Embolizing emulsion for the treatment of inflammatory hypervascularization associated with musculoskeletal disorders - Patent Application 20070123333

Abstract

The present invention relates to an embolization emulsion comprising an iodized oil and an aqueous phase containing a water-soluble contrast agent for use in the treatment of inflammatory hypervascularization associated with musculoskeletal disorders.

Description

[Technical field]

[0001] The present invention is in the field of musculoskeletal disorders. More specifically, the present invention relates to an embolizing composition for use in the treatment of inflammatory hypervascularization associated with musculoskeletal disorders. [Background technology]

[0002] Musculoskeletal disorders (MSDs) affect bones, muscles, joints, tendons, and / or ligaments. They are the most common cause of disability worldwide, resulting in millions of outpatient visits each year (James et al., 2017). In fact, in the United States alone, an estimated 50% of adults are affected by MSDs, and MSDs outnumber all other conditions in causing lost work days (United States Bone and Joint Initiative, 2018). The most common MSDs include arthritis, low back and neck pain, and trauma (e.g., from repetitive motion, overuse, falls), which results in damage to soft tissues and / or fractures. Of particular note, in relatively young and active patients, joint disorders such as tennis elbow, frozen shoulder, and arthritis of the knee or wrist are common causes of disability.

[0003] Pain is one of the earliest and most common symptoms of MSD and is often associated with inflammation at the affected site, in addition to stiffness, tenderness, weakness and / or swelling or deformation. In the case of inflammatory joint conditions, intractable pain is particularly associated with partial or complete loss of function.

[0004] Primary treatment of MSD involves the administration of pharmaceutical compositions (e.g., painkillers including opioids, nonsteroidal anti-inflammatory drugs, muscle relaxants, and corticosteroid injections), which are generally accompanied by non-pharmacological treatment methods (e.g., the use of hot / cold packs, physical therapy, exercise, self-management advice). However, long-term drug application may also result in liver and / or kidney dysfunction, ulcer formation, and even addiction in the case of opioids. Furthermore, the efficacy of treatment varies considerably from patient to patient, which makes it difficult to establish a defined protocol, and refractory MSD is frequent. As an example, in the case of frozen shoulder, approximately 30% of patients do not improve with primary treatment methods (Shaffer et al, 1992). However, for moderate MSD, which do not necessarily respond to primary treatments, but also do not warrant surgery, treatment options are limited. In fact, surgery is typically reserved for only the most severe MSD, which comes with its own set of drawbacks. In particular, surgery is associated with long recovery times, the risk of hospital acquired infections, and the risk of complications from general anesthesia, especially in the elderly.

[0005] Intra-arterial embolization represents an interesting alternative to the above treatments. While transcatheter arterial embolization (TAE) is commonly used to treat tumors (e.g., for devascularization prior to surgery or to deliver chemotherapy directly to tumors) and to manage bleeding (e.g., in postpartum hemorrhage or bleeding from synovitis in patients with hemophilia (see, e.g., Klamroth et al., 2009)), this technique has only recently been evaluated in the context of the treatment of MSDs.

[0006] Interest in applying embolization techniques to MSD arose from the observation that diseased tissues, such as tendons and tendon ligaments, undergo increased neovascularization when injured (see, e.g., Alfredson et al., 2003). In the case of MSD involving the joints, inflammation can induce synovial angiogenesis, leading to a redistribution of blood vessels within the synovium (Bonnet and Walsh, 2005). Okuno et al. (2013) first explored the possibility of treating refractory tendinopathies or enthesopathy with an embolization composition composed of a mixture of imipenem (an antibiotic of the carbapenem family), cilastatin sodium (an enzyme inhibitor that prevents its degradation into nephrotoxic metabolites), and Hexabrix® as an iodized contrast agent, administered by intra-arterial injection. Although only a small number of patients were initially tested, preliminary results showed that intra-arterial embolization could alleviate the unrelenting pain associated with refractory tendinopathy or enthesopathy (Okuno et al., 2013). However, patients may be allergic, especially to imipenem and / or cilastatin sodium. Moreover, the use of imipenem / cilastatin sodium is only authorized in many countries for the treatment of bacterial infections. Of note, the French Authority (HAS) and the European Medicines Agency (EMA), tasked with the evaluation of health products from a medical and economic point of view, recommend limiting the use of imipenem as much as possible, especially for severe infections caused by drug-resistant Enterobacteriaceae, in order to limit the development of antibiotic resistance. Obviously, imipenem / cilastatin sodium cannot be injected into peripheral arteries, since it is associated with a high risk of enhancing antibiotic resistance in Enterobacteriaceae and Pseudomonas aeruginosa, which are themselves involved in clinically high-risk sepsis. Thus, imipenem / cilastatin sodium is not a viable treatment option for MSD in the clinic.

[0007] More recently, calibrated microspheres (Embosphere®, Merit Medical) composed of trisacryl cross-linked with gelatin have been administered by geniculate artery embolization in clinical trials to evaluate their safety and efficacy in treating intractable knee pain associated with knee osteoarthritis (Isaacson and Bagla, 2018). Preliminary results showed a reduction in pain in the majority of patients. However, the microspheres are non-resorbable and result in a persistent occlusion in contrast to products containing a mixture of imipenem and cilastatin sodium. Indeed, when treating MSDs, a temporary occlusion is preferred because it allows vascular recanalization while reducing the risk of permanent tissue ischemia. Moreover, microspheres have been shown to be associated with an increased risk of adverse events. Notably, 16 minor complications were identified among 20 patients treated with polymethylmethacrylate (Embozene) microspheres (Bagla et al., 2020). Moreover, such particulate embolic agents are disadvantageous because they are not easily targeted in blood vessels and are not radiopaque, making them difficult to visualize under fluoroscopy / fluorography unless they are soaked in a contrast agent prior to injection. Moreover, the forceful injection of calibrated particles through a microcatheter or their dehydration can also result in the cracking of the sphere. Summary of the Invention [Problem to be solved by the invention]

[0008] In this regard, new embolization compositions are needed for the treatment of MSD. Such compositions should produce only temporary embolization, i.e. embolization lasting less than 30 days, thus limiting the risk of ischemia. Such compositions should be relatively inexpensive and widely available. In particular, such compositions should be available for the indicated use, rather than being prepared for the treatment of a specific medical condition, e.g., bacterial infection. [Means for solving the problem]

[0009] In the context of the present invention, the inventors have surprisingly found that a composition comprising an iodized oil and an aqueous phase comprising a water-soluble contrast agent can be used to treat inflammatory hypervascularization associated with musculoskeletal disorders.Indeed, embolization in a miniature pig model of osteoarthritis resulted in immediate disappearance of inflammatory hypervascularization in all animals tested.Furthermore, the embolization emulsion of the present invention advantageously has a greater embolization capacity than that of other compositions (e.g., microspheres) and is available at a lower price.

[0010] Thus, in a first aspect, there is provided herein an embolization emulsion comprising an iodized oil and an aqueous phase comprising a water soluble contrast agent for use in the treatment of inflammatory hypervascularization associated with musculoskeletal disorders.

