Embolic material for relieving or treating musculoskeletal pain comprising fast dissolving gelatin particles

Abstract

To provide an embolic material for relieving or treating musculoskeletal pain comprising gelatin particles.SOLUTION: The embolic material comprising gelatin particles can relieve or treat musculoskeletal pain by being injected into a blood vessel, embolized in the vessel, and then dissolves rapidly. The embolic material comprising gelatin particles can be effectively used as an embolic material in the medical fields and pharmaceutical industry for relieving or treating musculoskeletal pain in patients suffering from chronic pain associated with musculoskeletal disorders.SELECTED DRAWING: Figure 6

Description

[Technical Field]

[0001] The present invention relates to an embolic material for alleviating or treating musculoskeletal pain, and more particularly to an embolic material for alleviating or treating pain in musculoskeletal areas, which contains fast-dissolving gelatin particles. [Background technology]

[0002] Patients often seek treatment for chronic pain caused by various musculoskeletal disorders. While the pathophysiology of chronic pain has not yet been clearly established, various hypotheses have been studied and various treatment options have been recommended. The primary goal of treatment is to relieve pain and reduce inflammation in painful joints, tendons, and areas of pain, such as the knee, shoulder, hip, elbow, wrist, ankle, fingers, and toes. Examples of conservative treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroid injections, and extracorporeal shock wave therapy (ESWT). However, in some cases, recovery can be prolonged or even impossible despite conservative treatment. When conservative treatments are unsuccessful, surgery or interventions are the only treatment options.

[0003] Transcatheter arterial embolization (TAE) and transcatheter arterial microembolization (TAME) are new treatment options for patients with chronic pain unresponsive to natural or conservative treatments and can be considered before surgical treatment. Several previous studies on the mechanisms of musculoskeletal pain have suggested that abnormally developed new blood vessels and associated nerves may be the cause of pain and inflammation. Embolization of these abnormal new blood vessels can reduce inflammation by reducing the influx of inflammation-related cells and cytokines. Embolization can also suppress the growth of accompanying sensory nerves along the new blood vessels. Therefore, some medical centers have reported successful outcomes with TAE.

[0004] Previous studies have used imipenem / cilastatin sodium (IPM / CS) as an embolic agent, and TAE using IPM / CS has shown a high success rate. IPM / CS is approved by the US Food and Drug Administration (FDA) as an antibiotic due to its broad-spectrum activity against aerobic, anaerobic, gram-positive, and gram-negative bacteria. Because IPM / CS dissolves quickly (approximately 1 hour), it can be used as a temporary embolic agent during TAE. In TAE for chronic pain, IPM / CS is injected into abnormal neovasculature to induce temporary occlusion of the target vessel. However, because IPM / CS was originally developed as an antibiotic, it is not approved as an embolic agent.

[0005] Traditional embolic materials, such as gelatin sponge particles and microspheres, have been used for a long time, and their safety and efficacy have been thoroughly studied. The gelatin sponges used until now have been biological materials made from purified skin gelatin. They are primarily used as temporary embolic materials during vascular intervention procedures and take approximately four weeks to dissolve. Korean Patent Registration No. 10-1613403 discloses a method for manufacturing a gelatin drug delivery vehicle, which contains phosphate-buffered saline (PBS) or phosphate buffer (PB), and is ionically bonded to a liver cancer therapeutic agent.

[0006] Because these conventional gelatin particles take longer to dissolve than IPM / CS, the development of a new gelatin-based embolic material with a fast dissolution rate is necessary for their application in TAE and TAME to treat chronic pain. In other words, there is a need to develop a fast-dissolving embolic material that is safe for the human body and that introduces new physicochemical properties related to the dissolution rate of TAE and TAME gelatin particles, and is effective in alleviating and treating chronic pain associated with various musculoskeletal disorders. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Korean Patent Registration No. 10-1613403 (2016.04.11) [Non-patent literature]

[0008] [Non-Patent Document 1] Miyayama S, Yamakado K, Anai H, Abo D, Minami T, Takaki H, et al. Guidelines on the use of gelatin sponge particles in embolotherapy. Japanese Journal of Radiology 2014;32:242-250 (2014.02.08) Summary of the Invention [Problem to be solved by the invention]

[0009] The technical problem that the present invention aims to solve is to provide an embolic material for the relief or treatment of chronic musculoskeletal pain that has a fast dissolving time, is effective for embolization, and is safe for the human body, so that fast-dissolving gelatin particles can be applied to TAE and TAME to embolize the microvessels in musculoskeletal areas in patients who have suffered from chronic pain associated with various musculoskeletal diseases for a long period of time, thereby quickly alleviating and treating pain.

