Preparation method of oxidized cellulose embolism particles

Abstract

The invention discloses a preparation method of oxidized cellulose embolism particles, which comprises the following steps: dissolving cellulose in an organic solvent to obtain a cellulose solution; adding an oxidizing agent into the cellulose solution, and carrying out staged oxidation reaction to obtain a reaction solution containing oxidized cellulose; adding absolute ethyl alcohol into the reaction solution to terminate the reaction, filtering the reaction solution, washing the precipitate, and drying to obtain oxidized cellulose; and crushing and screening the oxidized cellulose to obtain the oxidized cellulose embolism particles. The oxidation degree is controlled through staged oxidation and effective adjustment of oxidation conditions, and the prepared oxidized cellulose embolization particles are good in dispersity and excellent in mechanical property.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of oxidized cellulose embolization particles. BACKGROUND

[0002] Embolization therapy is a surgical method of intentionally blocking the arterial or venous blood vessels through interventional means. The operation usually uses selective catheterization or direct puncture to deliver embolization agents to the target blood vessel system. The embolization agent promotes thrombosis in the blood vessels, thereby cutting off the blood supply, and ultimately achieving the purpose of killing tumor cells, controlling bleeding or restoring normal function of organs. At present, embolization therapy has been widely used in the treatment of various diseases, such as tumors, vascular malformations and hemorrhagic diseases.

[0003] Embolization agents can be divided into permanent and temporary types according to their residence time in the body, which mainly depends on the biodegradability of the embolization material. The commonly used permanent solid embolization materials in clinical practice include polyvinyl alcohol (PVA) particles, sodium alginate microspheres and micro-coil, etc. However, long-term retention of such permanent materials in the human body may have physical effects, trigger immune responses, and even cause serious complications (such as blood vessel perforation, inflammation and infection), which in extreme cases require secondary medical intervention, which to some extent limits their clinical application. In contrast, biodegradable embolization materials (such as gelatin sponge and polylactic acid) are more concerned, but they also have their own shortcomings. For example, although gelatin sponge particles have a mature preparation process and significant hemostatic effect, they can easily cause inflammatory reactions after surgery and often require anti-inflammatory treatment. The preparation process of polylactic acid material is relatively complex, and the acidic products produced during the degradation process can cause a decrease in local pH, which may cause abdominal pain, fever and other symptoms in patients.

[0004] Cellulose, as the most abundant renewable biological material, its derivative products have been widely used in many fields such as textiles, medical device manufacturing, etc. Oxidized cellulose is a derivative obtained by partial oxidation of cellulose, which has good biocompatibility and has many mature applications in the medical field: in the field of hemostatic gauze, its excellent water absorption and swelling capacity can effectively concentrate blood components, accelerate plasma coagulation and reduce blood loss; in the field of surgical sutures, it is widely used in surgical operations due to its excellent biocompatibility, degradability and tensile strength; in the field of tissue repair, it can be used to manufacture degradable medical stents, which are suitable for tissue repair and regenerative medicine; in addition, it can also be used as an excipient for drugs.

[0005] Although oxidized cellulose has been explored for various medical uses (especially in the field of hemostatic gauze and surgical suture, etc. has mature application) as a biocompatible degradable material, so far, there is no relevant report of its development as an embolic agent. This is mainly because the conventional oxidized cellulose has good water solubility, and is easy to absorb water and swell, which is difficult to meet the requirements of embolic agents. However, by adjusting the degree of oxidation, oxidized cellulose particle materials with good hydrophobicity and certain hydrophilicity can be prepared. Such materials neither completely dissolve nor aggregate in the vascular environment, but maintain good dispersibility, thereby becoming a very potential new embolic material. SUMMARY

[0006] The technical problem solved by the present application is to provide a method for preparing oxidized cellulose embolic particles, which controls the degree of oxidation by stage oxidation and effectively adjusts the oxidation conditions, so as to prepare oxidized cellulose embolic particles with good dispersibility and excellent mechanical properties.

[0007] To solve the above technical problems, the technical scheme of the present application is:

[0008] A method for preparing oxidized cellulose embolic particles, comprising the following steps:

[0009] (1) dissolving cellulose in an organic solvent to obtain a cellulose solution;

[0010] (2) adding an oxidizing agent to the cellulose solution to perform a stage oxidation reaction to obtain a reaction liquid containing oxidized cellulose;

[0011] (3) adding anhydrous ethanol to the reaction liquid to terminate the reaction, filtering the reaction liquid, and drying after washing the precipitate to obtain oxidized cellulose;

[0012] (4) crushing and sieving the above oxidized cellulose to obtain oxidized cellulose embolic particles.

