CN116710069A - Embolic emulsions for treating inflammatory vascular overformation associated with musculoskeletal disorders - Google Patents

Abstract

The present invention relates to an embolic emulsion comprising an iodinated oil and an aqueous phase comprising a water soluble contrast agent for use in the treatment of inflammatory vascular overformation associated with musculoskeletal disorders.

Description

Embolic emulsions for treating inflammatory vascular overformation associated with musculoskeletal disorders

Technical Field

The present invention is in the field of musculoskeletal disorders. More particularly to embolic compositions for use in the treatment of inflammatory vessel excessive formation associated with musculoskeletal disorders.

Background

Musculoskeletal disorders (MSD) affect bones, muscles, joints, tendons, and/or ligaments. Musculoskeletal disorders are the most common disabling cause worldwide, resulting in millions of outpatient visits each year (James et al, 2017). Indeed, in the united states alone, it is estimated that 50% of adults are affected by MSD, which is responsible for loss of days of work over all other conditions (us skeletal and joint advocates, 2018). The most common MSDs include arthritis, lower back and neck pain, and trauma (e.g., repetitive motion, overuse, trauma from falls), resulting in soft tissue injury and/or fracture. Of particular note, joint disorders such as tennis elbow, frozen shoulder and knee or wrist arthritis are common causes of disability in relatively young, active patients.

Pain is one of the earliest and most common symptoms of MSD, often associated with inflammation and stiffness, tenderness, weakness and/or swelling or deformation of the affected area. In the case of inflammatory joint pathologies, refractory pain is particularly associated with partial or complete loss of function.

First line treatment of MSD includes administration of pharmaceutical compositions (e.g., analgesics, including opioids, non-steroidal anti-inflammatory drugs, muscle relaxants, corticosteroid injections), often accompanied by non-drug treatment methods (e.g., use of hot/cold bags, physiotherapy, exercise, self-management advice). However, chronic administration can lead to liver and/or kidney dysfunction, ulceration, and even addiction to opioids. Furthermore, the therapeutic effect varies significantly from patient to patient, so it is difficult to establish a set of fixation protocols, and refractory MSD is common. For example, in the case of frozen shoulders, nearly 30% of patients have not improved with first line treatment (Shaffer et al, 1992). However, moderate MSD has limited therapeutic options, and moderate MSD does not necessarily respond to first line therapy, but does not require surgery. In practice, surgery is generally only applicable to the most severe MSD and has its own set of drawbacks. In particular, surgery is associated with long recovery times, risk of nosocomial infections, and risk of complications of general anesthesia, especially in elderly people.

Intra-arterial embolization is an attractive alternative to the therapies described above. Although Transcatheter Arterial Embolization (TAE) is commonly used to treat tumors (e.g., for preoperative atherectomy or direct delivery of chemotherapeutic drugs to tumors) and manage bleeding (e.g., in post-partum bleeding or synovitis bleeding in hemophiliacs (see, e.g., klamroth et al, 2009)), this technique has not been evaluated until recently in the context of treating MSD.

The interest in applying embolic techniques to MSD stems from the observation that affected tissues (e.g., tendons and tendon ends) experience increased neovascularization upon injury (see, e.g., alfredson et al, 2003). In the case of joint-related MSD, inflammation may induce synovial angiogenesis, resulting in redistribution of blood vessels within the synovium (Bonnet and Walsh, 2005). Okuno et al originally explored the use of a pharmaceutical composition prepared from imipenem (a carbapenem family antibiotic), cilastatin sodium (an enzyme inhibitor that prevents its breakdown to nephrotoxic metabolites) andthe possibility of an embolic composition consisting of a mixture of iodinated contrast agents to treat refractory tendinosis or attachment point disease by intra-arterial injection administration (2013). Although only a few patients were tested initially, preliminary results indicate that intraarterial embolization can alleviate persistent pain associated with refractory tendinosis or attachment point disease (Okuno et al, 2013). However, the patient may be on imipenem and/or cilastatin sodium Especially allergies. Furthermore, in many countries the use of imipenem/cilastatin sodium is only authorized for the treatment of bacterial infections. Notably, the french administration (HAS) and the European Medicines Administration (EMA) responsible for assessing health products from a medical and economic point of view recommend limiting as much as possible the use of imipenem, in particular the severe infection of resistant enterobacteria, to limit the development of antibiotic resistance. Clearly imipenem/cilastatin sodium cannot be injected into peripheral arteries, as this is associated with a high risk of enhancing antibiotic resistance of enterobacteria and pseudomonas aeruginosa, which are themselves responsible for the clinical high risk sepsis. Thus, imipenem/cilastatin sodium is not a clinically viable therapeutic option for MSD.

Recently, calibration microspheres consisting of gelatin crosslinked triacrylateMyriton Medical) has been administered in clinical trials via a knee arterial embolism to evaluate the safety and efficacy of treatment of refractory knee joint pain associated with knee osteoarthritis (Isaasson and Bagla, 2018). Preliminary results show pain relief in most patients. However, in contrast to products comprising a mixture of imipenem and cilastatin sodium, the microspheres are not absorbable and result in permanent occlusion. Indeed, in the treatment of MSD, temporary occlusion is preferred, as this allows vascular recanalization while reducing the risk of permanent tissue ischemia. Furthermore, microspheres have been shown to be associated with an increased risk of adverse events. In particular, 16 minor complications were found in 20 patients treated with polymethyl methacrylate (Embozene) microspheres (Bagla et al 2020). Furthermore, such particulate embolic agents are disadvantageous in that they are not easily targeted in blood vessels and do not have radiopacity, making them difficult to observe under fluoroscopy/fluoroscopy unless they are immersed in contrast prior to injection. In addition, forced injection or dehydration of calibration particles through the microcatheter may also lead to sphere breakage.

In this case, a new embolic composition is needed to treat MSD. Such a composition should only produce temporary embolism, i.e. embolism lasting less than 30 days, and thus limit the risk of ischemia. Such compositions should be relatively inexpensive and widely available. In particular, such compositions should be useful for the intended purpose, rather than remaining for use in a particular medical condition, such as treating a bacterial infection.

Disclosure of Invention

In the context of the present invention, the inventors surprisingly found that a composition comprising iodinated oil and an aqueous phase comprising a water-soluble contrast agent can be used for the treatment of inflammatory vascular overformation associated with musculoskeletal disorders. Indeed, embolism in a small pig model of osteoarthritis results in immediate disappearance of inflammatory vascular excessive formation in all test animals. Furthermore, the embolic emulsions of the present invention advantageously have greater embolic capacity than other compositions (e.g., microspheres) and are available at lower cost.