[0011] The term "embolization" refers to a process in which a material is injected into a blood vessel that then at least partially fills or occludes the blood vessel, resulting in a reduction or cessation of blood flow through the blood vessel. Thus, the term "embolization emulsion" as used herein refers to a composition that forms a partial or complete embolization or blockage upon application to a non-intestinal body fluid, usually blood. In one aspect, the embolization emulsion can reduce blood flow (e.g., at least 50%, 60%, 70%, 80%, 90% or 95% compared to blood flow before embolization). This can be particularly advantageous when large vessels or arteries are targeted. Alternatively, the embolization emulsion can induce a complete embolization or blockage. Preferably, the embolization emulsion provided herein induces a complete embolization. In this case, the blockage is temporary. Indeed, iodized oil is known to induce a transient embolization of the arterial circulation. The embolization emulsion is injected into the artery where blockage or occlusion is desired. Thus, the embolization emulsion is in liquid form when injected. With liquid embolic materials, the distance between the end of the microcatheter where the liquid embolic material exits the microcatheter and the target lesion may vary depending on the nature of the embolic agent, the flow conditions, the viscosity of the liquid embolic material, the size of the vessel, and / or the strength of the manual injection of the liquid embolic material.

[0012] Embolization can be selective or non-selective. "Selective embolization" refers to embolization in which a microcatheter is positioned directly into the artery involved in the hypervascularization to deliver the embolic emulsion. "Non-selective" or "shower" embolization refers to embolization in which a microcatheter is positioned proximal (i.e., at a distance) from the artery involved in the hypervascularization to deliver the embolic emulsion.

[0013] The emulsion may be an "oil-in-water" emulsion or a "water-in-oil" emulsion.

[0014] A "water-in-oil" emulsion (also called an "inverse" or "W / O" emulsion) is a dispersion of droplets of an aqueous phase in a lipid phase. An "oil-in-water" emulsion (also called a "direct" or "O / W" emulsion) is a dispersion of droplets of a lipid phase in an aqueous phase. The term "lipid phase" as used herein refers to a phase of a non-polar organic liquid, usually an oil, that is immiscible with water. Thus, the lipid phase preferably comprises an oil, more preferably an iodized oil. Even more preferably, the lipid phase consists of an oil, more preferably an iodized oil. "Aqueous phase" refers to the aqueous phase of a biphasic mixture. The aqueous phase comprises a water-soluble contrast agent. Thus, the aqueous phase comprises water and a water-soluble contrast agent. Optionally, the aqueous phase may further comprise water-soluble additives, such as buffers, pH adjusters, antioxidants, tonicity / osmolality adjusters and / or stabilizers.

[0015] Said emulsion is preferably a water-in-oil emulsion.Thus, the present invention preferably relates to an embolizing water-in-oil emulsion comprising an iodized oil and an aqueous phase comprising a water-soluble contrast agent for use in the treatment of inflammatory hypervascularization associated with musculoskeletal disorders.

[0016] "Iodized oil", as provided herein, comprises or consists of derivatives of iodized fatty acids, preferably ethyl esters of iodized fatty acids, more preferably ethyl esters of iodized fatty acids of poppy seed oil, olive oil, rapeseed oil, peanut oil, soybean oil or walnut oil, even more preferably ethyl esters of iodized fatty acids of poppy seed oil or olive oil. The term "fatty acid" refers to a saturated or unsaturated aliphatic carboxylic acid having a carbon-based chain of at least 4 carbon atoms. Natural fatty acids have a carbon-based chain of 4 to 28 carbon atoms (usually an even number). "Long chain fatty acid" refers to a length of 14 to 22 carbon atoms, and the term "very long chain fatty acid" refers to a length of more than 22 carbon atoms. In contrast, "short chain fatty acid" refers to a length of 4 to 10 carbon atoms, for example 6 to 10 carbon atoms, especially 8 or 10 carbon atoms. The skilled person is well aware of the relevant nomenclature and especially the usage. Ci to Cp indicate a series of Ci to Cp fatty acids, and Ci+Cp indicates the sum of Ci and Cp fatty acids. As an example, a fatty acid having 14 to 18 carbon atoms is described as "C14 to C18 fatty acid"; the sum of C16 and C18 fatty acids is described as C16+C18; for saturated fatty acids, the skilled artisan uses the following nomenclature Ci:0, where i is the number of carbon atoms of the fatty acid (thus palmitic acid is named with the nomenclature (C16:0)); for unsaturated fatty acids, the skilled artisan uses the following nomenclature Ci:xnN, where N is the position of the double bond in the unsaturated fatty acid starting from the carbon opposite the acid group, i is the number of carbon atoms of the fatty acid, and x is the number of double bonds (unsaturation) of this fatty acid (thus oleic acid is named with the nomenclature (C18:1 n-9).

[0017] Most preferably, the iodized oil comprises a mixture of iodized and non-iodized fatty acid ethyl esters of poppy seed oil. Alternatively, the iodized oil consists of a mixture of iodized and non-iodized fatty acid ethyl esters of poppy seed oil.

[0018] Poppy oil is preferably obtained from the seeds of Papaver somniferum var.nigrum (also known as black-flowered poppy), more preferably from Papaver somniferum var.nigrum. Poppy oil, also known as poppy seed oil, preferably also contains more than 80% unsaturated fatty acids, especially linoleic acid (C18:2 n-6) and oleic acid (C18:1 n-9), of which at least 70% is linoleic acid and at least 10% is oleic acid. Iodized oil is obtained from the iodination, preferably complete iodination, of oil, such as poppy oil, under conditions that allow the attachment of one iodine atom for each double bond of unsaturated fatty acids (Wolff, 2001), followed by transesterification.

[0019] The iodized oil according to the invention preferentially contains between 29% and 53% (w / w) of iodine, more preferentially between 37% and 39% (w / w). The iodized oil of the emulsion is in the lipid phase of the emulsion.

[0020] As examples of iodized oils, there may be mentioned Lipiodol® (a mixture of ethyl esters of iodized fatty acids of poppy oil, also called iodized poppy oil ethyl ester), Brassiodol® (derived from rapeseed (Brassica campestris)) oil), Yodiol® (derived from peanut oil), Oriodol® (derived from poppy oil, but in the form of fatty acid triglycerides) and Duroliopaque® (derived from olive oil).

[0021] Preferably, the iodized oil is a mixture of ethyl esters of iodized and non-iodized fatty acids of poppy seed oil (i.e. iodized poppy oil ethyl ester, also known as Lipiodol®). Lipiodol® is a light yellow / amber iodized oil commercialized by Guerbet. It is used for visualization, localization and / or vectorization during transarterial chemoembolization of hepatocellular carcinoma, especially in the intermediate stage in adults, and for selective hepatic arterial diagnosis of the extension of liver malignant lesions. This oil contains mainly (especially more than 84%) a mixture of ethyl esters of long-chain iodized fatty acids (especially C18 fatty acids) derived from poppy seed oil, preferably a mixture of ethyl monoiodostearate and ethyl diiodostearate. The iodized oil can also be an oil based on the monoiodized ethyl ester of stearic acid (C18:0) derived from olive oil (e.g. Duroliopaque®, as mentioned above).

