High-strength starch hydrogel microspheres and preparation method thereof
By using a variety of alkanes as dispersants and mixing amylopectin with crosslinking agents in the preparation of starch hydrogel microspheres, the problem of poor performance of existing starch microspheres is solved, and high-strength and stable microsphere preparation is achieved.
Patent Information
- Application Number
- CN202311761711.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-19
- Publication Date
- 2025-06-20
AI Technical Summary
The strength, elasticity and catheter passability of existing microspheres prepared by starch are poor, which affects the stability of the microspheres' use process.
In the process of preparing starch hydrogel microspheres, at least two C4-C15 alkanes in the oil phase are used as dispersants, and amylopectin is mixed with a crosslinking agent to form a reverse phase suspension polymerization system, and polymerization reaction is carried out to produce high-strength microspheres.
It improves the strength, elasticity and catheter passivity of the microspheres, thereby improving the stability of the microspheres' use process.
Smart Images
Figure CN120168694A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to the technical field of embolization microspheres, and more particularly, to a high-strength starch hydrogel microsphere and a preparation method thereof. Background Art
[0002] Embolization was initially developed by Sadek Hilal in 1968 and is a minimally invasive surgical technique. The aim is to block blood flow to a certain area of the body, thereby effectively shrinking tumors or occluding aneurysms, and it is currently applicable to the treatment of various malignant and benign tumors. Different indications have different requirements for the size and material of the embolic agent, so the selection of the embolic agent plays a crucial role in interventional embolization treatment.
[0003] As an excipient widely used in drug production, starch has sufficient sources, low price, non-toxicity, good biocompatibility and biodegradability, meeting the requirements of drug delivery systems. As a new type of degradable embolization microsphere product, starch microspheres have many characteristics that other embolization microspheres do not have, and they increasingly show their superiority in the application research of embolization microspheres, becoming a research hotspot at home and abroad. However, the current microspheres prepared from starch have poor properties such as strength, elasticity, and catheter passability, which affect the stability during the use of the microspheres. Summary of the Invention
[0004] The present application provides a high-strength starch hydrogel microsphere and a preparation method thereof, which can improve the stability of the microsphere during use.
[0005] In a first aspect, an embodiment of the present application provides a preparation method of a high-strength starch hydrogel microsphere, the method comprising:
[0006] Obtaining an oil phase, the oil phase comprising a dispersant and a surfactant, wherein the dispersant of the oil phase comprises at least two of alkanes having 4 to 15 carbon atoms;
[0007] Adding a cross-linking agent to the amylopectin solution to obtain an aqueous phase;
[0008] Mixing the aqueous phase and the oil phase to form an inverse suspension polymerization system, and then performing a polymerization reaction to obtain microspheres.
[0009] In the above implementation process, by using at least two dispersants as the dispersant of the oil phase, the properties of the prepared microspheres such as strength, elasticity, and catheter passability can be effectively improved, which is conducive to enhancing the stability during the use of the microspheres.
[0010] As an optional implementation manner, the dispersant of the oil phase comprises at least two of alkanes having 5 to 11 carbon atoms.
[0011] As an alternative embodiment, the dispersant for the oil phase comprises at least two of cyclohexane, n-nonane, n-decane, n-undecane, n-dodecane and n-tridecane.
[0012] As an alternative embodiment, the dispersant for the oil phase comprises a first dispersant and a second dispersant. The first dispersant comprises cyclohexane, and the second dispersant comprises at least one of n-nonane, n-decane, n-undecane, n-dodecane and n-tridecane.
[0013] As an alternative embodiment, the volume ratio of the first dispersant to the second dispersant is (0.5 to 1.5):(0.5 to 1.5).
[0014] As an alternative embodiment, the volume ratio of oil to water in the inverse suspension polymerization system is 100:32.5.
[0015] As an alternative embodiment, the amylopectin comprises corn amylopectin.
[0016] As an alternative embodiment, the aqueous phase comprises amylopectin, sodium trimetaphosphate and sodium tripolyphosphate; and / or
[0017] The oil phase comprises a dispersant, Span-60 and Tween-60.
[0018] In a second aspect, an embodiment of the present application provides a high-strength starch hydrogel microsphere, which is prepared by the method provided by the first method. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The drawings herein are incorporated into the specification and form a part of the specification, showing embodiments consistent with the present application, and are used together with the specification to explain the principles of the present application.