Accordingly, in a first aspect, provided herein is an embolic emulsion comprising an iodinated oil and an aqueous phase comprising a water-soluble contrast agent for use in the treatment of inflammatory vascular overformation associated with musculoskeletal disorders.

The term "embolization" refers to the process of injecting a material into a blood vessel, followed by at least partially filling or occluding the blood vessel, thereby reducing or stopping blood flow through the blood vessel. Thus, the term "embolic emulsion (embolizing emulsion)" as used herein refers to a composition that forms a partial or complete embolism or occlusion when administered to a non-intestinal bodily fluid, typically blood. In one aspect, the embolic emulsion can reduce blood flow (e.g., by at least 50%, 60%, 70%, 80%, 90%, or 95% compared to blood flow prior to embolization). This may be particularly advantageous when targeting large blood vessels or arteries. Alternatively, the embolic emulsion may induce complete embolism or occlusion. Preferably, the embolic emulsions provided herein induce complete embolism. In the present case, the occlusion is temporary. In fact, iodinated oils are known to induce transient embolization of arterial circulation. The embolic emulsion is injected into an artery that is in need of occlusion or occlusion. Thus, embolic emulsions are in liquid form upon injection. In the case of a liquid embolism, the distance between the end of the microcatheter from which the liquid embolism 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 embolism, the size of the blood vessel, and/or the strength of the manual injection of the liquid embolism.

The plug may be selective or nonselective. "Selective embolization" refers to embolization by placing a microcatheter directly into an artery responsible for vascular overformation to deliver an embolic emulsion. "non-selective" or "shower-type" embolization refers to embolization in which a microcatheter is placed proximal (i.e., a distance) to an artery responsible for vascular excessive formation to deliver an embolic emulsion.

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

A "water-in-oil" emulsion (also referred to as an "inverse" or "W/O" emulsion) is a dispersion of aqueous phase droplets in a lipid phase. An "oil-in-water" emulsion (also referred to as 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 the phase of any non-polar organic liquid (typically oil) that is not miscible with water. Thus, the lipid phase preferably comprises an oil, more preferably an iodinated oil. Even more preferably, the lipid phase consists of oil, more preferably iodinated oil. "aqueous phase" refers to the water-based phase of the biphasic mixture. The aqueous phase contains a water-soluble contrast agent. Thus, the aqueous phase comprises water and a water-soluble contrast agent. In some cases, the aqueous phase may further comprise water-soluble additives, such as buffers, pH adjusters, antioxidants, tonicity/permeation modifiers, and/or stabilizers.

The emulsion is preferably a water-in-oil emulsion. The invention thus preferably relates to an embolic water-in-oil emulsion comprising iodinated oil and an aqueous phase comprising a water-soluble contrast agent, for use in the treatment of inflammatory vascular overformation associated with musculoskeletal disorders.

The "iodinated oil" provided herein includes or consists of a derivative of iodinated fatty acids, preferably iodinated fatty acid ethyl esters, more preferably iodinated fatty acid ethyl esters of poppy oil, olive oil, rapeseed oil, peanut oil, soybean oil or walnut oil, even more preferably iodinated fatty acid ethyl esters of poppy 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 carbon-based chains of 4 to 28 carbon atoms (usually even). "Long chain fatty acids" refers to a length of 14 to 22 carbon atoms, and the term "ultralong chain fatty acids" refers to a length of more than 22 carbon atoms. In contrast, "short chain fatty acids" refer to those having a length of 4 to 10 carbon atoms, such as 6 to 10 carbon atoms, and particularly 8 or 10 carbon atoms. The relevant nomenclature and specific uses will be apparent to those skilled in the art: ci-Cp represents a series of Ci to Cp fatty acids, and Ci+Cp represents the sum of Ci and Cp fatty acids. For example, fatty acids having 14 to 18 carbon atoms are written as "C14-C18 fatty acids"; the sum of C16 fatty acids and C18 fatty acids is written as c16+c18; for saturated fatty acids, the skilled artisan will use the following nomenclature Ci 0, where i is the number of carbon atoms of the fatty acid (palmitic acid will therefore be designated by the nomenclature (C16:0)); for unsaturated fatty acids, the skilled artisan will use the nomenclature Ci x N-N, where N is the position of the double bond in the unsaturated fatty acid, i is the number of carbon atoms of the fatty acid starting from the carbon opposite the acid group, and x is the number of double bonds (unsaturation) of the fatty acid (hence oleic acid will be designated by the nomenclature (C18:1N-9)).

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

The poppy oil is preferably obtained from the poppy variety black poppy (Papaver somniferum var. Nigrum) (also known as black poppy), more preferably from the seeds of the poppy variety black poppy. The poppy oil is also called poppy seed oil, preferably contains more than 80% unsaturated fatty acids (especially linoleic acid (C18:2n-6) and oleic acid (C18:1n-9)), wherein at least 70% is linoleic acid and at least 10% is oleic acid. Iodinated oils are obtained by iodinating (preferably fully iodinated) oils such as poppy oil (Wolff, 2001) under conditions allowing one iodine atom per double bond of an unsaturated fatty acid, followed by transesterification.

The iodinated oil according to the present invention preferably contains 29 to 53% (w/w), more preferably 37 to 39% (w/w) iodine. The iodinated oil of the emulsion is in the lipid phase of the emulsion.

As examples of iodinated oils, mention may be made of(mixture of poppy oil iodinated fatty acid ethyl esters, also known as ethyl iodinated oil),>(from rapeseed (canola (Brassica compestis)) oil), - >(from peanut oil) and (ii) a>(derived from poppy oil but in the form of fatty acid triglycerides) and(from olive oil).

Preferably, the iodized oil is a mixture of iodized and non-iodized fatty acid ethyl esters of poppy seed oil (i.e., ethyl iodized oil, also known as)。/>Is a pale yellow/amber iodinated oil sold by Guerbet. It is particularly useful for visualization, localization and/or vectorization of hepatocellular carcinoma in the middle adult stage during arterial chemoembolization, and for selective hepatic artery diagnosis of the extension of hepatic malignant lesions. This oil contains mainly (in particular more than 84%) a mixture of long chain iodinated fatty acids (in particular C18 fatty acids) ethyl esters derived from poppy seed oil, preferably a mixture of ethyl monoiodostearate and ethyl diiodostearate. The iodinated oil may also be an oil based on ethyl monoiodide of stearic acid (C18:0) derived from olive oil (e.g. as mentioned above)。

The main features of (2) are shown in the following table:

compounds of formula (I)	Ratio in fatty acid mixture
		Ethyl palmitate (ethyl C16:0)	4.6% to 6.7% (w/w), preferably 4.8% (w/w)
Ethyl stearate (ethyl C18:0)	0.8% to 1.9% (w/w), preferably 1.2% (w/w)
		Ethyl monoiodo stearate	11.3% to 15.3% (w/w), preferably 13.4% (w/w)
Diiodistearoyl ethyl ester	73.5% to 82.8% (w/w), preferably 78.5% (w/w)

The following table providesOther features of (2):

iodine content	37% to 39% (w/w) (e.g. 480 mg/ml)
		Viscosity at 37 ℃	25mPa.s
Viscosity at 20 DEG C	50mPa.s
		Density of	At 20 ℃,1.268 to 1.290g/cm 3 Preferably 1.28g/cm 3

Preferably, the amount of iodinated oil present in the emulsion according to the invention does not exceed 15ml. Preferably, the lipid (or oil) phase consists essentially of iodinated oil, more preferably the lipid phase consists of iodinated oil as defined herein.

