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WO2020238148A1 - 一种应用于治疗脉管异常的乙醇泡沫硬化剂及制备方法 - Google Patents

一种应用于治疗脉管异常的乙醇泡沫硬化剂及制备方法 Download PDF

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WO2020238148A1
WO2020238148A1 PCT/CN2019/124643 CN2019124643W WO2020238148A1 WO 2020238148 A1 WO2020238148 A1 WO 2020238148A1 CN 2019124643 W CN2019124643 W CN 2019124643W WO 2020238148 A1 WO2020238148 A1 WO 2020238148A1
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foam
ethanol
tween
alcohol
hyaluronic acid
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PCT/CN2019/124643
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English (en)
French (fr)
Inventor
刘少华
张涵恕
杨爱军
刘怡然
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山东大学齐鲁医院
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Priority to US17/311,354 priority Critical patent/US11975099B2/en
Publication of WO2020238148A1 publication Critical patent/WO2020238148A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention belongs to the technical field of hardener material preparation, and specifically relates to an alcohol foam hardener applied to treat vascular abnormalities and a preparation method.
  • Vascular anomaly is a major disease that seriously endangers human health, including venous malformations, arteriovenous malformations, hemangioma and lymphatic malformations, among which venous malformations are the most common.
  • the disease can occur in any part of the human body, about 60% of which occur in the maxillofacial region.
  • the disease can seriously affect the appearance and function of the involved organs, and at the same time, it can be life-threatening due to complications such as infection, bleeding, and respiratory obstruction.
  • the disease often requires life-long treatment, and its social harm is no less than that of malignant tumors.
  • the current international treatment strategy for this disease is based on sclerotherapy, combined with comprehensive treatments such as surgery, laser, and interventional therapy.
  • the principle of sclerotherapy is to use drugs (sclerosing agents) to destroy the endothelial cells of the diseased blood vessels (lymphatic vessels) to achieve the purpose of treatment.
  • drugs sclerosing agents
  • anhydrous ethanol has the strongest sclerosing effect, but its side effects are the most serious.
  • liquid hardener can be mixed with air to make foam to form foam hardener.
  • the purpose of the present invention is to provide an alcohol foam sclerosing agent for treating vascular abnormalities and a preparation method.
  • the invention provides a foamed ethanol hardener and a preparation method thereof, which can significantly reduce its side effects while not changing its original therapeutic effect.
  • the technical solution of the present invention is:
  • an alcohol foam hardener applied to abnormal vasculature includes absolute alcohol, water, and non-ionic surfactant.
  • Vascular abnormalities include venous malformations, arteriovenous malformations, lymphatic malformations, and hemangioma.
  • the alcohol foam hardener further includes a stabilizer, and the stabilizer is hyaluronic acid or glycerin; preferably hyaluronic acid.
  • the addition of hyaluronic acid or glycerin to the alcohol foam hardener of the present invention can improve the stability of the alcohol foam hardener, improve the uniformity of the foam, extend the half-life of the foam, and have good stability.
  • the nonionic surfactant is composed of Tween and lecithin; preferably Tween 80 and egg yolk lecithin.
  • the mass composition of the ethanol foam hardener is 25-42% absolute ethanol, 0.5-2% Tween 80, 0-2% egg yolk lecithin (excluding 0), and the remainder is water.
  • Foam is an aggregation of microbubbles formed by a large amount of gas dispersed in a small amount of liquid, separated from each other by a liquid film, and has a certain geometric shape. It is a tiny multiphase, viscous and unstable system. Pure liquids, such as water and ethanol, cannot form stable foams. Liquids that can form stable foams must contain two or more components.
  • Ethanol with the molecular formula C 2 H 6 O, is the most common monohydric alcohol with surface activity, and the surface tension of its aqueous solution gradually decreases with increasing concentration.
  • Surfactant is a kind of substance with high surface activity.
  • the surface tension of its aqueous solution drops sharply at low concentrations.
  • the molecules are aligned to form a certain structure, such as foam, micelles, etc., and their molecules form micelles in the solvent
  • the lowest concentration is the critical micelle concentration (cmc value).
  • cmc value critical micelle concentration
  • surfactants are divided into ionic and non-ionic. Among them, non-ionic surfactants are widely used in pharmacy due to their low toxicity and hemolytic effect, stable chemical properties, and compatibility with most drugs. It is often used as a solubilizing, dispersing, emulsifying and suspending agent. Ethanol in the mixed solution will reduce the cmc value of the surfactant, but the combined use of two or more surfactants can improve the effect.
  • the mass composition of the ethanol foam hardener is 25-42% absolute ethanol, 0.5-2% Tween 80, 0-2% egg yolk lecithin (excluding 0), and 0-2% hyaluronic acid. (Excluding 0), the remainder is water.
  • the mass composition of the ethanol foam hardener is anhydrous ethanol 33.3-40.5%, Tween 80 0.6-0.7%, egg yolk lecithin 0.9-1.1%, hyaluronic acid 0.7-1.5%, and the remainder is water.