[0020] To more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, for those of ordinary skill in the art, other drawings can also be obtained based on these drawings without creative efforts.
[0021] Figure 1 is a flowchart of the method provided by the embodiment of the present application;
[0022] Figure 2 is a morphology diagram of the microsphere provided by Comparative Example 1 of the present application after replacement;
[0023] Figure 3 is a morphology diagram of the microsphere provided by Comparative Example 2 of the present application after replacement;
[0024] Figure 4 is a morphology diagram of the microsphere provided by Comparative Example 3 of the present application after replacement;
[0025] Figure 5 Morphology diagram of the microspheres provided in Comparative Example 4 of this application after replacement;
[0026] Figure 6 Morphology diagram of the microspheres provided in Comparative Example 5 of this application after replacement;
[0027] Figure 7 Morphology diagram of the microspheres provided in Comparative Example 6 of this application after replacement;
[0028] Figure 8 Morphology diagram of the microspheres provided in Example 1 of this application after replacement;
[0029] Figure 9 Morphology diagram of the microspheres provided in Example 2 of this application after replacement;
[0030] Figure 10 Morphology diagram of the microspheres provided in Example 3 of this application after replacement;
[0031] Figure 11 Morphology diagram of the microspheres provided in Example 4 of this application after replacement;
[0032] Figure 12 Morphology diagram of the microspheres provided in Example 5 of this application after replacement;
[0033] Figure 13 Morphology diagram of the microspheres provided in Comparative Example 1 of this application after sterilization;
[0034] Figure 14 Morphology diagram of the microspheres provided in Comparative Example 2 of this application after sterilization;
[0035] Figure 15 Morphology diagram of the microspheres provided in Comparative Example 3 of this application after sterilization;
[0036] Figure 16 Morphology diagram of the microspheres provided in Comparative Example 4 of this application after sterilization;
[0037] Figure 17 Morphology diagram of the microspheres provided in Comparative Example 5 of this application after sterilization;
[0038] Figure 18 Morphology diagram of the microspheres provided in Comparative Example 6 of this application after sterilization;
[0039] Figure 19 Morphology diagram of the microspheres provided in Example 1 of this application after sterilization;
[0040] Figure 20 Morphology diagram of the microspheres provided in Example 2 of this application after sterilization;
[0041] Figure 21 Morphology diagram of the microspheres provided in Example 3 of this application after sterilization;
[0042] Figure 22 Morphology diagram of the microspheres provided in Example 4 of this application after sterilization;
[0043] Figure 23 Morphology diagram of the microspheres provided in Example 5 of this application after sterilization;
[0044] Figure 24 Morphology diagram of the microspheres provided in Example 1 of this application after catheter passing test;
[0045] Figure 25 Morphology diagram of the microspheres provided in Example 2 of this application after catheter passing test;
[0046] Figure 26 Morphology diagram of the microspheres provided in Example 3 of this application after catheter passing test;
[0047] Figure 27 Morphology diagram of the microspheres provided in Example 4 of this application after catheter passing test;
[0048] Figure 28 Morphology diagram of the microspheres provided in Example 5 of this application after catheter passing test. Detailed implementation manners
[0049] To make the objectives, technical solutions and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings in the embodiments of this application. Obviously, the described embodiments are some but not all of the embodiments of this application. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of this application without creative efforts shall fall within the protection scope of this application.
[0050] Unless otherwise specifically stated, all kinds of raw materials, reagents, instruments and equipment used in this application can be obtained through market purchase or can be prepared by existing methods.
[0051] The various embodiments of the present application may exist in the form of a range; it should be understood that the description in the form of a range is only for convenience and brevity, and should not be construed as a rigid limitation on the scope of the present application; therefore, it should be considered that the range description has specifically disclosed all possible sub-ranges and individual values within that range. For example, it should be considered that the range description from 1 to 6 has specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and individual numbers within the range, such as 1, 2, 3, 4, 5, and 6, which applies regardless of the range. Additionally, whenever a numerical range is indicated herein, it means including any cited number (fraction or integer) within the indicated range.
