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EP-4259119-B1 - EMBOLIZING EMULSION FOR TREATMENT OF INFLAMMATORY HYPERVASCULARIZATION ASSOCIATED WITH MUSCULOSKELETAL DISORDERS

EP4259119B1EP 4259119 B1EP4259119 B1EP 4259119B1EP-4259119-B1

Inventors

  • SAPOVAL, MARC
  • DEL GIUDICE, Constantino
  • DEAN, Carole
  • PELLERIN, OLIVIER

Dates

Publication Date
20260506
Application Date
20211210

Claims (15)

  1. Embolizing emulsion comprising iodinated oil and an aqueous phase comprising a water-soluble contrast agent for use in the treatment of inflammatory hypervascularization associated with a musculoskeletal disorder.
  2. Embolizing emulsion for use according to claim 1, wherein the iodinated oil comprises a mixture of ethyl esters of iodinated and non-iodinated fatty acids of poppyseed oil.
  3. Embolizing emulsion for use according to claim 1 or 2, wherein the water-soluble contrast agent is an iodinated contrast agent.
  4. Embolizing 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, preferably ioversol.
  5. Embolizing emulsion for use according to any one of claims 1 to 4, wherein said emulsion is a water-in-oil emulsion.
  6. Embolizing water-in-oil emulsion for use according to claim 5, wherein the ratio of iodinated oil to the aqueous phase is at least 2:1 v/v.
  7. Embolizing emulsion for use according to any one of claims 3 to 6, wherein the concentration of iodine in the aqueous phase is comprised between 240 and 400 mg/mL.
  8. Embolizing emulsion for use according to any one of claims 1 to 7, wherein the viscosity of the composition is comprised between 40 et 140 mPa.s at 37°C.
  9. Embolizing emulsion for use according to any one of claims 1 to 8, wherein the emulsion droplet size is comprised between 10 and 100 µm.
  10. Embolizing emulsion for use according to any one of claims 1 to 9, wherein said composition: a) does not comprise a chemotherapeutic anticancer agent, and/or b) does not comprise nanoparticles or polymeric particles, preferably wherein said composition does not comprise any embolic particle.
  11. Embolizing emulsion for use according to any one of claims 1 to 10, wherein the musculoskeletal disorder affects the elbow, knee, wrist, shoulder, hip, heel, ankle, thumb and/or spine.
  12. Embolizing emulsion for use according to any one of claims 1 to 10, wherein the musculoskeletal disorder is selected from enthesopathies, tendinopathies, inflammatory rheumatoid diseases and carpel tunnel syndrome.
  13. Embolizing emulsion for use according to claim 12, wherein: - the enthesopathy is selected from Achilles tendon enthesopathy, epicondylitis, ankylosing spondylitis, Plantar fasciitis, shoulder rotator cuff syndrome, enthesopathy of elbow region, enthesopathy of wrist and/or carpus, olecranon bursitis, prepatellar bursitis, hand or wrist bursitis, enthesopathy of hip region, hip bursitis, enthesopathy of knee, enthesopathy of ankle, enthesopathy of tarsus, and enthesopathy of calcaneus, - the tendinopathy is selected from shoulder tendinitis, calcific tendinitis, Achilles tendinitis, biceps tendinitis, quadriceps tendinosis, lateral epicondylitis, medial epicondylitis, De Quervain's tenosynovitis, stenosing tenosynovitis, wrist tenosynovitis, patellar tendinopathy, or - the inflammatory rheumatoid disease is selected from osteoarthritis, cervical spondylosis, rheumatoid arthritis (RA), acute crystal arthritis, spondyloarthropathies, psoriatic arthritis), Sjogren's syndrome, scleroderma, infectious arthritis, plantar fasciosis, juvenile idiopathic arthritis, polymyalgia rheumatica, fibromyalgia, lupus, vasculitis.
  14. Embolizing emulsion for use according to any one of claims 1 to 13, wherein the musculoskeletal disorder is resistant or refractory to treatment with oral analgesics, anti-inflammatory medication, physical therapy, and/or corticosteroid injections.
  15. Embolizing emulsion for use according to any one of claims 1 to 14, wherein said treatment comprises administering the embolizing emulsion to at least one target artery supplying blood to the affected tissue(s).