  • Tween 80 and egg yolk lecithin have good biological safety and are internationally recognized pharmaceutical excipients, safe for low-dose intravenous injection.
  • ethanol solution can form air foam with the participation of nonionic surfactants.
  • the content of nonionic surfactant has a certain influence on the stability of the formed foam. Only when the content of nonionic surfactant matches the concentration of ethanol can a more stable foam be obtained.
  • the formation mechanism of the foam is that the gas is dispersed in the liquid to form a gas-liquid dispersion.
  • the inventor found that the non-ionic surfactants in the above-mentioned mass range and concentration range can be more compatible with the anhydrous ethanol in the above-mentioned mass range.
  • the foam can be formed well, and the hyaluronic acid in the above-mentioned quality range can be used to increase the foaming stability of the mixed solution.
  • the foam obtained has a uniform and stable texture and a longer half-life.
  • the effect of egg yolk lecithin and Tween 80 is: synergistic effect to make ethanol foam. Adding stabilizers beyond the above range will increase the risk of side effects in foam treatment.
  • hyaluronic acid is a stabilizer that can improve the stability of the formed foam.
  • the inventor found that adding hyaluronic acid and within a certain proportion range makes the foam uniform and dense, and the half-life is extended, so that The applicability of ethanol foam is better.
  • the inventor believes that adding a stabilizer exceeding the above range will reduce the ethanol concentration and affect the therapeutic effect.
  • egg yolk lecithin, Tween 80, absolute ethanol, water, and hyaluronic acid are mixed to obtain mixed solution A, and ethanol foam is prepared according to the Tessari method.
  • the process of preparing foam by the Tessari method is as follows: put the mixed solution A into a syringe, and use another syringe to draw sterile air, and the two syringes are connected by a medical three-way valve, according to the Tessari method before and after Several boluses are mixed to form ethanol foam.
  • volume ratio of the mixed solution A to the sterile air is 1:2-4.
  • the preparation process is carried out at room temperature.
  • the method of Tessari method to form bubbles is to inject back and forth through two syringes to fully mix the gas and liquid to form a bubble.
  • the mixed liquid A of ethanol has a certain surface tension. When the gas breaks through the surface of the mixed liquid, the surface tension of the mixed liquid A decreases, forming a gas-liquid separation; if the gas inside the foam cannot break through the liquid film, the foam will exist stably.
  • the volume ratio of mixed solution A to air affects the stability of the foam. Due to the particularity of ethanol foam, the inventor found that the volume ratio of mixed solution A to sterile air within the above range can make the ethanol foam more stable.
  • Lecithin also known as lecithin, is known as the "third nutrient" alongside protein and vitamins. It is a mixture of phospholipids extracted from plants or animals through physical processing methods. Lecithin is generally referred to as this mixture. It is widely distributed in nature and rich in resources. It is a natural nutritional supplement with low price and high nutritional value and physiological functions. The main functions include improving the body's nerve dysfunction and disorder, restoring brain function, enhancing memory, preventing cardiovascular system diseases and anti-aging, etc. It is widely used in the fields of medicine and food. In addition, lecithin is also a natural emulsifier and wetting agent. It is a non-ionic surfactant.
  • Lecithin is divided into soybean lecithin and egg yolk lecithin.
  • the egg yolk lecithin used in the present invention is intravenous injection.
  • Tween 80 (Tween 80, polysorbate 80) is a non-ionic surfactant that can be used as an emulsifier, dispersant, solubilizer or stabilizer, etc., and is widely used in medicines, food, etc. The pharmacological effects and safety of the drug have been thoroughly studied.
  • the present invention uses Tween 80 for intravenous injection.
  • Hyaluronic acid a physiologically active substance widely found in animals and humans, is distributed in human skin, joint synovial fluid, umbilical cord, aqueous humor, and ocular vitreous. It is a naturally degradable substance , Absorbable biomedical materials, which have high viscoelasticity, plasticity, permeability, unique rheological properties and good biocompatibility, etc., are widely used in the field of drug sustained release. Studies have reported that the application of hyaluronic acid in the treatment of vascular abnormalities is safe and effective.
  • the present invention uses medical hyaluronic acid injection.
  • the invention solves the problem that in the prior art, only absolute ethanol liquid can be used as a hardening agent.
  • the inventor has prepared an alcohol foam hardening agent, which has better effect, safer and fewer side effects than liquid absolute alcohol. .
  • the foam hardener prepared by the invention has long half-life, convenient application, simple preparation method and good clinical application effect.
  • Figure 1 is a schematic diagram of the preparation process of the Tessari method and a diagram of the foam formed in Example 5;
  • Figure 2 is an experimental diagram of CCK8 cells of Experimental Example 1;
  • Figure 3 is a picture of the plasma experiment of Test Example 2.
