20 days in the present invention;

[0067] Figure 25 This is the result of serum biochemical analysis of mice after treatment in the present invention. DETAILED DESCRIPTION

[0068] In order to make the present invention easier to understand, the specific implementation method of the present invention will be further described below in conjunction with the specific embodiments of the drawings. The following embodiments or drawings are used to help understand the present invention, but are not used to limit the scope of protection of the present invention.

[0069] Experimental Materials:

[0070] Ascorbic acid, valeryl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, N,N-dimethylacetamide, dichloromethane, deuterated dimethyl sulfoxide, petroleum ether, ethyl acetate, and glacial acetic acid were obtained from Beijing Myrida Technology Co., Ltd., Beijing, China; methanol, chloroform, and a normal-flow silica gel column were obtained from Changzhou Santai Technology Co., Ltd., Jiangsu, China; a 1-mL disposable sterile syringe was obtained from Shandong Xinhua Ande Medical Products Co., Ltd., Shandong, China; a disposable medical three-channel stopcock was obtained from Weihai Jierui Medical Products Co., Ltd., Shandong, China; 4% paraformaldehyde tissue fixative was used; and an H&E kit was obtained from Wuhan Sewell Biotechnology Co., Ltd., Wuhan, China.

[0071] Example 1

[0072] Synthesis of ascorbic acid esters:

[0073] Ascorbic acid ester, referred to as AAm, wherein m represents the total number of carbon atoms in the alkyl acyl chloride, and in the present invention, m=5-10, and its synthesis reaction route is as follows: Figure 1 The specific method is as follows:

[0074] Add 45 mL of N,N-dimethylacetamide (DMAC) and 10 mL of dichloromethane (DCM) to a 250 mL three-necked flask. Cool in an ice bath for 30 min. Continue to add 6.340 g (36 mmol) of ascorbic acid and stir until the solution is completely clear. Maintaining stirring in the ice bath, slowly add dropwise 3.617 g (30 mmol) of valeryl chloride, 4.038 g (30 mmol) of hexanoyl chloride, 4.459 g (30 mmol) of heptanoyl chloride, 4.880 g (30 mmol) of octanoyl chloride, 5.301 g (30 mmol) of nonanoyl chloride, and 5.722 g (30 mmol) of decanoyl chloride. After the addition is complete, raise the temperature to 25°C and continue the reaction for 12 h. After the reaction was completed, the solvent was partially removed by distillation under reduced pressure. 120 mL of ethyl acetate and 200 mL of distilled water were added to the remaining mixture for extraction. The separated aqueous layer was extracted again with 120 mL of ethyl acetate. The ethyl acetate layers were combined, and the organic phase was washed with saturated brine until no ascorbic acid remained (TLC monitoring). The organic phase was dried over anhydrous sodium sulfate for 1 hour, and the ethyl acetate was removed by distillation under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography using silica gel as the column packing and a petroleum ether / ethyl acetate system as the eluent. A series of gradient eluents were prepared to elute the crude products of different carbon chain lengths. The organic solvent in the receiving solution was removed by distillation under reduced pressure to obtain the target product, ascorbic acid ester.

[0075] The acyl chloride drop rate is controlled at 20-30 drops / minute; 1% glacial acetic acid is added to the eluent to enhance the elution ability.

[0076] The results of H NMR and MS of the ascorbic acid ester prepared by the above method are as follows: Figure 2-13 As shown:

[0077] AA5: 1 H NMR (400MHz, DMSO) δ5.28 (s, 1H), 4.67 (d, J = 1.8Hz, 1H), 4.16–4.00 (m, 2H),

[0078] 4.01–3.93(m,1H),2.33(t,J=7.4Hz,2H),1.53(p,J=7.4Hz,2H),1.37–1.22(m,2H),0.88(t,J=7.3Hz,3H).

[0079] (ESI)m / z:[MH] - calcd for C 11 H 16 O7 260.09,founded 258.9.