[0052] In the present application, unless otherwise stated, the orientation terms such as "upper" and "lower" specifically refer to the drawing directions in the drawings. Additionally, in the description of the specification of the present application, the terms "include", "comprise", etc. mean "including but not limited to". In this text, relational terms such as "first" and "second" are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. In this text, "and / or" describes the association relationship of associated objects, indicating that three relationships can exist. For example, A and / or B can represent: A exists alone, A and B exist simultaneously, and B exists alone. Where A and B can be singular or plural. In this text, "at least one" means one or more, and "a plurality" means two or more. "At least one kind", "at least one of the following items (pieces)" or similar expressions refer to any combination of these items, including any combination of single items (pieces) or plural items (pieces). For example, "at least one of a, b, or c", or, "at least one of a, b, and c" can both represent: a, b, c, a - b (i.e., a and b), a - c, b - c, or a - b - c, where a, b, and c can be single or multiple respectively.
[0053] Currently, the properties such as the strength, elasticity, and catheter passability of microspheres prepared from starch are not good, which affects the stability during the use of the microspheres. The inventor intends to provide a high-strength embolization microsphere to improve the stability during the use of the microsphere.
[0054] Figure 1 For the flowchart of the method provided by the embodiments of the present application, as Figure 1 shown, the embodiments of the present application provide a method for preparing high-strength starch hydrogel microspheres, and the method includes:
[0055] S1. Obtain an oil phase, which includes a dispersant and a surfactant. By using at least two dispersants together as the dispersant of the oil phase, the properties such as the strength, elasticity, and catheter passability of the prepared microspheres can be effectively improved, thereby facilitating the improvement of the stability during the use of the microspheres.
[0056] In some embodiments, the dispersant of the oil phase includes at least two of alkanes with C4 - C15. Further, the dispersant of the oil phase includes at least two of alkanes with C5 - C11. For example, the dispersant of the oil phase includes at least two of cyclohexane, n-nonane, n-decane, n-undecane, n-dodecane, and n-tridecane. The following takes the dispersant of the oil phase being two as an example: The dispersant of the oil phase includes a first dispersant and a second dispersant. The first dispersant includes cyclohexane, and the second dispersant includes at least one of n-nonane, n-decane, n-undecane, n-dodecane, and n-tridecane. Among them, the volume ratio of the first dispersant to the second dispersant is (0.5 - 1.5):(0.5 - 1.5).
[0057] In some embodiments, the oil phase includes a dispersant, Span - 60, and Tween - 60.
[0058] S2. Add a crosslinking agent to the amylopectin solution to obtain an aqueous phase.
[0059] In some embodiments, the amylopectin includes corn amylopectin. Corn amylopectin can be obtained by the following method: Accurately weigh 100 g of the purchased starch, add 3000 mL of DMSO and stir it at 200 RPM at room temperature for 24 hours. After stirring, centrifuge at 2000 RPM, take the supernatant and add it to 2 times the amount of n-butanol, let it stand for 24 hours and then centrifuge at 4000 RPM. Take the precipitate, wash it with n-butanol 3 times, remove DMSO and then filter. Boil and dissolve the filter cake with sufficient distilled water, let it stand and cool to 60 °C, add 10 g of thymol and stir well. Let it stand at room temperature for 3 days and filter to obtain the filtrate. Pre-cool the filtrate in a 4 °C refrigerator, then add an appropriate amount of ether to extract 3 times to remove thymol. Add a large amount of ethanol to the aqueous phase until the flocculent precipitate no longer increases, let it stand at room temperature for 3 days, filter to obtain the filter cake, dry it, and obtain a white powder, which is the extracted amylopectin.
[0060] In some embodiments, the aqueous phase includes amylopectin, sodium trimetaphosphate, and sodium tripolyphosphate.
[0061] S3. Mix the aqueous phase and the oil phase to form an inverse suspension polymerization system, and then carry out a polymerization reaction to obtain microspheres.
[0062] In some embodiments, the volume ratio of oil to water in the inverse suspension polymerization system is 100:32.5.
[0063] The present application also provides a high-strength starch hydrogel microsphere, which is prepared by the method provided above.
[0064] The microspheres are prepared based on the above method. The specific steps of the method can refer to the above embodiments. Since the microspheres adopt part or all of the technical solutions of the above embodiments, they at least have all the beneficial effects brought by the technical solutions of the above embodiments, which will not be described one by one here.
[0065] The present application will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are intended only to illustrate the present application and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are usually measured according to national standards. If there is no corresponding national standard, then the conditions recommended by the manufacturer are followed.
[0066] Preparation of corn amylopectin solution: Add 10g amylopectin and 1g NaOH to every 100ml distilled water, stir and heat until gelatinized and transparent, let stand and cool for later use.