Description

Background The present invention is in the field of musculoskeletal disorders. It more particularly relates to an embolizing composition for use in the treatment of inflammatory hypervascularization associated with musculoskeletal disorders. Musculoskeletal disorders (MSDs) affect the bones, muscles, joints, tendons, and/or ligaments. They are the most frequent cause of disability worldwide and result in millions of outpatient visits each year (James et al., 2017). Indeed, in the US alone an estimated 50% of adults are affected by MSDs, with MSDs outranking all other conditions as a cause of lost work days (United States Bone and Joint Initiative, 2018). The most common MSDs include arthritis, lower back and neck pain, and trauma (e.g., from repetitive motion, overuse, falls) which results in damage to soft tissues and/or bone fractures. Of particular note, joint disorders, such as tennis elbow, frozen shoulder, and arthritis of the knee or wrist, are a common cause of disability in relatively young, active patients. Pain is one of the earliest and most common symptoms of MSDs, and is often associated with inflammation of the affected area, along with stiffness, tenderness, weakness, and/or swelling or deformation. In the case of inflammatory joint pathologies, intractable pain is notably associated with a partial or complete loss of function. First-line treatment of MSDs includes the administration of pharmaceutical compositions (e.g., analgesics, including opioids, nonsteroidal anti-inflammatory drugs, muscle relaxants, corticosteroid injections), which are generally accompanied by non-pharmaceutical treatment methods (e.g., use of hot/cold packs, physical therapy, exercises, self-management advice). However, long-term medication can lead to liver and/or renal dysfunction, ulcer formation, and even addiction in the case of opioids. Furthermore, treatment efficacy varies significantly from one patient to the next, making it difficult to establish a set protocol, and refractory MSD is frequent. As an example, in the case of frozen shoulder, nearly 30% of patients do not improve with first-line treatment methods (Shaffer et al, 1992). However, treatment options are limited for moderate MSDs, which do not necessarily respond to first-line treatments but which also do not warrant surgery. Indeed, surgery is typically reserved for only the most severe MSDs and comes with its own set of drawbacks. In particular, surgery is associated with lengthy recovery times, a risk of nosocomial infection, as well as a risk of complications from general anesthesia, in particular in the elderly. Intra-arterial embolization represents an interesting alternative to the above therapies. While transcatheter arterial embolization (TAE) is commonly used in the treatment of tumors (e.g., for pre-operative devascularization or to deliver chemotherapeutic agents directly to a tumor) and to manage bleeding (e.g., in postpartum hemorrhage or bleeding from synovitis in patients with hemophilia (see e.g., Klamroth et al., 2009)), it is only more recently that this technique has been evaluated in the context of treating MSDs. The interest in applying embolization techniques to MSDs arised from the observation that affected tissues, such as tendons and entheses, undergo increased neovascularity when injured (see e.g., Alfredson et al., 2003). In the case of joint-related MSDs, inflammation may induce synovial angiogenesis, leading to a redistribution of the vessels within the synovium (Bonnet and Walsh, 2005). Okuno et al. initially explored the possibility of treating refractory tendinopathy or enthesopathy with an embolizing composition composed of a mixture of imipenem (an antibiotic of the carbapenem family), cilastatin sodium (an enzyme inhibitor which prevents its breakdown into nephrotoxic metabolites), and Hexabrix® as an iodinated contrast agent, administered by intra-arterial injection (2013). Although only a small number of patients were initially tested, preliminary results showed that intra-arterial embolization could relieve unrelenting pain associated with refractory tendinopathy or enthesopathy (Okuno et al., 2013). However, patients may notably be allergic to imipenem and/or to cilastatin sodium. In addition, the use of imipenem/cilastatin sodium is authorized solely for the treatment of bacterial infections in many countries. Of note, the French Authority tasked with the evaluation of health products from a medical and economic perspective (HAS) and the European Medicines Agency (EMA) recommend restricting the use of imipenem as much as possible, in particular to severe infections with drug resistant enterobacteria, to limit development of antibiotic resistance. Clearly, imipenem/cilastatin sodium cannot be injected in peripheral arteries as this is associated with a high risk of potentiating antibiotic resistance in enterobacteria and Pseudomonas aeruginosa which are themselves responsible for clinically high-risk septice