[0080] AA6: 1 H NMR (400MHz, DMSO) δ5.31 (s, 1H), 4.68 (d, J = 1.8Hz, 1H), 4.16–4.01 (m, 2H),

[0081] 3.97(d,J=7.5,5.9,1.8Hz,1H),2.31(d,J=7.4Hz,1H),1.60–1.47(m,2H),1.35–1.20(m,4H),0.92–0.81(m,3H).

[0082] (ESI)m / z:[MH] - calcd for C 12 H 18 O7 274.11,founded 272.9.

[0083] AA7: 1 H NMR (400MHz, DMSO) δ5.30 (s, 1H), 4.68 (d, J = 1.8Hz, 1H), 4.16–4.01 (m, 2H),

[0084] 3.98(d,J=6.8Hz,1H),2.32(t,J=7.4Hz,2H),1.54(t,J=7.4Hz,2H),1.33–1.19(m,6H),0.91–0.82(m,3H).

[0085] (ESI)m / z:[MH] -calcd for C 13 H 20 O7 288.12,founded 286.9.

[0086] AA8: 1 H NMR(400MHz,DMSO)δ5.31(d,J=6.3Hz,1H),4.68(d,J=1.8Hz,1H),4.15–

[0087] 4.01(m,2H),3.98(d,J=7.8Hz,1H),2.32(t,J=7.4Hz,2H),1.54(p,J=7.4Hz,2H),1.34–1.23(m,8H),0.90–0.82(m,3H).

[0088] (ESI)m / z:[M-H] - calcd for C 14 H 22 O7 302.14,founded 300.9.

[0089] AA9: 1 H NMR(400MHz,DMSO)δ5.29(s,1H),4.67(d,J=1.7Hz,1H),4.15–4.01(m,2H),

[0090] 4.04–3.93(m,1H),2.32(t,J=7.4Hz,2H),1.54(p,J=7.5Hz,2H),1.26(t,J=7.8Hz,3H),1.25(s,7H),0.90–0.82(m,3H).

[0091] (ESI)m / z:[M-H] - calcd for C 15 H 24 O7 316.15,founded 314.9.

[0092] AA10: 1 H NMR(400MHz,DMSO)δ5.32–5.27(m,1H),4.67(d,J=1.8Hz,1H),4.15–4.01

[0093] (m,2H),3.97(d,J=6.8Hz,1H),2.32(t,J=7.4Hz,2H),1.53(p,J=7.0Hz,2H),1.26(d,J=5.6Hz,12H),0.90–0.82(m,3H).

[0094] (ESI)m / z:[MH] - calcd for C 16 H 26 O7 330.17,founded 329.0.

[0095] Effect Example 1

[0096] Determination of critical micelle concentration of ascorbic acid esters:

[0097] The critical micelle concentration (CMC) is the minimum concentration at which a surfactant begins to form micelles. The lower the CMC value, the stronger the surfactant's ability to form micelles, and the more surface-active it can be at lower concentrations. If the pharmaceutical ingredient in a foam formulation is below the CMC, its foaming and foam stabilization properties may be insufficient. The present invention uses the spinning drop method to determine the CMC of AAm: AA5, AA6, AA7, AA8, AA9, and AA10 are accurately weighed and prepared into a series of aqueous solutions with a concentration gradient. 1 mL of each solution is pipetted into a sample tube, and the temperature and rotation speed are set for measurement. Three replicates are prepared for each concentration. A γ-logC curve is plotted using the logarithm of the concentration of the test compound (logC) and the measured surface tension (γ) as the horizontal and vertical coordinates. The concentration corresponding to the inflection point of the curve is the CMC value of the compound.

[0098] The results of the determination of the critical micelle concentration of ascorbic acid ester are as follows: Figure 14 As shown:

[0099] The CMC of AA5-AA10 gradually decreases, indicating that as the carbon chain length increases, the concentration at which the compound surface reaches saturation and adsorption decreases, and the surface activity increases.

