Polycyanoacrylic acid-cyanoacrylate embolization microspheres, methods of making and uses thereof

Abstract

The application relates to the technical field of medical devices, and discloses a poly-cyanoacrylic acid-cyanoacrylate embolism microsphere as well as a preparation method and application thereof. The method comprises the following steps: (1) a mixed solution of a cyanoacrylate compound, a dispersing agent and water is subjected to a polymerization reaction in the presence of an initiator to obtain poly-cyanoacrylate microspheres; and (2) the poly-cyanoacrylate microspheres obtained in the step (1) are added into lye to be subjected to a partial hydrolysis reaction, and poly-cyanoacrylic acid-cyanoacrylate embolism microspheres are obtained. The poly-cyanoacrylic acid-cyanoacrylate embolism microspheres can be used for preparing a vascular embolism treatment drug. The microspheres prepared by the application have the advantages of convenient preparation, uniform particle size, good elasticity, large drug loading capacity and the like, can be used for preparing a vascular embolism treatment drug, and have a good application prospect.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, specifically to a polycyanoacrylate-cyanoacrylate embolization microsphere, its preparation method, and its application. Background Technology

[0002] In recent years, embolization therapy has become an important interventional treatment method. Its principle involves using high-definition medical imaging equipment to inject a synthetic embolic material carrying anti-tumor drugs into a blood vessel through a catheter, guidewire, and other precision instruments. This causes the blood vessel to become blocked, thereby cutting off blood supply to the tumor site and releasing the anti-tumor drugs, leading to tumor shrinkage and necrosis. Embolization therapy, by blocking blood vessels supplying the tumor, malformed blood vessels, or bleeding blood vessels, has achieved good therapeutic effects in treating arteriovenous malformations, enlarged vascular tumors, uterine fibroids, uterine fibroids, and highly vascularized tumors.

[0003] Transcatheter embolization (TACE) involves injecting embolic material into a target blood vessel via a catheter. It offers advantages such as minimal invasiveness, high accuracy, strong operational controllability, rapid effectiveness, and few complications. Clinically, it is widely used to treat vascular lesions, hypervascular tumors, and organ dysfunction, and is one of the essential basic techniques in interventional radiology. Currently, microsphere-type embolic agents are the most widely used in clinical practice. Early embolic microspheres were mainly sodium alginate microspheres and polyvinyl alcohol microspheres, which generally suffered from uneven particle size, poor dispersibility, and poor elasticity, leading to drift, false embolism, and ectopic embolism during interventional procedures, causing damage to normal tissues.

[0004] Currently, the mainstream domestically produced products on the market are polyvinyl alcohol embolization microspheres. However, in clinical applications, they are prone to clogging microcatheters, affecting their usability. Moreover, drug loading performance requires functionalization with certain anionic groups, such as carboxyl and sulfonic acid groups, which results in weak drug loading capacity and limits their application. Summary of the Invention

[0005] The purpose of this invention is to overcome the problems of uneven particle size, poor dispersibility, poor elasticity, and poor drug loading capacity of existing embolization microspheres, and to provide a polycyanoacrylate-cyanoacrylate embolization microsphere, its preparation method, and its application.

[0006] To achieve the above objectives, the first aspect of the present invention provides a method for preparing polycyanoacrylate-cyanoacrylate embolic microspheres, the method comprising the following steps:

[0007] (1) In the presence of an initiator, a mixed solution of cyanoacrylate compound, dispersant and water is subjected to a polymerization reaction to obtain polycyanoacrylate microspheres;

[0008] (2) The polycyanoacrylate microspheres obtained in step (1) are added to an alkaline solution to undergo a partial hydrolysis reaction to obtain polycyanoacrylate-cyanoacrylate embolization microspheres.

[0009] The second aspect of the present invention provides a polycyanoacrylate-cyanoacrylate embolizing microsphere prepared by the preparation method described in the first aspect.

[0010] The third aspect of this invention provides the use of the polycyanoacrylate-cyanoacrylate embolizing microspheres described in the second aspect in the preparation of vascular embolization therapeutic drugs.