[0022] The main characteristics of Lipiodol® are provided in the table below.

[0023] [Table 1]

[0024] Further characteristics of Lipiodol® are provided in the table below.

[0025] [Table 2]

[0026] Preferably, the amount of iodized oil present in an emulsion according to the invention is less than or equal to 15 ml. Preferably, the lipid (or oil) phase consists essentially of iodized oil, more preferably the lipid phase consists of iodized oil as defined herein.

[0027] The density of the lipid phase of the emulsion is preferably between 1.10 and 1.30, more preferably between 1.20 and 1.30, even more preferably 1.28.

[0028] The term "water-soluble contrast agent" as used herein refers to a biocompatible (non-toxic) material that can be monitored (e.g., by X-ray imaging) when injected into a subject and is soluble in water. The water-soluble contrast agent is preferably radiopaque and therefore can be detected by X-ray imaging (e.g., on an angiogram or arteriogram). It may include barium sulfate or iodine, among others.

[0029] Preferably, the water-soluble contrast agent is an iodized contrast agent, i.e., it contains iodine. In an iodized contrast agent, the iodine may be bound to an ionic compound or an organic compound, in which case it is classified as a "non-ionic" compound. Examples of ionic iodinated contrast agents include meglumine diatrizoate (Hypaque®), metrizoate (Isopake®), iothalamate (Conray® and ioxaglate (Hexabrix®), meglumine amidotrizoate and meglumine ioxithalamate. Examples of non-ionic iodinated contrast agents include iobitridol (Xenetix®), iopamidol (lopamiron®, Isovue®), iomeprol (lomeron®), ioversol (Optiray®, Optiject®), iohexol (Omnipaque®), iopentol (Imag opaque®), ioxytol (Oxilan®), iopromide (Ultravist®), metrizamide (Amipaque®), iosarchol (Melitrast®), iotrolan (Isovist®), iodixanol (Visipaque®), iosimenol and iosimide (Univist®). The iodinated contrast agent may be in monomeric or dimeric form. It may have a high osmolality (i.e., 1200 mOsm / kg or more), a low osmolality (i.e., 500-900 mOsm / kg) or may be isotonic (i.e., approximately 290 mOsm / kg).

[0030] Preferably, the water-soluble iodinated contrast agent is non-ionic. Preferably, the water-soluble iodinated contrast agent has a low osmolality (i.e., 500-900 mOsm / kg) or is isotonic. Preferably, the water-soluble iodinated contrast agent comprises ioversol, iopamidol, iomeprol, iopromide, iohexol, iobitridol and iodixanol or a mixture of two or more thereof. More preferably, the water-soluble iodinated contrast agent is selected from the group consisting of ioversol, iopamidol, iomeprol, iopromide, iohexol, iobitridol and iodixanol, even more preferably iobitridol and ioversol, most preferably ioversol.

[0031] The ratio of lipid phase:aqueous phase (in other words the ratio of iodized oil:aqueous phase containing a water-soluble contrast agent as provided herein) is preferably at least 2:1 v / v so as to obtain an oil-in-water composition. In fact, a 1:1 v / v ratio between lipid phase and aqueous phase naturally favors an O / W orientation. If a water-in-oil emulsion is desired, the amount of iodized oil added must be increased. A ratio of iodized oil to aqueous phase of at least 2:1 v / v (also expressed as the ratio of iodized oil:aqueous phase or lipid phase:aqueous phase) allows to obtain a W / O emulsion. More preferably, the ratio of iodized oil:aqueous phase is at least 3:1 v / v or at least 4:1 v / v. In one embodiment, the ratio (v / v) of iodized oil:aqueous phase is comprised between 2:1 and 4:1, more particularly between 5:2 and 10:3. The ratio of iodized oil:aqueous phase (v / v) may in particular be equal to 3:1 or 4:1.

[0032] The concentration of the water-soluble contrast agent (e.g., ioversol) in the aqueous phase (i.e., in water) may be in the range of 500-750 mg / mL, more specifically 509-741 mg / mL. In particular, the concentration of the water-soluble contrast agent (e.g., ioversol) in the aqueous phase may be 509, 636, 678 or 741 mg / mL. Preferably, the concentration of iodine in the aqueous phase is in the range of 240-400 mg iodine / mL (mg I / mL), 240-350 mg I / mL or 240-320 mg I / mL). In particular, the concentration of iodine in the aqueous phase may be 240, 300, 320, 350, 370 or 400 mg I / mL. The iodine present in the aqueous phase comes from the iodized water-soluble contrast agent, and the iodine concentration ranges given above correspond to the above given ranges of water-soluble contrast agent concentrations when using conventional water-soluble contrast agents as disclosed above, in particular ioversol.

[0033] The lipid and aqueous phases may have the same density (in other words, they are of equal density) or different densities, with ioversol being one preferred iodized contrast agent; Optiray® 240, Optiray® 300, Optiray® 320, Optiray® 350 having densities of 1.281, 1.352, 1.371 and 1.405, respectively. Iobitridol (Xenetix®) is another preferred iodized contrast agent. Xenetix® 250 and Xenetix® 300 products have densities of 1.28 and 1.34, respectively. Preferably, the lipid and aqueous phases have the same density (in other words, they are of equal density) or similar densities (i.e., they differ from each other by no more than 10%).

[0034] The embolization emulsion may have a viscosity in the range of 70-200 mPa.s, preferably 120-170 mPa.s, more preferably 150-165 mPa.s, even more preferably 150-165 mPa.s at 20° C. and / or a viscosity in the range of 40-140 mPa.s, preferably 70-140 mPa.s, more preferably 80-130 mPa.s or even more preferably 90-130 mPa.s at 37° C. Viscosity values ​​can in particular be obtained using a Malvern Instruments Kinexus Pro rheometer with a 4° cone-plate cell with a diameter of 40 mm. The measurements are carried out at applied stresses in the range of 0.16-10 Pa.

[0035] As non-limiting examples, the size of the droplets in the emulsion (i.e., the aqueous phase droplets) can range from 1 to 500 μm, 1 to 200 μm, or 5 to 150 μm. Preferably, the emulsion droplet size ranges from 10 to 100 μm, more preferably from 10 to 80 μm, or even more preferably from 30 to 80 μm. The size can vary from droplet to droplet as long as it is within the desired size range. Preferably, the aqueous phase droplets are uniformly distributed. The droplet size and uniformity can be measured using an optical microscope (e.g., Leica DM2000 LED microscope). If droplet aggregates are observed, the droplets are not uniformly distributed.