  • A is fresh human anticoagulant blood
  • B is human anticoagulant blood after adding the sclerosing agent of Example 1
  • C is human anticoagulant blood after adding absolute ethanol.
  • Fig. 4 is an animal experiment picture of Test Example 3.
  • a and B are the comparison pictures of the ear margin experiment of two groups of New Zealand white rabbits, A is the injection of absolute ethanol, and B is the injection of the foam hardener of Example 1.
  • Figure 1 shows a schematic diagram of the process of preparing ethanol foam and a diagram of the prepared foam. It can be obtained that the ethanol foam is a microemulsified foam.
  • Example 2 The difference from Example 1 is that Tween 80 is not added and the egg yolk lecithin is 1.7 g. As a result, the solution cannot form foam.
  • Example 2 The difference from Example 1 is that egg yolk lecithin is not added, and Tween 80 is 1.7 g. As a result, the solution cannot form foam.
  • Example 2 The difference from Example 1 is 50 g of absolute ethanol and 47.2 g of water. The result is no foam.
  • the CCK8 cell experiment was carried out with different concentrations of ethanol aqueous solution, and the cells were umbilical vein endothelial cells.
  • the test is divided into blank group (no cells), control group (physiological saline and absolute ethanol), experimental group (volume fractions of ethanol aqueous solution are 10%, 20%, 30%, 40%, 50%, 60%, respectively) 70%, 80%, 90%), the specific curves are shown in Figure 2.
  • Each group in the figure is series 1 to series 6 from left to right, and series 1 to series 6 refers to six times under the same experimental conditions
  • the obtained results show that the ethanol aqueous solution with a volume fraction of 30-100% has good destructive ability and can cause necrosis of umbilical vein endothelial cells.
  • the present invention maximizes the concentration of ethanol in the mixed solution.
  • Plasma experiment Use absolute ethanol and the sclerosing agent liquid of Example 1 for plasma experiment, as shown in Figure 3A, to take 1 mL of fresh human anticoagulant blood, Figure 3C is to put absolute ethanol in a test tube, as shown in Figure 3B In order to add the hardener liquid of Example 1 into the test tube, as shown in Figure 3C, a large amount of reddish-brown solid matter was immediately formed in the test tube. The absolute ethanol coagulated the protein in the plasma, as shown in Figure 3B, the blood color in the test tube Slightly deeper, but no obvious solid precipitation, the sclerosing agent obtained in Example 1 will not coagulate the protein in the plasma.
  • the first experimental group the experimental subjects were 20 1.5kg New Zealand white rabbits, injected with 0.5mL of absolute ethanol; the second experimental group: the experimental subjects were 20 1.5kg New Zealand white rabbits, injected with 0.5mL The foam hardener of Example 1; the ear edges of the experimental subjects in the first experimental group and the second experimental group were intact and normal before the experiment.
  • the results of the first experimental group are shown in Figure 4A, where a is the reaction just after the injection, and extensive and large hematoma appears immediately at the ear edge, b is the reaction 3 days after the injection, the whole ear has obvious hematoma, and c is the reaction 7 days after the injection , The swelling is reduced, d is the reaction 25 days after the injection, local blood vessels and part of normal tissue are destroyed, causing the rabbit ear edge tissue defect; the results of the second experimental group are shown in Figure 4B, where a is the reaction just after the injection, tube The cavity is filled with foam sclerosing agent, and there is no obvious abnormality around the tube. b is the reaction after 3 days of injection, and local hematoma appears.
  • c is the reaction 7 days after the injection.
  • the hematoma basically subsided, only The inflammation around the ear veins was obvious.
  • d was the reaction after 25 days of injection. The blood vessels disappeared and there was no obvious change in local normal tissues.
  • foam hardener of the present invention has slight side effects on local normal tissues.
  • Example 2 Ethanol foam sclerotherapy, once a month, 2 times in total, each time about 5ml, 2 months later, the sclerotherapy effect is significant .
  • the treatment method is: Example 2 Ethanol foam sclerotherapy, one treatment, 1ml, and it has been cured.
  • the lower lip mass has been worsened for more than 50 years.
  • the diagnosis is: lower lip vein malformation.
  • the treatment method is: Example 2 Ethanol foam sclerotherapy, one treatment, 0.5ml, and good therapeutic effect , Has been cured.
  • the treatment method is: Example 2 ethanol foam sclerotherapy, once a month, 2 treatments, each time about 2ml, has been cured.
  • Tongue mass was found for 1 year, and the diagnosis was: tongue vein malformation.
  • the treatment method is: Example 2 ethanol foam sclerotherapy, one treatment, 1ml, and healed.
  • the right neck mass was found for more than 10 years, and the diagnosis was: right neck venous malformation type IV.
  • the treatment method was: DSA using ethanol foam sclerotherapy in Example 2 under DSA, once a month, a total of 3 treatments ,Approximately 8ml each time, a better therapeutic effect has been achieved and has been cured.