[0100] Table 1 Critical micelle concentration and surface tension values

[0101]

[0102] Effect Example 2

[0103] Study on the properties of ascorbic acid ester monolayer:

[0104] The π-A isotherm can be used to observe the alignment of the compounds of the present invention at the gas-liquid interface, such as the surface of bubbles in foam formulations. This is typically measured in a Langmuir trough using the "hanging plate method": 5.20 mg of AA5, 5.48 mg of AA6, 5.76 mg of AA7, 6.04 mg of AA8, 6.32 mg of AA9, and 6.60 mg of AA10 are weighed and dissolved in 2 mL of chloroform to prepare a 0.01 mol / L stock solution. This is then diluted with chloroform to a 0.001 mol / L working solution for later use. Prior to the experiment, the Langmuir trough and slide are cleaned three times with anhydrous ethanol and three times with ultrapure water. A saturated, but not overflowing, amount of 25°C pure water is added to the Langmuir trough as a subphase. The slide is subjected to a compression-expansion cycle. The surface pressure fluctuation during the entire process must be less than 0.2 mN / m to indicate the absence of surface-active impurities on the liquid surface. Using a microsyringe, 100 μL of sample is evenly applied as a tiny droplet onto the subphase surface. The sample is allowed to stand for 20 minutes until the organic solvent evaporates completely, resulting in a Langmuir monolayer. Once the monolayer is formed, a slide bar is set to compress the sample at a speed of 5 mm / s. Once compression is complete, a π-A isotherm is automatically plotted on the computer. This experiment is repeated three times for each sample. The static elastic modulus, Es, can be obtained by differentiating the π-A isotherm.

[0105] The results of the plotting of the ascorbic acid ester π-A isotherm and the curve of the static elasticity of the monolayer changing with the surface pressure are shown in Figure 2. Figure 15 , Figure 16 As shown:

[0106] When AA5-AA10 undergoes a transition from gas phase (G) to liquid phase (L), the average molecular area shows an increasing trend from small to large, and no other phase transitions or collapse of the monolayer are shown within the measurement range of the instrument, indicating good compressibility.

[0107] Effect Example 3

[0108] Preparation and characterization of ascorbyl ester foam formulations:

[0109] Preparation of foam formulations: AAm was weighed and dissolved in 1 mL of normal saline to prepare a 1%-4% (w / v) AAm solution in normal saline. Two 1 mL syringes were filled with 200 μL of the above solution and 600 μL of air, respectively. The syringes were connected to two adjacent ports of a three-way valve assembly, with the other port closed. The syringe pistons were repeatedly pushed and pulled 40 times. AA5 and AA6 failed to produce stable foams, and AA10 was excluded due to its poor solubility. Stable foams of AA7, AA8, and AA9 were obtained.

[0110] 30 seconds after the foam is prepared, its microscopic morphology is observed using an optical microscope and photographed and recorded. Figure 17As shown: Under naked eye observation, the bubble particle size of AA7 and AA8 is significantly larger than that of AA9 foam, and the contact with the lesion is not as sufficient as that of AA9, indicating that the preparation effect of AA7 and AA8 foam is poor.

[0111] The microscopic morphology of the foam was processed using imageJ software, and the bubbles were counted and their diameters were measured. Figure 18 As shown: AA9 has the smallest foam particle size D = 43.86 ± 28.29 μm at a concentration of 4%.

[0112] After preparing the foam, inject all the foam into a single syringe, disconnect the three-way valve, and place it vertically. Start timing and continuously observe the foam at the bottom. The time when liquid begins to form is the foam's exudation time. When the volume of liquid formed at the bottom reaches 100 μL, the foam's half-life is determined. Visual observation of exudation time can yield significant errors, so a foam drainage rate fitting curve is used to improve accuracy. The vertical intercept is the foam's exudation time.

[0113] The foam bleeding time and foam half-life of the three compounds are as follows Figure 19-20 As shown:

[0114] The water exudation time of AA7 initially increased and then decreased with increasing drug concentration, while the water exudation time of AA8 and AA9 increased with increasing drug concentration. The half-life of AA7 and AA8 initially increased and then decreased with increasing drug concentration, while the half-life of AA9 increased with increasing drug concentration. At a concentration of 1%, the foam water exudation time and foam half-life of AA7-AA9 were similar. At concentrations of 2%-4%, the foam water exudation time and foam half-life of AA9 were significantly longer than those of AA7 and AA8. At a concentration of 4%, the water exudation time of AA9 was nearly 2 minutes, and the half-life reached approximately 22 minutes. This demonstrates that AA9 at a concentration of 4% can be used to prepare a foam sclerosant with optimal particle size distribution and stability, providing experimental evidence for its clinical application.

