Embolization microsphere for chronic musculoskeletal system pain control and preparation method and application thereof

Abstract

The invention provides an embolism microsphere for chronic musculoskeletal system pain control and a preparation method and application thereof, and belongs to the technical field of medicine. The polysaccharide-absorbable embolism microsphere is prepared by effectively wrapping antibiotic particles inside the polysaccharide-absorbable embolism microsphere. After the embolism microsphere reaches a target blood vessel, the antibiotic particles can be slowly released along with degradation of the polysaccharide microsphere, and the embolism microsphere provided by the invention is simple in preparation process, easy for large-scale production and capable of better meeting clinical use requirements.

Description

Technical Field

[0001] This invention relates to the field of medical technology, specifically to an embolic microsphere for chronic musculoskeletal pain control, its preparation method, and its application. Background Technology

[0002] Chronic musculoskeletal pain refers to a persistent pathological condition affecting muscles, bones, joints, tendons, and peripheral soft tissues, characterized by persistent abnormal pain sensation and limited motor function. Conservative therapy is generally considered the initial intervention in clinical practice; however, many patients respond poorly to conventional conservative treatment or cannot undergo open surgical intervention due to complex comorbidities, poor surgical tolerance, or other objective factors, creating challenges in diagnosis and treatment.

[0003] In recent years, transcatheter microembolization (TVI) technology has been increasingly used in the management of chronic musculoskeletal pain, attracting significant attention due to its minimally invasive nature, rapid recovery, and proven efficacy. In knee osteoarthritis pain, knee artery embolization has accumulated considerable case experience and formed preliminary evidence-based support. Furthermore, TVI is being systematically evaluated for intervention in other chronic musculoskeletal pain conditions such as frozen shoulder, tendon degeneration, and chronic low back pain, potentially offering novel solutions for these intractable pain syndromes.

[0004] Currently, imipenem / cilastatin sodium (IPM / CS) granules are one of the most widely used embolic agents in the field of chronic musculoskeletal pain embolization. IPM / CS is a broad-spectrum antibiotic with a particle size ranging from 10 to 70 μm. It gradually dissolves in the blood within several hours, making it a temporary embolic agent. When used for embolization of musculoskeletal target vessels such as the knee artery, this antibiotic granule has fewer adverse reactions such as skin discoloration and a low risk of embolization in non-target organs. However, IPM / CS has limitations such as the potential for antibiotic resistance and allergic reactions due to its short-term concentrated dissolution in the blood, and its in vivo embolization duration cannot meet the diverse application needs of musculoskeletal target vessels. Summary of the Invention

[0005] The purpose of this invention is to provide an embolic microsphere for musculoskeletal pain control and its preparation method. This embolic microsphere avoids the potential adverse reactions caused by the short-term concentrated dissolution of antibiotic particles and can also achieve sequential embolization of target vessels, prolonging the duration of target vessel embolization. Furthermore, the embolic microsphere preparation process provided by this invention is simple, easy to scale up, and better meets clinical needs.

[0006] The technical solution of this invention is implemented as follows:

[0007] This invention provides a method for preparing embolic microspheres for chronic musculoskeletal pain control. The method involves effectively encapsulating antibiotic particles inside absorbable polysaccharide embolic microspheres. After the embolic microspheres reach the target blood vessel, the antibiotic particles are slowly released as the polysaccharide microspheres degrade.

[0008] As a further improvement to the present invention, the following steps are included:

[0009] (1) Add cross-linking agent and antibiotic particles to polysaccharide aqueous solution, and stir thoroughly to obtain an aqueous solution in which antibiotic particles are uniformly dispersed;

[0010] (2) Add the dispersant to the organic solvent and stir to dissolve it to form a homogeneous oil phase solution;

[0011] (3) Slowly add the aqueous solution to the oil solution, stir until homogeneous, then add the crosslinking agent and heat the emulsion system to react;

[0012] (4) After the reaction is completed, the obtained microspheres are separated, washed and sieved, vacuum dried and then swollen in physiological saline to finally obtain absorbable composite embolization microspheres.

[0013] As a further improvement of the present invention, the polysaccharide in step (1) is selected from at least one of starch and dextran, and the mass ratio in the aqueous solution is 5-30%.

[0014] As a further improvement of the present invention, the crosslinking agent in step (1) is selected from at least one of epichlorohydrin, sodium trimetaphosphate, and citric acid, and the mass ratio in the aqueous solution is 0.2-2%.