  • Example 2 alcohol foam hardening treatment once a month, a total of 2 treatments, each time about 5ml, has been cured.
  • treatment method Example 2 alcohol foam sclerotherapy, once a month, a total of 3 treatments, each time about 10ml, get The better treatment effect has been cured.
  • the right cheek swelling was found for 5 years.
  • the diagnosis was: right cheek venous malformation.
  • the treatment method is: Example 2 ethanol foam sclerotherapy, one treatment, 2ml, and healed.
  • the treatment method was: Example 2 ethanol foam sclerotherapy, one treatment, 3ml, and healed.
  • treatment method is: Example 2 ethanol foam hardening treatment, one treatment, using 3ml, the effect is significant, has been cured.
  • the treatment method is: Example 2 alcohol foam sclerotherapy, once a month, a total of 3 treatments, each time about 6ml, get more Good treatment effect has been cured.
  • the foam sclerosing agent of the present invention has a good treatment effect on various venous malformations, the treatment process is simple, the treatment effect is obvious, there is no obvious adverse reaction, and it is safe and effective.

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Abstract

一种应用于脉管异常的乙醇泡沫硬化剂及制备方法，包括无水乙醇、水、吐温80、稳定剂。还包括透明质酸，无水乙醇32-42％、吐温80 0.5-2％、蛋黄卵磷脂0-25（不包括0）、透明质酸0-2％（不包括0），剩余为水。稳定剂为透明质酸或甘油，利用Tessari法制备泡沫，在不改变乙醇原有治疗效果的同时，显著降低其副作用。

Description

一种应用于治疗脉管异常的乙醇泡沫硬化剂及制备方法 技术领域
本发明属于硬化剂材料制备技术领域，具体涉及一种应用于治疗脉管异常的乙醇泡沫硬化剂及制备方法。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
脉管异常(Vascular Anomaly)是严重危害人类健康的重大疾病，包括静脉畸形、动静脉畸形、血管瘤和淋巴管畸形等疾病，其中以静脉畸形最为多见。该病可发生于人体任何部位，其中约60％发生于颌面部。根据发病部位和严重程度不同，该病一方面可以严重影响美观和受累及器官的功能，同时因为伴发感染、出血、呼吸道梗阻等并发症而危及生命。另一方面该病往往需要终生治疗，其社会危害性不亚于恶性肿瘤。
目前国际上对该疾病的治疗策略是以硬化治疗为主，结合手术、激光、介入治疗等其它多种手段的综合治疗。硬化治疗的原理是用药物(硬化剂)破坏病变的血管(淋巴管)内皮细胞，从而达到治疗目的。临床常用的硬化剂有无水乙醇、聚多卡醇和博莱霉素三种，其中硬化作用最强的是无水乙醇，但其副反应最严重。在硬化治疗过程中可以将液体硬化剂与空气混合制作成泡沫，形成泡沫硬化剂，后者具有比液体硬化剂效果更好、更安全、副作用更小等许多优势，而且这种优势相当显著。在上述三种硬化剂中，目前只有聚多卡醇能够制成泡沫，而无水乙醇和博莱霉素不能直接与空气形成泡沫。发明人发现，虽然无水乙醇是公认的作 用最强烈的硬化剂，但副作用最严重、最好发，主要是组织坏死，严重地限制了它的广泛应用。聚多卡醇作用温和，尽管制成泡沫后治疗效果显著提高，但它的治疗作用远远不及无水乙醇。
发明内容
针对上述现有技术中存在的问题，本发明的目的是提供一种应用于治疗脉管异常的乙醇泡沫硬化剂及制备方法。本发明提供一种泡沫化乙醇硬化剂及其制备方法，在不改变其原有治疗效果的同时，显著降低其副作用。