[0010] The technical problems that the present invention aims to solve are not limited to the above-mentioned technical problems, and other technical problems not mentioned will be clearly understood by a person having ordinary skill in the technical field to which the present invention pertains from the following description. [Means for solving the problem]

[0011] In order to achieve the above object, one aspect of the present invention provides an embolic material for alleviating or treating pain in musculoskeletal areas, which contains gelatin particles.

[0012] In one embodiment, the gelatin particles may have an average diameter of 10 to 1000 μm.

[0013] In one embodiment, the gelatin particles may be chemically or thermally crosslinked.

[0014] In one embodiment, the gelatin particles may be crosslinked with one or more crosslinkers selected from the group consisting of formaldehyde, glutaraldehyde, EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), NHS (N-hydroxysuccinimide), dialdehyde starch, epoxy compounds, glutaraldehyde glyoxal, glyoxal, 2,2-dimethoxy-2-phenylacetophenone, sodium tripolyphosphate (STPP), diacetaldehyde PEG, sucralaldehyde, diethyl squarate, epichlorohydrin, genipin, tannin, phenylpropanoid, catechin, resveratrol, flavonoid, and isoflavonoid.

[0015] In one embodiment, the gelatin particles may have a solubility in an aqueous medium of 50% or more 48 hours after the start of dissolution.

[0016] In one embodiment, the musculoskeletal site may be one or more sites selected from the group consisting of knees, shoulders, necks, elbows, wrists, ankles, fingers, and toes.

[0017] In one embodiment, the gelatin particles can be administered into a blood vessel to embolize within the blood vessel, thereby alleviating or treating musculoskeletal pain.

[0018] In one embodiment, the average dose of gelatin particles administered into the blood vessel may be 10 mg to 500 mg.

[0019] In one embodiment, the blood vessel may be selected from the group consisting of the femoral artery, the radial artery, the subclavian artery, and the brachial artery.

[0020] In one embodiment, the pain at the musculoskeletal site may be persistent for a period of six months or more. [Effects of the Invention]

[0021] According to the present invention, when fast-dissolving gelatin particles are injected into the blood vessels of patients with chronic pain caused by musculoskeletal diseases by transcatheter arterial embolization (TAE) or transcatheter arterial microembolization (TAME), significant pain relief without major side effects has been confirmed, and it has been found that alleviation and treatment of chronic pain by TAE can be performed safely and effectively with a high technical success rate.

[0022] Therefore, the embolic material containing the gelatin particles of the present invention can be usefully used as an embolic material for alleviating or treating pain associated with chronic musculoskeletal diseases that are refractory to conservative treatment, in the medical field and pharmaceutical industry, for alleviating or treating pain in musculoskeletal areas.

[0023] The effects of the present invention are not limited to the effects described above, but are understood to include all effects that can be inferred from the configuration of the invention described in the detailed description of the present invention or the claims. [Brief explanation of the drawings]

