Long-acting liposome composition for treating pain in joint disorders

Abstract

The present invention provides a long-acting liposome composition for treating pain or stimulation in a joint of a subject suffering from a joint disorder, in particular osteoarthritis. The compositions comprise phosphatidylcholine lipids as the only active ingredient and provide pain relief upon single administration or multiple administration at a frequency of once every four to twelve months.

Description

Technical Field

[0001] The present invention relates to liposomal pharmaceutical compositions for treating pain in joint disorders. Background Art

[0002] Osteoarthritis (OA) is the most common form of joint disease and is characterized by degradation of articular cartilage, osteophyte formation, bone remodeling, joint space narrowing, and joint inflammation. The etiology of OA is unknown but is believed to be multifactorial in nature and includes genetic, metabolic causes, mechanical injury, and inflammation. The prevalence of OA in the knee is higher than that of any other joint. Clinical manifestations of OA in the knee include pain in and around the joint (particularly when weight bearing is applied to the knee), joint stiffness after rest, and limited joint motion due to joint pain and / or stiffness. The end result of all forms of OA is often loss of joint or limb function, resulting in a significant economic burden on individuals and society. The diagnosis of OA is based on signs and symptoms and is usually confirmed by imaging studies or using laboratory tests to exclude concomitant inflammatory causes. As the pathophysiology of OA is unclear, current recommendations for the management of OA focus on relieving pain and stiffness and improving physical function as important goals of treatment. Nonsurgical treatment of OA focuses on reducing joint overload, physical therapy, and relieving pain and inflammation, usually through topical, systemic, or intra-articular (IA) administration of medications.

[0003] Currently, available medication regimens for most OA patients include non-opioid analgesics. This is primarily because long-term use of opioids to treat OA is generally discouraged due to a lack of information about benefits and the risk of addiction and other side effects. Therefore, agents such as acetaminophen / paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), counterirritants, glucosamine or chondroitin, corticosteroids, and injectable hyaluronic acid are commonly used. While these agents can be quite effective in providing transient pain relief, long-term use of NSAIDs has been associated with an increased risk of gastrointestinal bleeding, hypertension, cardiovascular events, congestive heart failure, and renal insufficiency. In terms of gastrointestinal side effects, NSAIDs and cyclooxygenase II (COX II) inhibitors in topical form are considered slightly safer than other NSAIDs, although COX II inhibitors are contraindicated in patients with a history of coronary artery disease (Mehta et al., Statistics in Medicine. 2011; 30(28): 3267-3284; Zhang et al., Clin Geriatr Med. 2010; 26: 355-369; Glyn-Jones et al., Lancet. 2015; 386: 376–387). Although corticosteroid injections reduce inflammation and relieve pain more quickly than NSAIDs, their relief is only temporary. Corticosteroid injections are usually given every three months, and the number of injections in the same joint is usually limited to four.

[0004] Due to the high incidence of side effects associated with long-term therapy with NSAIDs and corticosteroids, there is an urgent need for effective and safer alternative treatments for OA.

[0005] Hyaluronic acid (HA) injections are typically administered weekly for 3 to 5 weeks. Although HA injections have been found to be safe when used long-term, various studies have reported that they provide only minimal benefits. In addition, injectable HA compositions are known to have various side effects, such as difficulty with movement, muscle pain or stiffness, joint pain, and joint swelling or redness.

[0006] The lubrication of cartilage within synovial joints requires a complex interaction of several mechanical and molecular factors, resulting in reduced friction between the opposing surfaces of the articular cartilage. In healthy, weight-bearing joints, a layer of lubricating molecules covers the surface of the articular cartilage and acts as a boundary lubricant, enabling almost frictionless movement of the joint. The lubricant components of synovial fluid (SF) include, among others, hyaluronic acid, lubricin, and surfactant phospholipids. Various studies have been conducted to evaluate the efficacy of phospholipids in joint lubrication.

[0007] US Patent 6800298 discloses dextran-based hydrogel compositions containing lipids, particularly phospholipids, for lubricating mammalian joints.

[0008] US Patent Application 2005 / 0123593 relates to a composition comprising glycosaminoglycans encapsulated in a liposomal delivery system for intra-articular administration to treat osteoarthritis.

[0009] US Patent 8895054 relates to a method for joint lubrication and / or prevention of cartilage wear using liposomes consisting essentially of a phospholipid membrane having a phase transition temperature in the range of about 20°C to about 39°C.

[0010] International patent application WO 2019 / 038763 relates to a pharmaceutical composition for joint lubrication, comprising a non-ionic tonicity agent containing a polyol and a liposome based on glycerophospholipids or sphingomyelin having a phase transition temperature below the joint temperature.

[0011] International patent application WO 2003 / 000191 relates to a composition and method for treating arthritis comprising a combination of one or more glycosaminoglycans and one or more hyaluronidase inhibitors, wherein the hyaluronidase inhibitor may be selected from heparan sulfate, dextran sulfate and xylose sulfate, and wherein hyaluronic acid may be co-encapsulated with the hyaluronidase inhibitor in liposomes.

[0012] There remains an unmet need for therapeutically effective pharmaceutical compositions for joint lubrication that will provide a sustained effect while reducing the potential for side effects associated with frequent intra-articular administration. Summary of the invention

[0013] The present invention provides a liposome formulation for treating pain or irritation in a joint of a subject with a joint disorder. The formulation of the present invention comprises a liposome as an active ingredient, which comprises a phospholipid membrane having a phase transition temperature slightly lower than the physiological temperature of the joint (i.e., in the range of about 20°C to about 39°C). Thus, the liposome is in a liquid disordered (LD) phase when applied to a synovial joint.

[0014] It is now disclosed for the first time that a single intra-articular injection of a liposomal pharmaceutical composition according to the principles of the present invention provides pain relief to a subject, wherein the pain relief persists for six months. Specifically, nominally significantly reduced pain scores were obtained by WOMAC A pain score, and statistically significantly reduced pain scores were obtained by weekly averages of daily knee pain scores obtained by VAS and the patient's overall assessment. Pain relief was also manifested as a reduction in the amount of rescue medication used to relieve pain. In addition, the liposomal composition was found to be safe and well tolerated. Therefore, administration of the liposomal composition once or more than once every three months is beneficial for the treatment of joint disorders, particularly osteoarthritis.

[0015] According to one aspect, the present invention provides a liposome composition for use in a method of treating pain or irritation in the joints of a subject suffering from a joint disorder, the method comprising administering a single intra-articular injection of the liposome composition once or every 4 to 12 months, the composition comprising a phosphatidylcholine (PC) selected from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-pentacosanoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythro-C16 and combinations thereof as the only active ingredient.

[0016] According to another aspect, the present invention provides a method for treating pain or irritation in the joints of a subject suffering from a joint disorder, the method comprising administering a single intra-articular injection of a liposome composition once or every 4 to 12 months, the composition comprising a phosphatidylcholine (PC) selected from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-pentacosanoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythro-C16 and combinations thereof as the only active ingredient.

[0017] In yet another aspect, the present invention provides a use of a liposome composition comprising a phosphatidylcholine (PC) selected from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-pentacoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythro-C16 and combinations thereof as the only active ingredient, for the preparation of a medicament for a method of treating pain or irritation in the joints of a subject suffering from a joint disorder, the method comprising administering a single intra-articular injection of the liposome composition once or every 4 to 12 months.

[0018] In one embodiment, treating pain or irritation in a subject's joint with a joint disorder comprises reducing at least one of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) A pain score, the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) B stiffness score, the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) C disability score, the patient's global assessment of disease activity (PtGA) by a visual analog scale (VAS), the weekly average of the daily overall pain score obtained by a visual analog scale (VAS), the weekly average of the daily joint pain score obtained by a visual analog scale (VAS), the cumulative amount of rescue medication used to relieve pain, and the urinary collagen C-terminal cross-linked telopeptide (CTX) type II level as compared to a baseline or untreated control. Each possibility represents an independent embodiment.

[0019] In another embodiment, the reduction is at least 5% reduction compared to baseline or untreated control. In yet another embodiment, the reduction is at least 10% reduction compared to baseline or untreated control. In other embodiments, the reduction is at least 15% reduction compared to baseline or untreated control. In other embodiments, the reduction is at least 20% reduction compared to baseline or untreated control. In certain embodiments, the reduction is at least 25% reduction compared to baseline or untreated control. In various embodiments, the reduction is at least 30% reduction compared to baseline or untreated control. In specific embodiments, the reduction is at least 40% reduction compared to baseline or untreated control. In exemplary embodiments, the reduction is at least 50% reduction compared to baseline or untreated control.

[0020] In some embodiments, the subject has a baseline WOMAC A pain score of ≥2, and the WOMAC A pain score is reduced by at least 0.5 points. In other embodiments, the subject has a baseline WOMAC A pain score of ≥2, and the WOMAC A pain score is reduced by at least 0.75 points. In other embodiments, the subject has a baseline WOMAC A pain score of ≥2, and the WOMAC A pain score is reduced by at least 1 point.

[0021] In certain embodiments, the subject's baseline weekly average of daily joint pain scores obtained by VAS is ≥50mm, and the weekly average of daily joint pain scores obtained by VAS is reduced by at least 5. In various embodiments, the subject's baseline weekly average of daily joint pain scores obtained by VAS is ≥50mm, and the weekly average of daily joint pain scores obtained by VAS is reduced by at least 10. In other embodiments, the subject's baseline weekly average of daily joint pain scores obtained by VAS is ≥50mm, and the weekly average of daily joint pain scores obtained by VAS is reduced by at least 15. In other embodiments, the subject's baseline weekly average of daily joint pain scores obtained by VAS is ≥50mm, and the weekly average of daily joint pain scores obtained by VAS is reduced by at least 20. In other embodiments, the subject's baseline weekly average of daily joint pain scores obtained by VAS is in the range of 50mm to 90mm, including each value in the specified range.

[0022] In one embodiment, the liposomal composition is administered once. In an alternative embodiment, the liposomal composition is administered once every four months. In other alternative embodiments, the liposomal composition is administered once every six months. In other embodiments, the liposomal composition is administered once every 26 weeks. According to some embodiments, the administration of the liposomal composition provides pain relief to the subject for more than three months after administration. According to other embodiments, the administration of the liposomal composition provides pain relief to the subject for at least six months after administration.