The density of the lipid phase of the emulsion is preferably from 1.10 to 1.30, more preferably from 1.20 to 1.30, even more preferably 1.28.

The term "water-soluble contrast agent" as used herein refers to a biocompatible (non-toxic) material that is capable of being monitored (e.g., by radiography) and that is soluble in water when injected into a subject. The water-soluble contrast agent is preferably radio-opaque and can therefore be detected radiographically (e.g., on angiography or arterial). The water-soluble contrast agent may in particular comprise barium sulfate or iodine.

Preferably, the water-soluble contrast agent is an iodinated contrast agent. Thus, the water-soluble contrast agent contains iodine. In iodinated contrast agents, iodine may be bound to ionic or organic compounds, where bound to organic compounds, iodinated contrast agents are classified as "nonionic" compounds. Examples of ionic iodinated contrast agents include diatrizoic meglumine Alpha-diatrizoic acidIophthalic acid salt->Iodic acid->An Jige naftifine and ioxirane. Examples of nonionic iodinated contrast agents include iobiol +.>IopamidolI Meipril->Ioversol-> Iohexol->Iodine spray holder>Ioxilan->IopromideMethylubiglucamine->Iodine-containing salmeterol>Iotrolan->Iodixanol->Iometriol (iosimenol) and ioxetine +.>Iodinated contrast agents may be in monomeric or dimeric form. It may have a high osmotic pressure (i.e., 1200mOsm/kg or more), a low osmotic pressure (i.e., 500-900 mOsm/kg), or an isoosmotic pressure (i.e., about 290 mOsm/kg).

Preferably, the water-soluble iodinated contrast agent is nonionic. Preferably, the water-soluble iodinated contrast agent has a low osmotic pressure (i.e., 500 to 900 mOsm/kg) or an isoosmotic pressure. Preferably, the water-soluble iodinated contrast agent comprises ioversol, iopamidol, iomeprol, iopromide, iohexol, ioversol, 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, ioversol and iodixanol, even more preferably ioversol and ioversol, most preferably ioversol.

The ratio of lipid phase to aqueous phase (in other words, the ratio of iodinated oil to aqueous phase comprising the water-soluble contrast agent provided herein) is preferably at least 2:1v/v, such that an oil-in-water composition is obtained. Indeed, a 1:1v/v ratio between the lipid and aqueous phases naturally favors the O/W direction. In the case where a water-in-oil emulsion is required, the addition amount of iodinated oil must be increased. The ratio of iodinated oil to aqueous phase of at least 2:1v/v (also denoted as iodinated oil to aqueous phase or lipid phase to aqueous phase) makes it possible to obtain a W/O emulsion. More preferably, the ratio of iodinated oil to aqueous phase is at least 3:1v/v or at least 4:1v/v. In one aspect, the ratio of iodinated oil to aqueous phase (v/v) is between 2:1 and 4:1, more particularly between 5:2 and 10:3. The ratio (v/v) of iodinated oil to aqueous phase may be in particular equal to 3:1 or 4:1.

The concentration of the water-soluble contrast agent (e.g., ioversol) in the aqueous phase (i.e., water) is 500 to 750mg/mL, more particularly 509 to 741mg/mL. In particular, the concentration of the water-soluble contrast agent (e.g., ioversol) in the aqueous phase may be 509, 636, 678, or 741mg/mL. Preferably, the concentration of iodine in the aqueous phase is 240 to 400mg iodine/mL (mg I/mL), 240 to 350mg I/mL, or 240 to 320mg I/mL. In particular, the concentration of iodine in the aqueous phase may be 240, 300, 320, 350, 370 or 400mg I/mL. Iodine present in the aqueous phase is derived from iodinated water-soluble contrast agents, and when using conventional water-soluble contrast agents of the type disclosed above, in particular ioversol, the above-described iodine concentration ranges correspond to the above-described water-soluble contrast agent concentration ranges.

The lipid and aqueous phases may have the same density (in other words they have equal densities) or different densities, ioversol being a preferred iodinated contrast agent;240、/>300、/>320、350 have a density of 1.281, 1.352, 1.371 and 1.405, respectively, iohexol +.>Is another preferred iodinated contrast agent. />250 and->The density of the 300 product was 1.28 and 1.34, respectively. Preferably, the lipid phase and the aqueous phase have the same density (in other words, the lipid phase and the aqueous phase have equal Or similar densities (i.e. densities of the lipid phase and the aqueous phase differ from each other by no more than 10%).

The viscosity of the embolic emulsion is 70 to 200mpa.s, preferably 120 to 170mpa.s, more preferably 150 to 165mpa.s, even more preferably 150 to 165mpa.s, and/or 40 to 140mpa.s, preferably 70 to 140mpa.s, more preferably 80 to 130mpa.s, even more preferably 90 to 130mpa.s, at 37 ℃. The viscosity values may in particular be obtained using a Malvern Instruments Kinexus Pro rheometer having a 4 ° cone-plate unit of 40mm diameter. The measurement was carried out under an applied stress of 0.16 to 10 Pa.

As one non-limiting example, the size of the droplets in the emulsion (i.e., the aqueous phase droplets) may be 1 to 500 μm, 1 to 200 μm, or 5 to 150 μm. Preferably, the emulsion droplet size is from 10 to 100 μm, more preferably from 10 to 80 μm, or even more preferably from 30 to 80 μm. The size may vary from droplet to droplet as long as they are within the desired size range. Preferably, the aqueous phase droplets are uniformly distributed. Droplet size and uniformity can be measured using an optical microscope (e.g., leica DM2000 LED microscope). If aggregation of droplets is observed, these droplets are unevenly distributed.