[0024] [Figure 1] This is an angiogram of the knee of a 65-year-old woman who presented with right knee pain and pain on the lateral and medial aspects of the knee joint. Based on knee radiographs, the patient was diagnosed with Kellgren-Lawrence grade 2 osteoarthritis of the knee. The right common femoral artery was punctured anteriorly, and superficial femoral arteriography was performed. [Figure 2]This is an angiogram of the right knee joint, showing abnormal proliferation originating from the lateral descending artery on the lateral side of the right knee joint (arrow). [Figure 3] An angiogram of a vessel selected using a microcatheter and embolized with 1.2 mL of fast-dissolving gelatin particles. [Figure 4] Angiography revealed further abnormal proliferation in the medial knee joint. (a) The descending genicular artery was selected, and (b) embolization was performed using 2.2 mL of fast-dissolving gelatin particles. [Figure 5] This is a knee angiogram of a patient who underwent embolization. No abnormal growth was observed in the right knee (arrow) during the final angiogram. The patient's baseline VAS score was 8, which decreased to 2 immediately after the procedure. The patient reported pain of 4 on a visual analog scale (VAS) for approximately 24 hours. The VAS score remained at 2 until the 6-month follow-up assessment. [Figure 6] This figure shows the change in mean VAS scores over time. In this study, all 33 patients had a 6-month follow-up period. The mean VAS scores at baseline, immediately after transcatheter arterial embolization (TAE), 1 day after TAE, 1 week after TAE, 1 month after TAE, 3 months after TAE, and 6 months after TAE were 6.67, 3.09, 4.64, 2.67, 2.30, 2.24, and 2.27, respectively (P<0.05 for baseline vs. immediately after TAE and immediately after TAE vs. 1 day after TAE). [Figure 7] This shows the results of visually inspecting the dispersion of gelatin particles when thermal crosslinking conditions were selected. [Figure 8] This is a result of observing a dispersion of gelatin particles under a microscope when thermal crosslinking conditions were selected. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention provides an embolic material containing gelatin particles for the relief or treatment of pain in musculoskeletal areas. In the case of musculoskeletal pain, abnormally developed neovascularization and nerves associated with the musculoskeletal system may be the cause of pain and inflammation. Therefore, embolization of such abnormal neovascularization can alleviate inflammation by reducing the influx of inflammation-related cells and cytokines. The embolic material for the relief or treatment of pain in musculoskeletal areas of the present invention is an embolic material used in a treatment process to control pain by injecting gelatin particles into painful vascular sites to form an embolism.

[0026] In this case, the gelatin used as the material for the gelatin particles can be any gelatin material that can maintain a solid or gel state for a certain period of time when in contact with water and prevent the movement of liquids such as blood, and is preferably mammalian-derived gelatin or fish-derived gelatin. The weight-average molecular weight of the gelatin can be 15,000 to about 400,000, preferably 30,000 to 300,000, more preferably 50,000 to 200,000, and most preferably 65,000 to 100,000. The gelatin used in the present invention can be obtained from mammalian collagen or fish collagen, and can also be commercially obtained as needed.

[0027] In the present invention, it has been confirmed that, among gelatin particles used in conventional embolization, gelatin particles of a particular particle size, when used in peripheral blood vessels of a particular musculoskeletal site, cause embolization within a short time, then dissolve, effectively relieving long-term pain in the untreatable musculoskeletal site. Therefore, the gelatin particles used in the present invention have a size that allows them to be injected into microvessels such as joints, solidify or gel within a short time, and then dissolve. Preferably, the average particle size of the gelatin particles in the present invention is 10 to 1000 μm, more preferably 20 to 800 μm, 30 to 500 μm, 40 to 300 μm, 50 to 150 μm, etc., and most preferably 80 to 100 μm.

[0028] In one embodiment, the gelatin particles may be cross-linked using a cross-linking agent, which may be chemical or thermal. In the case of chemical crosslinking, the crosslinking agent may be one or more selected from, but is not limited to, formaldehyde, glutaraldehyde, EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), (used alone or together with NHS (N-hydroxysuccinimide)), dialdehyde starch, epoxy compounds, glutaraldehyde glyoxal, glyoxal, 2,2-dimethoxy-2-phenylacetophenone, sodium tripolyphosphate (STPP), diacetaldehyde, sucralaldehyde, diethyl squarate, epichlorohydrin, genipin, tannins, phenylpropanoids, catechins, resveratrol, flavonoids (such as quercetin), and isoflavonoids (such as isoflavone). The crosslinking during thermal crosslinking may be carried out at a temperature of 120°C or higher, preferably 130°C or higher.

[0029] In the present invention, the rapid dissolution and fast solubility of the gelatin particles can reduce the occurrence and duration of ischemic pain. Therefore, the solubility of the gelatin particles in an aqueous medium may be 50% or more 48 hours after the start of dissolution, preferably 80% or more 48 hours, more preferably 98% or more 48 hours, even more preferably 92% or more 24 hours, 98% or more 48 hours, and most preferably 87% or more 30 minutes, 89% or more 3 hours, 92% or more 24 hours, and 98% or more 48 hours. The solubility of the gelatin particles in an aqueous medium may refer to the solubility in aqueous media such as water, physiological saline, blood, serum, and other aqueous media that can be used in the human body.

[0030] The embolic material of the present invention relieves or treats pain occurring in a musculoskeletal area, and the musculoskeletal area may be one or more areas selected from the group consisting of knees, shoulders, neck, elbows, wrists, ankles, fingers, and toes, but is not limited to these.