[0015] As a further improvement of the present invention, the mass ratio of the antibiotic particles in the aqueous solution in step (1) is 3-6%.

[0016] As a further improvement of the present invention, the dispersant in step (2) is at least one of Span 60, Span 65, Span 80 and Span 85; the organic solvent is at least one of butyl acetate, ethyl acetate, methyl acetate, propyl acetate, cyclohexane, liquid paraffin and isopropyl palmitate; the mass percentage of the dispersant in the oil phase solution is 1-10%.

[0017] As a further improvement of the present invention, the crosslinking agent in step (3) is selected from at least one of epichlorohydrin, sodium trimetaphosphate, and citric acid, and the mass ratio in the emulsion system is 0.2-2%.

[0018] As a further improvement of the present invention, the stirring speed is 300-3000 rpm, the heating temperature is 40-60℃, and the heating time is 2-4h.

[0019] The present invention further protects an embolic microsphere for chronic musculoskeletal pain control prepared by the above-described preparation method.

[0020] The present invention further protects the use of the above-mentioned embolic microspheres for the control of chronic musculoskeletal pain in the preparation of a medicament for treating chronic musculoskeletal pain.

[0021] The present invention has the following beneficial effects:

[0022] The absorbable composite embolization microspheres provided by this invention can encapsulate antibiotic particles inside the microspheres, avoiding the rapid and concentrated dissolution of antibiotic particles after direct contact with blood, thus reducing the risk of potential drug resistance and allergic reactions.

[0023] The absorbable composite embolization microspheres provided by this invention can achieve sequential embolization in vivo. After the first embolization is completed, as the degradable polysaccharide microspheres are enzymatically absorbed, antibiotic particles can be gradually released from the composite microspheres, thereby embolizing peripheral blood vessels and maintaining the embolization time.

[0024] The absorbable composite embolization microspheres provided by this invention are all biodegradable and absorbable in vivo, avoiding the risk of ectopic embolism associated with the use of permanent microspheres.

[0025] The antibiotic particles encapsulated in the absorbable composite embolization microspheres provided by this invention can prevent possible postoperative tissue infections.

[0026] The embolic microspheres for musculoskeletal pain control provided by this invention have a simple and controllable preparation process, mild reaction conditions that are easy to scale up, support large-scale production, and meet the clinical needs for high-quality, low-cost batch preparation and application. Attached Figure Description

[0027] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0028] Figure 1 An optical microscope image (magnification: 40×) of the absorbable composite embolization microspheres prepared in Example 1 of the present invention.

[0029] Figure 2 This is an optical microscope image (magnification: 40×) of the absorbable composite embolization microspheres prepared in Example 2 of the present invention.

[0030] Figure 3An optical microscope image (magnification: 40×) of the absorbable composite embolization microspheres prepared in Example 3 of the present invention.

[0031] Figure 4 This is a scanning electron microscope image of the cross-section of the absorbable composite embolization microspheres prepared in Example 3 of the present invention.

[0032] Figure 5 This is a scanning electron microscope image (scale bar is 20 μm) of the cross-section of the absorbable composite embolization microspheres prepared in Example 1 of the present invention.

[0033] Figure 6 This is a scanning electron microscope image (scale bar is 20 μm) of the cross-section of the absorbable composite embolization microspheres prepared in Example 2 of the present invention.

[0034] Figure 7 This is a scanning electron microscope image (scale bar is 20 μm) of the cross-section of the absorbable composite embolization microspheres prepared in Example 3 of the present invention.

[0035] Figure 8 The images show DSA images of the absorbable composite embolization microspheres prepared in Example 1 and the embolization microspheres obtained in Comparative Example 1 used for right renal artery embolization in rabbits. 8a is a DSA image of the right kidney of a rabbit before the right renal artery embolization procedure. 8b and 8c are DSA images of the right kidney of a rabbit immediately after injection of the absorbable composite embolization microspheres prepared in Example 1 and one day after the procedure, respectively. 8d is a DSA image of the right kidney of a rabbit one day after injection of the absorbable composite embolization microspheres prepared in Comparative Example 1. Detailed Implementation

[0036] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0037] Example 1

[0038] This embodiment provides a method for preparing embolic microspheres for chronic musculoskeletal pain control, comprising the following steps:

[0039] 1) Sodium trimetaphosphate and IPM / CS (imipenem / cilastatin) antibiotic granules were added to a 20% starch aqueous solution. After thorough stirring, an aqueous solution in which the antibiotic granules were uniformly dispersed was obtained. The amounts of sodium trimetaphosphate and IPM / CS antibiotic granules added were 2% and 3%, respectively.