[0023] In various embodiments, the liposome composition comprises a plurality of liposomes having a phosphatidylcholine concentration of about 50 mM to about 300 mM, including each value within the specified range. In specific embodiments, the liposome composition comprises a plurality of liposomes having a phosphatidylcholine concentration of about 100 mM to about 200 mM, including each value within the specified range.

[0024] In various embodiments, the liposome composition comprises 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) as the only active ingredients. In a specific embodiment, the liposome composition comprises DMPC and DPPC in a molar ratio of 25:75 to 70:30, including iterations of all ratios within the specified range. In other specific embodiments, the liposome composition comprises DMPC and DPPC in a molar ratio of 40:60 to 50:50, including iterations of all ratios within the specified range. In a specific embodiment, the molar ratio of DMPC to DPPC is about 45:55. In other embodiments, the liposome composition comprises DMPC in a weight percentage range of about 1% (w / w) to about 10% (w / w) and DPPC in a weight percentage range of about 2% (w / w) to about 12% (w / w), including each value within the specified range. In other embodiments, the liposome composition comprises between about 20 mg to about 700 mg of DMPC and between about 30 mg to about 900 mg of DPPC, including each value within the specified range. In a specific embodiment, the liposome composition comprises between about 45 mg to about 300 mg of DMPC and between about 60 mg to about 400 mg of DPPC, including each value within the specified range.

[0025] According to some embodiments, the liposome composition is administered in a volume between about 0.5 ml and about 10 ml, including each value within the specified range. In a specific embodiment, the liposome composition is administered in a volume between about 1 ml and about 6 ml, including each value within the specified range. In a more specific embodiment, the liposome composition is administered in a volume of about 3 ml.

[0026] In some embodiments, the liposome composition comprises a plurality of liposomes selected from small unilamellar vesicles (SUV), large unilamellar vesicles (LUV), giant unilamellar vesicles (GUV), oligolamellar vesicles (OLV), multilamellar vesicles (MLV), multivesicular liposomes (MVL), and mixtures or combinations thereof. Each possibility represents an independent embodiment. In one embodiment, the liposome is a multilamellar vesicle (MLV).

[0027] In certain embodiments, the size of the liposomes is in the range of about 0.3 μm to about 50 μm, including each value in the specified range. In other embodiments, the size of the liposomes is in the range of about 0.5 μm to about 10 μm, including each value in the specified range.

[0028] According to some embodiments, the liposome composition comprises a fluid medium containing water or a buffer. In other embodiments, the buffer is a histidine buffer. According to other embodiments, the fluid medium further comprises a tonicity agent selected from low molecular weight polyols and sugar alcohols. In one embodiment, the tonicity agent is a polyol. In another embodiment, the polyol is a linear polyol. In other embodiments, the polyol is selected from mannitol, sorbitol, glycerol, lactitol, maltitol, dextrose, lactose, trehalose and combinations thereof. Each possibility represents an independent embodiment. In a specific embodiment, the polyol is mannitol. According to various embodiments, the weight ratio between the multiple liposomes and the polyol is in the range of about 6: 1 to about 2: 1, including iterations of all ratios within the specified range. In other embodiments, the polyol is present in the liposome composition with a weight percentage in the range of about 0.05% (w / w) to about 10% (w / w), including each value within the specified range.

[0029] According to certain embodiments, the liposome composition has a pH in the range of about 5 to about 8, including each value in the specified range.

[0030] According to some embodiments, the composition is for use in alleviating knee pain in osteoarthritis patients.

[0031] From the detailed description given below, other embodiments and the entire scope of application of the present invention will become apparent. However, it should be understood that the detailed description and specific examples, although indicating preferred embodiments of the present invention, are given only by way of illustration, because for those skilled in the art, various changes and modifications within the spirit and scope of the present invention will become apparent based on the detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 A schematic diagram of the Phase IIb study design is shown.

[0033] Figure 2 The distribution of subjects participating in the study is shown.

[0034] Figure 3 WOMAC A pain results are shown over the 26-week study period. *: p<0.05, not adjusted for multiplicity.

[0035] Figure 4 WOMAC C physical function over the 26-week study is shown.

[0036] Figure 5 Weekly averages of daily knee pain over the 26-week study are shown.

[0037] Figure 6 Patient Global Assessment of Disease Activity over the 26-week study period is shown.

[0038] Figure 7 Weekly averages of daily overall pain over the 26-week study are shown.

[0039] Figure 8 The cumulative weekly amount (mg) of rescue medication used over the 26-week study is shown.

[0040] Fig. 9 Shown is a graph of the change in urinary collagen C-terminal cross-linked telopeptide (CTX) type II (μg / mol) over time compared to baseline over the 12-week study.

[0041] Fig. 10A Baseline-adjusted mean plasma DMPC concentrations (ng / mL) are shown.

[0042] Fig. 10B Baseline-adjusted mean plasma DPPC concentrations (ng / mL) are shown. DETAILED DESCRIPTION

[0043] The present invention provides a liposome formulation for treating pain or irritation of a mammalian joint, wherein pain relief is manifested for more than three months, preferably at least six months after a single administration. Thus, the liposome formulation of the present invention is a long-acting composition with improved efficacy and reduced adverse reactions caused by frequent administration.

[0044] Drugs known to date for OA-related pain relief are usually administered in a repeated regimen in order to achieve a long-term effect. For example, HA, which is widely used for intra-articular injections to treat lower limb osteoarthritis, is rapidly degraded by reactive oxygen species (ROS), limiting its residence time in the joint (Conrozier et al., Rheumatol Ther. 2014; 1(1):45-54).

[0045] In another study, 40 patients with unilateral knee osteoarthritis were randomized into two groups and received a single injection of an aqueous dispersion of multilamellar vesicles (MLV) composed of DMPC and DPPC or hyaluronic acid. Although the MLV composition showed a faster onset of pain relief compared to HA, long-term effects were not confirmed. Specifically, the MLV composition had the highest efficacy 14 days after administration, and the relative change in pain from day 14 to day 90 showed a steady decline (Kandel et al., Meeting: 2014 ACR / ARHP Annual Meeting). The conclusion was that the pain relief effect was faster than HA and lasted up to 3 months. Therefore, it was completely unforeseeable that a single intra-articular injection of a liposome composition containing a combination of DMPC and DPPC in the form of MLV could reduce joint pain and improve function in OA patients over a period of more than three months. The composition of the present invention was demonstrated to provide pain relief that lasted for six months after a single injection, as demonstrated by various criteria including WOMACA pain scores, weekly averages of daily knee pain scores obtained via VAS, patient global assessment, and reduction in rescue medication use for pain relief. Furthermore, a 3 ml dose of the liposomal composition produced unexpected efficacy compared to a 6 ml dose. Furthermore, when the above efficacy of the composition of the present invention was compared to a commercially available composition containing a corticosteroid active ingredient, The former was shown to exert superior efficacy when compared to published efficacy in its Phase 3 trial. Finally, patient compliance was improved due to reduced frequency of administration.

[0046] Thus, the present invention provides a long-acting liposomal composition comprising a plurality of liposomes useful for treating patients suffering from joint disorders, wherein the composition is administered as a treatment regimen once or once every four to twelve months, including each value within the specified time length.

[0047] The term "long-acting" as used herein refers to a composition that provides an extended or sustained effect to a local site of action in a subject or provides an extended or sustained effect duration in a subject. Therefore, a therapeutic effect can be obtained over a period of time that lasts more than four, five, six, seven, eight, nine, ten, eleven, twelve months or longer. Each possibility represents an independent embodiment. Surprisingly, effective treatment is achieved at the local site of action, and there is substantially no systemic effect, as demonstrated by plasma levels indicating endogenous lipid concentrations.

[0048] The term "liposome" as used herein refers to a vesicle characterized in that the internal aqueous center is surrounded by a lipid membrane that generally comprises a phospholipid bilayer. Exemplary phospholipids include, but are not limited to, phosphatidylcholine (PC), phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, or any derivative or combination thereof. Each possibility represents an independent embodiment. Within the scope of the present invention, suitable phosphatidylcholine includes, but is not limited to, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and mixtures or combinations thereof. Each possibility represents an independent embodiment. Suitable phosphatidylethanolamines include, but are not limited to, 1,2-dilauroyl-L-phosphatidyl-ethanolamine (DLPE), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (DPhPE), 1,3-dipalmitoyl-sn-glycero-2-phosphoethanolamine (1,3-DPPE), 1-palmitoyl-3-oleoyl-sn-glycero-2-phosphoethanolamine (1,3-POPE), biotin-phosphatidylethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and mixtures or combinations thereof. Each possibility represents an independent embodiment. Suitable phosphatidylglycerols include, but are not limited to, 1,2-dimyristoyl-sn-glycero-3-(phospho-rac-(1-glycerol)) (DMPG), 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), 1,2-distearoylphosphatidylglycerol (DSPG), and mixtures or combinations thereof. Each possibility represents an independent embodiment.

[0049] According to some embodiments, liposomes suitable for use in the pharmaceutical compositions of the present invention do not include membrane active sterols, such as cholesterol, in their bilayers.

[0050] In some aspects and embodiments, the liposomes are composed of phosphatidylcholine (PC) selected from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-pentacoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythro-C16 and combinations thereof. Each possibility represents an independent embodiment.

[0051] According to some embodiments of the present invention, the total concentration of phosphatidylcholine in the pharmaceutical composition is in the range of about 20mM to about 500mM, including each value in the specified range. In other embodiments, the concentration is in the range of about 50mM to about 300mM, including each value in the specified range. In other embodiments, the concentration is in the range of about 100mM to about 200mM, including each value in the specified range. In other embodiments, the concentration is in the range of about 130mM to about 170mM, including each value in the specified range. In certain embodiments, the total concentration of DMPC and DPPC is about 150mM.

[0052] Preferably, the liposome contains a combination of DMPC and DPPC as the only active ingredient. In some embodiments, the liposome is essentially composed of DMPC and DPPC. In other embodiments, the molar percentage ratio of DMPC to DPPC is in the range of about 25:75 to about 70:30, including iterations of all ratios within the specified range. In other embodiments, the molar percentage ratio of DMPC to DPPC is in the range of about 30:70 to about 65:25, about 35:65 to about 60:30 or about 40:60 to about 55:45, including iterations of all ratios within the specified range. Each possibility represents an independent embodiment. In certain embodiments, the molar percentage ratio of DMPC to DPPC is about 45:55. In other embodiments, the molar percentage ratio of DMPC to DPPC is about 25:75.