[0013] Preferably, in step (1), the organic solvent is selected from one or more of N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide.

[0014] Preferably, in step (1), the cellulose is α-cellulose with a purity of ≥98%, and the concentration of the cellulose solution is 8-12wt%.

[0015] Preferably, in step (2), the oxidizing agent is a composite system of 2,2,6,6-tetramethylpiperidine-1-oxyl radical and sodium hypochlorite.

[0016] Preferably, in step (2), the staged oxidation reaction is first adding 2,2,6,6-tetramethylpiperidine-1-oxyl radical to the cellulose solution to perform a first oxidation reaction, and then adding sodium hypochlorite solution to perform a second oxidation reaction, and nitrogen is introduced into the reaction system during the reaction process, and the pH of the reaction system is adjusted to 9.0.

[0017] Preferably, in step (2), during the first oxidation treatment, the amount of 2,2,6,6-tetramethylpiperidine-1-oxyl radical added is 0.7-0.9 times the molar number of the hydroxyl groups contained in the cellulose, the temperature during the first oxidation is 13-17℃, and the time is 0.8-1.1h.

[0018] Preferably, in step (2), during the second oxidation treatment, the amount of sodium hypochlorite solution added is 1.0-1.2 times the molar number of the hydroxyl groups contained in the cellulose, the temperature during the second oxidation is 23-27℃, and the time is 5-6h.

[0019] Preferably, the average particle size of the oxidized cellulose embolism particles is 100-500μm.

[0020] Due to the adoption of the above technical solutions, the present application has at least the following beneficial effects:

[0021] The present application provides a preparation method of oxidized cellulose embolism particles, which realizes precise control of the oxidation degree of cellulose through staged oxidation and the conditions of staged oxidation, and obtains oxidized cellulose embolism particles with balanced hydrophilicity and hydrophobicity, good dispersibility and excellent mechanical properties, which can be used for vascular embolism of various solid tumors including liver cancer.

[0022] In the present application, TEMPO and NaClO are used as oxidizing agents for the staged oxidation of cellulose. First, TEMPO radical is used as the main oxidizing agent at low temperature. TEMPO is a high-selectivity oxidizing agent that preferentially and efficiently oxidizes the primary hydroxyl group at the C6 position of the cellulose glucose unit to a carboxyl group. Low temperature limits the intensity of the reaction and the occurrence of side reactions, and the amount of TEMPO is effectively adjusted to adjust the number of oxidized primary hydroxyl groups, thereby avoiding over-oxidation. In the second oxidation, sodium hypochlorite is added at a slightly higher temperature. At this time, part of the carboxyl groups have been generated in the system, and NaClO can further oxidize the cellulose under certain pH conditions to oxidize the primary hydroxyl groups that have not completely reacted in the first stage, and slightly oxidize the secondary hydroxyl groups to generate ketone or aldehyde groups. By adjusting the conditions of the first and second oxidations, the present application effectively adjusts the oxidation degree of the oxidized cellulose, thereby precisely adjusting the dispersibility of the oxidized cellulose particles.

[0023] The surface of the prepared oxidized cellulose embolism particle has certain carboxyl groups, which will partially ionize into negative carboxylate ions in a physiological pH environment, thereby introducing negative charges on the surface of the oxidized cellulose particle; the same charges carried on the surface of the particle will generate strong electrostatic repulsion, thereby ensuring that the oxidized cellulose particle has good dispersibility in the blood vessel, so that the particle can smoothly pass through the microcatheter and uniformly embolize the target blood vessel, avoiding catheter blockage and uneven embolization.

[0024] The raw materials selected in the application have a wide source, and the cellulose, solvent and oxidizing agent used can realize industrialized production, so the application has strong practicability and wide application prospect. DETAILED DESCRIPTION

[0025] In order to more clearly understand the above-mentioned purposes, features and advantages of the present application, the schemes of the present application will be further described below. It should be noted that the embodiments of the present application and the features in the embodiments can be combined with each other without conflict.

[0026] In the following description, many specific details are set forth in order to provide a thorough understanding of the present application, but the present application can also be implemented in other different manners from those described herein; obviously, the embodiments in the description are only some embodiments of the present application, rather than all the embodiments.

