Process method for producing vascular hardener

Abstract

The invention relates to the technical field of medical vascular hardeners, in particular to a process method for producing a vascular hardener, which comprises the following steps: introducing ethylene oxide into laurinol and triethylamine, and reacting to obtain a polydodecanol crude product; after recrystallization and purification, adding a certain amount of an additive to prepare polydocanol, adding a certain amount of water for injection into the polydocanol, and carrying out microporous filtration to obtain a polydocanol solution; before use, a polydocanol solution is prepared into stable polydocanol foam through a Tesari method, namely the vascular hardener. The vascular hardener obtained by the method is a foam hardener, and has certain foam stability and vascular replacement capability. The process has the advantages of simple preparation method and low raw material price, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of medical vascular sclerosing agents, and in particular to a process for producing vascular sclerosing agents. Background Art

[0002] Sclerosant is a corrosive chemical agent used to treat varicose veins or vascular malformations, which has a killing effect on the diseased vascular endothelium. The therapeutic mechanism is that after it is injected into the blood vessels, it contacts the vascular endothelium and causes the cells to be damaged and fall off, thereby causing the platelets and coagulation factors in the blood to aggregate naked in the collagen tissue, and under the action of the coagulation factors, a thrombus is formed to achieve a therapeutic effect. According to the classification of the mechanism of action, the sclerosants reported so far are mainly divided into three categories: detergents, chemical and penetrating. Cleansing sclerosants mainly include sodium morrhuate, STS, polidocanol and ethanolamine oleate; chemical sclerosants mainly include chromated glyceride and anhydrous ethanol; penetrating sclerosants include hypertonic saline, hypertonic glucose solution and Sclerodex.

[0003] Among them, anhydrous ethanol has a strong erosive effect and can quickly cause tissue necrosis. It is the most efficient liquid sclerosant for the treatment of vascular malformations. However, the strong erosive effect is accompanied by many difficult-to-control complications, such as peripheral nerve damage, central nervous system depression, epileptic seizures, etc., and the incidence of complications increases with the increase in the dosage of treatment. Polydocanol has fixed hydrophilic and hydrophobic ends, which can be arranged in a directional manner on the surface of the solution, significantly reducing the surface tension of the solution and forming foam. Because it is painless when injected into the blood vessel, has few allergic reactions, no hemolysis occurs, and has significant efficacy, it has become the most widely used foam sclerosant in my country. At present, foam sclerosing has good therapeutic efficacy and safety, and there is a trend of gradually replacing liquid sclerosing therapy. However, extravascular necrosis and ulcers may occur during the use of polydocanol, so the concentration should be appropriately reduced during the application process. However, with the growing demand for medical and health services, in order to improve the treatment effect of venous malformations, an ideal sclerosant is needed, which should have almost no adverse reactions and be specific to malformed veins. Summary of the invention

[0004] In view of the problems existing in the background technology, the present invention provides a process for producing a vascular sclerosant. The method is simple to operate and can significantly improve the performance of the vascular sclerosant. The method is achieved through the following technical solutions: Step a: adding lauryl alcohol and triethylamine into a reaction kettle, and then slowly introducing ethylene oxide in batches after degassing and dehydration, and reacting for 5 to 6 hours at a temperature of 80 to 95° C. and a pressure of 0.3 to 0.4 MPa; Step b: After the reaction is completed, filter and concentrate to obtain a crude product of polidocanol; Step c: adding acetonitrile to the crude polidocanol for recrystallization and purification, and then adding a certain amount of additives to obtain polidocanol, wherein the additives are selected from one or more of xanthan gum, sorbitan fatty acid, egg yolk lecithin, and hyaluronic acid; Step d: adding a certain amount of water for injection to polidocanol, and performing microfiltration to obtain a polidocanol solution; Step e: Before use, the polydocanol solution obtained in step d is subjected to the Tessari method to obtain a stable polydocanol foam, i.e., a vascular sclerosant.