[0040] 2) Add Span 80 to isopropyl palmitate and stir to dissolve to form a homogeneous oil phase solution, wherein the content of Span 80 is 3%.

[0041] 3) Slowly add the aqueous phase to the oil phase solution and stir at 300 rpm to form a water-in-oil emulsion reaction system. Then add 1% epichlorohydrin and heat at 50°C for 4 hours.

[0042] After the reaction was completed, the obtained microspheres were separated, washed, and sieved. After being vacuum dried at 50°C for 8 hours, they were fully swollen with physiological saline to obtain absorbable starch composite embolization microspheres. Figure 1 An optical microscope image of the absorbable composite embolization microspheres prepared in Example 1 (magnification: 40×). Figure 5 The image shows a scanning electron microscope (SEM) image of the cross-section of the absorbable composite embolization microspheres prepared in Example 1 (scale bar is 20 μm).

[0043] Example 2

[0044] This embodiment provides a method for preparing embolic microspheres for chronic musculoskeletal pain control, comprising the following steps:

[0045] 1) Epichlorohydrin and IPM / CS (imipenem / cilastatin) antibiotic granules were added to a 15% dextran aqueous solution, and the mixture was stirred thoroughly to obtain an aqueous solution in which the antibiotic granules were uniformly dispersed. The amounts of epichlorohydrin and IPM / CS antibiotic granules added were 1% and 2%, respectively.

[0046] 2) Add Span 60 to ethyl acetate and stir to dissolve to form a homogeneous oil phase solution, wherein the content of Span 60 is 2%.

[0047] 3) Slowly add the aqueous phase to the oil phase solution and stir at 400 rpm to form a water-in-oil emulsion reaction system. Then add 1% sodium trimetaphosphate and heat at 60°C for 2 hours.

[0048] After the reaction was completed, the obtained microspheres were separated, washed, and sieved. After being vacuum dried at 80°C for 4 hours, they were fully swollen with physiological saline to obtain absorbable dextran composite embolization microspheres. Figure 2 An optical microscope image (magnification: 40×) of the absorbable composite embolization microspheres prepared in Example 2. Figure 6 The image shows a scanning electron microscope (SEM) image of the cross-section of the absorbable composite embolization microspheres prepared in Example 2 (scale bar is 20 μm).

[0049] Example 3

[0050] This embodiment provides a method for preparing embolic microspheres for chronic musculoskeletal pain control, comprising the following steps:

[0051] 1) Citric acid and IPM / CS (imipenem / cilastatin) antibiotic granules were added to a 30% starch aqueous solution. After thorough stirring, an aqueous solution in which the antibiotic granules were uniformly dispersed was obtained. The amounts of citric acid and IPM / CS antibiotic granules added were 2% and 4%, respectively.

[0052] 2) Add Span 85 to cyclohexane and stir to dissolve to form a homogeneous oil phase solution, wherein the content of Span 85 is 4%.

[0053] 3) Slowly add the aqueous phase to the oil phase solution and stir at 500 rpm to form a water-in-oil emulsion reaction system. Then add 2% citric acid and heat at 80°C for 1 hour.

[0054] 4) After the reaction is complete, the obtained microspheres are separated, washed and sieved, and then vacuum dried at 60°C for 6 hours. After being fully swollen with physiological saline, absorbable starch composite embolization microspheres are obtained. Figure 3 An optical microscope image (magnification: 40×) of the absorbable composite embolization microspheres prepared in Example 3 of the present invention. Figure 4 This is a scanning electron microscope image of the cross-section of the absorbable composite embolization microspheres prepared in Example 3. Figure 7 The image shows a scanning electron microscope (SEM) image of the cross-section of the absorbable composite embolization microspheres prepared in Example 3 (scale bar is 20 μm).

[0055] Comparative Example 1

[0056] 1) Sodium trimetaphosphate was added to a 30% starch aqueous solution and stirred thoroughly to obtain an aqueous solution, wherein the amount of sodium trimetaphosphate added was 4%.

[0057] 2) Add Span 85 to n-butyl acetate and stir to dissolve to form a homogeneous oil phase solution, wherein the content of Span 85 is 8%.

[0058] 3) Slowly add the aqueous phase to the oil phase solution and stir at 400 rpm to form a water-in-oil emulsion reaction system. Then add 2% sodium trimetaphosphate and heat at 80°C for 1 hour.