[0027] In order to further understand the present application, the preferred embodiments of the present application will be described below in combination with the embodiments, but it should be understood that these descriptions are only for further illustrating the features and advantages of the present application, rather than limiting the claims of the present application.

[0028] Embodiment 1

[0029] A preparation method of an oxidized cellulose embolism particle, comprising the following steps:

[0030] (1) α-cellulose (purity ≥ 98%) is dissolved in 50 ml of a mixed solvent of N-methyl pyrrolidone and dimethyl sulfoxide (the volume ratio of N-methyl pyrrolidone to dimethyl sulfoxide is 3:1) at 8°C to obtain a cellulose solution with a concentration of 8 wt%;

[0031] (2) Under a nitrogen atmosphere, 2,2,6,6-tetramethylpiperidine-1-oxyl radical (the addition amount is 0.7 times the molar number of the hydroxyl groups contained in the cellulose) is added to the cellulose solution of step (1), and the reaction is carried out at 13°C for 0.8 h, the temperature is raised to 23°C, sodium hypochlorite solution (the addition amount is 1.0 times the molar number of the hydroxyl groups contained in the cellulose) is added, and the reaction is carried out at constant temperature for 5 h, and the pH of the reaction system is adjusted to 9.0 during the above reaction process;

[0032] (3) After the reaction is completed, the reaction solution of step (2) is cooled to room temperature, anhydrous ethanol is added to the reaction solution to terminate the reaction, the reaction solution is filtered, the precipitate is washed with anhydrous ethanol and dried to obtain oxidized cellulose;

[0033] (4) The above oxidized cellulose is crushed and sieved to obtain oxidized cellulose embolism particles with an average particle size of 300 μm.

[0034] Example 2

[0035] A method for preparing oxidized cellulose embolism particles, comprising the following steps:

[0036] (1) α-cellulose (purity ≥ 98%) is dissolved in 50 ml of a mixed solvent of N-methyl pyrrolidone and dimethyl sulfoxide (the volume ratio of N-methyl pyrrolidone to dimethyl sulfoxide is 3:1) at 9°C to obtain a cellulose solution with a concentration of 9 wt%;

[0037] (2) Under a nitrogen atmosphere, 2,2,6,6-tetramethylpiperidine-1-oxyl radical is added to the cellulose solution of step (1) (the addition amount is 0.8 times the molar number of hydroxyl groups contained in the cellulose), and the reaction is carried out at 14°C for 0.9 h, the temperature is raised to 24°C, sodium hypochlorite solution is added (the addition amount is 1.0 times the molar number of hydroxyl groups contained in the cellulose), and the reaction is carried out at constant temperature for 5.5 h. During the above reaction process, the pH of the reaction system is adjusted to 9.0;

[0038] (3) After the reaction is completed, the reaction solution of step (2) is cooled to room temperature, anhydrous ethanol is added to the reaction solution to terminate the reaction, the reaction solution is filtered, the precipitate is washed with anhydrous ethanol and dried to obtain oxidized cellulose;

[0039] (4) The above oxidized cellulose is crushed and sieved to obtain oxidized cellulose embolism particles with an average particle size of 300 μm.

[0040] Example 3

[0041] A method for preparing oxidized cellulose embolism particles, comprising the following steps:

[0042] (1) α-cellulose (purity ≥ 98%) is dissolved in 50 ml of a mixed solvent of N-methyl pyrrolidone and dimethyl sulfoxide (the volume ratio of N-methyl pyrrolidone to dimethyl sulfoxide is 3:1) at 9°C to obtain a cellulose solution with a concentration of 9 wt%;

[0043] (2) Under a nitrogen atmosphere, 2,2,6,6-tetramethylpiperidine-1-oxyl radical (added in an amount of 0.85 times the molar number of the hydroxyl groups contained in the cellulose) was added to the cellulose solution of step (1), and the reaction was carried out at 15°C for 1.0 h, and then the temperature was raised to 25°C, and a sodium hypochlorite solution (added in an amount of 1.1 times the molar number of the hydroxyl groups contained in the cellulose) was added, and the reaction was carried out at a constant temperature for 5.5 h, and the pH of the reaction system was adjusted to 9.0 during the above reaction;

[0044] (3) After the reaction was completed, the reaction solution of step (2) was cooled to room temperature, and anhydrous ethanol was added to the reaction solution to terminate the reaction, and the reaction solution was filtered, and the precipitate was washed with anhydrous ethanol and then dried to obtain oxidized cellulose;

[0045] (4) The above oxidized cellulose was crushed and sieved to obtain oxidized cellulose embolization particles having an average particle size of 400 μm.