[0005] Preferably, the specific preparation method of step a is: adding lauryl alcohol and triethylamine in a mass ratio of 20:1 into a reaction kettle, slowly raising the temperature to 80-95° C. under vacuum conditions after degassing and dehydration, reacting for 5-6 hours at a pressure of 0.3-0.4 MPa, and slowly introducing ethylene oxide during this process until the reaction is completed.

[0006] Further preferably, the method for degassing and dehydrating in step a is: adding a molecular sieve desiccant to the reactor, then evacuating the reactor and blowing in nitrogen for replacement, and repeating this three times.

[0007] Preferably, the specific preparation method of step b is: after the reaction is completed, hydrochloric acid is added to adjust the pH value to neutral, insoluble matter is removed by filtering, and the crude product of polydocanol is obtained after concentration.

[0008] Preferably, the operating steps of the recrystallization purification in step c are: first dissolve the crude polydocanol in acetonitrile at 100°C to prepare a nearly saturated solution, filter while hot to remove insoluble impurities, cool the filtrate to allow crystals to precipitate from the supersaturated solution, filter by vacuum, separate the filter cake from the mother liquor, wash with a small amount of petroleum ether, and dry. This step is repeated three times.

[0009] Preferably, the specific preparation method of step d is: adding a certain amount of water for injection to polidocanol to prepare a 0.5% polidocanol solution, and filtering and sterilizing with a 3.015 nm ultrafiltration membrane to obtain the polidocanol solution.

[0010] Preferably, the Tessari method in step e is: two disposable syringes are connected through a medical three-way connection, and the polidocanol solution and gas are quickly pushed and mixed between the two syringes to obtain foam.

[0011] Further preferably, the ratio of the polydocanol solution to the gas is 1:3, and the gas is indoor air.

[0012] Compared with the existing technology, the beneficial effects of the present invention are: Polidocanol is an internationally commonly used sclerosant. It forms foam when mixed with gas. After being injected into the blood vessels, it forms an embolus to replace the corresponding volume of blood, blocking the blood flow. It is not easily diluted and washed away by the blood, which prolongs the action time of the drug on the blood vessel wall. Foam stability and vascular replacement capacity are important indicators for evaluating foam vascular sclerosants. The higher the foam stability, the larger the contact area with vascular endothelial cells and the longer the time. The vascular replacement capacity includes the farthest replacement distance and replacement time. The greater the vascular replacement capacity, the greater the distance the sclerosant pushes away the blood after being injected into the blood vessel, and the longer the time.

[0013] After adding xanthan gum, fatty acid sorbitan, egg yolk lecithin, and hyaluronic acid to polidocanol in the present invention, the time that the foam stays in the blood vessel is significantly prolonged, and the minimum residence time is more than 2 times greater than when no addition is made. As the amount added increases, the residence time also continues to rise. When the amount added reaches 20g, the residence time reaches the maximum value. On this basis, even if the amount added continues to increase, the stability is not improved. The vascular replacement ability shows the same changes. Among them, when the additive is xanthan gum, the foam stability and vascular replacement ability are the strongest. In addition, the performance of the vascular sclerosant does not change significantly when the preparation process of the present invention is slightly changed. DETAILED DESCRIPTION

[0014] In order to make the application, technical scheme and advantages of the present invention more clear, the present invention is described in detail in conjunction with specific embodiments. It should be understood that the embodiments are only used to illustrate the present invention, but not to limit the protection scope of the present invention. All simple improvements to the preparation method of the present invention under the premise of the concept of the present invention belong to the protection scope of the present invention. Embodiment 1:

[0015] 1 kg of lauryl alcohol and 0.07 L of triethylamine were added to the reactor, and a molecular sieve desiccant was added to the reactor. The reactor was then evacuated and replaced with nitrogen gas, and the process was repeated three times. The temperature was then slowly raised to 80 ° C under vacuum conditions, and the reaction was carried out at a pressure of 0.3 MPa for 5 hours. During this process, ethylene oxide was slowly introduced until the reaction was completed. After the reaction was completed, hydrochloric acid was added to adjust the pH value to neutral, and the insoluble matter was removed by filtration. After concentration, the crude polydocanol was obtained. The crude polydocanol was first heated and dissolved in acetonitrile to prepare a nearly saturated solution, and the insoluble impurities were removed by hot filtration. The filtrate was cooled to precipitate crystals from the supersaturated solution, and the filter cake was separated from the mother liquor, washed with a small amount of petroleum ether, and dried. This step was repeated three times. After purification, a certain amount of water for injection was added to the polydocanol to prepare a 0.5% polydocanol solution.