[0036] The aqueous phase may further comprise one or more water-soluble additives. The one or more additives may in particular be a buffer, a pH adjuster, an antioxidant, a tonicity / osmolality adjuster, a density adjuster and / or a stabilizer. The additives in particular have no therapeutic effect in the body. Preferably, the aqueous phase comprises a buffer, more preferably tromethamine. Preferably, the aqueous phase comprises a stabilizer, more preferably calcium disodium edetate. Preferably, the pH of the aqueous phase is adjusted to a pH of 6.0 to 7.2, preferably with hydrochloric acid or sodium hydroxide.

[0037] While the embolization emulsion provided herein may contain additional additives such as those described above, it preferably does not contain any additional "active" ingredients, by which is meant herein a component that has therapeutic activity in the body.

[0038] Preferably, the first example of the active ingredient that is not present in embolization emulsion is chemotherapy anticancer drug.In fact, since emulsion is used in the treatment of inflammatory hypervascularization associated with musculoskeletal disorders, the presence of such drug is inconvenient.The non-limiting examples of such chemotherapy anticancer drug include anthracycline, mitomycin C, platinum complex, radioactive element, alkylating / amine methylating agent, mitotic inhibitor / tubulin inhibitor, topoisomerase inhibitor, pyrimidine antagonist, guanidine antagonist, folic acid antagonist, etc. More specifically, chemotherapy anticancer drugs excluded from the present emulsion are doxorubicin, epirubicin, idarubicin, nemorubicin, mitoxantrone, pirarubicin, paclitaxel, cisplatin, carboplatin, oxaliplatin, lobaplatin, cyclophosphonamide, mitomycin C, fotemustine, irinotecan, mitoxantrone, everolimus, sorafenib, 5-fluorouracil, methotrexate, gemcitabine, carmustine, dacabazine, etoposide, vinorelbine, topotecan, estramustine, and any combination thereof.

[0039] Thus, the embolizing emulsion preferably does not include a chemotherapeutic anti-cancer agent. More preferably, the embolizing emulsion does not include any of the chemotherapeutic anti-cancer agents listed above.

[0040] Further examples of active ingredients that are preferably not present in the embolization emulsion are nanoparticles or polymer particles, more preferably embolic particles. Indeed, while nanoparticles or polymer particles can be used as alternative embolization agents, they are not desirable in the context of the present invention. In particular, non-resorbable nanoparticles or polymer particles can lead to persistent occlusion, which can cause ischemia. Resorbable nanoparticles or polymer particles can lead to inflammation and / or thrombus formation as a result of their partial degradation and distal migration of the particles or fragments. Thus, they are not desirable in the context of the present invention. The term "nanoparticles" as used herein refers to solid particles having an average diameter of about 1 nm to about 500 nm. More specifically, the embolization emulsion does not include polyester-based nanoparticles (e.g., polylactide-based nanoparticles, polyglycolic acid (polyglycolide), lactide-glycolide copolymers, lactide-glycolide-co-polyethylene glycol copolymers, polyorthoesters, polyanhydrides, polybutylacetone, polyvalerolactone, polymalic acid, polylactones). The term "polymeric particle" as used herein refers to a particle that includes one or more types of polymers (e.g., polyesters (e.g., poly[hydroxy acids], poly[cyclic esters], etc.), polycarbonates, polyorthoesters, polyanhydrides, polycyanoacrylates (e.g., polyalkylcyanoacrylates or "PACA"), and polyphosphazines). The polymeric particle may be a nanoparticle.

[0041] The term "embolic particle" refers to any solid or non-dissolved material that forms an embolism or blockage upon application to non-intestinal body fluids, usually blood. Embolic particles may more specifically include nanoparticles and / or embolic particles. The particles may be spheroidal or oblong, or may have an irregular geometric shape. In contrast, the embolization emulsions provided herein are composed of liquid materials (e.g., an aqueous phase containing iodized oil and a water-soluble contrast agent).

[0042] Thus, the embolizing emulsion is preferably free of nanoparticles or polymeric particles. Even more preferably, the composition is free of embolic particles.

[0043] The term "musculoskeletal disorder" or "MSD" as used herein refers to any disease or condition in which the function of the musculoskeletal system (e.g., muscle, ligament, tendon, cartilage, bursa, joint, or bone) of a subject is impaired. MSDs can be localized or systemic; they can be acute or chronic, more preferably chronic. In the case of chronic MSDs, they can be continuously present or recur sporadically (e.g., erythema). MSDs can be due to behavioral, environmental, traumatic, immunological, degenerative, and / or genetic factors, and / or can be associated with a systemic disease. As an example, MSDs can be at least partially due to repetitive movements or strenuous activities, for example, in the workplace or associated with sports. Thus, in one aspect, MSDs are sports injuries. MSDs include strains, sprains, fractures, twists, tears, inflammatory rheumatoid diseases, enthesopathies, and tendon disorders (e.g., tendinitis and tendonitis). MSDs may particularly affect the elbows, knees, wrists, shoulders, hips, heels, ankles, thumbs or spine (more specifically the cervical, spinal or lumbosacral spine).

[0044] The term "inflammatory rheumatic disease" or "inflammatory rheumatic disease" refers to a disease that produces acute or chronic inflammation, especially in joints, but can also affect other tissues, such as muscle or connective tissue. The inflammation can be localized and / or systemic, and often occurs as a result of autoimmune disorders. As non-limiting examples, inflammatory rheumatic diseases include osteoarthritis (e.g., knee or hip osteoarthritis), cervical spondylosis, rheumatoid arthritis (RA), acute crystal arthritis (e.g., gout), spondyloarthropathy (ankylosing spondylitis (AS) and psoriatic arthritis (PsA)), Sjogren's syndrome, scleroderma, infectious arthritis, plantar fasciitis, juvenile idiopathic arthritis, polymyalgia rheumatica, fibromyalgia, lupus, and vasculitis.

[0045] The term "enthesopathy" refers to disorders involving the attachment of tendons or ligaments to bone. Enthesopathy includes, among others, Achilles enthesopathy, epicondylitis, ankylosing spondylitis, plantar fasciitis, rotator cuff syndrome and related disorders, enthesopathy of the elbow area, enthesopathy of the wrist and carpals, olecranon bursitis, prepatellar bursitis, bursitis of the hand or wrist, enthesopathy of the hip area, hip bursitis (e.g., trochanteric bursitis, iliopsoas bursitis), enthesopathy of the knee, enthesopathy of the ankle, enthesopathy of the tarsus, and enthesopathy of the calcaneus (e.g., inferior calcaneal bursitis).

[0046] The term "tendinopathy" refers to disorders or injuries of tendons. Tendinopathy includes shoulder tendinitis, calcific tendinitis (rotator cuff tendinitis), Achilles tendinitis, biceps tendinitis, quadriceps tendinopathy, lateral epicondylitis (tennis elbow), medial epicondylitis (golfer's elbow), De Quervain's tendinitis, stenosing tenosynovitis (trigger finger / thumb), wrist tendinopathy, and patellar tendinopathy, among others.