[0053] In some embodiments, the total concentration of DMPC and DPPC is in the range of about 10 mg / ml to about 500 mg / ml, including each value in the specified range. In other embodiments, the concentration is in the range of about 30 mg / ml to about 300 mg / ml, including each value in the specified range. In other embodiments, the concentration is in the range of about 50 mg / ml to about 200 mg / ml, including each value in the specified range. In certain embodiments, the total concentration of DMPC and DPPC is about 100 mg / ml.

[0054] In some embodiments, the concentration of DMPC is in the range of about 1 mg / ml to about 250 mg / ml, including each value within the specified range. In other embodiments, the concentration of DMPC is in the range of about 10 mg / ml to about 100 mg / ml, including each value within the specified range. In other embodiments, the concentration of DMPC is in the range of about 20 mg / ml to about 70 mg / ml, including each value within the specified range. In certain embodiments, the concentration of DMPC is about 46 mg / ml.

[0055] In some embodiments, the concentration of DPPC is in the range of about 5 mg / ml to about 300 mg / ml, including each value in the specified range. In other embodiments, the concentration of DPPC is in the range of about 20 mg / ml to about 200 mg / ml, including each value in the specified range. In other embodiments, the concentration of DPPC is in the range of about 30 mg / ml to about 90 mg / ml, including each value in the specified range. In certain embodiments, the concentration of DPPC is about 60 mg / ml.

[0056] In some embodiments, the combination of DMPC and DPPC is present in the pharmaceutical composition at a weight percentage in the range of about 0.1% (w / w) to about 40% (w / w), about 0.5% (w / w) to about 30% (w / w), about 3% (w / w) to about 30% (w / w), or about 1% (w / w) to about 20% (w / w), of the total weight of the pharmaceutical composition, including each value within the specified range. In certain embodiments, DMPC and DPPC are present in the pharmaceutical composition at a weight percentage of about 10% (w / w).

[0057] According to the principles of the present invention, the pharmaceutical composition comprises about 20 mg to about 700 mg of DMPC and about 30 mg to about 900 mg of DPPC, including each value within the specified range. According to some embodiments, the composition comprises about 20 mg to about 450 mg of DMPC and about 30 mg to about 550 mg of DPPC, including each value within the specified range. According to other embodiments, the composition comprises about 40 mg to about 300 mg of DMPC and about 50 mg to about 500 mg of DPPC, including each value within the specified range. According to other embodiments, the composition comprises about 100 mg to about 200 mg of DMPC and about 150 mg to about 250 mg of DPPC, including each value within the specified range. In one embodiment, the composition comprises about 180 mg of DPPC. In another embodiment, the composition comprises about 60 mg of DPPC. In other embodiments, each dose of the pharmaceutical composition comprises about 365 mg of DPPC. In a certain embodiment, each dose of the pharmaceutical composition comprises about 140 mg of DMPC. In another embodiment, each dose of the pharmaceutical composition comprises about 45 mg DMPC. In a certain embodiment, each dose of the pharmaceutical composition comprises about 275 mg DMPC.

[0058] It should be emphasized that the liposomes used in the liposome composition of the present invention are used as active ingredients themselves, rather than as carriers of pharmaceutically active agents. According to some embodiments, the phospholipids of DMPC and DPPC are used as the only active ingredients in the pharmaceutical composition of the present invention. Therefore, according to the principles of the present invention, the pharmaceutical composition is substantially free of any additional pharmaceutically active agents. In some embodiments, the term "substantially free of any additional pharmaceutically active agents" used herein refers to the pharmaceutical composition containing less than a therapeutically effective amount of the pharmaceutically active agent known to be used for joint lubrication, treatment of joint dysfunction, alleviation of joint pain, stimulation and / or wear or any combination thereof. In some embodiments, the term "known for" used herein refers to a pharmaceutically active agent being approved for the specified use at the time of the present invention. In other embodiments, the term "known for" refers to a pharmaceutically active agent being mentioned in scientific literature and / or patents as being suitable for the specified use.

[0059] In some embodiments, the liposome composition of the present invention does not include a pharmaceutically active agent as a lubricant, such as, in particular, a glycosaminoglycan or a pharmaceutically acceptable salt, ester or derivative thereof. In certain embodiments, the glycosaminoglycan is hyaluronic acid or a salt or ester containing hyaluronic acid. In certain embodiments, hyaluronic acid is not encapsulated in the liposome. In addition or alternatively, hyaluronic acid is not dispersed in the fluid medium. In some currently preferred embodiments, the liposome composition is substantially free of hyaluronic acid or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the term "substantially free of" used in conjunction with hyaluronic acid refers to that the composition contains hyaluronic acid or a salt or ester thereof that is less than a therapeutically effective amount. In other embodiments, the term "substantially free of" refers to that the composition comprises less than a detectable amount of hyaluronic acid or a salt or ester thereof.

[0060] In some embodiments, the liposome composition of the present invention does not include a pharmaceutically active agent that is a lubricant selected from the group consisting of superficial zone protein (SZP), lubricin, proteoglycan 4, and analogs and derivatives thereof.

[0061] In some embodiments, the liposome compositions of the present invention do not include a pharmaceutically active agent that is an anti-inflammatory agent, such as xylitol, betamethasone, prednisolone, piroxicam, aspirin, flurbiprofen, (+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hydroxyurea disalicylate, diflunisal, ibuprofen, fenoprofen, fenamate, ketoprofen, nabumetone, naproxen, diclofenac, indomethacin, sulindac, tolmetin, etodolac, ketorolac, oxaprozin, celecoxib, meclofenamic acid, mefenamic acid, oxybutazone, phenylbutazone, salicylates, or phytosphingosine-based agents.

[0062] In some embodiments, the liposome compositions of the present invention do not include a pharmaceutically active agent that is an antiviral agent, such as acyclovir, nelfinavir, or ribavirin. In some embodiments, the liposome compositions of the present invention do not include a pharmaceutically active agent that is an anti-infective agent, such as benzalkonium chloride or chlorhexidine.

[0063] In some embodiments, the liposome composition of the present invention does not include a pharmaceutically active agent that is an antibiotic, including antibiotics belonging to the classes of penicillins, cephalosporins, aminoglycosides, macrolides, carbapenems and penems, monocyclic β-lactams, β-lactamase inhibitors, tetracyclines, polypeptide antibiotics, chloramphenicol and its derivatives, polyether ionophores, and quinolones. Examples of such antibiotics include ampicillin, dapsone, chloramphenicol, neomycin, cefaclor, cefdroxil, cephalexin, cephradine, erythromycin, clindamycin, lincomycin, amoxicillin, ampicillin, bacampicillin, carbenicillin, dicloxacillin, cyclopentyl penicillin, picloxacillin, hetacillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, ticarcillin, rifampicin, tetracycline, fusidic acid, lincomycin, novobiocin, and spectinomycin.

[0064] In some embodiments, the liposome composition of the present invention does not include a pharmaceutically active agent that is a steroid. The term "steroid" as used herein refers to naturally occurring steroids and their derivatives, as well as synthetic or semisynthetic steroid analogs with steroid-like activity. The steroid can be a glucocorticoid or a corticosteroid. Examples of specific natural and synthetic steroids include aldosterone, beclomethasone, betamethasone, budesonide, clopredniol, cortisone, cortivazole, deoxycorticosterone, desonide, desoximetasone, dexamethasone, fluocortol, fluclosan, flumethasone, flunisolide, fluocinolone, fluocinolone acetate, fluocort butyl, fluocortol, fluocortol, fluorometholone, flurandrenolide, fluticasone, halcinonide, hydrocortisone, icomethasone, methylprednisolone, methylprednisolone, paramethasone, prednisolone, prednisone, tixocortol or triamcinolone, and their corresponding pharmaceutically acceptable salts or derivatives.

[0065] It should be noted that the liposome composition of the present invention preferably does not contain propylene glycol.It should also be noted that the liposome composition of the present invention preferably does not contain dextran.

[0066] According to the principles of the present invention, the liposome has a structure of a small unilamellar vesicle (SUV), a large unilamellar vesicle (LUV), a giant unilamellar vesicle (GUV), an oligolamellar vesicle (OLV), a multilamellar vesicle (MLV), a multivesicular liposome (MVL), or a mixture or combination thereof, or takes the form described above. Each possibility represents an independent embodiment. The liposome may be a monolamellar liposome, or according to some embodiments may be a multilamellar vesicle (MLV) liposome. According to other embodiments, the liposome may also be a multilamellar vesicle (LMVV) or a dehydrated rehydrated vesicle (DRV) liposome.

[0067] In some currently preferred embodiments, the liposomes take the form of multilamellar vesicles (MLVs).In certain such embodiments, the liposomes have more than one membrane.

[0068] According to some embodiments, the liposomes have an average diameter greater than about 0.3 μm, greater than about 0.5 μm, greater than about 0.8 μm, or greater than about 1 μm. Each possibility represents an independent embodiment. The average diameter of the liposomes may be less than about 10 μm, 8 μm, 7 μm, 6 μm, or 5 μm. Each possibility represents an independent embodiment. According to some embodiments, the liposomes have an average diameter in the range of about 0.3 μm to about 10 μm, including each value in the specified range. According to other embodiments, the liposomes have an average diameter in the range of about 0.5 μm to about 9 μm, including each value in the specified range. According to other embodiments, the liposomes have an average diameter in the range of about 1 μm to about 8 μm, including each value in the specified range. According to other embodiments, the liposomes have an average diameter in the range of about 3 μm to about 5 μm, including each value in the specified range.

[0069] The terms "mean diameter" and "mean particle size" are used interchangeably herein and refer in some embodiments to the mean diameter of the liposomes derived from the particle size distribution based on a digital distribution model. In some embodiments, the term refers to the mean diameter of the liposomes derived from the particle size distribution based on a volume distribution model. In other embodiments, the term refers to the mean diameter of the liposomes derived from the particle size distribution based on a surface area distribution model. The particle size distribution can be determined, in particular, by laser diffraction and / or by a Coulter counter method.