[0031] In one embodiment, the gelatin particles are administered into a blood vessel to embolize the blood vessel, thereby alleviating or treating pain in a musculoskeletal area. Therefore, the average dose of gelatin particles administered into a blood vessel may be preferably 10 to 500 mg, more preferably 50 to 400 mg, and most preferably 100 to 300 mg. The blood vessel may be a component of the blood circulation system, such as a vein, artery, or capillary. The blood vessel may be selected from the group consisting of the femoral artery, radial artery, subclavian artery, and brachial artery, but is not limited thereto.

[0032] IPM / CS has been used as an embolic material. Microspheres have been used as an embolic material in transcatheter arterial embolization (TAE) for pain-related musculoskeletal disorders. IPM / CS is mixed with contrast media to form crystalline particles that can cause a temporary embolic effect. Although IPM / CS produces a temporary embolic effect in blood vessels and dissolves almost completely within 24 hours, it was originally developed as an antibiotic and has not yet been approved as an embolic material. Unlike IPM / CS, gelatin particles have long been used as an embolic material for vascular embolization, demonstrating their convenience, usefulness, and stability. Therefore, in this invention, gelatin particles are used for transcatheter arterial embolization (TAE) and transcatheter arterial microembolization (TAME). However, since the dissolution time of conventional gelatin particles is longer (typically 7 to 28 days) than that of IPM / CS, we use more rapidly dissolving gelatin particles to achieve a similar effect to IPM / CS. Specifically, the novel fast-dissolving gelatin particles used in one embodiment of the present invention are particles used in transcatheter arterial microembolization (TAME), also known as embolization for pain relief in musculoskeletal disorders. The fast-dissolving gelatin particles used in one embodiment of the present invention had a particle diameter of 50 to 150 μm (average 90 μm) and showed a solubility of 87% at 30 minutes, 89% at 3 hours, 92% at 24 hours, and 98% at 48 hours. In this study, the technical success rate at 6 months after surgery was 100%, and the clinical success rate was 75.76%. This clinical success rate is similar to the average rates reported in previous studies using IPM / CS as an embolic material.

[0033] In the present invention, the gelatin particles are administered into blood vessels to cause embolism, thereby inhibiting the growth of sensory nerves that grow along the new blood vessels that have developed at the painful area, thereby alleviating or treating pain in musculoskeletal areas.

[0034] In one embodiment, the pain in the musculoskeletal region may be chronic pain, particularly, but not limited to, chronic pain that has lasted for 6 months or more. The embolic material for treating pain in the musculoskeletal region, which contains the gelatin particles of the present invention, was administered to patients who had not been relieved by various conservative treatments, had reported pain that had lasted for 6 months or more, and desired other treatments that could be performed before surgery, and the presence or absence of pain relief or therapeutic effects was confirmed.

[0035] The present invention will be described in more detail below with reference to examples. However, the following examples are for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention.

[0036] <Example> 1. Preparation of gelatin particles (1)Chemical crosslinking [Production of formaldehyde solution (FA)] 1) 50 mL of distilled water was placed in a 50 mL centrifuge tube using a micropipette. 2) Reduce 88 μL of distilled water and add 88 μL of 36-38% formaldehyde solution. 3) The solution was divided into 11.75 mL portions for use.

[0037] [Gelatin particle (IPZA) manufacturing] 1) Dissolve gelatin in distilled water (7 g gelatin, 100 mL distilled water). -The amount of distilled water was measured using a mass cylinder. -Checked the temperature (50°C). 2) The gelatin solution was transferred to a 1 L beaker and the temperature was confirmed to drop. -Checked the temperature (40°C). 3) When the temperature of the gelatin solution reached 40°C, the FA solution prepared in advance was added. 4) Stir using a mixer (at maximum strength for 7 minutes). 5) The gelatin foam was transferred to a plate and immediately placed in the freezer (-50°C, 40 hours). 6) The frozen gelatin foam was freeze-dried. 7) The freeze-dried gelatin foam was crushed. 8) The crushed gelatin particles were fractionated using a sieve.