[0115] Effect Example 4

[0116] Hemolytic Safety Evaluation of Ascorbic Acid Esters:

[0117] To evaluate the erythrocyte-destructive effect of AA9, a hemolysis assay was used: fresh blood was collected from healthy KM mice and placed in a centrifuge tube containing 3.2% sodium citrate. The tube was gently inverted to mix, and then centrifuged at 720 g for 10 minutes to pellet the erythrocytes. The upper plasma and leukocyte layer were carefully aspirated, and an appropriate amount of normal saline was added. The tube was gently inverted to mix, and then centrifuged again. This was repeated 4-5 times to remove impurities from the plasma. Normal saline was then added to the washed erythrocytes to prepare a 4% (v / v) erythrocyte suspension. Equal volumes of the erythrocyte suspension were then mixed with a series of AA9 solutions at varying concentrations in a centrifuge tube and mixed to achieve final concentrations of 10, 100, 200, 300, 400, 500, and 600 μg / mL, respectively. The tubes were incubated at 37°C for 2 hours, centrifuged at 720 g for 10 minutes, and 200 μL of the supernatant was transferred to a 96-well plate. The physiological saline-treated group was used as the negative control group, and the deionized water-treated group was used as the positive control group. The absorbance of each well at 540 nm was measured using a multifunctional microplate reader, and the hemolysis rate was calculated.

[0118] Hemolysis test results Figure 21 As shown, from left to right, the saline group, the deionized water group, the 10 μg / mL, 100 μg / mL, 200 μg / mL, 300 μg / mL, 400 μg / mL, 500 μg / mL, and 600 μg / mL groups. At concentrations of 400 μg / mL or less, the hemolysis rate was less than 10%, indicating minimal damage to erythrocytes. When the concentration increased to 500 μg / mL, the supernatant color began to darken, and the hemolysis rate significantly increased, reaching 27.50% ± 2.52%, indicating a significant increase in erythrocyte damage. When the concentration continued to increase to 600 μg / mL, the supernatant color deepened to reddish-brown, and the hemolysis rate rose to 40.93% ± 1.60%, indicating a high degree of erythrocyte damage. These experimental results demonstrate that AA9 has a very low hemolytic risk at a concentration of 4%, demonstrating high blood safety.

[0119] Effect Example 5

[0120] In vivo evaluation of vascular sclerosis treatment effects:

[0121] Twenty-four female Kunming mice aged 3-5 weeks and weighing 25g-30g were randomly divided into two groups. 40μL of normal saline solution and 4% AA9 sclerosant foam were injected into the tail vein of each group of mice. The tail morphology of the mice was recorded under natural light and yellow light before administration and 6h, 2d, 5d, 10d, 15d, and 20d after administration. Laser speckle imaging technology was used to dynamically visualize the tail vein blood vessels of the mice and screenshots were saved. Figure 22As shown, there was no significant change in the tail vein of mice in the normal saline group before and after injection (vascular signal was unobstructed). 6 hours after the injection of 4% AA9, obvious thrombosis (blood flow signal interruption) could be observed at the injection site, and no other thrombosis or tissue necrosis occurred outside the injection site. When observed on the 5th day, the thrombus was still maintained. When observed on the 10th day, it was found that the diameter of the blood vessel had decreased. When observed on the 15th day, it was found that the blood vessels at the administration site had disappeared. When observed on the 20th day, there was no recanalization of the blood vessels. On the 20th day after administration, the mice were randomly killed, and the injection site of the tail vein of the mice was taken, fixed with 4% paraformaldehyde, embedded in paraffin, and sliced. Histological changes were observed by H&E staining. As shown Figure 23 As shown, H&E staining results showed that the 4% AA9 sclerosant foam group had a large amount of new fibrous tissue at the administration site, the blood vessels were completely fibrotic, and the lumen structure was absent. The tail vein administration site of the mouse was successfully occluded. These experimental results demonstrate the effectiveness of the present invention in treating vascular sclerotherapy.