[0070] According to one embodiment, the MLV is defined by an average diameter in the range of 0.3 μm to 10 μm, including each value in the specified range. According to another embodiment, the MLV is defined by an average diameter in the range of 0.5 μm to 9 μm, including each value in the specified range. According to other embodiments, the MLV is defined by an average diameter in the range of 1 μm to 8 μm, including each value in the specified range. According to other embodiments, the MLV is defined by an average diameter in the range of 3 μm to 5 μm, including each value in the specified range.

[0071] Included within the scope of the present invention are liposome compositions having a defined phase transition temperature of the liposome membrane that is below the temperature of a joint. As used herein, the term "phase transition temperature" refers in some embodiments to the temperature at which a liposome undergoes a solid ordered (SO) to liquid disordered (LD) phase transition. The phase transition temperature of the liposome can be assessed by differential scanning calorimetry (DSC). DSC thermograms can be examined to assess various parameters of the phase transition temperature including Ton (which represents the temperature at which the SO-LD phase transition begins) and T off (which represents the temperature at which the SO-LD phase transition ends during the heating scan), and T p and T m , which respectively represent the pre-phase transition (T p ) and the main phase transition (T m ) during which the maximum change in heat capacity occurs. In some embodiments, the term "phase transition temperature" refers to T m . In other embodiments, the term "phase transition temperature" refers to the temperature range of the SO to LD phase transition. In accordance with the principles of the present invention, the compositions disclosed herein have a phase transition temperature in the range of about 20°C to about 39°C, including each value within the specified range. In some embodiments, the phase transition temperature of the liposomes is in the range of about 33°C to about 37°C, including each value within the specified range. In some embodiments, DMPC and DPPC form a lipid bilayer, which becomes highly hydrated and vesicled above the SO to LD phase transition temperature to form lipid vesicles (liposomes). The liposome bilayer can be in a solid ordered (SO) phase or in a liquid disordered (LD) phase. The transition between the SO to LD phase involves an endothermic first-order phase transition, referred to as the primary phase transition. T m is the temperature at which the maximum change in heat capacity occurs during the SO to LD phase transition.

[0072] According to the principles of the present invention, the liposomes are suspended or dispersed in a fluid medium. The fluid medium can be selected from a buffer and water. Each possibility represents an independent embodiment. In some embodiments, the fluid medium comprises a buffer. In certain embodiments, the buffer comprises a histidine buffer. The concentration of the histidine buffer can be in the range of about 0.5 mg / ml to about 10 mg / ml, including each value in the specified range. In certain embodiments, the concentration of the histidine buffer is about 2 mg / ml. In some embodiments, the concentration of the histidine buffer is in the range of about 1 mM to about 50 mM, including each value in the specified range. In certain embodiments, the concentration of the histidine buffer is about 10 mM. Histidine can be present in the composition in the form of dissolved hydrochloride or acetate. In certain embodiments, the liposome composition further comprises a trace amount of inorganic acid, such as hydrochloric acid.

[0073] In other embodiments, the liposome composition includes a tonicity agent. In some embodiments, the term "tonicity agent" as used herein refers to an agent used to reduce local irritation by preventing osmotic shock at the application site. As shown in WO 2019 / 038763, the contents of which are incorporated herein by reference in their entirety, a polyol nonionic tonicity agent is added to a pharmaceutical composition comprising glycerophospholipid-based liposomes having a phase transition temperature below joint temperature, resulting in a reduction in the coefficient of friction of cartilage compared to a liposome composition without a polyol.

[0074] According to the principles of the present invention, the polyol can be selected from low molecular weight polyols and sugar alcohols. Each possibility represents an independent embodiment. In some embodiments, the polyol is a linear polyol. In other embodiments, the polyol is a cyclic polyol. The non-limiting examples of the polyol suitable for the liposome composition of the present invention include mannitol, sorbitol, glycerol, dextrose, lactose, trehalose, lactitol and maltitol. Each possibility represents an independent embodiment. In some currently preferred embodiments, the polyol is mannitol.

[0075] In some embodiments, the liposome composition comprises a combination of polyols, such as a combination of mannitol and glycerol. The liposome composition may further comprise a combination of a polyol and an additional tonicity agent. In some embodiments, the polyol does not include xylitol.

[0076] It should be emphasized that, according to some currently preferred embodiments, the tonicity agent is not encapsulated in the liposome. In some embodiments, the term "encapsulated" as used herein refers to a tonicity agent concentration inside the liposome that is significantly higher than the tonicity agent concentration in the medium outside the liposome. The term "inside the liposome" should be understood to encompass at least one internal aqueous phase of the liposome. The term "concentration" may include osmotic concentration. In some embodiments, the term "significantly higher" as used herein refers to a concentration difference of at least about 90%. In some embodiments, a polyol is not encapsulated in the liposome. In other embodiments, mannitol is not encapsulated in the liposome.

[0077] According to other embodiments, the concentration of polyols within the liposomes is substantially the same as the concentration of polyols in the medium outside the liposomes. According to other embodiments, the concentration of mannitol within the liposomes is substantially the same as the concentration of mannitol in the medium outside the liposomes. In some embodiments, the term "substantially the same" as used herein refers to a concentration difference of less than about 15%. In other embodiments, the term "substantially the same" refers to a concentration difference of less than about 10%, less than about 5%, less than about 2.5%, or less than about 1%. Each possibility represents an independent embodiment.

[0078] In some embodiments, the liposomes are not freeze-dried. In other embodiments, the liposomes are not freeze-dried and / or thawed prior to administration to the joint.

[0079] In some embodiments, the concentration of the polyol in the liposome composition is in the range of about 0.5 to about 100 mg / ml, including each value in the specified range. In other embodiments, the concentration of the polyol is in the range of about 1 to about 70 mg / ml, including each value in the specified range. In other embodiments, the concentration of the polyol is in the range of about 2.5 to about 60 mg / ml, including each value in the specified range. In other embodiments, the concentration of the polyol is in the range of about 5 to about 50 mg / ml, including each value in the specified range. In other embodiments, the concentration of the polyol is in the range of about 30 to about 50 mg / ml, including each value in the specified range. In certain embodiments, the concentration of the polyol is in the range of about 5 to about 30 mg / ml, including each value in the specified range.

[0080] In some embodiments, the concentration of mannitol in the liposome composition is in the range of about 1mg / ml to about 70mg / ml, including each value in the specified range. In other embodiments, the concentration of mannitol is in the range of about 10mg / ml to about 70mg / ml, including each value in the specified range. In other embodiments, the concentration of mannitol is in the range of about 10mg / ml to about 50mg / ml, including each value in the specified range. In certain embodiments, the concentration of mannitol is about 40mg / ml. In other embodiments, the concentration of mannitol is about 20mg / ml.

[0081] In some embodiments, the concentration of glycerol in the liposome composition is in the range of about 0.5 mg / ml to about 50 mg / ml, including each value in the specified range. In other embodiments, the concentration of glycerol is in the range of about 1 mg / ml to about 40 mg / ml, including each value in the specified range. In other embodiments, the concentration of glycerol is in the range of about 5 mg / ml to about 30 mg / ml, including each value in the specified range. In certain embodiments, the concentration of glycerol is about 20 mg / ml. In other embodiments, the concentration of glycerol is about 10 mg / ml.

[0082] In some embodiments, the concentration of the polyol in the liposome composition is in the range of about 50mM to about 500mM, including each value in the specified range. In other embodiments, the concentration of the polyol is in the range of about 100mM to about 400mM, including each value in the specified range. In other embodiments, the concentration of the polyol is in the range of about 200mM to about 300mM, including each value in the specified range. The polyol can be selected from mannitol and glycerol.

[0083] In some embodiments, the polyol is present in the liposome composition in an amount of about 0.05% (w / w) to about 10% (w / w), about 0.1% (w / w) to about 7% (w / w), about 0.5% (w / w) to about 10% (w / w), or about 1% (w / w) to about 5% (w / w), of the total weight of the liposome composition, including each value within the specified range. In certain embodiments, the weight percentage of the polyol is about 4% (w / w). In other embodiments, the weight percentage of the polyol is about 2% (w / w).

[0084] In some embodiments, mannitol is present in the liposome composition in a weight percentage ranging from about 0.1% (w / w) to about 7% (w / w), about 0.5% (w / w) to about 10% (w / w), or about 1% (w / w) to about 7% (w / w), of the total weight of the liposome composition, including each value within the specified range. In certain embodiments, the weight percentage of mannitol is about 4% (w / w).

[0085] In some embodiments, glycerol is present in the liposome composition in a weight percentage ranging from about 0.05% (w / w) to about 5% (w / w) or about 0.5% (w / w) to about 5% (w / w), based on the total weight of the liposome composition, including each value within the specified range. In certain embodiments, the weight percentage of glycerol is about 2% (w / w).

[0086] In some embodiments, the liposome composition administered to the subject comprises about 10 mg to about 700 mg of polyol, including each value within the specified range. In some embodiments, the liposome composition comprises about 20 mg to about 500 mg of polyol, including each value within the specified range. In other embodiments, the liposome composition comprises about 20 mg to about 350 mg of polyol, including each value within the specified range. In other embodiments, the liposome composition comprises about 40 mg to about 250 mg of polyol, including each value within the specified range. In some embodiments, the liposome composition comprises about 10 mg to about 175 mg of polyol, including each value within the specified range. In other embodiments, the liposome composition comprises about 20 mg to about 125 mg of polyol, including each value within the specified range. In some embodiments, the liposome composition comprises about 40 mg to about 700 mg of polyol, including each value within the specified range. In other embodiments, the liposome composition comprises about 100 mg to about 500 mg of polyol, including each value within the specified range.

[0087] In some embodiments, the liposome composition comprises about 20 mg to about 350 mg mannitol, including each value within the specified range. In some embodiments, the liposome composition comprises about 40 mg to about 250 mg mannitol, including each value within the specified range. In a certain embodiment, the liposome composition comprises about 120 mg mannitol. In another embodiment, the liposome composition comprises about 40 mg mannitol. In other embodiments, the liposome composition comprises about 250 mg mannitol.