[0038] (2) Preparation of gelatin particles by thermal crosslinking 1) 7 g of gelatin (160-175 bloom) and 100 mL of distilled water were prepared and dissolved on a hot plate while stirring. 2) Once the gelatin was completely dissolved, it was transferred to a beaker (1 L) and the gelatin solution was allowed to cool to 40°C. 3) The gelatin solution at 40°C was whipped for 7 minutes. 4) Transfer the gelatin foam to a plate and freeze it for 1 day. 5) Freeze-drying was carried out (for 3 days). 6) The freeze-dried gelatin sponge particles (GSP) were taken out and placed in a beaker, and the opening was covered with KIMTECH to prevent dust from entering. 7) The oven temperature (135°C) was adjusted, and once the temperature had stabilized (which took 2 hours and 30 minutes), the GSP in the beaker was quickly added. 8) The vacuum pump was operated (for 24 hours from the time the vacuum pump was turned on). 9) The GSP was removed and allowed to cool at room temperature. 10) Grinding was carried out. 11) Fractionation (sieving) was performed using a sieving machine. (The yield can be increased by collecting the residue after sieving and sieving it again.) 12) Blister packaging was performed. 13) Gamma ray sterilization was performed.

[0039] (3) Selection of thermal crosslinking conditions The thermal crosslinking temperature was set to 135°C, and a dispersion stability test and microscopic observation of gelatin particles were carried out as follows.

[0040] [Dispersion stability test] In order to prepare gelatin particles that can be stably dispersed without dissolving when mixed with saline and contrast medium for embolization procedures, the temperature and time during thermal crosslinking of gelatin particles were compared and analyzed. The results are shown in Table 1 below.

[0041] [Table 1]

[0042] [Microscopic observation of gelatin particles] Gelatin particles (Lot: 190523) were dissolved in a saline:contrast agent (1:1) solution to a concentration of 10 mg / mL, and the dispersion was observed visually and microscopically. The manufacturing conditions for the gelatin particles are shown in Table 2 below.

[0043] [Table 2]

[0044] The results of visual observation of the gelatin particle dispersion are shown in FIG. 7, and the results of microscopic observation are shown in FIG.

[0045] As shown in Figure 7, a comparative analysis of the solubility of samples 1, 2, 3, and 4 prepared using the thermal crosslinking method and the commercially available embolic material product 5, "EGgel S PLUS (Engain Co., Ltd., Korea)," was conducted. It was visually confirmed that samples 1, 2, and 3 dissolved without dispersing when mixed with a mixture of saline and contrast agent, whereas samples 4 and 5 did not dissolve and dispersed while maintaining their sponge structure.

[0046] Furthermore, as shown in Figure 8, after samples 1, 2, 3, 4, and 5 were mixed with a mixture of saline and contrast agent, the mixture was examined under an optical microscope. It was confirmed that samples 1, 2, and 3 were almost completely dissolved when mixed with the mixture of saline and contrast agent, and did not maintain the sponge-structured particles, whereas samples 4 and 5 were dispersed without dissolving, and the sponge structure was confirmed.

[0047] 2. Embolization procedure (1)Patient In this study, TAE was performed on patients with musculoskeletal disorders. Patients enrolled in this study reported pain that had not improved with various conservative treatments, lasted for more than 6 months, and desired other treatments before the procedure.

[0048] This retrospective study was conducted at a tertiary care center after institutional review board approval. All patients provided informed consent to undergo TAE as an alternative treatment.

[0049] All patients were adults aged 18 or over who had chronic pain (VAS score of 5 or more) due to musculoskeletal disorders for at least six months. Musculoskeletal disorders were diagnosed based on symptoms and the results of imaging tests such as X-rays, ultrasound, and MRI (magnetic resonance imaging).

[0050] Diagnoses included osteoarthritis (OA), lateral and medial epicondylitis, and adhesive capsulitis. Patients presented with chronic pain unresponsive to conservative treatments (over 6 months), including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroid injections, physical therapy, and ESWT. Patients under 18 years of age and those with infection at the site of pain were excluded. Patient selection was based on a multidisciplinary approach, involving the collaboration of interventional radiologists and orthopedic surgeons.

[0051] This study enrolled 29 patients (33 cases) between August 2019 and January 2020. Treatment was performed to improve chronic knee pain (OA, 23 cases), elbow pain (lateral epicondylitis, 4 cases; medial epicondylitis, 5 cases), and shoulder pain (adhesive capsulitis, 1 case). Sixteen patients were male and 17 were female, with a mean age of 60 ± 10.9 years (range, 37-80 years). The mean duration of symptoms was 29.6 ± 17.4 months (range, 6-60 months; median, 30 months). Previous conservative treatments included analgesics (nonsteroidal anti-inflammatory drugs), physical therapy, corticosteroid injections, and ESWT. All patients with knee pain had mild to moderate OA, as determined by radiography or magnetic resonance imaging (MRI) as equivalent to Kellgren-Lawrence grade 2 or 3.