[0047] As further examples, MSDs also include neck strain, osteoporosis, Baker's cyst, adhesive capsulitis (frozen shoulder), carpal tunnel syndrome, tarsal tunnel syndrome, radial tunnel syndrome, hand-arm vibration syndrome, knee meniscus injuries, degenerative disc disease, lumbago / herniated disc, digital neuritis, thoracic outlet compression syndrome, Dupuytren's contracture, sesamoiditis, and Lyme disease.

[0048] Preferably, the MSD disorder affects the elbow, knee, wrist, shoulder, hip, heel, ankle, thumb and / or spine. When the MSD affects the spine, it more preferably affects the cervical spine, spinal column or lumbosacral spine.

[0049] Preferably, the MSD is selected from enthesopathy, tendinopathy, inflammatory rheumatoid disease and carpal tunnel syndrome. More preferably, the MSD is - an enthesopathy selected from Achilles enthesopathy, epicondylitis, ankylosing spondylitis, plantar fasciitis, rotator cuff syndrome, enthesopathy of the elbow area, enthesopathy of the wrist and / or carpals, olecranon bursitis, prepatellar bursitis, bursitis of the hand or wrist, enthesopathy of the hip area, hip bursitis, enthesopathy of the knee, enthesopathy of the ankle, enthesopathy of the tarsus and enthesopathy of the calcaneus, - a tendonopathy selected from shoulder tendinitis, calcific tendinitis, Achilles tendinitis, biceps tendinitis, quadriceps tendinopathy, lateral epicondylitis, medial epicondylitis, De Quervain's tendinitis, stenosing tenosynovitis, wrist tendinitis, patellar tendinopathy, or - Inflammatory rheumatoid diseases selected from osteoarthritis, cervical spondylosis, rheumatoid arthritis (RA), acute crystalloid arthritis, spondyloarthropathy, psoriatic arthritis, Sjogren's syndrome, scleroderma, infectious arthritis, plantar fasciitis, juvenile idiopathic arthritis, polymyalgia rheumatica, fibromyalgia, lupus, and vasculitis It is.

[0050] Even more preferably, the MSD is selected from tennis elbow, adhesive capsulitis, osteoarthritis, syndrome or Achilles tendinitis.

[0051] The MSD may be resistant to one or more treatments (e.g., first-line treatments, e.g., pharmacological treatments, e.g., oral analgesics, anti-inflammatory medications, corticosteroid injections, or physical therapy). An MSD that is "resistant" to a treatment does not respond to the treatment and / or has a reduced ability to produce a significant response (e.g., partial and / or complete response) with treatment at the maximum recommended dose, duration, and / or frequency. Tolerance may be acquired, particularly when a chronic MSD requires continuous treatment (i.e., it occurs over time). As a specific example, pain is opiate-resistant when inadequate analgesia is achieved at a level of opiate treatment that results in intolerable side effects. In some cases, the MSD is refractory. The term "refractory" as used herein refers to an MSD that does not respond to at least two different pharmacological therapies (such as those described above). The at least two different therapies preferably have different mechanisms of action.

[0052] Preferably, the MSD is resistant or refractory to treatment with oral analgesics, anti-inflammatory medications, physical therapy and / or corticosteroid injections.

[0053] A further aspect of the present invention relates to an embolization emulsion as provided herein for use in the treatment of inflammatory hypervascularization associated with musculoskeletal disorders, said treatment comprising administering the embolization emulsion to at least one target artery supplying blood to an affected tissue. The embolization emulsion of the present invention results in the formation of a temporary embolism. Preferably, embolization of the target artery lasts for less than 24 hours. More preferably, embolization of the target artery lasts for 6-12 hours.

[0054] The term "inflammatory hypervascularization," as used herein, refers to an increase in the number or concentration of blood vessels that is associated with inflammation. This may involve de novo blood vessel formation (i.e., angiogenesis), the formation of new blood vessels from existing vessels (e.g., the growth of new capillaries from postcapillary venules), and / or an increase in the diameter of existing arterial vessels (i.e., arteriogenesis).

[0055] The present invention also includes the use of an embolization emulsion as provided herein for the manufacture of a medicament for treating inflammatory hypervascularization associated with musculoskeletal disorders.

[0056] The present invention also includes the use of an embolizing emulsion as provided herein in the treatment of inflammatory hypervascularization associated with musculoskeletal disorders.

[0057] Further provided herein is a method for treating inflammatory hypervascularization associated with musculoskeletal disorders in a subject in need thereof.More specifically, the method for treating inflammatory hypervascularization associated with musculoskeletal disorders in a subject in need thereof comprises administering a therapeutically effective amount of an embolization emulsion as provided herein.

[0058] The term "treatment", as used herein, refers to the alleviation of symptoms of MSD (i.e., associated with inflammatory hypervascularization) or the inhibition of further progression or aggravation of said symptoms. The term "treatment", as used herein, can also refer to delaying the onset of symptoms, reducing the severity of symptoms upon onset, or reducing the frequency of disease episodes. Similarly, the term "effective amount" as used herein in relation to an embolizing emulsion or a "therapeutically effective amount" of an embolizing emulsion refers to an amount of an agent that alleviates, in whole or in part, symptoms associated with MSD, or stops or slows further progression or aggravation of those symptoms. In particular, an "effective amount" refers to an amount that is effective in achieving a desired therapeutic result. A therapeutically effective amount may be administered, in particular in one or more administrations, in particular each administration occurring at different sites within the affected area or at different affected areas (e.g., different joints in the case of generalized osteoarthritis). In particular, a therapeutically effective amount of the embolizing emulsion is administered in one, two, three or more injections over a given period of time and / or into different arteries (e.g., in the same joint or in different joints). A therapeutically effective amount is also one in which any toxic or detrimental effects of the compounds of the invention are outweighed by the therapeutically beneficial effects.

[0059] "Subject" refers to any mammal, and more specifically may be any human individual regardless of their age. Specifically, a subject may be a human adult or child. The term "adult" as used herein refers to an individual who is at least 16 years of age. The term "child" includes infants aged 0-1 year, as well as children aged 1-8 years, 8-12 years, and 12-16 years.

[0060] 1. A method of treating inflammatory hypervascularization associated with a musculoskeletal disorder in a subject in need thereof, comprising: - providing an embolization composition comprising an iodized oil and an aqueous phase comprising a water-soluble contrast agent; - temporarily embolizing at least one artery supplying blood to the affected tissue with an embolic composition, preferably by transcatheter arterial embolization. Further provided herein is a method comprising:

[0061] According to a further aspect, the present invention relates to a kit comprising an iodized oil and a water-soluble contrast agent as provided herein, and instructions for administering the immunogenic or immunotherapeutic composition described herein to a subject. The water-soluble contrast agent may be provided in lyophilized form or in an aqueous phase. The iodized oil and the water-soluble contrast agent may be provided in separate containers. In this case, the embolization emulsion may be prepared by mixing the iodized oil and the aqueous phase containing the water-soluble contrast agent before administration. Alternatively, the iodized oil and the aqueous phase may be provided in the same container (e.g., as an emulsion that can be administered directly). In this case, the emulsion further comprises a stabilizer. [Brief description of the drawings]