[0011] The beneficial technical effects achieved by the present invention through the above technical solution are as follows:

[0012] The present invention provides a method for preparing polycyanoacrylate-cyanoacrylate embolizing microspheres. Water is used as the medium, and a composite dispersant is added. A cyanoacrylate compound is added dropwise under high-speed stirring. Initiated by an initiator, the resulting polymer microspheres are treated with acid, centrifuged or filtered, washed with purified water, and then subjected to a saponification reaction (partial hydrolysis reaction) to obtain partially hydrolyzed cyanoacrylate microspheres. These microspheres have advantages such as convenient preparation, uniform particle size, good elasticity, and high drug loading capacity, and can be used to prepare vascular embolization therapeutic drugs, showing promising application prospects. Detailed Implementation

[0013] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0014] The first aspect of this invention provides a method for preparing polycyanoacrylate-cyanoacrylate embolic microspheres, the method comprising the following steps:

[0015] (1) In the presence of an initiator, a mixed solution of cyanoacrylate compound, dispersant and water is subjected to a polymerization reaction to obtain polycyanoacrylate microspheres;

[0016] (2) The polycyanoacrylate microspheres obtained in step (1) are added to an alkaline solution to undergo a partial hydrolysis reaction to obtain polycyanoacrylate-cyanoacrylate embolization microspheres.

[0017] This invention obtains partially hydrolyzed cyanoacrylate embolized microspheres by partially hydrolyzing the prepared polycyanoacrylate microspheres. The unhydrolyzed ester groups not only provide support for the microspheres but also act as internal plasticizers, resulting in microspheres with good elasticity.

[0018] In some embodiments of the present invention, the initiator is selected from at least one of piperazine, lysine, cystine, cysteine, arginine, homoarginine, polyethyleneimine, and polylysine.

[0019] In this invention, the selected initiator has multiple active centers per molecule, which can initiate the polymerization reaction of cyanoacrylate compounds, thereby crosslinking the cyanoacrylate polymer and further improving the elasticity of the generated three-dimensional polymer.

[0020] In some embodiments of the present invention, the mass ratio of the initiator to the cyanoacrylate compound is 0.0001-0.1:1, preferably 0.015-0.025:1.

[0021] In some embodiments of the present invention, the cyanoacrylate compound is selected from at least one of n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-hexyl cyanoacrylate, n-octyl cyanoacrylate, isooctyl cyanoacrylate, sec-octyl cyanoacrylate, methoxyethyl cyanoacrylate, and ethoxyethyl cyanoacrylate.

[0022] The cyanoacrylate compounds used in this invention are selected from those with relatively long chains. Methyl cyanoacrylate and ethyl cyanoacrylate cannot be used in the preparation of microspheres due to their inherent toxicity. The toxicity of the longer-chain cyanoacrylate compounds meets the requirements. Furthermore, the longer chain length also provides an internal plasticizing effect, resulting in microspheres with good elasticity.

[0023] In some embodiments of the present invention, the mass ratio of water to cyanoacrylate compound is 0.2-20:1, preferably 10:1.

[0024] In some embodiments of the present invention, the dispersant is a composite dispersant, comprising a primary dispersant and an auxiliary dispersant; the primary dispersant is selected from at least one of polyacrylic acid, acrylic acid-acrylate copolymer, maleic acid-acrylic acid copolymer, ethylene-acrylic acid copolymer, styrene-acrylic acid copolymer, polymethacrylic acid, methacrylic acid-methacrylate copolymer, ethylene-methacrylic acid copolymer, and styrene-methacrylic acid copolymer; the auxiliary dispersant is selected from at least one of polyethylene glycol and its derivatives, ethylene glycol-propylene glycol copolymers (e.g., poloxamer 188) and its derivatives (e.g., Plurafac LF901), cellulose derivatives, polydextrose, and polyvinyl alcohol.

[0025] In this invention, the primary dispersant in the selected composite dispersant is a polycarboxylic acid compound, a weakly acidic substance that can inhibit the polymerization reaction of cyanoacrylate in water. It also has a structure similar to cyanoacrylate and possesses a certain degree of solubility. Furthermore, it ionizes in the aqueous phase to generate a large number of acidic anions, effectively maintaining the stability of the droplets. During the polymerization reaction of cyanoacrylate, it prevents grafting reactions that could lead to phase inversion, thus effectively maintaining the stability of the suspension system. The auxiliary dispersant is a nonionic surfactant, which can reduce the surface tension of the system. By adjusting the amount of auxiliary dispersant, the droplet size can be controlled.

[0026] In some embodiments of the present invention, the mass ratio of the main dispersant, the auxiliary dispersant and water is 0.01-20:0.01-20:100.