[0016] The above 0.5% polydocanol solution was divided into four parts, and 10g, 15g, 20g and 25g of xanthan gum were added respectively. The polydocanol solutions were filtered and sterilized using a 3.015nm ultrafiltration membrane and named as polydocanol a, polydocanol b, polydocanol c and polydocanol d respectively.

[0017] Foam stability test Connect two disposable syringes through a medical tee, draw the polidocanol solution and room air into a 10ml disposable syringe at a ratio of 1:3, quickly push between the two syringes 40-50 times to mix, and make stable polidocanol foam. Push all the foam into one syringe at once for the last push. Remove the syringe containing all the foam from the tee and place it vertically upside down on a horizontal table. Start timing at this moment and observe the changes in the foam. Count the time when the amount of liquid precipitated from the bottom of the syringe is half the volume of the original mixed solution. Repeat each group of experiments ten times to calculate the average value.

[0018] Table 1 Foam stability test results

[0019] Foam blood replacement ability experiment The foam was prepared by the Tessari method. After the foam was prepared, the bottom three-way was immediately opened and 3 mL of foam was injected into the simulated blood vessel. The farthest distance the foam reached and the time taken to retreat the first 4 cm were recorded.

[0020] Table 2 Results of the foam blood replacement test

[0021] Embodiment 2: 1 kg of lauryl alcohol and 0.07 L of triethylamine were added to the reactor, and a molecular sieve desiccant was added to the reactor. The reactor was then evacuated and replaced with nitrogen gas, and the process was repeated three times. The temperature was then slowly raised to 80 ° C under vacuum conditions, and the reaction was carried out at a pressure of 0.3 MPa for 5 hours. During this process, ethylene oxide was slowly introduced until the reaction was completed. After the reaction was completed, hydrochloric acid was added to adjust the pH value to neutral, and the insoluble matter was removed by filtration. After concentration, the crude polydocanol was obtained. The crude polydocanol was first heated and dissolved in acetonitrile to prepare a nearly saturated solution, and the insoluble impurities were removed by hot filtration. The filtrate was cooled to precipitate crystals from the supersaturated solution, and the filter cake was separated from the mother liquor, washed with a small amount of petroleum ether, and dried. This step was repeated three times. After purification, a certain amount of water for injection was added to the polydocanol to prepare a 0.5% polydocanol solution.

[0022] The above 0.5% polydocanol solution was divided into four parts, and 10g, 15g, 20g and 25g of fatty acid sorbitan were added respectively. The polydocanol solutions were filtered and sterilized with a 3.015nm ultrafiltration membrane and named as polydocanol e, polydocanol f, polydocanol g and polydocanol h respectively.

[0023] Foam stability test Connect two disposable syringes through a medical tee, draw the polidocanol solution and room air into a 10ml disposable syringe at a ratio of 1:3, quickly push between the two syringes 40-50 times to mix, and make stable polidocanol foam. Push all the foam into one syringe at once for the last push. Remove the syringe containing all the foam from the tee and place it vertically upside down on a horizontal table. Start timing at this moment and observe the changes in the foam. Count the time when the amount of liquid precipitated from the bottom of the syringe is half the volume of the original mixed solution. Repeat each group of experiments ten times to calculate the average value.

[0024] Table 3 Foam stability test results

[0025] Foam blood replacement ability experiment The foam was prepared by the Tessari method. After the foam was prepared, the bottom three-way was immediately opened and 3 mL of foam was injected into the simulated blood vessel. The farthest distance the foam reached and the time taken to retreat the first 4 cm were recorded.