[0062] [Figure 1] Porcine model of osteoarthritis. (A, B) Representative angiograms of the shoulder 7 days after alcohol injection showing hypervascularization (arrows) and early venous return (*). (C, D) Example angiograms of an untreated shoulder 20 days after alcohol injection showing persistent hypervascularization (arrows). [Diagram 2] Efficacy of embolization emulsion in a porcine model of osteoarthritis. Representative comparison of baseline (A) and post-embolization (B) angiograms with Lipiodol® emulsion showing no signs of hypervascularization. [Diagram 3] Histological staining of untreated (control) limbs compared to limbs treated with embolization emulsion: (A) untreated skin, (B) treated skin, (C) untreated tendon, (D) treated tendon. [Figure 4] Illustration of the durability of embolization with Lipiodol® / Ioversol emulsion. (A) Exemplary angiogram performed over time on pig #1 with administration of LUF / Optiray® to the left shoulder. (B) Exemplary angiogram performed over time on pig #2 with administration of LUF / Optiray® to the inferior pole artery of the left kidney. [Diagram 5] Effect of joint embolization in a clinical trial. Six patients with knee osteoarthritis were evaluated over time for (A) pain and (B) functional impairment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063] The following examples are included to demonstrate preferred embodiments of the invention. All subject matter described or shown in the following examples and accompanying drawings is intended as illustrative and not limiting. The following examples include any alternatives, equivalents and modifications that may be determined by one of ordinary skill in the art. EXAMPLES

[0064] 1. Materials and Methods 1.1 Osteoarthritis model Four minipigs weighing 17-25 kg were kept in separate cages in an environmentally controlled animal research facility with food and water available ad libitum.

[0065] All procedures were performed under general anesthesia with a mixture of ketamine (50 mg / kg) and xylazine (5 mg / kg) IM. Minipigs were ventilated through a mask using oxygen-enriched room air at a rate of 20 breaths per minute and a tidal volume of 45-50 ml.

[0066] 1.1.1 Preparation of embolization emulsion Lipiodol® emulsion was compounded with 3 cc of Ioversol contrast agent (Optiray® 240, Guerbet, France) and 9 cc of Lipiodol® (Guerbet, France) by repeated back and forth pumping of two 20 ml syringes through a three-way stopcock.

[0067] 1.1.2 Osteoarthritis porcine model Direct puncture was performed above the right shoulder and below both knees under fluoroscopy using a standard 18G catheter (Angiocath, BD medical, Utah, USA). Chronic inflammation was induced by injection of 5 ml of pure ethanol (100%) in the right shoulder and both knee joints. The left shoulder joint was used as a control.

[0068] Seven days after generating the model, puncture of the right femoral artery was performed under ultrasound guidance, followed by selective angiography of the bilateral subclavian and femoral arteries using a 4Fr Cobra catheter (Terumo, Tokyo, Japan) to evaluate the presence of hypervascularization in the four joints.

[0069] After selective catheterization of the right subclavian artery, superselective catheterization of the hypervascularized sites was performed using a 2.7 Fr microcatheter (Progreat®, Terumo, Tokyo, Japan). Complete embolization was obtained by injection of Lipiodol® emulsion until stasis (selective embolization; right shoulder). In addition, catheterization of the right femoral artery was performed, followed by nonselective ("shower") embolization from a Cobra catheter (nonselective embolization; right knee). After embolization, angiographic controls were performed to evaluate the immediate technical success.

[0070] No embolization was performed in the left knee (positive control for the model). Hemostasis was obtained by manual compression of the puncture site and the animals were awakened.

[0071] Fourteen days after embolization, selective control angiograms were performed at the subclavian and femoral arteries to assess the patency of the parent vessels at follow-up via the left common femoral approach, after which the minipigs were sacrificed.

[0072] 1.1.3 Histological evaluation Immediately after sacrifice, attachment and tendon samples were obtained from four joints and fixed in 10% formaldehyde for histological analysis. Samples were processed, embedded in paraffin, and sectioned by standard procedures. Specifically, each section was stained with hematoxylin and eosin (H&E). An independent pathologist analyzed the samples and characterized the lesions. The pathologist was blinded to the treatment the minipigs received.

[0073] 1.1.4 Study endpoints The presence of hypervascularization associated with histological signs of subacute inflammatory disease confirmed the successful generation of the animal model.

[0074] The primary efficacy endpoint was successful embolization of the target vessel with disappearance of inflammatory hypervascularization on angiography immediately after embolization.

[0075] The primary safety endpoint was met when all of the following criteria were observed: patency of the parent vessel on angiographic control 14 days after embolization, absence of non-targeted embolization, and absence of joint and skin necrosis.

[0076] 1.1.5 Statistics All data were analyzed by SPSS 20.0 (SPSS Inc., Chicago, IL, USA). Categorical variables were expressed as absolute values ​​and percentages and compared with chi-squared tests. Numerical variables were expressed as mean ± standard deviation and compared with paired Student's t-tests. p < 0.05 (two-tailed) was considered statistically significant for all analyses.

[0077] 1.2 Evaluation of the characteristics of Lipiodol® / Ioversol emulsions Two 45 kg healthy pigs were anesthetized and injected intra-arterially by an interventional procedure using a fluoroscope. The interventional procedure of embolization is a minimally invasive technique performed under image guidance (in this case X-ray with the use of a fluoroscope) and a catheter is used for the administration of the embolization product.

[0078] The stability of two different products was evaluated: 1. Imipenem / cilastatin, Mylan (IPM / CS) To prepare the suspension, 500 mg of IPM / CS powder was suspended in 10 ml of ioversol contrast agent (Optiray® 300, Guerbet). The suspension was placed in a 10 mL syringe and divided into 3 mL syringes through a three-way stopcock. The suspension was pumped 20 times to obtain a uniform suspension. 2. Lipiodol® Ultra Fluid (LUF) based emulsion with a 3:1 ratio (3 volumes of Lipiodol® to 1 volume of contrast agent Ioversol (Optiray® 300)), also referred to herein as "LUF / Optiray®". 6 mL of Lipiodol® was placed in a 10 mL syringe which was split by a three-way stopcock into a 3 mL syringe previously filled with 2 mL of Optiray® 300 (Guerbet). The solution was pumped 20 times (starting by pushing Optiray® into Lipiodol®) to obtain a homogenous and stable emulsion.

[0079] Uniformity / stability was assessed by visual inspection over time.

[0080] The durability of embolization was further evaluated with LUF / Optiray® emulsion, which was injected into different target arteries as detailed in the table below.

[0081] [Table 3]

[0082] Prior to embolization with LUF / Optiray®, angiography of the embolization target site was performed using an autoinjector to map the injection site and select the target vessel using the following protocol: flow rate: 4 mL / s, 8 mL of Xenetix® 300 (iobitridol, 300 mg iodine / mL; Guerbet) injected.