为了解决以上技术问题，本发明的技术方案为：
一方面，一种应用于脉管异常的乙醇泡沫硬化剂，包括无水乙醇、水、非离子型表面活性剂。
脉管异常包括静脉畸形、动静脉畸形、淋巴管畸形、血管瘤等。
在一些实施例中，乙醇泡沫硬化剂还包括稳定剂，稳定剂为透明质酸或甘油；优选为透明质酸。
本发明的乙醇泡沫硬化剂中加入透明质酸或甘油可以提高乙醇泡沫硬化剂的稳定性，提高泡沫的均一性，延长泡沫的半衰期，稳定性好。
在一些实施例中，非离子性表面活性剂由吐温、卵磷脂组成；优选为吐温80和蛋黄卵磷脂。
在一些实施例中，乙醇泡沫硬化剂的质量组成为无水乙醇25-42％、吐温80 0.5-2％、蛋黄卵磷脂0-2％(不包括0)、剩余为水。
泡沫是由大量气体分散在少量液体之中形成微泡的集聚体，并以液体薄膜相互隔离，且具有一定的几何形状，是一种微小多相、粘状而不稳定的体系。纯液体，如水、乙醇等，不能形成稳定的泡沫，能形成稳定泡沫的液体必须含有两个及以上组分。
乙醇(ethanol)，分子式C 2H 6O，是最常见的一元醇，具有表面活性，其水溶液的表面张力随浓度升高而逐渐下降。其水溶液体系中存在氢键：摩尔分数0-0.236(体积分数0-50％)时,分子之间几乎维持着纯水的缔合状态,水分子缔合结构占主；0.236-0.735时(50％-89％),体系具有最强的氢键缔合状态；当0.735-1.000(89％-100％)时,分子之间几乎维持着纯乙醇的缔合状态,乙醇分子缔合结构占主要地位。发明人发现，0-50％的乙醇溶液理论上可制备成泡沫，而更高浓度的乙醇溶液不能形成泡沫；在实践中，可形成泡沫的乙醇溶液浓度接近50％，但50％的乙醇溶液不能形成泡沫。
表面活性剂是一类具有很高的表面活性的物质，其水溶液的表面张力在低浓度时即急剧下降，分子定向排列形成一定结构，如泡沫、胶束等，其分子在溶剂中形成胶束的最低浓度即临界胶束浓度(cmc值)，当达到该值时溶液表面张力降到最低值，是表面活性剂起泡能力的重要指标。表面活性剂又分为离子型、非离子型，其中非离子型表面活性剂由于其毒性和溶血作用较小，化学性质稳定，能与大多数药物配伍等优点，在药剂学上应用较广，常用作增溶、分散、乳化、混悬剂。混合溶液中乙醇会降低表面活性剂的cmc值，但两种及以上表面活性剂联用可以提高作用效果。
在一些实施例中，乙醇泡沫硬化剂的质量组成为无水乙醇25-42％、吐温80 0.5-2％、蛋黄卵磷脂0-2％(不包括0)、透明质酸0-2％(不包括0)，剩余为水。
进一步的，乙醇泡沫硬化剂的质量组成为无水乙醇33.3-40.5％、吐温80 0.6-0.7％、蛋黄卵磷脂0.9-1.1％、透明质酸0.7-1.5％，剩余为水。
吐温80及蛋黄卵磷脂具有良好的生物安全性，是国际公认的药用辅料，低剂量静脉注射安全。
如上所述，无水乙醇不能直接与空气混合制备为泡沫是因为乙醇不具有亲水 和疏水两个极性，但乙醇溶液在非离子表面活性剂的参与下可以形成空气泡沫。非离子表面活性剂的含量对形成的泡沫的稳定性具有一定的影响，非离子表面活性剂的含量与乙醇的浓度相适配才能得到较为稳定的泡沫。泡沫的形成机理为气体分散于液体中形成气液分散体，发明人发现，在上述质量范围内和浓度范围内的非离子表面活性剂与所述质量范围内的无水乙醇相适配能够更好地成泡，同时可配合上述质量范围内的透明质酸增加混合溶液成泡的稳定性，得到的泡沫质地均一稳定，且半衰期较长。
蛋黄卵磷脂及吐温80的作用为：协同作用使乙醇产生泡沫，加入超过上述范围的稳定剂，会使增加泡沫治疗出现副反应的风险。
透明质酸的作用为，透明质酸是一种稳定剂，能够提高形成的泡沫的稳定性，发明人发现，加入透明质酸并且在一定比例范围内，使泡沫均一致密，且半衰期延长，使乙醇泡沫的应用性更好。发明人认为，加入超过上述范围的稳定剂，会使乙醇浓度降低，影响治疗效果。
第二方面，上述乙醇泡沫硬化剂的制备方法，具体步骤为：
将蛋黄卵磷脂、吐温80、无水乙醇、水混合，得到混合溶液A，按照Tessari法制备得到乙醇泡沫。
在一些实施例中，将蛋黄卵磷脂、吐温80、无水乙醇、水、透明质酸混合，得到混合溶液A，按照Tessari法制备得到乙醇泡沫。
在一些实施例中，Tessari法制备泡沫的过程为：将混合溶液A放入一个注射器中，在用另一个注射器抽取无菌空气，两个注射器之间通过医用三通阀连接，按照Tessari法前后推注若干次混合成为乙醇泡沫。
进一步，混合溶液A与无菌空气的体积比为1：2-4。
进一步，制备过程在室温下进行。
Tessari法成泡的方法是通过两个注射器前后推注，使气体与液体充分混匀形成泡沫。乙醇的混合液体A具有一定的表面张力，当气体冲破混合液体的表面，混合液体A的表面张力减小，形成气液分离；如果泡沫内部的气体无法冲破液膜，那么泡沫就会稳定存在。混合溶液A与空气的体积比，影响泡沫的稳定性，由于乙醇泡沫的特殊性，发明人发现，在上述范围内的混合溶液A与无菌空气的体积比，能够使乙醇泡沫更稳定。