[0027] In some embodiments of the present invention, the conditions for the polymerization reaction in step (1) include: a temperature of 40-100°C, preferably 50-60°C; and a time of 2-16 hours, preferably 3-6 hours.

[0028] In some embodiments of the present invention, acid is added after the polymerization reaction in step (1) to obtain polycyanoacrylate microspheres. The purpose is to remove excess initiator.

[0029] In some embodiments of the present invention, after the partial hydrolysis reaction described in step (2), the mixture is cooled to room temperature and then acid is added to adjust the pH value to 4-6.5 to obtain polycyanoacrylate-cyanoacrylate embolic microspheres. The aim is to ensure that the microspheres exist in the form of acid, and that the product of the saponification reaction is the corresponding alkali metal salt, thus guaranteeing the formation of the corresponding acid after the addition of acid.

[0030] In some embodiments of the present invention, the acid solution is selected from at least one of citric acid, malic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, phosphoric acid, and oxalic acid.

[0031] In some embodiments of the present invention, the concentration of the acid solution is 5-20 wt%.

[0032] In some embodiments of the present invention, the alkaline substance in the alkaline solution is selected from at least one of sodium ethoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, and lithium hydroxide.

[0033] In some embodiments of the present invention, the molar ratio of the alkaline substance to the polycyanoacrylate microspheres, based on the polymerization units in the polycyanoacrylate microspheres, is 0.10-1:1, preferably 0.60-1:1.

[0034] In some embodiments of the present invention, the conditions for the partial hydrolysis reaction in step (2) include: a temperature of 40-80°C, preferably 60°C; and a time of 2-5 hours, preferably 3 hours.

[0035] According to a particularly preferred embodiment of the present invention, a method for preparing polycyanoacrylate-cyanoacrylate embolic microspheres includes the following steps:

[0036] (1) After mixing the dispersant and water evenly, add cyanoacrylate compounds dropwise, heat to 40-100℃ and then add initiator solution dropwise. After reacting for 2-16 hours, add acid solution, filter, wash, centrifuge and dry to obtain polycyanoacrylate microspheres.

[0037] The initiator is selected from at least one of piperazine, lysine, cystine, cysteine, arginine, homoarginine, polyethyleneimine, and polylysine;

[0038] The dispersant is a composite dispersant, comprising a primary dispersant and an auxiliary dispersant; the primary dispersant is selected from at least one of polyacrylic acid, acrylic acid-acrylate copolymer, maleic acid-acrylic acid copolymer, ethylene-acrylic acid copolymer, styrene-acrylic acid copolymer, polymethacrylic acid, methacrylic acid-methacrylate copolymer, ethylene-methacrylic acid copolymer, and styrene-methacrylic acid copolymer; the auxiliary dispersant is selected from at least one of polyethylene glycol and its derivatives, ethylene glycol-propylene glycol copolymer and its derivatives, cellulose derivatives, polydextrose, and polyvinyl alcohol;

[0039] (2) Add the polycyanoacrylate microspheres obtained in step (1) to the alkaline solution and perform a partial hydrolysis reaction at 40-80℃ for 2-5 hours. After cooling to room temperature, add acid solution and adjust the pH value to 4-6.5. Filter, wash the solid repeatedly with purified water and ethanol, and dry at 30-50℃ to obtain polycyanoacrylate-cyanoacrylate embolization microspheres.

[0040] The second aspect of the present invention provides a polycyanoacrylate-cyanoacrylate embolizing microsphere prepared by the preparation method described in the first aspect.

[0041] In some embodiments of the present invention, the average particle size of the embolization microspheres is 50-1000 μm.

[0042] In some embodiments of the present invention, the polydispersity coefficient of the embolization microspheres is 0.035-0.042.

[0043] The third aspect of this invention provides the use of the polycyanoacrylate-cyanoacrylate embolizing microspheres described in the second aspect in the preparation of vascular embolization therapeutic drugs.

[0044] The present invention will be described in detail below through embodiments.

[0045] Unless otherwise specified in the following examples and comparative examples, all conditions were performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available products.