[0046] Example 4

[0047] A method for preparing oxidized cellulose embolization particles, comprising the following steps:

[0048] (1) α-Cellulose (purity ≥ 98%) was dissolved in 50 ml of a mixed solvent of N-methylpyrrolidone and dimethyl sulfoxide (volume ratio of N-methylpyrrolidone to dimethyl sulfoxide: 3:1) at 10°C to obtain a cellulose solution having a concentration of 12 wt%;

[0049] (2) Under a nitrogen atmosphere, 2,2,6,6-tetramethylpiperidine-1-oxyl radical (added in an amount of 0.9 times the molar number of the hydroxyl groups contained in the cellulose) was added to the cellulose solution of step (1), and the reaction was carried out at 17°C for 1.1 h, and then the temperature was raised to 27°C, and a sodium hypochlorite solution (added in an amount of 1.2 times the molar number of the hydroxyl groups contained in the cellulose) was added, and the reaction was carried out at a constant temperature for 6 h, and the pH of the reaction system was adjusted to 9.0 during the above reaction;

[0050] (3) After the reaction was completed, the reaction solution of step (2) was cooled to room temperature, and anhydrous ethanol was added to the reaction solution to terminate the reaction, and the reaction solution was filtered, and the precipitate was washed with anhydrous ethanol and then dried to obtain oxidized cellulose;

[0051] (4) The above oxidized cellulose was crushed and sieved to obtain oxidized cellulose embolization particles having an average particle size of 400 μm.

[0052] Comparative Example 1

[0053] This comparative example differs from Example 4 in that, in step (1), an equal amount of N-methylpyrrolidone was used instead of dimethyl sulfoxide, and the other operations were the same as in Example 4.

[0054] Comparative Example 2

[0055] The comparative example is different from example 4 in that in step (1), an equal amount of dimethyl sulfoxide is used instead of N-methyl pyrrolidone, and the other operations are the same as in example 4.

[0056] Comparative example 3

[0057] The comparative example is different from example 4 in that in step (2), the specific process is:

[0058] Under a nitrogen atmosphere, 2,2,6,6-tetramethylpiperidine-1-oxyl free radical is added to the cellulose solution of step (1) (the amount added is 2.1 times the number of moles of hydroxyl groups contained in the cellulose), and the reaction is carried out at 17°C for 7.1 h. During the above reaction process, the pH of the reaction system is adjusted to 9.0. The other operations are the same as in example 4.

[0059] Comparative example 4

[0060] The comparative example is different from example 4 in that in step (2), the specific process is:

[0061] Under a nitrogen atmosphere, sodium hypochlorite solution is added to the cellulose solution of step (1) (the amount added is 2.1 times the number of moles of hydroxyl groups contained in the cellulose), and the reaction is carried out at 27°C for 7.1 h. During the above reaction process, the pH of the reaction system is adjusted to 9.0. The other operations are the same as in example 4.

[0062] Comparative example 5

[0063] The comparative example is different from example 4 in that in step (2), the amount of 2,2,6,6-tetramethylpiperidine-1-oxyl free radical added is 0.5 times the number of moles of hydroxyl groups contained in the cellulose, and the other operations are the same as in example 4.

[0064] Comparative example 6

[0065] The comparative example is different from example 4 in that in step (2), the amount of 2,2,6,6-tetramethylpiperidine-1-oxyl free radical added is 1.0 times the number of moles of hydroxyl groups contained in the cellulose, and the other operations are the same as in example 4.

[0066] Comparative example 7

[0067] The comparative example is different from example 4 in that in step (2), the amount of sodium hypochlorite solution added is 0.8 times the number of moles of hydroxyl groups contained in the cellulose, and the other operations are the same as in example 4.

[0068] Comparative example 8

[0069] The comparative example is different from example 4 in that in step (2), the amount of sodium hypochlorite solution added is 1.4 times the number of moles of hydroxyl groups contained in the cellulose, and the other operations are the same as in example 4.