The aqueous phase may also contain one or more water-soluble additives. The one or more additives may be, inter alia, buffers, pH adjusters, antioxidants, tonicity/osmotic modifiers, density modifiers and/or stabilizers. The one or more additives are particularly devoid of any therapeutic effect in the body. Preferably, the aqueous phase comprises a buffer, more preferably tromethamine. Preferably, the aqueous phase comprises a stabilizer, more preferably disodium calcium edetate. Preferably, the pH of the aqueous phase is adjusted to a pH of 6.0-7.2, preferably with hydrochloric acid or sodium hydroxide.

While the embolic emulsions provided herein may contain additional additives such as those described above, preferably do not contain any additional "active" ingredients. An "active ingredient" as used herein refers to a component that is therapeutically active in vivo.

A first example of an active ingredient that is preferably not present in an embolic emulsion is a chemotherapeutic anticancer agent. In fact, the presence of such agents would be detrimental as the emulsions are used to treat inflammatory vascular overformation associated with musculoskeletal disorders. Non-limiting examples of such chemotherapeutic anti-cancer agents include anthracyclines, mitomycin C, platinum complexes, radioactive elements, alkylating/aminomethylating agents, antimitotic/tubulin inhibitors, topoisomerase inhibitors, pyrimidine antagonists, guanidine antagonists, folic acid antagonists, and the like. More particularly, the chemotherapeutic anti-cancer agent excluded from the present emulsions is doxorubicin, epirubicin, idarubicin, nemorubicin, mitoxantrone, pirarubicin, paclitaxel, cisplatin, carboplatin, oxaliplatin, lobaplatin, cyclophosphamide, mitomycin C, fotemustine, irinotecan, mitoxantrone, everolimus, sorafenib, 5-fluorouracil, methotrexate, gemcitabine, carmustine, dacarbazine, etoposide, vinorelbine, topotecan, estramustine, and any combination thereof.

Thus, the embolic emulsion preferably does not contain a chemotherapeutic anticancer agent. More preferably, the embolic emulsion does not contain any of the chemotherapeutic anti-cancer agents described above.

Another example of an active ingredient that is preferably not present in the embolic emulsion is a nanoparticle or a polymer particle, more preferably an embolic particle. Indeed, while nanoparticles or polymer particles may be used as alternative embolic agents, they are undesirable in the context of the present invention. In particular, non-absorbable nanoparticles or polymer particles can cause permanent occlusion, resulting in ischemia. Absorbable nanoparticles or polymer particles may cause inflammation and/or thrombosis due to their partial degradation and migration of the particles or fragments distally. Therefore, they are not desirable in the context of the present invention. The term "nanoparticle" as used herein refers to solid particles having an average diameter between about 1nm and about 500 nm. More particularly, the embolic emulsion does not comprise polyester-based nanoparticles (e.g., polyacetate-based nanoparticles, polyglycolides, lactide-glycolide copolymers, copolymers of lactide-glycolide-co-polyethylene glycol, polyorthoesters, polyanhydrides, polybutylacetone, polyglutarides, polymalic acid, polylactones). The term "polymer particles" as used herein refers to particles comprising 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 polyphosphazenes). The polymer particles may be nanoparticles.

The term "embolic particle" refers to any solid or undissolved substance that forms an embolism or occlusion when applied to a non-intestinal bodily fluid (typically blood). The embolic particles may more particularly comprise nanoparticles and/or embolic particles. The particles may be spheroids or rectangular or have an irregular geometry. In contrast, embolic emulsions provided herein are composed of liquid materials (e.g., iodinated oil and an aqueous phase containing a water-soluble contrast agent).

Thus, the embolic emulsion also preferably does not contain nanoparticles or polymer particles. Even more preferably, the composition does not comprise any embolic particles.

The term "musculoskeletal disorder" or "MSD" as used herein refers to any disease or disorder in which the musculoskeletal system (e.g., muscle, ligament, tendon, cartilage, bursa, joint, or bone) of a subject is impaired. MSD may be a local or systemic disorder; it may be acute or chronic, more preferably chronic. In the case of chronic MSDs, they may persist or recur (e.g., attack) on occasion. MSD may be due to behavioral, environmental, traumatic, immunological, degenerative and/or genetic factors and/or may be associated with systemic diseases. For example, the MSD may be caused, at least in part, by repeated or vigorous movements, for example, in a workplace or sports environment. Thus, in one aspect, MSD is sports injury. MSD includes strain, sprain, fracture, torsion, tear, inflammatory rheumatoid disease, attachment point disease, and tendinopathy (such as tendinitis and tenosynovitis). MSD can significantly affect the elbow, knee, wrist, shoulder, buttocks, heel, ankle, thumb and/or spine (more particularly cervical, dorsal or lumbosacral spine).

The term "inflammatory rheumatoid disease" or "inflammatory rheumatic disease" refers to a disease that produces acute or chronic inflammation, especially in joints, although other tissues, such as muscle or connective tissue, may also be affected. Inflammation may be local and/or systemic, and in many cases is caused by autoimmune diseases. AS non-limiting examples, inflammatory rheumatoid diseases include osteoarthritis (e.g., knee or hip osteoarthritis), cervical spondylosis, rheumatoid Arthritis (RA), acute crystalline arthritis (e.g., gout), spondyloarthropathies (ankylosing spondylitis (AS) and psoriatic arthritis (PsA)), sjogren's syndrome, scleroderma, infectious arthritis, plantar fasciitis, juvenile idiopathic arthritis, polymyalgia rheumatica, fibromyalgia, lupus, and vasculitis.

The term "attachment point disease" refers to disorders involving the attachment of tendons or ligaments to bone. The attachment point disease mainly includes Achilles tendon attachment point disease, epicondylitis, ankylosing spondylitis, plantar fasciitis, rotator cuff syndrome and related diseases, elbow attachment point disease, wrist and carpal attachment point disease, olecranon bursitis, patellar anterior bursitis, hand or wrist bursitis, hip joint area attachment point disease, hip joint bursitis (e.g., rotor bursitis, iliofacial bursitis), knee joint attachment point disease, ankle joint attachment point disease, tarsal attachment point disease and calcaneal attachment point disease (e.g., subcapsulitis).

The term "tendinopathy" refers to a disorder or injury to a tendon. Tendinosis mainly includes rotator cuff tendinitis, achilles tendinitis, biceps tendinitis, quadriceps tendinitis, lateral epicondylitis (tennis elbow), medial epicondylitis (golf elbow), radius styloid stenosinusitis (De Quervain's tenosynovitis), stenotic tenosynovitis (trigger finger/thumb), wrist tenosynovitis, and patellar tendinosis.