[0046] In the following examples, all raw materials used were commercially available, as shown in Table 1:

[0047] Table 1 Partial List of Raw Materials

[0048]

[0049]

[0050] Example 1:

[0051] 1) Add purified water (200g) to a four-necked flask, stir, and then add polyacrylic acid (M). n =3000, 0.2g) and poloxamer 188 (0.4g), under high-speed stirring, n-butyl cyanoacrylate (20g) was added dropwise, heated to 50℃, L-lysine (0.5g) solution was added dropwise, and the reaction was continued at this temperature for 4h. 50g of citric acid (5%) aqueous solution was added dropwise, stirred for 30min, cooled, filtered, and the microspheres were washed with purified water (50mL*3) and dried at 50℃ to obtain white microspheres (18.8g) for later use;

[0052] 2) Add sodium hydroxide (2.0 g, 50 mmol), ethanol (5 g) and purified water (5 g) to a three-necked flask. While stirring, add white microspheres (10 g, 65 mmol), heat to 60 °C, and allow partial hydrolysis to occur for 3 h. Add methanesulfonic acid (5%) solution to adjust the pH to 6.0, filter, and wash the microspheres with purified water, ethanol and n-hexane in sequence. Dry to obtain embolization microspheres (6.8 g).

[0053] Example 2:

[0054] 1) Add purified water (200g) to a four-necked flask, stir, and then add polyacrylic acid (M). n =3000, 0.5g) and hydroxypropyl methylcellulose (0.2g), under high-speed stirring, n-butyl cyanoacrylate (20g) was added dropwise, heated to 60℃, and polyethyleneimine (M n =600, 0.5g) solution, and then continue the reaction at this temperature for 3h. Add 50g of citric acid (5%) aqueous solution, stir for 30min, cool down, filter, wash the microspheres with purified water (50mL*3), dry at 50℃ to obtain white microspheres (17.8g), for later use;

[0055] 2) Add potassium hydroxide (3.2 g, 41 mmol), ethanol (5 g) and purified water (5 g) to a three-necked flask. While stirring, add white microspheres (10 g, 65 mmol), heat to 60 °C, react for 3 h, add methanesulfonic acid (5%) solution, adjust pH to 6.2, filter, wash the microspheres with purified water, ethanol and n-hexane in sequence, and dry to obtain embolization microspheres (7.2 g).

[0056] Example 3:

[0057] 1) Add purified water (200g) to a four-necked flask, stir, and then add polymethyl methacrylate (M). n =8000, 0.2g) and Polydextrose (0.3g), under high speed stirring, n-butyl cyanoacrylate (20g) was added dropwise, heated to 50℃, piperazine (0.5g) solution was added dropwise, and then the reaction was continued at this temperature for 6h. 50g of citric acid (5%) aqueous solution was added dropwise, stirred for 30min, cooled, filtered, and the microspheres were washed with purified water (50mL*3) and dried at 50℃ to obtain white microspheres (19.2g) for later use;

[0058] 2) Add sodium hydroxide (1.5g, 37.5mmol), ethanol (5g) and purified water (5g) to a three-necked flask. While stirring, add white microspheres (10g, 65mmol), heat to 60℃, react for 3h, add methanesulfonic acid (5%) solution, adjust pH to 6.1, filter, wash the microspheres with purified water, ethanol and n-hexane in sequence, and dry to obtain embolization microspheres (7.4g).

[0059] Example 4:

[0060] 1) Add purified water (200g) to a four-necked flask, and while stirring, add polyacrylic acid (0.4g), polydextrose (0.2g) and Plurafac LF901 (0.3g). While stirring at high speed, add n-butyl cyanoacrylate (20g) dropwise, heat to 50℃, add L-lysine (0.3g) solution dropwise, and continue the reaction at this temperature for 6h. Add 50g of citric acid (5%) aqueous solution dropwise, stir for 30min, cool, filter, wash the microspheres with purified water (50mL*3), and dry at 50℃ to obtain white microspheres (18.6g) for later use.

[0061] 2) Add sodium hydroxide (1.2g, 30mmol), ethanol (5g) and purified water (5g) to a three-necked flask. While stirring, add white microspheres (10g, 65mmol), heat to 60℃, react for 3h, add methanesulfonic acid (5%) solution, adjust pH to 6.0, filter, wash the microspheres with purified water, ethanol and n-hexane in sequence, and dry to obtain embolization microspheres (6.9g).

[0062] Comparative Example 1

[0063] Prepared according to the method of Example 1, except that in step (2), the polycyanoacrylate microspheres obtained in step (1) are added to sodium hydroxide (5.2g, 130mmol) to ensure complete hydrolysis of the ester groups.

[0064] Test case

[0065] The average particle size, polydispersity index, elasticity, and doxorubicin (doxorubicin) loading of the embolic microspheres prepared in Examples 1-4 were tested using the following methods:

[0066] Average particle size and polydispersity index: The particle size of 100 microspheres in each scanning electron microscope image was counted using the Nano measure, and the average particle size (Dn) and polydispersity index (PDI) were calculated.