[0070] The performance parameters of the oxidized cellulose embolization particles prepared in the above examples and comparative examples are as follows:

[0071] 1. The physical performance test was performed on the oxidized cellulose embolization particles prepared in the above examples and comparative examples, and the TA.XT.plus C texture meter system was used for detection, a 6 mm probe was selected, the trigger force was 0.1 g, the embolization particles were compressed to 0% deformation, and the holding time was 60 sec.

[0072] 2. The oxidized cellulose embolization particles in the above examples and comparative examples were respectively dispersed in water, 0.9 wt% physiological saline and iodized oil developing solution to prepare a dispersion liquid with a weight fraction of 10%, and the dispersion and stability of the embolization particles were observed after standing at room temperature for 8 h.

[0073] The above test results are shown in Table 1.

[0074] Table 1

[0075]

[0076]

[0077] From the above test results, it can be seen that, relative to the comparative examples, the mechanical properties and dispersibility of the oxidized cellulose embolization particles prepared by effectively controlling the solvent composition, the amount of oxidizing agent, the type of oxidizing agent, the pH of the oxidation system, the oxidation temperature and other conditions can be good, and can be used in tumor embolization products.

[0078] The principles and implementation modes of the present application are described by applying specific examples in this paper, and the above examples are only used to help understand the method of the present application and its core idea, including the best mode, and also enable any person skilled in the art to practice the present application, including manufacturing and using any device or system, and implementing any combined method. It should be noted that, for those skilled in the art, without departing from the principles of the present application, some improvements and modifications can be made to the present application, and these improvements and modifications also fall within the protection scope of the claims of the present application. The scope of patent protection of the present application is defined by the claims, and can include other embodiments that can be thought of by those skilled in the art. If these other embodiments have structural elements similar to the literal expression of the claims, or if they include equivalent structural elements that are not substantially different from the literal expression of the claims, then these other embodiments should also be included in the scope of the claims.

Claims

1. A process for the preparation of oxidized cellulose embolization particles, characterized in that, The method comprises the following steps: (1) dissolving cellulose in an organic solvent to obtain a cellulose solution; (2) adding an oxidant to the cellulose solution to perform a staged oxidation reaction to obtain a reaction solution containing oxidized cellulose; (3) adding anhydrous ethanol to the reaction solution to terminate the reaction, filtering the reaction solution, and drying the precipitate after washing to obtain oxidized cellulose; (4) crushing and screening the oxidized cellulose to obtain oxidized cellulose embolus particles.

2. A process for the preparation of an oxidized cellulose pellet for use in embolization according to claim 1, characterized in that, In step (1), the organic solvent is selected from one or more of N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide.

3. A process for the preparation of an oxidized cellulose pledget according to claim 1, characterized in that, In step (1), the cellulose is α-cellulose with a purity of ≥98%, and the concentration of the cellulose solution is 8-12 wt%.

4. The method for preparing oxidized cellulose embolic particles according to claim 1, characterized in that, In step (2), the oxidant is a composite system of 2,2,6,6-tetramethylpiperidine-1-oxyl and sodium hypochlorite.

5. The method for preparing oxidized cellulose embolic particles according to claim 2, characterized in that, In step (2), the staged oxidation reaction is first adding 2,2,6,6-tetramethylpiperidine-1-oxyl to the cellulose solution to perform a first oxidation reaction, then adding a sodium hypochlorite solution to perform a second oxidation reaction, and introducing nitrogen into the reaction system for protection during the reaction process, and adjusting the pH of the reaction system to 9.

0.

6. A process for the preparation of an oxidized cellulose pellet for use in embolization according to claim 5, characterized in that, In step (2), during the first oxidation treatment, the addition amount of 2,2,6,6-tetramethylpiperidine-1-oxyl is 0.7-0.9 times the molar number of the hydroxyl groups contained in the cellulose, the temperature during the first oxidation is 13-17℃, and the time is 0.8-1.1 h.

7. A process for the preparation of an oxidized cellulose pellet for use as a medical device according to claim 5, characterized in that, In step (2), during the second oxidation treatment, the addition amount of the sodium hypochlorite solution is 1.0-1.2 times the molar number of the hydroxyl groups contained in the cellulose, the temperature during the second oxidation is 23-27℃, and the time is 5-6 h.

8. The method for preparing oxidized cellulose embolic particles according to claim 1, characterized in that, The average particle size of the oxidized cellulose embolus particles is 100-500 μm.

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