As another example, MSD also includes cervical tension, osteoporosis, becker's cyst, adhesive capsulitis (frozen shoulder), carpal tunnel syndrome, tarsal tunnel syndrome, radial tunnel syndrome, arm vibration syndrome, knee joint meniscus injury, degenerative disc disease, disc rupture/herniation, finger neuritis, chest outlet compression syndrome, metacarpal tendinous contracture (Dupuytren's contracture), ungstate, lyme disease, and the like.

Preferably, the MSD disorder affects the elbow, knee, wrist, shoulder, buttocks, heel, ankle, thumb and/or spine. When the MSD affects the spine, it more preferably affects the cervical, dorsal or lumbosacral spine.

Preferably, the MSD is selected from the group consisting of adhesion point disease, tendinopathy, inflammatory rheumatoid disease and carpal tunnel syndrome. More preferably, the MSD is:

The attachment point disease is selected from the group consisting of Achilles tendon attachment point disease, epicondylitis, ankylosing spondylitis, plantar fasciitis, rotator cuff syndrome, elbow attachment point disease, wrist and/or carpal attachment point disease, olecranon bursitis, anterior patella bursitis, hand or wrist bursitis, hip joint region attachment point disease, hip joint bursitis, knee joint attachment point disease, ankle joint attachment point disease, tarsal bone attachment point disease and calcaneal attachment point disease,

the tendinopathy is selected from the group consisting of scapulohumeral periarthritis, calcified tendinitis, achilles tendinitis, biceps tenositis, quadriceps femoris tendinitis, lateral epicondylitis, medial epicondylitis, narrow tenosynovitis of the radius styloid process, stenotic tenosynovitis, wrist tenosynovitis, patellar tendinitis, and

-inflammatory rheumatoid diseases selected from osteoarthritis, cervical spondylosis, rheumatoid Arthritis (RA), acute crystalline arthritis, spondyloarthropathies, psoriatic arthritis, sjogren's syndrome, scleroderma, infectious arthritis, plantar fasciitis, juvenile idiopathic arthritis, polymyalgia rheumatica, fibromyalgia, lupus, vasculitis.

Even more preferably, the MSD is selected from tennis elbow, adhesive arthritis, osteoarthritis, syndrome or achilles tendinitis.

MSD may be resistant to one or more treatments (e.g., first line treatment, e.g., drug treatment, such as oral analgesics, anti-inflammatory agents, corticosteroid injections, or physical therapy). MSD that is "resistant" to treatment is not responsive to treatment and/or has a reduced ability to produce a significant response (e.g., partial and/or complete response) at the maximum recommended dose, duration, and/or frequency of treatment. Resistance may be achieved (i.e., developed over time), particularly when chronic MSD requires continuous treatment. As a particular example, pain is anti-opioid when insufficient analgesia is achieved at opioid therapeutic levels and results in intolerable side effects. In some cases, MSD is refractory. The term "refractory" as used herein refers to MSD that does not respond to at least two different drug treatments (such as those described above). The at least two different treatments preferably have different mechanisms of action.

Preferably, the MSD is resistant or refractory to oral analgesic, anti-inflammatory, physical therapy and/or corticosteroid injection treatment.

Yet another aspect of the invention relates to an embolic emulsion provided herein for use in treating inflammatory vascular overformation associated with musculoskeletal disorders, wherein the treatment comprises administering the embolic emulsion to at least one target artery supplying blood to one or more affected tissues. The embolic emulsions of the present invention cause the formation of temporary embolisms. Preferably, one or more target arterial embolisms last for less than 24 hours. More preferably, the one or more target arterial embolisms last for 6-12 hours.

The term "inflammatory vessel excessive formation" as used herein means an increase in the number or concentration of blood vessels, and it is related to inflammation. It may involve the formation of new blood vessels (i.e., neovascularization), the formation of new blood vessels from existing blood vessels (e.g., the growth of new capillaries from the posterior venules of capillaries), and/or the increase in the diameter of existing arterial blood vessels (i.e., arterial generation).

The invention also includes the use of an embolic emulsion provided herein in the manufacture of a medicament for treating inflammatory vessel excessive formation associated with musculoskeletal disorders.

The invention also includes the use of the embolic emulsions provided herein to treat inflammatory vessel excessive formation associated with musculoskeletal disorders.

Also provided herein are methods of treating inflammatory vessel excessive formation associated with musculoskeletal disorders in a subject in need thereof. More particularly, a method of treating inflammatory vessel excessive formation associated with a musculoskeletal disorder in a subject in need thereof comprises administering a therapeutically effective amount of an embolic emulsion provided herein.

The term "treatment" as used herein refers to alleviating symptoms of MSD (i.e., associated with excessive inflammatory vessel formation), or inhibiting further progression or worsening of the symptoms. The term "treatment" as used herein may also refer to a delay in the appearance of symptoms, a decrease in the severity of symptoms at the time of appearance, or a decrease in the frequency of onset of disease. Similarly, the term "effective amount" as used herein in the context of embolic emulsions, or "therapeutically effective amount" of embolic emulsions, refers to an amount of an agent that completely or partially alleviates symptoms associated with MSD, or stops or slows further progression or worsening of such symptoms. In particular, an "effective amount" refers to an amount effective to achieve the desired therapeutic result. The therapeutically effective amount may be administered, inter alia, in one or more administrations, particularly wherein each administration occurs at a different site or different affected area within the affected area (e.g., at a different joint in the case of systemic osteoarthritis). In particular, a therapeutically effective amount of the embolic emulsion is administered in one, two, three, or more injections and/or to different arteries (e.g., in the same joint or different joints) over a given period of time. A therapeutically effective amount is also an amount by which any toxic or detrimental effects of the compounds of the invention are outweighed by the therapeutically beneficial effects.

"subject" refers to any mammal, more particularly any human subject, regardless of age. In particular, the subject may be a human adult or child. The term "adult" is used herein to refer to individuals at least 16 years old. The term "child" includes infants between 0 and 1 year old and children between 1 and 8 years old, between 8 and 12 years old and between 12 and 16 years old.

Also provided herein are methods of treating inflammatory vascular overformation associated with a musculoskeletal disorder in a subject in need thereof, wherein the inflammatory vascular overformation affects one or more tissues of the subject, the method comprising:

-providing an embolic composition comprising iodinated oil and an aqueous phase comprising a water-soluble contrast agent, and

-temporarily embolizing with said embolization composition, preferably via transcatheter arterial embolization, at least one artery supplying blood to one or more affected tissues.