[0067] Comparative Example 1:
[0068] Aqueous phase preparation: Under stirring conditions, add 7.5 ml of an aqueous solution containing 1.5 g of STMP (sodium trimetaphosphate) and 0.15 g of STPP (sodium tripolyphosphate) to 25 ml of the pullulan solution, and stir for 5 minutes to mix thoroughly.
[0069] Under stirring conditions, add 1g Span-60 and 0.5g Teween-60 to 100ml cyclohexane to form a continuous oil phase; after stirring for a period of time, add the water phase to the oil phase. After fully mixing, stir, the reaction temperature is 50°C, react for 3 hours, then stir at room temperature overnight, stand, add a certain amount of ethanol, filter, wash with ethanol 3 times and then dry. The resulting powder is starch microspheres, which can be re-dissolved in water and sieved to obtain starch hydrogel microspheres of different particle sizes.
[0070] Comparative Example 2:
[0071] The cyclohexane in Comparative Example 1 was replaced by n-nonane.
[0072] Comparative Example 3:
[0073] The cyclohexane in Comparative Example 1 was replaced by n-decane.
[0074] Comparative Example 4:
[0075] The cyclohexane in Comparative Example 1 was replaced with n-undecane.
[0076] Comparative Example 5:
[0077] Replace the cyclohexane in Comparative Example 1 with n-dodecane.
[0078] Comparative Example 6:
[0079] Replace the cyclohexane in Comparative Example 1 with n-tridecane.
[0080] Example 1:
[0081] Aqueous phase preparation: Under stirring conditions, add 7.5 ml of an aqueous solution containing 1.5 g of STMP (sodium trimetaphosphate) and 0.15 g of STPP (sodium tripolyphosphate) to 25 ml of amylose solution, and stir for 5 minutes to mix well.
[0082] Under stirring conditions, add 1 g of Span-60 and 0.5 g of Teween-60 to 100 ml of a mixed solvent (50 ml of cyclohexane, 50 ml of n-nonane) to form a continuous phase oil phase; after stirring for a period of time, add the aqueous phase to the oil phase. After thorough mixing, stir, the reaction temperature is 50 °C, react for 3 hours, then stir at room temperature overnight, let stand, add a certain amount of ethanol, filter, wash with ethanol 3 times and then dry. The obtained powder is starch microspheres. After re-dissolving in water and passing through a sieve, starch hydrogel microspheres with different particle sizes can be obtained.
[0083] Example 2:
[0084] Replace the n-nonane in Example 1 with n-decane.
[0085] Example 3:
[0086] Replace the n-nonane in Example 1 with n-undecane.
[0087] Example 4:
[0088] Replace the n-nonane in Example 1 with n-dodecane.
[0089] Example 5:
[0090] Replace the n-nonane in Example 1 with n-tridecane.
[0091] Perform replacement on the microspheres provided in Examples 1 to 5 and Comparative Examples 1 to 6: Take 100 mL of the 300 - 600 micron microspheres after screening for each group and add 100 ml of normal saline. Let stand until the microspheres settle and form layers, then remove the upper clear liquid, and pour 100 ml of normal saline again. Repeat the above operation more than three times to obtain replacement microspheres with normal saline as the storage medium. Take pictures with an optical microscope to observe the morphology of the microspheres. The results are as Figures 2 to 12 shown. It can be seen from Figures 2 to 12 that the microspheres in each group have formed good spherical shapes and have good spherical appearances. Among them, a small amount of fragments appeared in Comparative Example 4 and Comparative Example 5.
[0092] The microspheres provided in Examples 1 to 5 and Comparative Examples 1 to 6 after replacement were subjected to mechanical property tests: The 300 - 600 - micron microspheres after replacement were subjected to stress tests using a texture analyzer to obtain the corresponding strength and elasticity. The results are shown in the following table:
[0093]
[0094]
[0095] As can be seen from the above table, the microspheres prepared by the method provided in the embodiments of the present application have relatively high strength. Compared with the microspheres provided in the comparative examples, the strength has increased from 0.602 g to 14.301 g.