[0088] In some embodiments, the liposome composition has an osmotic pressure weight molar concentration in the range of about 200mOsm to about 600mOsm, including each value in the specified range. In other embodiments, the liposome composition has an osmotic pressure weight molar concentration in the range of about 250mOsm to about 500mOsm, including each value in the specified range. In other embodiments, the liposome composition has an osmotic pressure weight molar concentration in the range of about 250mOsm to about 400mOsm, including each value in the specified range. In certain embodiments, the liposome composition has an osmotic pressure weight molar concentration of about 300mOsm. In certain such embodiments, the liposome composition is isotonic.

[0089] In some embodiments, the weight ratio between the liposomes and the polyol is in the range of about 30: 1 to about 1: 2, including iterations of all ratios within the specified range. In other embodiments, the weight ratio between the liposomes and the polyol is in the range of about 15: 1 to about 2: 1, including iterations of all ratios within the specified range. In other embodiments, the weight ratio between the liposomes and the polyol is in the range of about 10: 1 to about 2: 1, including iterations of all ratios within the specified range. In other embodiments, the weight ratio between the liposomes and the polyol is in the range of about 6: 1 to about 2: 1, including iterations of all ratios within the specified range. In other embodiments, the weight ratio between the liposomes and the polyol is in the range of about 10: 1 to about 6: 1, including iterations of all ratios within the specified range.

[0090] In some embodiments, the weight ratio between the liposomes and mannitol is in the range of about 10: 1 to about 1: 1, including all iterations of ratios within the specified range. In other embodiments, the weight ratio between the liposomes and mannitol is in the range of about 6: 1 to about 2: 1, including all iterations of ratios within the specified range. In certain embodiments, the weight ratio between the liposomes and mannitol is about 4: 1.

[0091] In some embodiments, the weight ratio between the liposomes and glycerol is in the range of about 15: 1 to about 2: 1, including iterations of all ratios within the specified range. In other embodiments, the weight ratio between the liposomes and glycerol is in the range of about 12: 1 to about 2: 1, including iterations of all ratios within the specified range. In other embodiments, the weight ratio between the liposomes and glycerol is in the range of about 10: 1 to about 6: 1, including iterations of all ratios within the specified range.

[0092] The pH of the liposome composition can be in the range of about 5 to about 8, including each value in the specified range. In some embodiments, the pH is in the range of about 6 to about 7, including each value in the specified range. In certain embodiments, the pH of the liposome composition is about 6.5.

[0093] In some embodiments, the pH of the liposome composition can be adjusted by using an inorganic acid or base. Non-limiting examples of suitable inorganic acids include hydrochloric acid and sulfuric acid. Each possibility represents an independent embodiment. Non-limiting examples of suitable inorganic bases include sodium hydroxide and potassium hydroxide. Each possibility represents an independent embodiment.

[0094] According to some embodiments, the liposome composition consists essentially of the nonionic tonicity agent including a polyol, liposomes, and a fluid medium for suspending the liposomes, as described herein. In some embodiments, the term "consisting essentially of" means that the only active ingredient of the composition is the indicated active ingredient (i.e., the liposome), however, other substances that are used to stabilize, preserve, or control the molar osmotic pressure concentration, viscosity, and / or pH of the formulation but are not directly involved in the therapeutic effect of the liposomes and / or phospholipids may also be included. In some embodiments, the term "consisting of" refers to a composition containing the liposomes, tonicity agents, fluid medium, and pharmaceutically acceptable excipients.

[0095] According to various embodiments of the present invention, the liposome composition can be sterilized and, if necessary, can be mixed with auxiliary agents such as preservatives, stabilizers, wetting agents, synthetic emulsifiers, other salts for affecting osmotic pressure, colorants and / or aromatic substances, etc., which do not deleteriously react with the liposomes.

[0096] According to the principles of the present invention, the liposome composition disclosed herein can be used for treating pain or irritation in the joints of subjects with joint disorders, the method comprising applying the liposome composition to the joint cavity once or once every 4 to 12 months. In one embodiment, a single administration (i.e., a single dose) is sufficient to exert its therapeutic effect, thereby eliminating the need for additional injections. The term "single dose" used herein means that a dose of the liposome composition effectively relieves pain or irritation in the subject's joints for a long time. In some embodiments, the term "long time" used herein refers to a time period of more than three months. In other embodiments, the term "long time" refers to a time period of at least four months. In other embodiments, the term "long time" refers to a time period of at least five months. In other embodiments, the term "long time" refers to a time period of at least six months. In other embodiments, the term "long time" refers to a time period of at least 26 weeks. In other embodiments, the term "long time" refers to a time period of at least seven months. In other embodiments, the term "long time" refers to a time period of at least eight months. In other embodiments, the term "long time" refers to a time period of at least nine months. In other embodiments, the term "long time" refers to a time period of at least ten months. In other embodiments, the term "long term" refers to a period of at least eleven months. In other embodiments, the term "long term" refers to a period of at least twelve months. According to some embodiments, the single dose provides pain relief for the subject for at least four months after administration. According to other embodiments, the single dose provides pain relief for the subject for at least five months after administration. According to other embodiments, the single dose provides pain relief for the subject for at least six months after administration. According to other embodiments, the single dose provides pain relief for the subject for at least seven months after administration. According to other embodiments, the single dose provides pain relief for the subject for at least eight months after administration. According to other embodiments, the single dose provides pain relief for the subject for at least nine months after administration. According to some embodiments, the single dose provides pain relief for the subject for at least ten months after administration. According to other embodiments, the single dose provides pain relief for the subject for at least eleven months after administration. According to other embodiments, the single dose provides pain relief for the subject for at least twelve months after administration. According to some embodiments, the frequency of administration of the single dose of the liposome composition does not exceed once every six months. According to some embodiments, the frequency of administration of the single dose of the liposomal composition does not exceed once every eight months. According to certain embodiments, the method does not include administering an additional dose of the liposomal composition into the joint cavity. In some embodiments, the single dose of the liposomal composition provides perceptible pain relief to the subject.

[0097] In other embodiments, the composition is administered once every four, five, six, seven, eight, nine, ten, eleven, twelve months or longer. Each possibility represents an independent embodiment. According to the principles of the present invention, the effect (i.e., pain relief) exerted by the composition lasts for at least four, five, six, seven, eight, nine, ten, eleven, twelve months or longer time period. Each possibility represents an independent embodiment.

[0098] According to the principles of the present invention, the liposome composition provides treatment for a subject suffering from joint disorders. The term "joint disorder" as used herein should be deemed to mean any ailment (congenital, autoimmune or other), injury or disease of the joint region that causes joint degeneration, pain, reduced mobility, inflammation, irritation or physiological disturbance and dysfunction. The disorder may be associated with reduced joint secretion and lubrication, or may result from complications of knee or hip replacement. The term "treatment" as used herein means to cover the relief of pain.

[0099] Specific joint disorders within the scope of the present invention include, but are not limited to, insufficient joint secretion and / or lubrication caused by arthritis, conditions including joint erosion in rheumatoid arthritis, osteoarthritis, osteoarthritis in rheumatoid arthritis patients, traumatic joint injuries (including sports injuries), joint locking (e.g., in the temporomandibular joint (TMJ)), arthrocentesis post-state, arthroscopic surgery, open joint surgery, including knee or hip replacement in mammals, preferably humans. In certain embodiments, the joint disorder is osteoarthritis.

[0100] In some embodiments, the liposomal composition can be used to reduce knee pain in osteoarthritis patients.

[0101] According to the principles of the present invention, the treatment of pain or irritation in the joint includes reducing at least one of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) A pain score, the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) B stiffness score, the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) C disability score, the patient global assessment of disease activity (PtGA) by a visual analog scale (VAS), the weekly average of the daily overall pain score obtained by a visual analog scale (VAS), the weekly average of the daily joint pain score obtained by a visual analog scale (VAS), the cumulative amount of rescue medication used to relieve pain, and the urinary collagen C-terminal cross-linked telopeptide (CTX) type II level. Each possibility represents an independent embodiment. The pain relief can be further determined by various pain assessment methods known in the art, such as, but not limited to, the OMERACT OARSI responder criteria and the patient acceptable symptom state (PASS). Each possibility represents an independent embodiment.

[0102] The term "baseline" as used herein refers to a period of time before starting the liposome composition treatment of the present invention. In certain embodiments, the term "baseline" as used herein refers to a period of time before starting the liposome composition treatment of the present invention, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 1 year. Each possibility represents an independent embodiment.

[0103] According to some aspects and embodiments, the subject has a baseline WOMAC A pain score of ≥ 2. For example, the baseline WOMAC A pain score can be about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0. Each possibility represents an independent embodiment.

[0104] According to other aspects and embodiments, the baseline of the experimenter is obtained by VAS daily joint pain score weekly average ≥ 50mm. According to other aspects and embodiments, the baseline of the experimenter is obtained by VAS daily joint pain score weekly average ≥ 50mm to ≤ 90mm, including each value in the specified range. For example, the baseline is obtained by VAS daily joint pain score weekly average can be about 55mm, about 60mm, about 65mm, about 70mm, about 75mm, about 80mm, about 85mm or about 90mm. Each possibility represents an independent embodiment.

[0105] In certain embodiments, the therapeutic effect is compared to an untreated control. The term "control" as used herein refers to an untreated subject with a joint disorder. In one embodiment, the subject with the joint disorder is not treated with a composition of the invention. In another embodiment, the subject with the joint disorder is not treated with a known treatment method for the joint disorder.

[0106] According to some embodiments, the subject has a blood pressure greater than or equal to about 40 kg / m 2 In other embodiments, the subject has a BMI of greater than or equal to about 35 kg / m 2 In other embodiments, the subject has a BMI of less than about 35 kg / m 2 In other embodiments, the subject has a BMI greater than or equal to about 30 kg / m 2 According to other embodiments, the subject has a BMI of less than about 30 kg / m 2 In other embodiments, the subject has a BMI of less than about 29 kg / m 2 In other embodiments, the subject has a BMI of less than about 28 kg / m 2 In other embodiments, the subject has a BMI of less than about 27 kg / m 2 In other embodiments, the subject has a BMI of less than about 26 kg / m 2 In certain embodiments, the subject has a BMI of less than about 25 kg / m 2 In various embodiments, the subject has a BMI of about 18.5 to about 30 kg / m 2 In other embodiments, the subject has a BMI of about 18.5 to about 25 kg / m 2 In other embodiments, the subject has a BMI of about 30 to about 35 kg / m 2 A BMI within a range that includes every value within the specified range.