[0059] 4) After the reaction is complete, the obtained microspheres are separated, washed and sieved, and then vacuum dried at 60°C for 6 hours. After being fully swollen with physiological saline, absorbable starch embolization microspheres are obtained.

[0060] Test Example 1

[0061] Using the renal artery of a common New Zealand white rabbit as the target vessel, the embolization efficacy of absorbable polysaccharide composite embolization microspheres encapsulated with IPM / CS antibiotic particles was verified.

[0062] Experimental methods:

[0063] An embolic microsphere mixture was prepared according to a ratio of embolic microspheres: normal saline: contrast agent = 1:1:2. Under DSA fluoroscopy, the embolic microsphere suspensions obtained in Example 1 and Comparative Example 1 were slowly injected into the lower segment of the renal artery branch of the right kidney of rabbits via catheter at an injection rate of 0.8 mL / min. The endpoint of embolization was confirmed under DSA fluoroscopy after injection, while preventing reflux of the embolic agent. The embolization status of the target vessel was observed by angiography immediately after the procedure and on postoperative day 1. Figure 8 Image a is a DSA image of the rabbit's right kidney before a right renal artery embolization procedure.

[0064] Experimental results:

[0065] The results showed that after slow injection of approximately 10 ml of the embolization microsphere mixture, complete embolization of the lower branch vessels of the rabbit renal artery was achieved. Figure 8 (b) The embolization microspheres were prepared according to Example 1. One day after the procedure, as the starch in the composite embolization microspheres of Example 1 was gradually enzymatically hydrolyzed, the IPM / CS particles were gradually released along with the starch hydrolysis, and the distal peripheral vessels of the lower segment of the right kidney remained embolized. Figure 8 c). One day after surgery, the starch in the microspheres obtained in Comparative Example 1 was gradually enzymatically hydrolyzed, and recanalization occurred in the target vessel of the lower segment of the right kidney in the rabbit. Figure 8 d).

[0066] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing embolic microspheres for chronic musculoskeletal pain control, characterized in that, This product is prepared by effectively encapsulating antibiotic particles inside absorbable polysaccharide embolization microspheres. After the embolization microspheres reach the target blood vessel, the antibiotic particles can be slowly released as the polysaccharide microspheres degrade.

2. The preparation method according to claim 1, characterized in that, Includes the following steps: (1) Add cross-linking agent and antibiotic particles to polysaccharide aqueous solution, and stir thoroughly to obtain an aqueous solution in which antibiotic particles are uniformly dispersed; (2) Add the dispersant to the organic solvent and stir to dissolve it to form a homogeneous oil phase solution; (3) Slowly add the aqueous solution to the oil solution, stir until homogeneous, then add the crosslinking agent and heat the emulsion system to react; (4) After the reaction is completed, the obtained microspheres are separated, washed and sieved, vacuum dried and then swollen in physiological saline to finally obtain absorbable composite embolization microspheres.

3. The preparation method according to claim 2, characterized in that, The polysaccharide mentioned in step (1) is selected from at least one of starch and dextran, and its mass ratio in the aqueous solution is 5-30%.

4. The preparation method according to claim 2, characterized in that, The crosslinking agent mentioned in step (1) is selected from at least one of epichlorohydrin, sodium trimetaphosphate, and citric acid, with a mass ratio of 0.2-2% in the aqueous solution.

5. The preparation method according to claim 2, characterized in that, The mass ratio of the antibiotic particles in the aqueous solution in step (1) is 3-6%.

6. The preparation method according to claim 2, characterized in that, The dispersant in step (2) is at least one of Span 60, Span 65, Span 80 and Span 85; the organic solvent is at least one of butyl acetate, ethyl acetate, methyl acetate, propyl acetate, cyclohexane, liquid paraffin and isopropyl palmitate; the mass percentage of the dispersant in the oil phase solution is 1-10%.

7. The preparation method according to claim 2, characterized in that, The crosslinking agent mentioned in step (3) is selected from at least one of epichlorohydrin, sodium trimetaphosphate, and citric acid, and its mass ratio in the emulsion system is 0.2-2%.

8. The preparation method according to claim 2, characterized in that, The stirring speed is 300-3000 rpm, the heating temperature is 40-60℃, and the heating time is 2-4 hours.

9. An embolic microsphere for chronic musculoskeletal pain control, prepared by the method according to any one of claims 1-8.

10. The use of the embolic microspheres for chronic musculoskeletal pain control as described in claim 9 in the preparation of a medicament for treating chronic musculoskeletal pain.

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