[0052] (2) Embolization procedure Arterial access was achieved via the common femoral artery (CFA) or radial artery. Under local anesthesia, percutaneous arterial access was achieved using a 5-Fr introducer sheath (Terumo, Tokyo, Japan) via the CFA (28 patients) or a 4-Fr sheath (Terumo) via the radial artery (5 patients).

[0053] Baseline arteriography was performed using a 4-Fr or 5-Fr angiographic catheter (Glidecath, non-taper angle; Terumo) via the superficial femoral artery in patients with knee pain (Figure 1) and via the subclavian and brachial arteries in patients with shoulder or elbow pain. Arteriography detected abnormal neovascularization at the site of pain (Figure 2, arrow). A coaxial 1.9 Fr microcatheter (Tellus; Asahi Intecc, Nagoya, Japan) and a 0.016-inch microguidewire (Meister; Asahi Intecc) were used to superselect the corresponding artery at the target site. Through this microcatheter, fast-dissolving gelatin particles were injected without reflux until flow in the selected artery significantly slowed and reached near stasis (Figures 3 and 4a). Angiography was performed again to confirm that the abnormal staining was no longer clearly visible (Figures 4b and 5b). After the procedure was completed, hemostasis was achieved at the puncture site using a closure device (Mynx; Cordis Corporation, New Jersey, USA) for the CFA or a radial compression device (PreludeSYNC; Merit Medical Systems, South Jordan, Utah, USA) for the radial artery. Patients whose CFA was occluded with a closure device were allowed to walk after four hours of complete bed rest and confirmation that there were no complications at the puncture site. For the radial artery, patients were allowed to rest for two hours with a radial compression device attached to their wrist. Patients were discharged on the day of the procedure or one day after admission, depending on their preference.

[0054] In all cases, fast-dissolving gelatin particles (IPZA; Engain Co., Gyeonggi-do, Korea) with diameters of 50–150 μm (average, 90 μm) were used. The particles were mixed with normal saline (100 mg), saline (2 mL), and contrast agent (8 mL) at the time of surgery. Physical property testing revealed that the solubility of the fast-dissolving gelatin particles in saline was 87% at 30 minutes, 89% at 3 hours, 92% at 24 hours, and 98% at 48 hours. The fast-dissolving gelatin particles were mixed with normal saline and iodinated contrast agent (Visipaque; GE Healthcare, Little Chalfont, UK) using a pumping method with multiple tubes to allow visualization during fluoroscopy and delivery.

[0055] (3) Evaluation and follow-up Patient clinical information, imaging data, electronic records, picture storage, and procedures reported in communication systems were reviewed.Technical success was defined as selective embolization of at least one donor artery in the painful area.

[0056] Pain intensity was recorded using a 10-point visual analog scale (VAS), with 0 indicating no pain and 10 indicating maximum pain. VAS scores were assessed at baseline, immediately after the procedure, and 1 day, 1 week, 1 month, 3 months, and 6 months after the procedure. Clinical success was defined as a VAS score reduction of 50% or more from the baseline value. Side effects were assessed during or after the procedure and were documented and included changes in skin color at the treatment site, hematoma at the puncture site, muscle weakness, paresthesia, and allergic reactions to iodinated contrast.

[0057] (4) Statistical analysis Categorical variables were expressed as percentages, and continuous variables were expressed as means and standard deviations. The Wilcoxon signed-rank test was used to compare baseline and sequential follow-up VAS scores. Student's t-test was used to analyze changes in VAS scores over time after treatment. P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS software (version 17.0; SPSS, Chicago, IL, USA).

[0058] 3.Results The technical success rate was 100% (33 / 33). Rapidly dissolving gelatin particles were used for all procedures, and the average volume of embolic material used was 4.3 ± 1.9 mL (100 mg gelatin particles: 2 mL saline: 8 mL contrast medium). The average number of arteries per embolization was 1.8 ± 0.8.