[0107] According to some embodiments, the pain relief is manifested as a relative change from baseline, i.e., at least one of the scores detailed above is lower. In some embodiments, the pain relief is manifested as a reduction in all of the above scores. For example, at least one of joint pain VAS, overall pain VAS, WOMAC pain score, WOMAC stiffness score, WOMAC disability score, WOMAC comprehensive score, PGA, rescue drug consumption, and urine CTX II level is reduced by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least at least 35%, at least 40%, at least 45%, at least 50% or more, and is considered to provide the treatment of the joint disorder. Each possibility represents an independent embodiment.

[0108] According to certain embodiments, the pain relief is manifested as a decrease of at least 0.5 points in the WOMAC pain score compared to a baseline or untreated control. According to other embodiments, the pain relief is manifested as a decrease of at least 0.75 points in the WOMAC pain score compared to a baseline or untreated control. According to other embodiments, the pain relief is manifested as a decrease of at least 1 point in the WOMAC pain score compared to a baseline or untreated control. According to various embodiments, the pain relief is manifested as a decrease of at least 1 point in the WOMAC pain score compared to a baseline or untreated control between about 10 weeks to about 26 weeks after administration, including each value within the specified range. According to other embodiments, the pain relief is manifested as a decrease of at least 1 point in the WOMAC pain score compared to a baseline or untreated control at about 12 weeks after administration. According to other embodiments, the pain relief is manifested as a decrease of at least 1 point in the WOMAC pain score compared to a baseline or untreated control at about 26 weeks after administration.

[0109] According to some embodiments, the pain relief is manifested as a decrease of at least 1 point in the WOMAC disability score compared to baseline or untreated control between about 10 weeks to about 26 weeks after administration, including each value in the specified range. According to certain embodiments, the pain relief is manifested as a decrease of at least 1 point in the WOMAC disability score compared to baseline or untreated control at about 12 weeks after administration. According to other embodiments, the pain relief is manifested as a decrease of at least 1 point in the WOMAC disability score compared to baseline or untreated control at about 26 weeks after administration.

[0110] According to various embodiments, the pain relief is manifested as a decrease of at least 5 mm in the weekly average of the daily joint pain score obtained by VAS compared to the baseline or untreated control. According to certain embodiments, the pain relief is manifested as a decrease of at least 10 mm in the weekly average of the daily joint pain score obtained by VAS compared to the baseline or untreated control. According to other embodiments, the pain relief is manifested as a decrease of at least 15 mm in the weekly average of the daily joint pain score obtained by VAS compared to the baseline or untreated control. According to other embodiments, the pain relief is manifested as a decrease of at least 20 mm in the weekly average of the daily joint pain score obtained by VAS compared to the baseline or untreated control. According to specific embodiments, the pain relief is manifested as a decrease of at least 30 mm in the weekly average of the daily joint pain score obtained by VAS compared to the baseline or untreated control between about 10 weeks to about 26 weeks after administration, including each value in the specified range. According to other embodiments, the pain relief is manifested as a decrease of at least 30 mm in the weekly average of the daily joint pain score obtained by VAS compared to the baseline or untreated control at about 12 weeks after administration. According to other embodiments, the pain relief is demonstrated by achieving a decrease of at least 30 mm in the weekly mean of daily joint pain scores obtained by VAS at about 26 weeks after administration compared to baseline or untreated control.

[0111] According to certain embodiments, the pain relief is achieved between about 10 weeks to about 26 weeks after administration, with a decrease of at least 30 in the patient's global assessment compared to baseline or untreated control, including each value in the specified range. According to some embodiments, the pain relief is achieved at about 12 weeks after administration, with a decrease of at least 30 in the patient's global assessment compared to baseline or untreated control. According to other embodiments, the pain relief is achieved at about 26 weeks after administration, with a decrease of at least 30 in the patient's global assessment compared to baseline or untreated control.

[0112] According to various embodiments, the pain relief is manifested as a decrease of at least 15% in the average weekly value of overall pain compared to baseline or untreated control between about 10 weeks to about 26 weeks after administration, including each value in the specified range. According to other embodiments, the pain relief is manifested as a decrease of at least 15% in the average weekly value of overall pain compared to baseline or untreated control at about 12 weeks after administration. According to other embodiments, the pain relief is manifested as a decrease of at least 15% in the average weekly value of overall pain compared to baseline or untreated control at about 26 weeks after administration.

[0113] According to other embodiments, the pain relief is manifested as a reduction in rescue medication consumption, including a reduction in oral administration of systemic pain relief medications such as, but not limited to, acetaminophen / paracetamol, NSAIDs, opioids, and the like.

[0114] According to some embodiments, the onset of pain relief is achieved between about 1 day to about 2 weeks after administration, including each value within the specified range. According to other embodiments, the onset of pain relief is achieved between about 3 days to about 2 weeks after administration, including each value within the specified range. According to other embodiments, the onset of pain relief is achieved between about 4 days to about 1.5 weeks after administration, including each value within the specified range. According to specific embodiments, the onset of pain relief is achieved about 1 week after administration.

[0115] According to various embodiments, maximum pain relief is achieved between about 3 weeks to about 26 weeks after administration, including each value within the specified range. According to other embodiments, maximum pain relief is achieved between about 4 weeks to about 26 weeks after administration, including each value within the specified range. According to other embodiments, maximum pain relief is achieved between about 5 weeks to about 26 weeks after administration, including each value within the specified range. According to other embodiments, maximum pain relief is achieved between about 6 weeks to about 26 weeks after administration, including each value within the specified range. According to other embodiments, maximum pain relief is achieved between about 7 weeks to about 26 weeks after administration, including each value within the specified range. According to specific embodiments, maximum pain relief is achieved at about 6 to 7 weeks after administration, and the pain relief lasts for at least 26 weeks.

[0116] In some embodiments, the liposome compositions disclosed herein provide a response rate of at least 30%, 40% or 50% in subjects to which the liposome compositions are administered. Each possibility represents an independent embodiment. In some specific embodiments, the liposome compositions disclosed herein provide a response rate of about 30% to about 50% in subjects to which the liposome compositions are administered, including each value within the specified range.

[0117] According to the principles of the present invention, the joint can be any one of a knee joint, a hip joint, an ankle joint, a shoulder joint, an elbow joint, a tarsal joint, a wrist joint, an interphalangeal joint, and an intervertebral joint. Each possibility represents an independent embodiment. In certain embodiments, the joint is a knee joint.

[0118] In some embodiments, the liposome composition is in a form suitable for parenteral administration. Parenteral administration of the liposome composition of the present invention to the patient's joint cavity can be carried out by a method selected from intra-articular injection, arthroscopic administration and surgical administration. Each possibility represents an independent embodiment. Therefore, in some embodiments, the liposome composition is prepared in a form suitable for administration by a route selected from intra-articular injection, arthroscopic administration and surgical administration. Each possibility represents an independent embodiment. In some currently preferred embodiments, the liposome composition is administered by intra-articular injection.

[0119] According to various embodiments of the present invention, the liposome composition can be applied with a volume of about 0.5ml to about 10ml, including each value within the specified range. In other embodiments, the liposome composition is applied with a volume of about 1ml to about 6ml, including each value within the specified range. In certain embodiments, the liposome composition is applied with a volume of about 3ml. In other embodiments, the liposome composition is applied with a volume of about 1ml. In other embodiments, the liposome composition is applied with a volume of about 6ml. The composition can be dispensed in a vial or in a single injection, or is actually used in any other convenient manner. The composition can also be provided in a pre-filled syringe.

[0120] Subjects contemplated for administration of the liposome compositions of the present invention include mammals, such as, but not limited to, humans and other primates.

[0121] According to some embodiments, the treatment regimen of the present invention provides the same or better therapeutic efficacy as commercially available compositions, reducing the incidence of side effects and / or reducing the severity of side effects at the local and / or systemic level. Side effects known to be associated with commercially available compositions include, but are not limited to, difficulty in movement, muscle pain or stiffness, joint pain, and joint swelling or redness. Administration of the liposome composition of the present invention once or once every 4 to 12 months can reduce the incidence or severity of these side effects. In some embodiments, these side effects are completely avoided.

[0122] Thus, the present invention provides a method of improving tolerance to treatment in a subject with a joint disorder, the method comprising reducing the frequency of administration to a therapeutically effective regimen of once or once every 4 to 12 months by administering a liposome composition of the present invention. In certain embodiments, improving tolerance comprises reducing the frequency of injections. In other embodiments, improving tolerance comprises reducing the frequency of injection site reactions. In other embodiments, improving tolerance comprises improving patient compliance.

[0123] Throughout the description and claims of this specification, references without a specific number include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "liposomes" is a reference to one or more liposomes. Throughout the description and claims of this specification, plural forms of words also include singular referents unless the context clearly dictates otherwise. It should be noted that the term "and" or the term "or" is generally used in its sense including "and / or" unless the context clearly dictates otherwise.

[0124] Throughout the description and claims of this specification, the words “comprise” and “comprising” and variations thereof mean “including but not limited to”, and are not intended to (and do not) exclude other parts, additives, components, integers or steps.

[0125] As used herein, the term "about" when referring to a measurable value such as an amount, duration, etc., is meant to encompass variations of ±10%, more preferably ±5%, even more preferably ±1% from the stated value, as such variations are suitable for performing the disclosed methods.

[0126] The following examples are presented to more fully illustrate some embodiments of the present invention. However, they should never be interpreted as limiting the broad scope of the present invention. Those skilled in the art can easily design many variations and modifications of the principles disclosed herein without departing from the scope of the present invention.

[0127] Example

[0128] Example 1 - Phase IIb Randomized, Double-Blind, Placebo-Controlled, Single-Administration, Multiple-Dose Study

[0129] A Phase IIb clinical trial was conducted to evaluate the safety and efficacy of a single intra-articular (IA) injection of a liposome suspension containing 46.1 mg / ml DMPC and 60.2 mg / ml DPPC at a concentration of 150 mM in patients with symptomatic knee OA. The fluid medium of the suspension contained histidine buffer and mannitol tonicity agent. As a control, a placebo sample containing the fluid medium but without liposomes was used.

[0130] Subject inclusion criteria:

[0131] 1. Male or female aged ≥40 years at the time of screening.