[0083] Embolization was then performed as follows: - Angiography of selected sites was performed before embolization with approximately 1 mL of Xenetix® 300 (Guerbet) per injection. This image made it possible to determine the degree of repermeabilization of the embolized vessels after downstream administration of the embolization product. - The product (prepared as described above) was injected until the selected site was completely filled, corresponding to approximately 1.5 mL for each embolization. The injections were performed with a 2.4 Fr DraKon™ microcatheter (Guerbet). - Angiograms were performed with approximately 1 mL of Xenetix® 300 at 1, 2, 3, 4, 5, 6, 8, 10, 15 and 20 minutes after administration of the product. - CT scans were performed 1 hour after the end of all embolization procedures to detect and evaluate the persistence of embolization at the injection target site.

[0084] The durability of embolization resulting from LUF / Optiray® was determined by comparing the kinetics observed angiographically over time (ie, 1-20 min as above).

[0085] 1.3 Clinical Evaluation of Lipiodol® / Ioversol Embolization Emulsion in Humans 1.3.1 Knee osteoarthritis Patients presented to the clinic with painful knee osteoarthritis and were considered for inclusion in a Phase 1, single-arm, open-label clinical trial (ClinicalTrials.gov Identifier: NCT04733092). Inclusion criteria were: A diagnosis of osteoarthritis of the knee according to the American College of Rheumatology (ACR) classification and primary inflammatory osteoarthritis of the target joint defined by a score of ≥2 according to the Kellgren and Lawrence classification; Patients who are not suitable for surgery (or refuse surgery), - Visual analogue scale (VAS) pain ≥ 40 mm despite at least 3 months of analgesic treatment; Failure or intolerance of treatment with NSAIDs and / or tramadol and / or acetaminophen and / or failure or intolerance of strong opioid medications (morphine, codeine) or patient refusal; and Failure or patient refusal of corticosteroid infiltration Includes:

[0086] Six patients were included in the trial. Knee joints were embolized with a 3:1 v / v Lipiodol® / ioversol emulsion and clinical examinations were performed at follow-up. Pain was assessed on a visual analog scale (VAS) of 0 to 100 mm, with 100 mm being the worst pain expected. Pain is expressed as a percentage of pre-embolization baseline. Functional impairment was assessed by the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire on a scale of 0 to 96 (see McConnell et al., 2001). Higher scores indicate worse function. Functional impairment is expressed as a percentage of baseline WOMAC score.

[0087] 1.3.2. Frozen shoulder Based on initial preclinical (porcine study) and clinical (knee osteoarthritis) safety results, one patient presenting with frozen shoulder was treated by embolizing the joint with a 3:1 v / v Lipiodol® / ioversol emulsion.

[0088] 2.Results 2.1 Osteoarthritis model in miniature pigs As illustrated in Table 2 below, the osteoarthritis model was successfully induced in all animals. Indeed, all joints subjected to alcohol injection showed hypervascularization at baseline angiography and histological signs of subacute inflammatory disease of the joint 7 days after injection (12 / 12 joints, 100%). Specifically, histological samples showed signs of chronic ischemia in all joints after alcohol injection. No signs of hypervascularization or chronic inflammation were observed in negative control joints (4 / 4 joints, 100%).

[0089] [Table 4]

[0090] Successful embolization using Lipiodol® emulsion with immediate disappearance of hypervascularization was obtained in all treated joints (8 / 8, 100%; see Table 3). One minipig died 3 days after embolization, before control angiography, from Mycoplasma pneumonia not associated with embolization.

[0091] In angiographic controls performed 14 days after embolization, patency of the target vessels was observed in all cases (see Table 3). Reduction of hypervascularization was also observed in 5 / 6 joints (83.3%), partial reduction in 4 / 6 joints (66.7%), and complete disappearance in one joint (1 / 6, 16.7%).

[0092] [Table 5]

[0093] Transient skin signs of ischemia, characterized by a rash, were observed in all four joints treated with nonselective embolization (4 / 4, 100%). These signs disappeared a few days after embolization in all cases. The pigs did not show clinical signs of pain or deterioration in their normal daily behavior. No signs of ischemia were observed in the joints treated with embolization (8 / 8, 100%). In the histological analysis performed 14 days after embolization, no signs of skin or synovial necrosis were observed (see Table 3).

[0094] 2.2 Comparison of stability of Lipiodol® / ioversol emulsions compared to imipenem / cilastatin The IPM / CS suspension is homogeneous after preparation. Five minutes after preparation, the IPM / CS powder tends to settle, showing phase separation. Thus, IPM / CS is not stable over time. In contrast, the LUF / Optiray® emulsion is stable and homogeneous after preparation and does not show phase separation during the entire experiment. A stable emulsion ensures homogeneous distribution of the product at the target site with higher therapeutic efficacy.

[0095] 2.3 Assessment of durability of embolization with Lipiodol® / ioversol emulsion 2.3.1 Radiopacity of the product LUF / Optiray® emulsions are detectable by fluoroscopic imaging during injection due to the radiopacity of Lipiodol®. After administration, the radiopacity of Lipiodol® persists in the blood vessels and is detectable up to 8 minutes after administration.

[0096] 2.2.3 Embolic properties Target arteries injected with LUF / Optiray® emulsion were completely repermeabilized 8 minutes after product administration, indicating that embolization was successful and transient. Moreover, embolization was reproducible and predictable. Indeed, as illustrated in FIG. 4, Xenetix® 300 completely repermeabilized two different target arteries in two different animals 8 minutes after product administration in all arterial networks evaluated.

[0097] 2.4 Clinical evaluation in humans 2.4.1. Knee osteoarthritis The clinical outcomes at the most recent available follow-up are provided in Figure 5 and summarized in Table 4 below.

[0098] [Table 6]

[0099] 6 / 6 patients showed a reduction in pain as reported on the VAS scale and 5 / 6 patients reported a reduction in functional disability as determined on the WOMAC scale. When self-reported, 5 / 6 patients reported a more significant improvement, while 2 / 6 patients indicated that they were able to regain physical activity.

[0100] During the course of embolization, patient 1 experienced erythema for 2 days and periarticular edema for 4 days, both of which were mild and did not require initiation of treatment. Patient 2 experienced mild erythema, which did not require treatment and resolved within 4 hours. Patient management was slightly modified by applying ice packs to the knee during embolization. With this modification, no erythema or edema was noted thereafter.

[0101] None of the six patients developed other signs of complications / toxicity.

[0102] 2.4.2. Frozen shoulder Six months after embolization, clinical examination of the patient presenting with frozen shoulder showed a mild improvement in shoulder mobility with a 20° improvement in external rotation and a very significant improvement in pain (with a >50% reduction in opiate analgesic treatment).

[0103] 3. Conclusion In their study using an osteoarthritis porcine model, the inventors surprisingly demonstrated the efficacy of the emulsion according to the invention in treating inflammatory hypervascularization associated with musculoskeletal disorders. In particular, the emulsion successfully embolized hypervascular sites, as confirmed by the immediate disappearance of hypervascularization in all embolized joints. Moreover, hypervascularization was successfully treated regardless of whether a selective or non-selective approach was used for embolization. Importantly, the procedure was safe with angiographic controls observed in all joints, with patency of the donor artery. No non-targeted embolization was observed with the selective approach. While transient skin ischemia was observed during the perioperative period when non-selective embolization was performed, this disappeared several days after the procedure without histological evidence at 14 days and clinical signs of pain / discomfort.