卵磷脂，又称为蛋黄素，被誉为与蛋白质、维生素并列的“第三营养素”，是一种从植物或动物中通过物理加工方法提取出来的磷脂混合物,一般用卵磷脂来统称这种混合物。其在自然界中分布广泛,资源丰富,是一种天然的营养补品,价格低廉,具有很高的营养价值和生理功能。主要作用包括改善机体神经功能障碍及紊乱、恢复脑功能、增强记忆力、防止心血管系统疾病及抗衰老等,广泛应用于医药及食品领域。此外，卵磷脂还是一种天然的乳化剂和湿润剂，属于非离子型表面活性剂,除具有医疗、营养，保健功能外,常作为静脉脂肪注射液的乳化剂,使用浓度一般12mg/ml。卵磷脂又分为大豆卵磷脂与蛋黄卵磷脂，本发明使用的为静脉注射用蛋黄卵磷脂。
吐温80(Tween 80，聚山梨醇酯80)，是一种非离子型表面活性剂，可用作乳化剂、分散剂、增溶剂或稳定剂等，并广泛应用于药物、食品等，它的药理作用及安全性已得到深入研究。本发明使用的为静脉注射用吐温80。
透明质酸(hyaluronic acid，HA)，一种广泛存在于动物和人体的生理活性物质，在人皮肤、关节滑膜液、脐带、房水及眼玻璃体中均有分布，是一种可天然降解、可吸收的生物医学材料，它具有高粘弹性、可塑性、渗透性、独特的流变学特性以及良好的生物相容性等，被广泛应用于药物缓释领域。已有研究报道透明质酸在治疗脉管异常中的应用是安全有效的。本发明使用的为医用透明质酸注射液。
本发明的有益效果：
本发明解决了现有技术中只能应用无水乙醇液体作为硬化剂的问题，发明人制备了一种乙醇泡沫硬化剂，相比与液体的无水乙醇效果更好、更安全、副作用更小。
本发明制备的泡沫硬化剂，半衰期长，应用方便，制备方法简单，临床应用效果好。
附图说明
构成本发明的一部分的说明书附图用来提供对本申请的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。
图1为实施例5中Tessari法制备过程示意和形成的泡沫的图；
图2为试验例1的CCK8细胞试验图；
图3为试验例2的血浆实验的图片，A为新鲜的人抗凝血，B为加入实施例1硬化剂后的人抗凝血，C为加入无水乙醇后的人抗凝血。
图4为试验例3的动物实验图片，A和B分别为两组新西兰大耳白兔的耳缘实验对照图，A为注射无水乙醇，B为注射实施例1的泡沫硬化剂。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本发明提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本申请的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它 们的组合。
下面结合实施例对本发明进一步说明。
实施例1
分别将无水乙醇40.5g、水56.7g、吐温80 0.6g、蛋黄卵磷脂1.1g、透明质酸1.1g混合。混合液抽入一个注射器中，另用一个注射器抽取无菌空气，室温下，用临床上通用的泡沫制作方法---Tessari法，按照液体：空气＝1:3的比例制备乙醇泡沫，形成均一、稳定、致密的泡沫，且泡沫半衰期在1min以上。
实施例2
分别将无水乙醇37.8g、水59.9g、吐温80 0.6g、蛋黄卵磷脂1g、透明质酸0.7g混合。混合液抽入一个注射器中，另用一个注射器抽取无菌空气，室温下，用临床上通用的泡沫制作方法---Tessari法，按照液体：空气＝1:3的比例制备乙醇泡沫，形成均一、稳定、致密的泡沫，且泡沫半衰期在1min以上。
实施例3
分别将无水乙醇35g、水62.6g、吐温80 0.6g、蛋黄卵磷脂1.1g、透明质酸0.7g混合。混合液抽入一个注射器中，另用一个注射器抽取无菌空气，室温下，用临床上通用的泡沫制作方法---Tessari法，按照液体：空气＝1:3的比例制备乙醇泡沫，形成均一、稳定、致密的泡沫，且泡沫半衰期在1min以上。
实施例4
分别将无水乙醇33.3g、水64.4g、吐温80 0.7g、蛋黄卵磷脂0.9g、透明质酸0.7g混合。混合液抽入一个注射器中，另用一个注射器抽取无菌空气，室温下，用临床上通用的泡沫制作方法---Tessari法，按照液体：空气＝1:3的比例制备乙醇泡沫，形成均一、稳定、致密的泡沫，且泡沫半衰期在1min以上。
实施例5
分别将无水乙醇40.5g、水56.3g、吐温80 0.6g、蛋黄卵磷脂1.1g、透明质酸1.5g混合。混合液抽入一个注射器中，另用一个注射器抽取无菌空气，室温下，用临床上通用的泡沫制作方法---Tessari法，按照液体：空气＝1:3的比例制备乙醇泡沫，形成均一、稳定、致密的泡沫，且泡沫半衰期比实施例1更长。
如图1所示为制备乙醇泡沫过程的示意图和制备得到的泡沫的图，可以得到，乙醇泡沫为微小乳化状泡沫。
对比例1
与实施例1不同的是不加入吐温80，蛋黄卵磷脂为1.7g，结果为溶液不能形成泡沫。
对比例2
与实施例1不同的是不加入蛋黄卵磷脂，吐温80为1.7g，结果为溶液不能形成泡沫。
对比例3
与实施例1不同的是无水乙醇50g，水为47.2g。结果为不成泡沫。
试验例1