According to a further aspect, the present invention relates to a kit comprising an iodinated oil as provided herein and a water soluble contrast agent, and instructions for administering an immunogenic or immunotherapeutic composition as described herein to a subject. The water-soluble contrast agent may be provided in lyophilized form or in aqueous form. The iodinated oil and the water-soluble contrast agent may be provided in separate containers. In this case, the embolic emulsion may be prepared by mixing the iodinated oil with an aqueous phase containing a water-soluble contrast agent prior to administration. Alternatively, the iodinated oil and aqueous phase may be provided in the same container (e.g., as an emulsion, which may be applied directly). In this case, the emulsion also includes a stabilizer.

Drawings

Fig. 1. Pig model of osteoarthropathy. (a, B) shoulder representative angiography 7 days after alcohol injection, showed excessive vessel formation (arrow) and early venous return (x). (C, D) an untreated shoulder angiography example 20 days after injection of alcohol, showed persistent vascular overformation (arrow).

Figure 2. Effect of embolic emulsions in porcine models of osteoarthropathy. Baseline (A) and use ofRepresentative angiographic comparisons after emulsion embolization (B) showed no signs of vessel excessive formation.

Figure 3 histological staining of untreated (control) limbs compared to limbs treated with embolic emulsions. (a) untreated skin, (B) treated skin, (C) untreated tendons, (D) treated tendons.

FIG. 4 is usedGraphical representation of embolic persistence of ioversol emulsion. (A) Applied to the left shoulderExemplary angiography performed over time for pig number 1. (B) Administration to the subrenal arteryExemplary angiography performed over time for pig number 2.

Fig. 5. Role of joint embolism in clinical trial. (A) Pain and (B) functional impairment were assessed over time in 6 knee osteoarthritis patients.

Detailed Description

The following examples are included to demonstrate preferred embodiments of the invention. All subject matter set forth or shown in the following examples and figures is to be interpreted as illustrative and not in a limiting sense. The following embodiments include any alternatives, equivalents, and modifications that may be determined by those skilled in the art.

1.Materials and methods

1.1 osteoarthritis model

Four minipigs weighing 17-25kg were housed in separate cages from an environmental controlled animal research facility. Food and water are provided as a free-feeding.

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

1.1.1 preparation of embolic emulsions

The emulsion is prepared by using 3cc ioversol contrast agent (/ -)>240, guerbet, france) and 9cc +.>(Guerbet, france) two 20ml syringes were repeatedly pumped back and forth through a 3-way stopcock.

1.1.2 pig model for osteoarthropathy

The right upper shoulder and bilateral lower knees were directly punctured under fluoroscopy using a standard 18G catheter (BD media, utah). 5ml of absolute ethanol (100%) was injected at the right shoulder and both knee joints to induce chronic inflammation. The left shoulder joint was used as a control.

7 days after model creation, the right femoral artery was punctured under ultrasound guidance, and then the bilateral subclavian and femoral arteries were selectively angiographed using a 4Fr Cobra catheter (Terumo, tokyo takok co.) to assess whether there was excessive vascular formation in the 4 joints.

After insertion of the right subclavian selective catheter, a 2.7Fr microcatheter was usedTokyo taylor co ltd, japan) performs a super-selective catheterization of regions with excessive blood supply vessels. By injection->Emulsion until stagnation (selective embolization; right shoulder) achieved complete embolization. In addition, catheterization was performed on the right femoral artery and non-selective ("shower") embolization (non-selective embolization; right knee) was performed from the Cobra catheter. Following embolization, angiographic controls were performed to assess immediate technical success.

The left knee was not embolized (model positive control). Hemostasis is obtained by manually pressing the puncture site and waking up the animal.

A selective control angiography was performed at 14 days after the embolism, at subclavian and femoral arteries, to assess the patency of the parent vessel at follow-up through the left common femoral artery access. Thereafter, the minipigs were sacrificed.

1.1.3 histological evaluation

Tendon attachment points and tendon samples were obtained from 4 joints immediately after sacrifice and histologically analyzed with 10% formaldehyde fixation. Samples were processed according to standard procedures, embedded in paraffin and sectioned. Specifically, each section was stained with hematoxylin and eosin (H & E). A separate pathologist analyzed the samples and characterized the lesions. Pathologists are not aware of the treatment received by mini-pigs.

1.1.4 end point of study

The presence of vascular overformation associated with histological signs of subacute inflammatory diseases confirms the successful creation of animal models.

The main efficacy endpoint was successful embolization of the target vessel, and the inflammatory vessel overformation disappeared when angiography was performed immediately after embolization.

The primary safety endpoint was reached when all of the following criteria were observed: tumor-bearing vessels were unobstructed for angiographic controls 14 days after embolization, without non-target embolization, without joint and skin necrosis.

1.1.5 statistics

All data were analyzed by SPSS 20.0 (SPSS inc., chicago, il. The classification variables are expressed as absolute values and percentages and compared using the chi-square test. Numerical variables are expressed as mean ± standard deviation and compared using paired student t test. In all assays, p <0.05 (double sided) was considered statistically significant.

1.2Evaluation of ioversol emulsion characteristics

Two 45kg healthy pigs were anesthetized and intra-arterial injection was performed by interventional procedures using fluoroscopy. Embolic intervention procedures are minimally invasive procedures, conducted under image guidance (in this case using fluoroscopy for X-rays), wherein the catheter is used to administer the embolic product.

The stability of two different products was evaluated:

1. imipenem/cilastatin, michelia (IPM/CS)

To prepare a suspension, 500mg of IPM/CS powder was suspended in 10ml of ioversol contrast agent300, guerbet). The suspension was placed in a 10mL syringe and branched to a 3mL syringe by a 3-way stopcock. The suspension was pumped 20 times to obtain a homogeneous suspension.

2. Based onUltra Emulsion of Fluid (LUF) in a ratio of 3:1 (3 volume +.>With 1 volume contrast agent ioversol (>300 Also referred to herein as +.>Will 6 mL->Placed in a 10mL syringe branched with a 3-way stopcock to the previous 2mL +.>300 (Guerbet) in a 3mL syringe. The solution was pumped 20 times (first +.>Push->In) to obtain a homogeneous stable emulsion.

Uniformity/stability was assessed by visual inspection over time.

UsingEmulsion further evaluates embolic persistence:

will beInjections into different target arteries are detailed in the following table.

Table 1: implantation protocol-target region

NA: is not applicable.

In usePrior to embolization, the embolized target region was angiographically imaged using an auto-injector to map the injection region and select the target vessel, using the following protocol: flow rate: 4mL/s, 8mL +.>300 (iobitol, 300mg iodine/mL; guerbet).

The embolization was then performed as follows:

about 1mL per injection300 (Guerbet), angiography of the selected region prior to embolization. This image allows determining the degree of remodelling of the embolic blood vessel after downstream administration of the embolic product.

