JP-7855311-B2 - Treatment of bone marrow disorders using polysulfated polysaccharides

Inventors

• クリシュナン，ラヴィ
• レニー，ポール

Assignees

• パラダイム バイオファーマシューティカルズ リミテッド

Dates

Publication Date

20260508

Application Date

20180806

Priority Date

20170804

Claims (9)

1. A pharmaceutical composition for improving knee function in a person having bone marrow edema lesions evaluated by magnetic resonance imaging (MRI) and Kellgreen-Lawrence (3-4) knee osteoarthritis, and requiring treatment thereof, The pharmaceutical composition comprises pentosan polysulfate or an acceptable salt thereof. The aforementioned human was one who had failed to treat the knee with corticosteroids. The aforementioned treatment involves intramuscular administration of the pharmaceutical composition at a dose of approximately 1-2 mg/kg of human body twice, three times, or daily for six weeks, so as to improve knee joint function by approximately 23% to approximately 89% as determined by the Lysholm knee joint score. The aforementioned pharmaceutical composition.
2. The pharmaceutical composition according to claim 1, wherein the function of the knee joint is improved by approximately 23% to approximately 43%.
3. The pharmaceutical composition according to claim 2, wherein the function of the knee joint is improved by approximately 23% to approximately 35%.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pentosan polysulfate (PPS) is selected from the group consisting of sodium pentosan polysulfate (NaPPS), magnesium pentosan polysulfate (MgPPS), calcium pentosan polysulfate (CaPPS), and zinc pentosan polysulfate (ZnPPS).
5. The pharmaceutical composition according to claim 4, wherein the aforementioned pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS).
6. A pharmaceutical composition according to any one of claims 1 to 5 , which is administered to humans once a day or twice a week as part of a treatment regimen.
7. The pharmaceutical composition according to claim 6 , which is administered to humans in a treatment regimen twice a week.
8. The pharmaceutical composition according to claim 7 , which is administered to humans in a treatment regimen of twice a week, with an interval of at least three days and at most four days between doses.
9. The pharmaceutical composition according to claim 8 , which is administered to humans in a treatment regimen of twice a week for six weeks.

Description

This invention relates to the medical use of polysulfated polysaccharides and their compositions for the treatment of diseases or disorders associated with bone marrow pathology in the mammalian musculoskeletal system. Specifically, this invention relates to the use of polysulfated polysaccharides in the treatment of bone marrow edema lesions or modic endplate changes of the spine, as assessed by magnetic resonance imaging (MRI). Bone marrow edema lesions Bone marrow edema lesions (BMELs) are changes in the subchondral bone and are detected by MRI, which depicts the severity of symptoms, including pain ([1]–[3]) and cartilage degeneration ([4]–[7]), in patients with osteoarthritis. BMELs are generally evaluated using fat-suppressed proton density-weighted or T2-weighted sequences. In fat-suppressed T2-weighted and fat-suppressed proton density-weighted sequences, BMELs appear as extremely strong signals [8]. MRI signals associated with BMEL are thought to be due to increased concentrations of blood and interstitial fluid (including infiltrating macrophages) in areas of trabecular microfractures and trabecular collapse within the bone marrow [8]. Improved spatial resolution and multi-planar reconstruction suggest that 3D high-speed spin-echo sequencing may be useful, particularly for imaging cartilage [9]. Increasing data suggests that BMEL plays a crucial role in the pathogenesis of arthritis, including osteoarthritis of the knee. Knee Osteoarthritis Knee osteoarthritis (OA) is a disorder characterized by bone changes around the knee joint, progressive loss of articular cartilage, narrowing of the joint space, and ultimately complete joint failure. Knee OA results in knee pain, significant physical disability, and a reduced quality of life. Epidemiological studies suggest that in the United States, there are approximately 12 million people aged 50 and older with symptomatic knee OA, of which an estimated 7 million have BML (Beginner-Minute Lung). Patients with osteoarthritis of the knee may exhibit BMEL, which appears as an area of increased signal intensity on knee MRI. In the affected disease, BMEL is associated with knee pain [2], disease severity and progression, including radiological progression of osteoarthritis [10], and MRI-based cartilage loss ([5], [11]). Furthermore, in progressive osteoarthritis, BMEL is more likely to persist and enlarge in size, accompanied by increased associated cartilage loss [5]. In addition, the severity of BMEL has been shown to correlate with the risk of knee arthroplasty [12]. The strong association with BMEL, accompanied by pain and cartilage loss, has increased pharmaceutical interest in targeting this structural lesion to monitor the progression and treatment effectiveness of osteoarthritis of the knee ([13]–[15]). Chronic Low Back Pain Chronic low back pain (CLBP) is defined as persistent or fluctuating low back pain that lasts for at least three months. CLB, or back pain in general, is a costly condition that involves physical disability and increased medical use. Some patients with CLB show modic changes (MC), which are obvious bone marrow changes in the vertebrae, on MRI of the spine. Of the three types of modal cell carcinoma (MCC) classified as Type I, Type II, and Type III, Type I changes are low-intensity on T1-weighted imaging (T1WI) and hyperintense on T2-weighted imaging (T2WI), representing bone marrow edema and inflammation. Type II changes are hyperintense on T1WI and isointense or slightly hyperintense on T2WI, associated with the transformation of normal red hematopoietic bone marrow into yellow fatty marrow as a result of medulla ischemia. Type III modal changes are depicted as low-intensity on both T1WI and T2WI and are thought to represent subchondral osteosclerosis. Mixed Type I/II and Type II/III modal changes have also been reported, suggesting that these changes may be convertible from one type to another [15A]. Of the three classifications of muscle dysplasia (MC), Type I, Type II, and Type III, Type I is particularly associated with lower back pain, persistent symptoms, and poor outcomes. Epidemiological studies suggest that in the United States, there are approximately 9 million adults with CLBP (Colonel Lobe Pain), and an estimated 1.6 million of them have Type I MC. The economic costs of CLBP in the United States are estimated to range from $12.2 billion to $90.6 billion annually. Factors contributing to this economic impact include long-term functional loss, resulting loss of work productivity, medical expenses, and disability benefits. Patients with CLBP may exhibit micturition (MC). MC is evident on MRI of the spine and, based on published studies, is a bone marrow alteration of the vertebrae associated with low back pain. Findings from various studies have demonstrated that the presence of MC, particularly type I MC, correlates with low back pain, predicts persistent symptoms and illness, and is associated with poor outcomes. These f