[0067] Elasticity: When a microsphere sample is compressed by an external force, it deforms. When the sample is compressed to 50%, the pressure is removed and the microspheres begin to gradually recover their shape. If the microspheres can recover to a spherical shape and the structure remains intact without breakage, the sample is judged to have good elasticity; otherwise, it is considered poor.

[0068] Doxorubicin (doxorubicin) drug loading: tested according to the Chinese Pharmacopoeia method.

[0069] The results are shown in Table 2.

[0070] Table 2

[0071]

[0072]

[0073] As can be seen from the results in Table 2, the embolization microspheres prepared in Examples 1-4 have a particle size range of 50-1000 μm and a polydispersity index of 0.035-0.042, indicating that the microspheres have a very uniform particle size, good elasticity, and a drug loading capacity of more than 20 mg / g of doxorubicin, which is a large drug loading capacity.

[0074] This invention provides a method for preparing embolization microspheres. The prepared microspheres have the advantages of uniform particle size, good elasticity, and large drug loading capacity, which can meet the requirements of clinical use.

[0075] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing polycyanoacrylate-cyanoacrylate embolic microspheres, characterized in that, The method includes the following steps: (1) In the presence of an initiator, a mixed solution of cyanoacrylate compound, dispersant and water is subjected to a polymerization reaction to obtain polycyanoacrylate microspheres; The dispersant is a composite dispersant, comprising a primary dispersant and an auxiliary dispersant; the primary dispersant is polyacrylic acid or polymethacrylic acid; the auxiliary dispersant is at least one of polydextrose and Plurafac LF901; the mass ratio of the primary dispersant, the auxiliary dispersant, and water is 0.1-0.2:0.15-0.25:

100. (2) The polycyanoacrylate microspheres obtained in step (1) are added to an alkaline solution to undergo a partial hydrolysis reaction to obtain polycyanoacrylate-cyanoacrylate embolization microspheres. The alkaline substance in the alkaline solution is selected from at least one of sodium ethoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, and lithium hydroxide; the molar ratio of the alkaline substance to the polycyanoacrylate microspheres is 0.46-0.58:1, based on the polymerization units in the polycyanoacrylate microspheres.

2. The method according to claim 1, wherein, The initiator is piperazine or L-lysine; And / or, the mass ratio of the initiator to the cyanoacrylate compound is 0.015-0.025:

1.

3. The method according to claim 1, wherein, The cyanoacrylate compound is n-butyl cyanoacrylate; And / or, the mass ratio of water to cyanoacrylate compounds is 10:

1.

4. The method according to any one of claims 1-3, wherein, The conditions for the polymerization reaction in step (1) include: temperature of 40-100℃ and time of 2-16h.

5. The method according to any one of claims 1-3, wherein, The conditions for the polymerization reaction in step (1) include: a temperature of 50-60℃ and a time of 3-6h.

6. The method according to any one of claims 1-3, wherein, After the polymerization reaction described in step (1), acid solution is added to obtain polycyanoacrylate microspheres; And / or, after the partial hydrolysis reaction described in step (2), after cooling to room temperature, add acid solution and adjust the pH value to 4-6.5 to obtain polycyanoacrylate-cyanoacrylate embolization microspheres.

7. The method according to claim 6, wherein, The acid solution is selected from at least one of citric acid, malic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, phosphoric acid, and oxalic acid; And / or, the concentration of the acid solution is 5-20 wt%.

8. The method according to any one of claims 1-3, wherein, The conditions for the partial hydrolysis reaction in step (2) include: a temperature of 40-80℃ and a time of 2-5h.

9. The method according to any one of claims 1-3, wherein, The conditions for the partial hydrolysis reaction in step (2) include: a temperature of 60°C and a time of 3 hours.

10. Polycyanoacrylate-cyanoacrylate embolic microspheres prepared by the method according to any one of claims 1-9.

11. The polycyanoacrylate-cyanoacrylate embolic microspheres according to claim 10, wherein, The average particle size of the embolization microspheres is 50-1000 μm; And / or, the polydispersity index of the embolization microspheres is 0.035-0.

038.

12. The use of the polycyanoacrylate-cyanoacrylate embolization microspheres according to claim 10 or 11 in the preparation of vascular embolization therapeutic drugs.

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