细胞实验：利用不同浓度的乙醇水溶液，进行CCK8细胞实验，细胞为脐静脉内皮细胞。试验中分为空白组(无细胞)、对照组(生理盐水与无水乙醇)、实验组(乙醇水溶液的体积分数分别为10％、20％、30％、40％、50％、60％、70％、80％、90％),具体曲线如图2所示，图中每组从左至右依次为系列1-系列6，系列1-系列6指的是在同样的实验条件进行六次得到的结果，得到30-100％体积分数的乙醇水溶液均具有较好的破坏能力，能够使脐静脉内皮细胞坏死。考虑到实验误差及血液稀释作用，本发明尽量提高混合溶液中乙醇的浓度。
试验例2
血浆实验：利用无水乙醇和实施例1的硬化剂液体进行血浆实验，如图3A所示，为取新鲜人抗凝血1mL，如图3C为在试管内放入无水乙醇，如图3B为在试管内加入实施例1的硬化剂液体，如图3C所示，试管内立即形成大量红褐色固态物质，无水乙醇使血浆内的蛋白发生凝固，如图3B所示，试管内血液颜色略变深，但无明显固体析出，实施例1得到的硬化剂不会使血浆内的蛋白发生凝固。
试验例3
动物实验：第一实验组：实验对象为20只1.5kg新西兰大耳白兔，注射0.5mL无水乙醇液体；第二实验组：实验对象为20只1.5kg新西兰大耳白兔，注射0.5mL实施例1的泡沫硬化剂；第一实验组和第二实验组的实验对象实验之前的耳朵边缘均完好正常。
第一实验组的结果如图4A所示，其中a为刚注射后的反应，耳缘立即出现广泛大面积血肿，b为注射3天后的反应，整耳血肿明显，c为注射7天后的反应，肿胀减轻，d为注射25天后的反应，局部血管及部分正常组织被破坏，造成兔耳缘组织缺损；第二实验组的结果如图4B所示，其中a为刚注射后的反应，管腔内充满泡沫硬化剂，管周未见明显异常，b为注射3天后的反应，局部出现血肿，相比于注射无水乙醇症状较轻，c为注射7天后的反应，血肿基本消退，仅耳缘静脉周围炎症较明显，d为注射25天后的反应，血管消失，局部正常组织无明显变化。
说明本发明的泡沫硬化剂对局部正常组织副反应轻微。
试验例4
临床研究：患者主诉、诊断、治疗方法、治疗效果详细如下：
患者1
女，57岁，病史：自幼面部肿胀，近5年来加重，舌体肥大，影响语言和进食，伴打鼾，诊断为：面颈部巨大静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，每月一次，每次约10ml，3个月后，硬化治疗效果显著，待病变部位质地变韧之后，考虑手术修复。
患者2
男，25岁，病史：面部肿胀发现20年，逐渐加重，治疗方法为：实施例2乙醇泡沫硬化治疗，每月一次，共2次，每次约5ml，2个月后，硬化治疗效果显著。
患者3
女，19岁，病史：右下肢沉重感10年，运动时加重，诊断为：右下肢静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，每月一次，每次约10ml，2个月后，症状明显好转。待症状加重时继续治疗。
患者4
男，32岁，病史：阴茎勃起时龟头出现包块，婚后影响夫妻生活。诊断为：龟头静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，治疗一次，使用1ml，已经得到治愈。
患者5
女，22岁，病史：舌侧缘包块发现2年，诊断为：舌静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，治疗一次，使用1ml，已经得到治愈。
患者6
女，70岁，病史：下唇包块50余年，近来加重，诊断为：下唇静脉畸形， 治疗方法为：实施例2乙醇泡沫硬化治疗，治疗一次，使用0.5ml，取得较好的治疗效果，已经得到治愈。
患者7
女，60岁，病史：口底肿胀40多年，诊断为：口底静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，每月一次，共2次，每次约10ml，已经治愈。
患者8
女，50岁，病史：舌体反复肿胀30多年，诊断为：舌静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，每月一次，治疗2次，每次约2ml，已经治愈。
患者9
男，66岁，病史：舌头肿物发现1年，诊断为：舌静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，治疗一次，使用1ml，已经痊愈。
患者10
女，53岁，病史：面部肿胀40年，诊断为：上唇静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，每月一次，第一次约10ml，第二次约5ml，已经痊愈。
患者11
女，58岁，病史：右颈部包块发现10余年，诊断为：右颈部静脉畸形Ⅳ型，治疗方法为：DSA下利用实施例2乙醇泡沫硬化治疗，每月一次，共治疗3次，每次约8ml，取得较好的治疗效果，已经得到治愈。
患者12
男，61岁，病史：舌体包块半年，诊断为：右舌静脉畸形，治疗方法为：实 施例2乙醇泡沫硬化治疗，治疗一次，使用1ml，已经痊愈。
患者13
男，25岁，病史：咽部异物感10年，诊断为：软腭静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，每月一次，共治疗2次，每次约5ml，已经痊愈。