[0104] The inventors have also shown that the transient embolization induced by the emulsions of the invention is reproducible and therefore predictable.

[0105] The effectiveness of the emulsion according to the present invention in treating inflammatory hypervascularization has been further confirmed by human clinical trials.In fact, following embolization with emulsion, 5 / 6 patients with knee osteoarthritis reported reduced pain and improved joint function at the latest available follow-up, while only 2 / 6 patients reported minor side effects.The surprising effect of the emulsion provided herein has been further confirmed in another patient with frozen shoulder.

[0106] References Alfredson H,Ohberg L,Forsgren S,Is vasculo-neural ingrowth the cause of pain in chronic Achilles tendinosis?An investigation using ultrasonography and colour Doppler,immunohistochemistry,and diagnostic injections.Knee Surg Sports Traumatol Arthrosc.2003,11(5):334-338. Bagla S,Piechowiak R,Hartman T,Orlando J,Del Gaizo D,Isaacson A.Genicular Artery Embolization for the Treatment of Knee Pain Secondary to Osteoarthritis.J Vase Interv Radiol.2020 Jul;31(7):1096-1102. Bonnet CS,Walsh DA,Osteoarthritis,angiogenesis and inflammation.Rheumatology,2005;44(1):7-16. Isaacson and Bagla,Randomized Placebo-Controlled Single Blinded Study of Geniculate Artery Embolization for Knee Pain Secondary to Osteoarthritis,NCT number:NCT03362957,2018. James SL,Abate D,Abate KH,et al.Global,regional,and national incidence,prevalence,and years lived with disability for 354 diseases and injuries for 195 countries and territories,1990-2017:a systematic analysis for the Global Burden of Disease Study 2017.Lancet 2018;392:1789-858. Klamroth R,Gottstein S,Essers E,LandgrafH,Wilaschek M,Oldenburg J.Successful angiographic embolization of recurrent elbow and knee joint bleeds in seven patients with severeHaemophilia.Haemophilia 2009;15:247-252 McConnell S,Kolopack P,Davis AM.The Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC):a review of its utility and measurement properties.Arthritis Rheum.2001 Oct;45(5):453-61 Okuno Y,Matsumura N,Oguro S.Transcatheter arterial embolization using imipenem / cilastatin sodium for tendinopathy and enthesopathy refractory to nonsurgical management.J Vase Interv Radiol 2013;24:787-792 Shaffer, B; Tibone, JE; Kerlan, RK. Frozen shoulder. A long-term follow-up. J Bone Joint Surg Am 1992;74(5):738-746 United States Bone and Joint Initiative: The Hidden Impact of Musculoskeletal Disorders on Americans, Executive Summary, 4th ed., 2018. Rosemont, IL. Http: / / www.boneandjointburden.org. Accessed on Oct. 5, 2020. Available at Wolff, J. Physiology and Pharmacology of Iodized Oil in Goiter Prophylaxis. Medicine 2001;80(1):20-36.

Claims

1. An embolization emulsion comprising an iodized oil and an aqueous phase containing a water soluble contrast agent for use in the treatment of inflammatory hypervascularization associated with musculoskeletal disorders.

2. 2. The embolization emulsion for use according to claim 1, wherein said iodized oil comprises a mixture of iodized and non-iodized ethyl esters of fatty acids of poppy seed oil.

3. 3. The embolization emulsion for use according to claim 1 or 2, wherein said water-soluble contrast agent is an iodized contrast agent.

4. 4. The embolization emulsion for use according to claim 3, wherein said water soluble iodinated contrast agent is selected from the group consisting of ioversol, iopamidol, iomeprol, iopromide, iohexol, iobitridol and iodixanol.

5. An embolization emulsion for use as described in claim 3, wherein the water soluble iodinated contrast agent is ioversol.

6. The embolizing emulsion for use according to any one of claims 1 to 5, which is a water-in-oil emulsion.

7. 7. The embolizing water-in-oil emulsion for use according to claim 6, wherein the ratio of iodized oil to said aqueous phase is at least 2:1 v / v.

8. The embolizing emulsion for use according to any one of claims 3 to 7, wherein the concentration of iodine in the aqueous phase is comprised between 240 and 400 mg / mL.

9. The embolizing emulsion for use according to any one of claims 1 to 8, wherein the viscosity is comprised between 40 and 140 mPa.s at 37°C.

10. The embolizing emulsion for use according to any one of claims 1 to 9, wherein the emulsion droplet size is comprised between 10 and 100 μm.

11. a) does not contain chemotherapy anticancer drugs; and / or b) An embolizing emulsion for use according to any one of claims 1 to 10, which does not comprise nanoparticles or polymer particles.

12. The embolizing emulsion for use according to any one of claims 1 to 11, wherein the musculoskeletal disorder affects the elbow, knee, wrist, shoulder, hip, heel, ankle, thumb and / or spine.

13. The embolizing emulsion for use according to any one of claims 1 to 11, wherein the musculoskeletal disorder is selected from enthesopathy, tendinopathy, inflammatory rheumatoid diseases and carpal tunnel syndrome.

14. said enthesopathy is selected from Achilles enthesopathy, epicondylitis, ankylosing spondylitis, plantar fasciitis, rotator cuff syndrome, enthesopathy of the elbow region, enthesopathy of the wrist and / or carpals, olecranon bursitis, prepatellar bursitis, bursitis of the hand or wrist, enthesopathy of the hip region, hip bursitis, enthesopathy of the knee, enthesopathy of the ankle, enthesopathy of the tarsus and enthesopathy of the calcaneus, or - said tendinopathy is selected from shoulder tendinitis, calcific tendinitis, Achilles tendinitis, biceps tendinitis, quadriceps tendinopathy, lateral epicondylitis, medial epicondylitis, De Quervain's tendinitis, stenosing tenosynovitis, wrist tendinitis, patellar tendinopathy, or - the embolizing emulsion for use according to claim 13, wherein said inflammatory rheumatic disease is selected from osteoarthritis, cervical spondylopathy, rheumatoid arthritis (RA), acute crystalloid arthritis, spondyloarthropathy, psoriatic arthritis), Sjogren's syndrome, scleroderma, infectious arthritis, plantar fasciitis, juvenile idiopathic arthritis, polymyalgia rheumatica, fibromyalgia, lupus, vasculitis.

15. 15. The embolizing emulsion for use according to any one of claims 1 to 14, wherein said musculoskeletal disorder is resistant or refractory to treatment with oral analgesics, anti-inflammatory medication, physical therapy and / or corticosteroid injections.

16. The embolic emulsion for use according to any one of claims 1 to 15, wherein said treatment comprises administering said embolic emulsion to at least one target artery that supplies blood to an affected tissue.

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