[0132] 2. Radiographic evidence of knee OA on a standing AP view in conjunction with a fixed flexion frame (Synaflexor) to determine Kellgren Lawrence KL grade 2 or 3 in the index knee on an X-ray performed within the past 12 months.

[0133] 3. Chronic OA of the index knee confirmed by the American College of Rheumatology (ACR) criteria (clinical and radiographic) at screening.

[0134] 4. The index knee pain existed for at least 6 months before screening.

[0135] 5. Pain severity (index knee) during screening and last 24 hours before baseline, WOMAC (0-4 range; mean of 5 questions) pain score ≥2.

[0136] 6. Pain severity (index knee), VAS pain score ≥50 mm and ≤90 mm on ≥5 days in the 7 days prior to baseline.

[0137] 7. Index knee pain >15 days in the month prior to screening.

[0138] 8. Inadequate response or intolerance to previous acetaminophen / paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs).

[0139] 9. Able and willing to use only acetaminophen / paracetamol (not more than 4 grams per day) as rescue analgesia for knee pain.

[0140] 10. The frequency of non-pharmacological treatment (if applicable) was stable during the 4 weeks prior to the start of IP until the end of the study.

[0141] 11. Stable dose and regimen of topical analgesics (except the index knee) and nasal or inhaled corticosteroid use (if applicable) for at least 2 months prior to enrollment and throughout the study.

[0142] Primary endpoint:

[0143] The change in WOMAC A pain score at week 12 compared with baseline was used to determine the dosage of the liposomal composition.

[0144] Secondary endpoints:

[0145] Secondary efficacy endpoints were changes from baseline in:

[0146] - WOMAC A pain scores at week 26 and over time;

[0147] - WOMAC stiffness and disability subscores at week 12, week 26, and over time;

[0148] - Weekly means of daily knee pain scores by VAS at Week 12, Week 26 and over time;

[0149] - Weekly means of daily overall pain scores by VAS at Week 12, Week 26 and over time;

[0150] - PtGA of disease activity at week 12, week 26 and over time;

[0151] - Cumulative weekly use of rescue medication (acetaminophen / paracetamol) at Week 12, Week 26, and over time.

[0152] Exploratory endpoints:

[0153] - WOMAC A pain score improvement of 30% and 50% compared with baseline;

[0154] -Pharmacokinetic endpoints.

[0155] Study design and statistics:

[0156] The subjects were randomly divided into AF group according to the following factors: 1) BMI < 30 kg / m 2 , 30kg / m 2 ≤BMI<35 kg / m 2 and BMI ≥ 35 kg / m 2 ; BMI ≥ 40 kg / m 2 The upper limit of the number of subjects is 10% of the total number of subjects; 2) Index knee pain VAS ≤ 74, VAS ≥ 75 at baseline. BL WOMAC A pain score > 2.0; SD = 0.59. WOMAC A pain score compared with baseline was 0.80 for liposomal suspension and 0.52 for placebo, with a difference of 0.28 between the two groups. Power = 80%; α = 0.05. Approximately 72 subjects were assigned to each group (A, B, C and E groups).

[0157] Subjects received a single IA joint injection of either the liposomal suspension or placebo in the volumes outlined below.

[0158] □ Group A: single IA joint injection of liposome suspension (1 mL);

[0159] □ Group B: single IA joint injection of liposome suspension (3 mL);

[0160] □ Group C: single IA joint injection of liposome suspension (6 mL);

[0161] □ Group D: single IA joint injection of placebo (1 mL);

[0162] □ Group E: single IA joint injection of placebo (3 mL); and

[0163] □ Group F: single IA joint injection of placebo (6 mL).

[0164] For the primary efficacy endpoint, a mixed effects model (MMRM) was used for analysis with fixed effects for treatment group, study visit, treatment visit interaction, location, and baseline covariates. Treatment differences for all active substance groups (A, B, C) compared with 3 mL placebo (Group E) were estimated by least square means from the analysis model with 95% confidence intervals and associated two-sided p values. The study design is schematically shown in Figure 1 middle.

[0165] Efficacy evaluation:

[0166] Knee examination

[0167] Knee assessments were performed on both knees by blinded investigators at screening, baseline, and follow-up. At screening and baseline, the index knee was examined for any deformity, bruises, open wounds (i.e., abrasions), or surgical scars indicating a history of knee surgery (e.g., reconstructive surgery or total knee replacement, etc.). The index knee was palpated to determine the size of the erythema or knee effusion. Erythema or moderate (or large) knee effusions indicated conditions such as inflammatory arthritis, and therefore the subject was excluded from the study.

[0168] Patients receive X-ray and WOMAC pain scores at screening. According to screening and baseline pain reports (WOMAC and daily pain during the past seven days) and KL grade, the selection of index knee is carried out. If according to X-ray, daily pain scores in the past seven days and other knee-specific standards meet the conditions, the knee with the highest WOMAC pain score during baseline is selected as the index knee. If the knee with the highest pain score during baseline does not meet KL standards or daily pain standards, exclusion criteria 1 (non-target knee has moderate / severe pain) is applied, and no matter whether the other knee meets the qualifications, the subject is not screened.

[0169] WOMAC Assessment of Knee Osteoarthritis

[0170] The WOMAC survey includes 24 items divided into three subscales: pain (5 items), stiffness (2 items), and physical function (17 items). Subjects were asked a series of questions about their knee pain, knee stiffness, ability to perform daily activities such as using stairs, sitting up, lying in bed, and light or heavy housework. All items are scored on a scale of 0-4 (lower scores indicate lower symptoms or physical disability). The values ​​are summed to obtain a combined WOMAC score (WOMAC total score) or subscore (WOMAC A pain score, etc.), and the average of the total score and subscore is calculated on a 0-4 scale. The higher the score, the greater the degree of pain, stiffness, and high-level functional limitations.

[0171] Weekly average of daily knee pain obtained by VAS

[0172] The subjects were asked a question: “By clicking on the line, please indicate how much you have <l r>Average pain level in the knee." Subjects responded to the questions on a VAS scale (0-100), with lower numbers on the scale indicating less knee pain experienced.

[0173] Weekly average of daily overall pain scores obtained by VAS

[0174] The subjects were asked one question: "By clicking on the line, please indicate how much overall pain you experienced on average over the past 24 hours." The subjects responded to the question on a VAS scale (0-100), with lower numbers on the scale indicating lower levels of overall pain experienced.

[0175] Patient Global Assessment of Disease Activity

[0176] Participants rated their current overall condition of symptomatic knee OA using a VAS ("Taking into account all the ways in which knee OA has affected you, please indicate by clicking on the line how well you have been doing on average over the past 24 hours?").

[0177] Exploratory biomarkers

[0178] To assess biomarkers of osteoarthritis, blood samples were collected and analyzed to determine serum levels of MMPs, ADAMTS-4, ADAMTS-5, and huARGS. Urine samples were also collected to determine fasting urine levels of CTX I and CTX II.

[0179] Pharmacokinetic evaluation

[0180] Pharmacokinetic sampling (DMPC and DPPC) was performed at selected locations. Subjects received additional blood draws for pharmacokinetic measurements at the following time points: before IP (baseline) and 4 hours, 2 days, and 7 days after IP administration. DPPC and DMPC concentrations in human plasma were quantified using a validated LC-MS / MS method.

[0181] Safety Assessment:

[0182] Adverse events (AEs) are determined by the following assessments: laboratory assessments, including laboratory measurements of blood chemistry, hematology, and urinalysis; electrocardiogram assessments, including computerized 12-lead ECG recordings; physical examinations; and vital signs. Any relevant observations made at screening and baseline visits (including screening laboratory test results, and until a single dose of IP) are recorded on the AE eCRF, but are not considered AEs (TEAEs) that emerge during treatment and are reported separately from TEAEs. Any relevant observations after a single dose of IP are recorded as AEs in the subject's AE eCRF. AEs related to pre-existing conditions are recorded only if there is a deterioration in the nature, severity, or frequency of the pre-existing conditions during the study. The severity of the AE is characterized as: mild-if the AE is easily tolerated; moderate-if the AE is uncomfortable enough to interfere with daily activities; severe-if the AE interferes with normal daily activities; life-threatening-if the subject is at risk of death when the AE occurs; death-death associated with the AE.

[0183] result:

[0184] Similarities were observed among the 6 study groups. Discontinuation rates were low and similar across groups. The 6 mL liposomal suspension group (Group C) and the 3 mL placebo group (Group E) showed relatively high discontinuation rates. However, discontinuation was not due to AEs. Figure 2 The distribution of subjects is shown, where the treated subjects are presented according to their randomized treatment and N represents the number of subjects. Table 1 shows the baseline disease characteristics. The baseline disease parameters of the groups were comparable. For WOMAC A pain scores, most groups had more subjects in the ≤2.40 score group, but the distribution of WOMAC pain groups was almost equal for groups C and F.

[0185] Table 1.

[0186]

[0187]

[0188] Table 2 shows the analysis of the change in WOMAC A (pain) from baseline to Week 12. The unadjusted p value showed a statistically significant decrease in Group B (3 mL liposome suspension) compared to placebo ( Figure 3 ).

[0189] Table 2.

[0190]

[0191] Table 3 shows the analysis of the changes in WOMAC C (physical function) from baseline to Week 12 and Week 26. Although no statistically significant differences were found between any of the active substance groups and the placebo group, very slight numerical differences were observed between Group A and Group B (1 and 3 mL liposome suspension) ( Figure 4 ).

[0192] Table 3.

[0193]

[0194] Table 4 shows the analysis of the weekly mean daily knee pain scores over time from baseline. It was noted that there was a very slight numerical difference between Group A and Group B. However, both groups containing 1 mL and 3 mL of liposome suspension showed a statistically significant reduction early on (starting at Week 6) and this was maintained over time until Week 25. At Week 26, only Group B showed a statistically significant reduction ( Figure 5 ).

[0195] Table 4.

[0196]

[0197] Table 5 shows an analysis of the change in patient global assessment of disease activity from baseline to Week 12 and Week 26. Although no statistically significant decrease was observed in any of the active substance groups at Week 12, Group B containing 3 mL of liposome suspension showed a statistically significant decrease at Week 26 ( Figure 6 ).

[0198] Table 5.

[0199]

[0200]

[0201] The weekly average of overall pain showed significant benefit for both Groups A and B compared with placebo ( Figure 7 ).