[0026] Table 4 Foam blood replacement ability test results

[0027] Embodiment three: 1 kg of lauryl alcohol and 0.07 L of triethylamine were added to the reactor, and a molecular sieve desiccant was added to the reactor. The reactor was then evacuated and replaced with nitrogen gas, which was repeated three times. The temperature was then slowly raised to 80 ° C under vacuum conditions, and the reaction was carried out at a pressure of 0.3 MPa for 5 hours. During this process, ethylene oxide was slowly introduced until the reaction was completed. After the reaction was completed, hydrochloric acid was added to adjust the pH value to neutral, and the insoluble matter was removed by filtration. After concentration, the crude polydocanol was obtained. The crude polydocanol was first heated and dissolved in acetonitrile to prepare a nearly saturated solution, and the insoluble impurities were removed by hot filtration. The filtrate was cooled to precipitate crystals from the supersaturated solution, and the filter cake was separated from the mother liquor, washed with a small amount of petroleum ether, and dried. This step was repeated three times. After purification, a certain amount of water for injection was added to the polydocanol to prepare a 0.5% polydocanol solution.

[0028] The above 0.5% polydocanol solution was divided into four parts, and 10g, 15g, 20g and 25g of egg yolk lecithin were added respectively. The polydocanol solutions were filtered and sterilized using a 3.015nm ultrafiltration membrane and named polydocanol i, polydocanol j, polydocanol k and polydocanol l respectively.

[0029] Foam stability test Connect two disposable syringes through a medical tee, draw the polidocanol solution and room air into a 10ml disposable syringe at a ratio of 1:3, quickly push between the two syringes 40-50 times to mix, and make stable polidocanol foam. Push all the foam into one syringe at once for the last push. Remove the syringe containing all the foam from the tee and place it vertically upside down on a horizontal table. Start timing at this moment and observe the changes in the foam. Count the time when the amount of liquid precipitated from the bottom of the syringe is half the volume of the original mixed solution. Repeat each group of experiments ten times to calculate the average value.

[0030] Table 5 Foam stability test results

[0031] Foam blood replacement ability experiment The foam was prepared by the Tessari method. After the foam was prepared, the bottom three-way was immediately opened and 3 mL of foam was injected into the simulated blood vessel. The farthest distance the foam reached and the time taken to retreat the first 4 cm were recorded.

[0032] Table 6 Foam blood replacement ability test results

[0033] Embodiment four: 1 kg of lauryl alcohol and 0.07 L of triethylamine were added to the reactor, and a molecular sieve desiccant was added to the reactor. The reactor was then evacuated and replaced with nitrogen gas, and the process was repeated three times. The temperature was then slowly raised to 80 ° C under vacuum conditions, and the reaction was carried out at a pressure of 0.3 MPa for 5 hours. During this process, ethylene oxide was slowly introduced until the reaction was completed. After the reaction was completed, hydrochloric acid was added to adjust the pH value to neutral, and the insoluble matter was removed by filtration. After concentration, the crude polydocanol was obtained. The crude polydocanol was first heated and dissolved in acetonitrile to prepare a nearly saturated solution, and the insoluble impurities were removed by hot filtration. The filtrate was cooled to precipitate crystals from the supersaturated solution, and the filter cake was separated from the mother liquor, washed with a small amount of petroleum ether, and dried. This step was repeated three times. After purification, a certain amount of water for injection was added to the polydocanol to prepare a 0.5% polydocanol solution.

[0034] The above 0.5% polydocanol solution was divided into four parts, and 10g, 15g, 20g and 25g of hyaluronic acid were added respectively. The polydocanol solutions were filtered and sterilized using a 3.015nm ultrafiltration membrane and named polydocanol m, polydocanol n, polydocanol o and polydocanol p respectively.

[0035] Foam stability test Connect two disposable syringes through a medical tee, draw the polidocanol solution and room air into a 10ml disposable syringe at a ratio of 1:3, quickly push between the two syringes 40-50 times to mix, and make stable polidocanol foam. Push all the foam into one syringe at once for the last push. Remove the syringe containing all the foam from the tee and place it vertically upside down on a horizontal table. Start timing at this moment and observe the changes in the foam. Count the time when the amount of liquid precipitated from the bottom of the syringe is half the volume of the original mixed solution. Repeat each group of experiments ten times to calculate the average value.