患者14
女，30岁，病史：上唇包块20年，诊断为：上唇静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，治疗一次，使用3ml，已经痊愈。
患者15
男，39岁，病史：下巴包块30年，诊断为：下唇静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，每月一次，共治疗3次，每次约10ml，已经痊愈。
患者16
男，14岁，病史：面颈胸部肿胀数年，诊断为：面颈胸部静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，每月一次，共治疗3次，每次约10ml，取得较好的治疗效果，已经得到治愈。
患者17
男，48岁，病史：右颊部肿胀发现5年，诊断为：右颊部静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，治疗一次，使用2ml，已经痊愈。
患者18
女，47岁，病史：左面部外伤后肿胀不消退约1年，诊断为：左面部外伤性静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，治疗一次，使用3ml，已经痊愈。
患者19
男，16岁，病史：左腮腺区肿胀1年，诊断为：左腮腺区静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，治疗一次，使用3ml，疗效显著，已经痊愈。
患者20
女，49岁，病史：舌体肿胀40多年，诊断为：舌口底静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，每月一次，共治疗3次，每次约6ml，取得较好的治疗效果，已经得到治愈。
患者21
女，32岁，病史：口底肿胀20多年，诊断为：口底颈部静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，每月一次，共治疗3次，每次约6ml，取得较好的治疗效果，已经得到治愈。
患者22
男，47岁，病史：左颞部肿胀3年，诊断为：左颞部静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，治疗一次，使用4ml，疗效显著，已经痊愈。
患者23
女，66岁，病史：下唇肿胀3年，逐渐加重，诊断为：下唇静脉畸形，治疗方法为：实施例2乙醇泡沫硬化治疗，治疗一次，使用4ml，疗效显著，已经痊愈。
本发明的泡沫硬化剂对各种静脉畸形均具有较好的治疗效果，治疗过程简单，治疗效果明显，无明显不良反应，安全有效。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内， 所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种应用于脉管异常的乙醇泡沫硬化剂，其特征在于：包括无水乙醇、水、非离子型表面活性剂。
  2. 根据权利要求1所述的乙醇泡沫硬化剂，其特征在于：还包括稳定剂，稳定剂为透明质酸或甘油。
  3. 根据权利要求1所述的乙醇泡沫硬化剂，其特征在于：非离子性表面活性剂由吐温和卵磷脂组成；
    优选的，非离子性表面活性剂由吐温80和蛋黄卵磷脂组成。
  4. 根据权利要求3所述的乙醇泡沫硬化剂，其特征在于：乙醇泡沫硬化剂的质量组成为无水乙醇25-42％、吐温80 0.5-2％、蛋黄卵磷脂0-2％(不包括0)、剩余为水。
  5. 根据权利要求1-3任一所述的乙醇泡沫硬化剂，其特征在于：乙醇泡沫硬化剂的质量组成为无水乙醇25-42％、吐温80 0.5-2％、蛋黄卵磷脂0-2％(不包括0)、透明质酸0-2％(不包括0)、剩余为水；
    优选的，乙醇泡沫硬化剂的质量组成为无水乙醇33.3-40.5％、吐温80
    0.6-0.7％、蛋黄卵磷脂0.9-1.1％、透明质酸0-2％(不包括0)，剩余为水。
  6. 权利要求4所述的乙醇泡沫硬化剂的制备方法，其特征在于：将卵磷脂、吐温80、无水乙醇、水混合，得到混合溶液A，按照Tessari法制备得到乙醇泡沫。
  7. 权利要求5所述的乙醇泡沫硬化剂的制备方法，其特征在于：具体步骤为：将卵磷脂、吐温80、无水乙醇、水、透明质酸混合，得到混合溶液A，按照Tessari法制备得到乙醇泡沫。
  8. 根据权利要求6-7任一所述的制备方法，其特征在于：Tessari法制备泡沫的过程为：将混合溶液A放入一个注射器中，在用另一个注射器抽取无菌空气， 两个注射器之间通过医用三通阀连接，按照Tessari法前后推注若干次混合成为乙醇泡沫。
  9. 根据权利要求8所述的制备方法，其特征在于：混合溶液A与无菌空气的体积比为1：2-4。
  10. 根据权利要求8所述的制备方法，其特征在于：制备过程在室温下进行。
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