[0096] The microspheres provided in Examples 1 to 5 and Comparative Examples 1 to 6 after replacement were sterilized: The 300 - 600 - micron microspheres after replacement were sterilized by high - pressure steam sterilization (120 °C, 30 minutes). Then the sterilized microspheres were taken out and imaged with an optical microscope to evaluate the stability of the microspheres after sterilization. The results are as Figures 13 to 23 shown. It can be seen from the figure that in the groups of Comparative Examples 1 - 6, obvious fragments were generated in the microspheres after high - pressure steam sterilization, and it was also found in the mechanical tests that the microspheres in Comparative Examples 1 - 6 had lower strength. It can be seen that their lower strength makes the stability of these microspheres under the conditions of steam sterilization poor, which is not conducive to the application of embolization technology. While Examples 1 - 5 have relatively high strength and can maintain a good morphology after steam sterilization.
[0097] The microspheres provided by the group without fragment generation after sterilization were subjected to microsphere suspension test: Take 2 mL of the 300 - 600 - micron microspheres after replacement (only the group without fragment generation after sterilization), add 2 mL of contrast agent (iohexol 300), and after mixing evenly to reach a stable state, use a 20 - mL syringe for vertical tube timing to observe the suspension state of the microspheres.
[0098] Then a catheter passage test was carried out: The syringe filled with the contrast agent - microsphere suspension was connected to a 2.7F micro - catheter. The tail end of the micro - catheter was placed in a centrifuge tube, and then injected pulsatively at a speed of 1 mL / 1 min. The microspheres passing through the catheter were collected and imaged with an optical microscope to evaluate the stability of the microspheres after catheter injection. The results are as Figures 24 to 28 shown. It can be seen from the figure that in the groups of Examples 1 - 5, obvious fragments were generated in Examples 4 - 5 after experiencing suspension and catheter passage, while Examples 1 - 3 have a better morphology and are more suitable for the application of embolization.
[0099] In summary, the morphological results of the microspheres provided in Examples 1 to 5 and Comparative Examples 1 to 6 after each stage are shown in the following table:
[0100]
[0101]
[0102] The above are only specific embodiments of the present application, enabling those skilled in the art to understand or implement the present application. Various modifications to these embodiments will be obvious to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, the present application will not be limited to these embodiments shown herein, but rather to the broadest scope consistent with the principles and novel features claimed herein.
Claims
1. A method for preparing high-strength starch hydrogel microspheres, characterized in that, The method includes: obtaining an oil phase, where the oil phase includes a dispersant and a surfactant, and where the dispersant includes at least two of alkanes having 4 to 15 carbon atoms; adding a crosslinking agent to an amylopectin solution to obtain an aqueous phase; mixing the aqueous phase and the oil phase to form a reverse suspension polymerization system, and then carrying out a polymerization reaction to obtain microspheres.
2. The method for preparing high-strength starch hydrogel microspheres according to claim 1, characterized in that, The dispersant of the oil phase includes at least two of alkanes having 5 to 11 carbon atoms.
3. The method for preparing high-strength starch hydrogel microspheres according to claim 1, characterized in that, The dispersant of the oil phase includes at least two of cyclohexane, n-nonane, n-decane, n-undecane, n-dodecane, and n-tridecane.
4. The method for preparing high-strength starch hydrogel microspheres according to claim 3, characterized in that, The dispersant of the oil phase includes a first dispersant and a second dispersant, the first dispersant includes cyclohexane, and the second dispersant includes at least one of n-nonane, n-decane, n-undecane, n-dodecane, and n-tridecane.
5. The method for preparing high-strength starch hydrogel microspheres according to claim 4, characterized in that, The volume ratio of the first dispersant to the second dispersant is (0.5 to 1.5):(0.5 to 1.5).
6. The method for preparing high-strength starch hydrogel microspheres according to any one of claims 1 to 5, characterized in that, The volume ratio of oil to water in the reverse suspension polymerization system is 100:32.
5.
7. The method for preparing high-strength starch hydrogel microspheres according to any one of claims 1 to 5, characterized in that, The amylopectin includes corn amylopectin.
8. The method for preparing high-strength starch hydrogel microspheres according to any one of claims 1 to 5, characterized in that, The aqueous phase includes amylopectin, sodium trimetaphosphate, and sodium tripolyphosphate.
9. The method for preparing high-strength starch hydrogel microspheres according to any one of claims 1 to 5, characterized in that, The oil phase includes a dispersant, Span-60, and Tween-60.
10. A high-strength starch hydrogel microsphere, characterized in that, The microspheres are prepared by the method according to any one of claims 1 to 9.