[0036] Table 7 Foam stability test results

[0037] Foam blood replacement ability experiment The foam was prepared by the Tessari method. After the foam was prepared, the bottom three-way was immediately opened and 3 mL of foam was injected into the simulated blood vessel. The farthest distance the foam reached and the time taken to retreat the first 4 cm were recorded.

[0038] Table 8 Foam blood replacement ability test results

[0039] Embodiment five: 1 kg of lauryl alcohol and 0.07 L of triethylamine were added to the reactor, and a molecular sieve desiccant was added to the reactor. The reactor was then evacuated and replaced with nitrogen gas, and the process was repeated three times. The temperature was then slowly raised to 95 ° C under vacuum conditions, and the reaction was carried out at a pressure of 0.4 MPa for 6 hours. During this process, ethylene oxide was slowly introduced until the reaction was completed. After the reaction was completed, hydrochloric acid was added to adjust the pH value to neutral, and the insoluble matter was removed by filtration. After concentration, the crude polydocanol was obtained. The crude polydocanol was first heated and dissolved in acetonitrile to prepare a nearly saturated solution, and the insoluble impurities were removed by hot filtration. The filtrate was cooled to precipitate crystals from the supersaturated solution, and the filter cake was separated from the mother liquor, washed with a small amount of petroleum ether, and dried. This step was repeated three times. After purification, a certain amount of water for injection was added to the polydocanol to prepare a 0.5% polydocanol solution.

[0040] The above 0.5% polydocanol solution was divided into four parts, and 10g, 15g, 20g and 25g of xanthan gum were added respectively. The polydocanol solutions were filtered and sterilized using a 3.015nm ultrafiltration membrane and named polydocanol q, polydocanol r, polydocanol s and polydocanol t respectively.

[0041] Foam stability test Connect two disposable syringes through a medical tee, draw the polidocanol solution and room air into a 10ml disposable syringe at a ratio of 1:3, quickly push between the two syringes 40-50 times to mix, and make stable polidocanol foam. Push all the foam into one syringe at once for the last push. Remove the syringe containing all the foam from the tee and place it vertically upside down on a horizontal table. Start timing at this moment and observe the changes in the foam. Count the time when the amount of liquid precipitated from the bottom of the syringe is half the volume of the original mixed solution. Repeat each group of experiments ten times to calculate the average value.

[0042] Table 9 Foam stability test results

[0043] Foam blood replacement ability experiment The foam was prepared by the Tessari method. After the foam was prepared, the bottom three-way was immediately opened and 3 mL of foam was injected into the simulated blood vessel. The farthest distance the foam reached and the time taken to retreat the first 4 cm were recorded.

[0044] Table 10 Foam blood replacement ability test results

[0045] Comparative Example 1; 1 kg of lauryl alcohol and 0.07 L of triethylamine were added to the reactor, and a molecular sieve desiccant was added to the reactor. The reactor was then evacuated and replaced with nitrogen gas, and the process was repeated three times. The temperature was then slowly raised to 80 ° C under vacuum conditions, and the reaction was carried out at a pressure of 0.3 MPa for 5 hours. During this process, ethylene oxide was slowly introduced until the reaction was completed. After the reaction was completed, hydrochloric acid was added to adjust the pH value to neutral, and the insoluble matter was removed by filtration. After concentration, the crude polydocanol was obtained. The crude polydocanol was first heated and dissolved in acetonitrile to prepare a nearly saturated solution, and the insoluble impurities were removed by hot filtration. The filtrate was cooled to precipitate crystals from the supersaturated solution, and the filter cake was separated from the mother liquor, washed with a small amount of petroleum ether, and dried. This step was repeated three times. After purification, a certain amount of water for injection was added to the polydocanol to prepare a 0.5% polydocanol solution.

[0046] The results of the foam stability test and the foam blood replacement ability test conducted according to the method described in Example 1 are shown in the table below.