Product (prepared as described above) is injected until the selected area is completely filled, corresponding to about 1.5mL per embolism. The injection was with 2.4Fr DraKon ^TM Microcatheter (Guerbet).

About 1mL after 1, 2, 3, 4, 5, 6, 8, 10, 15 and 20 minutes after application of the product300 angiography is performed.

CT scan 1 hour after the end of all embolization procedures to detect and evaluate embolization persistence of the infused target region.

The persistence of the resulting embolism is determined by comparing the kinetics observed by angiography over time (i.e., from 1 to 20 minutes as described above). />

1.3Clinical evaluation of ioversol embolic emulsions in humans

1.3.1 knee osteoarthritis

Patients were diagnosed at the clinic for painful knee osteoarthritis and considered to incorporate a phase 1 single arm open label clinical trial (clinical trimals identifier: NCT 04733092). Inclusion criteria included:

according to the American society of rheumatology (ACR) classification, primary inflammatory knee osteoarthritis of a target joint defined for knee osteoarthritis is diagnosed, and according to the classification of Kellgren and Lawrence, the score is not less than 2,

Patients who do not meet the surgical conditions (or refuse surgery),

analog visual scale (VAS) pain ∈40mm, although analgesic treatment for at least 3 months,

NSAID and/or tramadol and/or acetaminophen treatment failure or intolerance, and/or powerful opioid (morphine, codeine) failure or intolerance or patient rejection, and

failure to infiltrate corticosteroid or rejection by patient.

The trial included 6 patients. 3:1v/v Li for knee jointIoversol emulsion embolism, clinical examination at follow-up. Pain was assessed on a Visual Analog Scale (VAS) of 0 to 100mm, 100mm being the most severe pain. Pain is expressed as a percentage of the pre-embolic baseline. Functional impairment was assessed on a scale of 0 to 96 by the university of western amp and university of macmatre arthritis index (Western Ontario and McMaster Universities Arthritis Index (WOMAC)) questionnaire (see McConnell et al, 2001). Higher scores indicate poorer functionality. Functional impairment is expressed as a percentage of baseline WOMAC score.

1.3.2. Frozen shoulder

Based on initial preclinical (porcine studies) and clinical (knee osteoarthritis) safety results, one patient with frozen shoulder was obtained by using 3:1v/v LiIoversol emulsion embolic joint treatment.

2.Results

2.1 miniature pig osteoarthritis model

The osteoarthritis model was successfully induced in all animals as shown in table 2 below. In fact, all joints receiving alcohol injection showed excessive vascularization at baseline angiography, and histological signs of subacute inflammatory disease of the joints (12/12 joints, 100%) were shown 7 days after injection. In particular, histological samples showed signs of chronic ischemia of all joints after alcohol injection. Signs of excessive vascularization or chronic inflammation were not observed in the negative control joints (4/4 joints, 100%).

TABLE 2 confirmation of effectiveness of animal models before embolism

Proliferation of blood vessels and connective tissue is considered to be a sign of chronic inflammation, with a = presence of macrophages, monocytes and lymphocytes

b = positive control is joint (left knee in our study) with alcohol injection without any embolism

c = negative control is joint without alcohol injection or embolism (left shoulder in our study)

In all joints treated, useThe emulsion successfully embolizes and the vessel overformation immediately disappeared (8/8, 100%; see Table 3). 1 pig died 3 days after embolization before control angiography, due to mycoplasma pneumonia unrelated to embolization.

In angiographic controls performed 14 days after embolization, patency of the target vessel was observed in all cases (see table 3). A decrease in vascular overformation was also observed in 5/6 joints (83.3%), a partial decrease was observed in 4/6 joints (66.7%), and a complete disappearance was observed in one joint (1/6, 16.7%).

TABLE 3 determination of embolic safety and efficacy by angiographic and histological evaluation

Na=inapplicable to

a = positive control is a joint (left knee in our study) with alcohol injection without any embolism

b = negative control is joint without alcohol injection or embolism (left shoulder in our study)

c = successful embolization defined as the disappearance of vascular overformation in the immediate angiographic control

Transient cutaneous ischemic signs (4/4, 100%) characterized by rash were observed in all 4 joints treated with non-selective embolism. In all cases, these signs disappeared a few days after embolization. Pigs do not show any clinical signs of pain or deterioration in daily normal behavior. No ischemic signs (8/8, 100%) were observed in the joints treated with embolism. No signs of skin or synovial necrosis were observed in histological analysis performed 14 days after embolization (see table 3).

2.2Stability comparison of ioversol emulsion with imipenem/cilastatin

The IPM/CS suspension was homogeneous after preparation. After 5 minutes of preparation, the IPM/CS powder tended to settle, showing phase separation. Thus, the IPM/CS will not stabilize over time. In contrast to this, the process is performed,the emulsion was stable and homogeneous after preparation and did not show any phase separation throughout the experiment. The stable emulsion ensures uniform distribution of the product in the target area and has higher therapeutic effect.

2.3Evaluation of ioversol emulsion embolic durability

2.3.1 radiopacity of the product

The emulsion can be detected during injection by fluoroscopic imaging, which benefits fromIs impermeable to the radiation. After administration, the administration of +>Radiopacity persists in the blood vessel until 8 minutes after administration is detected.

2.2.3 embolic Properties

Injection ofThe target artery of the emulsion was completely re-permeabilized 8 minutes after product administration, indicating successful and short embolization. Furthermore, embolization is repeatable and predictable. In fact, as shown in FIG. 4, +.>300 two different target arteries of two different animals were completely re-permeabilized after 8 minutes of product administration in all arterial networks evaluated. />

2.4 human clinical assessment

2.4.1. Osteoarthritis of knee joint

The clinical results of the last obtained follow-up are summarized in table 4 below, see fig. 5.

TABLE 4 determination of embolic efficacy by pain and functional injury assessment

	Newly obtained follow-up	Pain and pain	Functional impairment	Global results of patient reporting
					Patient 1	For 3 months	-83％	-62％	Obviously improve and restore physical activity
Patient 2	For 3 months	-42％	-47％	Obviously improve
					Patient 3	For 3 months	-28％	39％	Does not improve
Patient 4	1 month	-39％	-38％	Obviously improve
					Patient 5	1 month	-18％	-29％	Obviously improve and restore physical activity
Patient 6	1 month	-75％	-50％	Obviously improve

According to the VAS scale report, 6/6 patients showed pain relief, with 5/6 patients reporting reduced functional impairment as determined according to the WOMAC scale. Upon self-reporting, 5/6 patients further reported significant improvement, with 2/6 patients indicating that physical activity could be recovered.