[0059] The follow-up period was 6 months for all 33 patients. The mean VAS scores at baseline, immediately after TAE, 1 day after TAE, 1 week after TAE, 1 month after TAE, 3 months after TAE, and 6 months after TAE were 6.67, 3.09, 4.64, 2.67, 2.30, 2.24, and 2.27, respectively (P<0.05 for baseline vs. immediately after TAE and immediately after TAE vs. 1 day after TAE, Figure 6). The clinical success rate, defined as a reduction in VAS scores by half or more, was 75.76% (24 / 33) at 6 months after surgery. The overall mean pain score gradually decreased during the follow-up period. However, in 18 of the 33 patients, pain was worse several hours after surgery than immediately after surgery. Pain improved after an average of 24 to 48 hours. The mean preoperative baseline VAS score for patients participating in the study was 6.67 points. The mean VAS score decreased to 3.09 immediately after surgery but significantly increased to 4.64 the day after surgery (Figure 6). Painkillers were administered to control the pain, and the pain improved before the follow-up examination one week later. The location of postoperative pain correlated with the distribution of embolized blood vessels. This suggested that the pain was temporary ischemic pain due to embolization. The rapid dissolution of gelatin particles may reduce the occurrence and duration of ischemic pain. Furthermore, smaller gelatin particles may embolize a wider range of peripheral vascular branches, potentially causing ischemic pain.

[0060] No major side effects were reported after embolization. A temporary erythematous skin reaction at the embolization site occurred in 22 patients (66.7%), and hematomas at the puncture site (groin over the CFA) occurred in 3 patients. One patient experienced a mild allergic reaction to iodinated contrast medium (skin rash and itching). No new muscle weakness or paresthesia were reported.

[0061] The above description of the present invention is for illustrative purposes only, and those skilled in the art may easily modify the present invention into other specific forms without changing the technical spirit or essential features of the present invention. Therefore, the above-described embodiments are illustrative in all respects and not limiting. For example, each component described as a single component may be implemented in a distributed form, and similarly, each component described as a distributed component may be implemented in a combined form.

[0062] The scope of the present invention is defined by the claims that follow, and all modifications and variations that fall within the meaning and scope of the claims and their equivalents are intended to be included within the scope of the present invention.

Claims

1. Contains gelatin particles An embolic material for alleviating or treating pain in musculoskeletal areas, characterized by:

2. The gelatin particles have an average diameter of 10 μm to 1000 μm. The embolic material for relieving or treating pain in musculoskeletal areas according to claim 1.

3. The gelatin particles are chemically or thermally crosslinked. The embolic material for relieving or treating pain in musculoskeletal areas according to claim 1.

4. The gelatin particles are formed by dissolving formaldehyde, glutaraldehyde, EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), NHS (N-hydroxysuccinimide), dialdehyde starch, and epoxy compounds. crosslinked with one or more crosslinkers selected from the group consisting of glutaraldehyde glyoxal, glyoxal, 2,2-dimethoxy-2-phenylacetophenone, sodium tripolyphosphate (STPP), diacetaldehyde PEG, scleraldehyde, diethylsquarate, epichlorohydrin, genipin, tannin, phenylpropanoid, catechin, resveratrol, flavonoid, and isoflavonoid. The embolic material for relieving or treating pain in musculoskeletal areas according to claim 1.

5. The gelatin particles have a solubility in an aqueous medium of 50% or more 48 hours after the start of dissolution. The embolic material for relieving or treating pain in musculoskeletal areas according to claim 1.

6. The musculoskeletal site is one or more sites selected from the group consisting of knees, shoulders, necks, elbows, wrists, ankles, fingers, and toes. The embolic material for relieving or treating pain in musculoskeletal areas according to claim 1.

7. The gelatin particles are administered into a blood vessel to embolize the blood vessel, thereby alleviating or treating musculoskeletal pain. The embolic material for relieving or treating pain in musculoskeletal areas according to claim 1.

8. The average dose of gelatin particles administered into the blood vessel is 10 mg to 500 mg. The embolic material for relieving or treating pain in musculoskeletal areas according to claim 7.

9. The blood vessel is one selected from the group consisting of the femoral artery, the radial artery, the subclavian artery, and the brachial artery. The embolic material for relieving or treating pain in musculoskeletal areas according to claim 7.

10. The musculoskeletal pain has been present for a period of six months or more. The embolic material for relieving or treating pain in musculoskeletal areas according to claim 1.

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