[0047] Table 11 Experimental results

[0048] It can be seen from the experimental results of the above examples 1 to 5 and comparative example 1 that after adding xanthan gum, fatty acid sorbitan, egg yolk lecithin, and hyaluronic acid to polydocanol, the time the foam stays in the blood vessels is significantly extended, and the minimum residence time is more than 2 times higher than when not added. With the increase in the amount of addition, the residence time also continues to rise. When the amount of addition reaches 20g, it reaches the maximum value. At this time, even if the amount of addition continues to increase, the stability is not improved. The vascular replacement ability shows the same changes. Comprehensive analysis found that the foam stability and vascular replacement ability are the strongest when the additive is xanthan gum.

[0049] In addition, by comparing Example 1 with Example 5, it is found that the performance of the vascular sclerosant does not change significantly when the preparation process of the present invention is slightly changed.

[0050] To sum up, the above are only preferred embodiments of the present invention and are not intended to limit the present invention in any form. Any equivalent changes, modifications and evolutions made by technicians familiar with the profession without departing from the scope of the technical solution of the present invention using the disclosed technical content are regarded as equivalent embodiments of the present invention. At the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the technical solution of the present invention.

Claims

1. A process for producing a vascular sclerosing agent, characterized in that: The following steps are involved: Step a: adding lauryl alcohol and triethylamine into a reaction kettle, and slowly introducing ethylene oxide in batches after degassing and dehydration, and reacting at a temperature of 80-95°C and a pressure of 0.3-0.4MPa for 5-6 hours; Step b: After the reaction is completed, filter and concentrate to obtain a crude product of polidocanol; Step c: adding acetonitrile to the crude polidocanol for recrystallization and purification, and then adding a certain amount of additives to obtain polidocanol, wherein the additives are selected from one or more of xanthan gum, sorbitan fatty acid, egg yolk lecithin, and hyaluronic acid; Step d: adding a certain amount of water for injection to polidocanol, and performing microfiltration to obtain a polidocanol solution; Step e: Before use, the polydocanol solution obtained in step d is subjected to the Tessari method to obtain a stable polydocanol foam, i.e., a vascular sclerosant.

2. The process for producing a vascular sclerosing agent according to claim 1, characterized in that: The specific preparation method of step a is as follows: lauryl alcohol and triethylamine are added into a reaction kettle in a mass ratio of 20:1, and after degassing and dehydration, the temperature is slowly raised to 80-95° C. under vacuum conditions, and the reaction is carried out at a pressure of 0.3-0.4 MPa for 5-6 hours, during which ethylene oxide is slowly introduced until the reaction is completed.

3. The process for producing a vascular sclerosing agent according to claim 1, characterized in that: The method of degassing and dehydrating in step a is: adding a molecular sieve desiccant into the reaction kettle, then evacuating the reaction kettle and blowing in nitrogen for replacement, and repeating this process three times.

4. The process for producing a vascular sclerosing agent according to claim 1, characterized in that: The specific preparation method of step b is: after the reaction is completed, add hydrochloric acid to adjust the pH value to neutral, filter out insoluble matter, and concentrate to obtain the crude product of polydocanol.

5. The process for producing a vascular sclerosing agent according to claim 1, characterized in that: The operation of recrystallization purification in step c is as follows: first dissolve the crude polydocanol in acetonitrile at 100°C to prepare a nearly saturated solution, filter while hot to remove insoluble impurities, cool the filtrate to allow crystals to precipitate from the supersaturated solution, filter by vacuum, separate the filter cake from the mother liquor, wash with a small amount of petroleum ether, and dry. This step is repeated three times.

6. The process for producing a vascular sclerosing agent according to claim 1, characterized in that: The specific preparation method of step d is: add a certain amount of water for injection to polydocanol to prepare a 0.5% polydocanol solution, and use a 3.015nm ultrafiltration membrane to filter and sterilize to obtain the polydocanol solution.

7. The process for producing a vascular sclerosing agent according to claim 1, characterized in that: The Tessari method in step e is: two disposable syringes are connected through a medical three-way connection, and the polidocanol solution and gas are quickly pushed and mixed between the two syringes to obtain foam.

8. The process for producing a vascular sclerosing agent according to claim 7, characterized in that: The ratio of the polydocanol solution to gas is 1:3, and the gas is indoor air.

Images