[0122] Effect Example 6

[0123] In vivo safety evaluation:

[0124] Twenty-four female Kunming mice aged 3-5 weeks and weighing 25g-30g were randomly divided into two groups. 40μL of saline solution and 4% AA9 sclerosant foam were injected into the tail vein of each group. On the 20th day after injection, the mice were euthanized, and the hearts, livers, spleens, lungs, and kidneys of the mice were collected, fixed with 4% paraformaldehyde, embedded in paraffin, and sectioned for H&E staining. Figure 24 As shown, no major organs of the mice showed thrombosis or other pathological changes, indicating that 4% AA9 foam sclerosant has low organ toxicity and a low risk of systemic thrombosis. Blood was collected, serum was separated, and blood biochemical indicators of the mice were tested. Liver function-related indicators such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transferase (γ-GT) and albumin (ALB), renal function-related indicators such as urea (UREA), creatinine (CR) and uric acid (UA), and myocardial enzyme indicators such as creatine kinase (CK) and lactate dehydrogenase (LDH). The results are shown in Figure 2. Figure 25 As shown, all blood biochemical parameters of mice injected with 4% AA9 foam sclerosant remained within normal reference ranges, indicating that AA9 does not significantly affect these blood biochemical parameters during sclerotherapy. These experimental results demonstrate that 4% AA9 foam sclerosant has excellent systemic safety at effective therapeutic doses.

Claims

1. An ascorbic acid fatty acid ester compound, characterized in that: The structure is as follows: n＝1～10。 2. An ascorbic acid fatty acid ester compound according to claim 1, characterized in that, n＝3～8。 3. A method for preparing the ascorbic acid fatty acid ester compound according to claim 1 or 2, characterized in that: The following steps are involved: Step 1: Add the solvent and ascorbic acid to the reaction system under stirring in an ice bath; Step 2: Slowly add n-alkyl acyl chloride dropwise under stirring in an ice bath. After the addition is complete, heat to 25°C and continue the reaction. Step 3: After the reaction is completed, extract, wash, and dry to obtain a crude product; Step 4: Separate and purify the crude product to obtain ascorbic acid ester.

4. A pharmaceutical composition, characterized in that The invention comprises the ascorbic acid fatty acid ester compound 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 ascorbic acid fatty acid ester compound is amyl ascorbate, hexyl ascorbate, heptyl ascorbate, octyl ascorbate, nonyl ascorbate, decyl ascorbate or a combination thereof.

6. Use of the ascorbic acid fatty acid ester compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, or the pharmaceutical composition according to claim 4 or 5, in preparing a sclerosing agent in sclerotherapy.

7. Use of the ascorbic acid fatty acid ester compound 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. An ascorbyl ester foam preparation for sclerotherapy, characterized in that The foam is prepared by using the ascorbic acid fatty acid ester compound according to claim 1 or 2. When used, the ascorbic acid fatty acid ester compound is dissolved in physiological saline, two medical syringes respectively filled with the ascorbic acid fatty acid ester compound solution and air are connected through a medical three-way valve, and the syringe pistons are repeatedly pushed and pulled to fully mix the solution and the gas between the two syringes to obtain foam; the mass volume concentration of the ascorbic acid fatty acid ester compound in the prepared ascorbic acid fatty acid ester compound solution is 0.1%-10%.

9. A freeze-dried injection of the ascorbic acid ester foam preparation for sclerotherapy according to claim 8, characterized in that: When used, the freeze-dried foam preparation is dissolved with sterile water for injection or a specific solvent and prepared into a foam dosage form for administration by the Tessari method; the mass volume concentration of the ascorbic acid fatty acid ester compound in the prepared ascorbic acid fatty acid ester compound solution is 0.1%-10%; the specific solvents include glycerol solution and 1,2-propylene glycol solution.

10. Use of the ascorbic acid ester foam preparation for sclerotherapy according to claim 8 or the lyophilized injection of the ascorbic acid ester foam preparation for sclerotherapy according to claim 9 in the preparation of a medicament for treating hemangioma, varicose veins and vascular malformation.

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