During the embolization, patient 1 had developed erythema for 2 days and periarticular edema for 4 days, both of which were of low intensity and did not require initiation of treatment. Patient 2 developed mild erythema, did not require treatment, and resolved within 4 hours. Patient management was slightly altered by placing the ice bag on the knee during embolization. With this change, no erythema or edema is described hereafter.

None of the 6 patients had any other complications/toxic signs.

2.4.2. Frozen shoulder

Clinical examination of frozen shoulder patients 6 months after embolism shows that the degree of shoulder joint movement is slightly improved, the outward rotation is increased by 20 degrees, the pain improvement is very obvious, and the opioid analgesic treatment is reduced by more than 50 percent.

3.Conclusion(s)

In a study using a porcine model of osteoarthropathy, the inventors surprisingly showed the efficacy of the emulsion according to the invention in the treatment of inflammatory vascular overformation associated with musculoskeletal disorders. In particular, the emulsion successfully embolizes areas of vascular overformation as evidenced by the immediate disappearance of vascular overformation in all embolized joints. Furthermore, vascular excessive formation is successfully treated, whether by selective or non-selective methods. Importantly, the procedure was safe, with patency of the donor artery observed in angiographic controls of all joints. No non-target embolisms were observed in the selective method. Although transient skin ischemia was observed during the perioperative period in which non-selective embolization was performed, it disappeared a few days after surgery, without any histological evidence at 14 days, nor clinical signs of pain/discomfort.

The inventors have also shown that transient embolisms induced by the emulsions of the present invention are repeatable and therefore predictable.

Human clinical trials further demonstrate the efficacy of the emulsions according to the invention in the treatment of inflammatory vascular excessive formation. Indeed, after emulsion embolism, 5/6 knee osteoarthritis patients reported pain relief in the latest follow-up visit, with improvement in joint function, only 2/6 patients reporting any minor side effects. The surprising effect of the emulsions provided herein was further demonstrated in another frozen shoulder patient.

Reference to the literature

Alfredson H,Ohberg L,Forsgren S,Is vasculo-neural ingrowth the cause of pain in chronic Achilles tendinosisAn 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.2020Jul；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 nationalincidence,prevalence,and years lived with disability for 354 diseases andinjuries for 195 countries and territories,1990-2017:a systematic analysisfor the Global Burden of Disease Study 2017.Lancet 2018；392:1789-858.

Klamroth R,Gottstein S,Essers E,Landgraf H,Wilaschek M,Oldenburg J.Successful angiographic embolization of recurrent elbow andknee joint bleeds in seven patients with severe haemophilia.Haemophilia2009；15:247-252

McConnell S,Kolopack P,Davis AM.The Western Ontario andMcMaster Universities Osteoarthritis Index(WOMAC):a review of itsutility and measurement properties.Arthritis Rheum.2001Oct；45(5):453-61

Okuno Y,Matsumura N,Oguro S.Transcatheter arterial embolizationusing imipenem/cilastatin sodium for tendinopathy and enthesopathyrefractory to nonsurgical management.J Vase Interv Radiol 2013；24:787-792

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Claims (15)

1. An embolic emulsion comprising an iodinated oil and an aqueous phase containing a water soluble contrast agent for use in the treatment of inflammatory vascular overformation associated with musculoskeletal disorders.

2. The embolic emulsion for use of claim 1, wherein said iodinated oil comprises a mixture of iodinated and non-iodinated fatty acid ethyl esters of poppy seed oil.

3. The embolic emulsion for use of claim 1 or 2, wherein said water-soluble contrast agent is an iodinated contrast agent.

4. An embolic emulsion for use as in claim 3, wherein the water-soluble iodinated contrast agent is selected from the group consisting of ioversol, iopamidol, iomeprol, iopromide, iohexol, ioversol, and iodixanol, preferably ioversol.

5. The embolic emulsion for use of any of claims 1 to 4, wherein said emulsion is a water-in-oil emulsion.

6. The embolic water-in-oil emulsion for use of claim 5, wherein the ratio of said iodinated oil to said aqueous phase is at least 2:1v/v.

7. The embolic emulsion for use of any of claims 3 to 6, wherein the concentration of iodine in the aqueous phase is between 240 and 400 mg/mL.

8. The embolic emulsion for use of any of claims 1 to 7, wherein the viscosity of the composition is between 40 and 140mpa.s at 37 ℃.

9. Embolic emulsion for use according to any one of claims 1 to 8, wherein the emulsion droplet size is between 10 and 100 μιη.

10. The embolic emulsion for use of any of claims 1 to 9, wherein said composition:

a) Does not contain chemotherapeutic anticancer agents, and/or

b) Does not comprise nanoparticles or polymer particles, preferably wherein the composition does not comprise any embolic particles.

11. The embolic emulsion for use of any of claims 1-10, wherein said musculoskeletal disorder affects the elbow, knee, wrist, shoulder, buttocks, heel, ankle, thumb, and/or spine.

12. The embolic emulsion for use of any of claims 1-10, wherein said musculoskeletal disorder is selected from the group consisting of pick-up point disease, tendinopathy, inflammatory rheumatoid diseases, and carpal tunnel syndrome.

13. The embolic emulsion for use of claim 12, wherein:

the attachment point disease is selected from the group consisting of achilles tendon attachment point disease, epicondylitis, ankylosing spondylitis, plantar fasciitis, rotator cuff syndrome, elbow attachment point disease, wrist and/or carpal attachment point disease, olecranon bursitis, anterior patellar bursitis, hand or wrist bursitis, hip joint region attachment point disease, hip joint bursitis, knee joint attachment point disease, ankle joint attachment point disease, tarsal bone attachment point disease and calcaneal attachment point disease,

-the tendinopathy is selected from the group consisting of acrotendinitis, calcified tendinitis, achilles tendinitis, biceps tenositis, quadriceps femoris tendinitis, lateral epicondylitis, medial epicondylitis, radius styloid stenotic tenosynovitis, wrist tenosynovitis, patellar tendinitis, or

-the inflammatory rheumatoid disease is selected from osteoarthritis, cervical spondylosis, rheumatoid Arthritis (RA), acute crystalline arthritis, spondyloarthropathies, psoriatic arthritis, sjogren's syndrome, scleroderma, infectious arthritis, plantar fasciitis, juvenile idiopathic arthritis, polymyalgia rheumatica, fibromyalgia, lupus, vasculitis.

14. The embolic emulsion for use of any of claims 1-13, wherein said musculoskeletal disorder is resistant or refractory to oral analgesic, anti-inflammatory, physiotherapy and/or corticosteroid injection treatment.

15. The embolic emulsion for use of any of claims 1-14, wherein said treatment comprises administering said embolic emulsion to at least one target artery supplying blood to affected tissue.