[0202] Table 6 shows an analysis of the change in weekly cumulative amount (mg) of rescue medication use from baseline to Week 12 and Week 26. Both the 1 mL and 3 mL liposome groups showed an overall trend toward decreased rescue medication use. This decrease was greater in Group A (1 mL group), which met statistical significance at Week 12 and Week 26. In addition, this group showed an early statistically significant decrease, beginning at Week 8, which was maintained over time until Week 26 ( Figure 8 ).

[0203] Table 6.

[0204]

[0205] Table 7 shows the safety summary. The incidence of AEs and discontinuations due to AEs was similar between groups. The incidence of study drug-related AEs was higher in the 6 mL active and placebo groups (Groups C and F, respectively). The incidence of study procedure-related AEs was higher in Groups B and C. No treatment-emergent deaths or AESIs were reported. The incidence of SAEs was low and similar between groups - none was considered related to study drug. Most AEs were mild to moderate.

[0206] Table 7.

[0207]

[0208] Fig. 9 Changes in the urine biomarker CTX-II are shown. The reduction in CTX-II observed in Group B indicates a reduction in disease severity.

[0209] The liposome suspension of the present invention is Compared with the published efficacy data, is an extended-release corticosteroid composition approved for the treatment of osteoarthritis knee pain. Tables 8 and 9 show the changes from baseline to Week 12 in WOMAC A (pain) and WOMAC C (physical function), respectively. The decrease from baseline was greater when the liposomal suspension was used. In contrast, the score decreased more in the placebo group of the liposomal composition.

[0210] Table 8.

[0211]

[0212]

[0213] Table 9.

[0214]

[0215] There were no meaningful changes in any of the biomarkers evaluated, with the exception of the change from baseline in urinary CTX II levels, where a trend toward a decrease over time was observed in the 3 mL liposome group (Group C) compared with placebo, which reached statistical significance at Week 12 (P=0.041).

[0216] Table 10 shows the absolute number and percentage of subjects with a ≥30% and ≥50% reduction in WOMAC A pain score. It was observed that at weeks 12, 16, and 20, the responder rate of ≥30% was higher in Group A compared to Group E (P<0.05), and at weeks 8 and 20, the responder rate of ≥30% was higher in Group B compared to Group E (P<0.05). It was observed that at weeks 1, 8, 16, 20, and 26, the responder rate of ≥50% was higher in Group A compared to Group E (P<0.05), at weeks 8, 16, 20, and 26, the responder rate of ≥50% was higher in Group B compared to Group E (P<0.05), and at weeks 1, 2, and 4, the responder rate of ≥50% was higher in Group C compared to Group E (P<0.05). Thus, responder rates of ≥ 50% were observed for 1 mL and 3 mL of the liposomal suspension of the invention compared to treatment with 3 mL of placebo, beginning at Week 8 and continuing through Week 26. At most time points, these numbers were numerically higher for the 3 mL group compared to the 1 mL group of the liposomal suspension of the invention.

[0217] Table 10.

[0218]

[0219]

[0220] *Compared to 3 mL placebo.

[0221] Figures 10A-10B Shown is the plasma DMPC and DPPC concentration of average baseline adjustment until 168 hours after IP administration based on improved pharmacokinetic analysis.Quantifiable DMPC and DPPC levels were observed in the pre-administration samples, indicating that DMPC and DPPC are endogenous in the systemic circulation.From pre-administration to post-administration time point, plasma DMPC and DPPC concentrations did not change significantly.In addition, between liposome suspension of the present invention (AC group) and corresponding placebo group (DF group), the baseline-adjusted concentration and exposure of DMPC and DPPC seem to be suitable.

[0222] In summary, there was a trend toward a decrease in WOMAC A pain scores in groups A and B compared with group E, with a greater decrease in group B. At week 12, the unadjusted P values ​​for multiplicity compared with group E were: group B (P=0.047) and group A (P=0.152). Sensitivity analysis of the primary efficacy endpoint based on FAS and combined groups D, E, and F showed that group B had lower baseline-adjusted WOMAC A pain scores at week 12 compared with group E: -0.28 (-0.484, -0.068), P=0.018 (multiplicity adjusted), P=0.009 (unadjusted).

[0223] For the change in WOMAC A pain score over time, both Group A and Group B showed a trend toward decrease compared to Group E. The estimated treatment differences between Group B and Group E were -0.27 (-0.494, -0.039), P = 0.022 at Week 16, and -0.23 (-0.454, -0.009), P = 0.041 at Week 20 (P value not adjusted for multiplicity). In addition, numerical decreases were also observed in Group B compared to Group E at Week 8 and continued to Weeks 12, 16, and 20 (P = 0.055, P = 0.051, P = 0.022, and P = 0.041, respectively). The decreases in Group A and Group C were numerically lower than those in Group B, and no difference was observed between Group C and Group E.

[0224] There were no differences in the change from baseline in WOMAC B stiffness scores among groups A, B, C, and E at any time point, with the exception of a worsening (i.e., increase) in the score in group C compared with group E at week 26 [0.28 (0.028, 0.535), P = 0.030].

[0225] Regarding the change from baseline in WOMAC C disability score, a decreasing trend was observed in both Group A and Group B compared with Group E. At Week 20, a numerically greater improvement (i.e., decrease) in the score was observed in Group A compared with Group E [-0.22 (-0.437, -0.010), P = 0.040].

[0226] For the change from baseline in the weekly mean VAS score for daily knee pain, both Groups A and B showed an early and sustained trend toward decrease over time compared with Group E. Reductions were observed in Group A compared with Group E at Weeks 3 and 4 and from Weeks 6 to 25 [Week 25: -9.1 (-17.16, -1.02), P = 0.027]. Reductions were observed in Group B compared with Group E from Weeks 6 to 26 [Week 26: -11.8 (-20.35, -3.27), P = 0.007]. The magnitude of these decreases was numerically greater in Group B compared with Group A at most time points.

[0227] For the change from baseline in the weekly mean VAS score of daily total pain, there was a trend over time for both groups A and B compared with group E. Reductions were observed in group A compared with group E at week 4, week 6 to week 17, and week 20 to week 26 [week 26: -8.8 (-17.37, -0.30), P = 0.042]. Reductions were observed in group B compared with group E at weeks 7 to 9, weeks 11 to 14, week 16, and week 26 [week 26: -9.9 (-19.12, -0.62), P = 0.037]. Reductions were observed in group C compared with group E from week 4 to week 7 [week 7: -8.2 (-16.14, -0.16), P = 0.046].

[0228] For the change from baseline in PtGA, both groups A and B showed a trend toward decrease compared with group E. The estimated treatment differences between groups B and E were -9.4 (-17.72, -1.08), P = 0.027, at week 16 and -9.1 (-17.63, -0.57), P = 0.037, at week 26.

[0229] From week 8 onwards, a trend towards decreased WOMAC C disability scores was observed in groups A, B, and C compared with group E.

[0230] In terms of the weekly cumulative amount of rescue medication use, groups A, B, and C showed a trend toward lower values ​​compared with group E. From week 8, the greatest difference between group A and group E was observed [week 26: -1109.4 mg (-1855.37, -363.48), P = 0.004].

[0231] There were no differences in the changes from baseline in MMP-1, MMP-2, MMP-9, ADAMTS-4, ADAMTS-5, huARGS, and urinary CTX I concentrations between groups A, B, and C and group E at any time point (weeks 1, 2, and 4). The exceptions were: (1) a decrease in MMP-9 was observed in group A at week 2, which was different from the increase observed in group E [-41.90 μg / L (-79.065, -4.735), P = 0.027]; (2) an increase in ADAMTS-4 was observed in group B at week 1, which was different from the decrease observed in group E [895.4 pmol / mL (21.33, 1769.56), P = 0.045]; and (3) a decrease in CTX I was observed in group B at week 4, which was different from the increase observed in group E [-0.115 mg / mol (-0.2135, -0.0172), P = 0.021].

[0232] Regarding the change in urinary CTX II levels from baseline, a decreasing trend over time was observed in Group B compared with Group E, with a difference of -96.1 mg / mol (-188.40, -3.89) observed at Week 12, P = 0.041.

[0233] It was observed that the responder rates ≥30% were higher in Group A compared with Group E at Week 12 (75.8% vs. 59.7%, P=0.014), Week 16 (74.5% vs. 59.2%, P=0.034), and Week 20 (81.4% vs. 61.1%, P=0.002), and the responder rates ≥30% were higher in Group B compared with Group E at Week 8 (77.2% vs. 62.2%, P=0.048) and Week 20 (77.2% vs. 61.1%, P=0.036).

[0234] For responder rates of ≥50%, a trend was observed for Groups A and B to show higher responder rates compared to Group E starting at Week 8 and continuing through Week 26. These numbers were numerically higher in Group B compared to Group A at most time points. The rates were observed to be higher in Group A compared to Group E at Week 1 (35.0% vs. 23.1%, P=0.033), Week 8 (50.0% vs. 33.8%, P=0.023), Week 16 (53.1% vs. 32.4%, P=0.012), Week 20 (57.7% vs. 38.9%, P=0.017), and Week 26 (56.1% vs. 38.0%, P=0.020). The ratios were observed to be higher in Group B compared to Group E at Week 8 (54.4% vs. 33.8%, P=0.014), Week 16 (61.0% vs. 32.4%, P=0.002), Week 20 (58.2% vs. 38.9%, P=0.048), and Week 26 (55.7% vs. 38.0%, P=0.044). The ratios were observed to be higher in Group C compared to Group E at Week 1 (35.1% vs. 23.1%, P=0.023), Week 2 (37.0% vs. 24.0%, P=0.021), and Week 4 (46.4% vs. 30.7%, P=0.024).

[0235] Quantifiable levels of DMPC and DPPC were observed in pre-dose samples of all groups, indicating that DMPC and DPPC are endogenous compounds in the systemic circulation. Baseline-adjusted pharmacokinetic parameters of DMPC and DPPC in treatment groups A, B, and C (C max The AUC and AUC) were comparable or lower than those in the corresponding groups D, E, and F, indicating that systemic exposure to endogenous DMPC and DDPC levels was not increased after intra-articular administration of the liposomes.

[0236] The liposomes were safe and well tolerated, with no differences compared to placebo in safety assessments, as assessed by adverse events (AEs), clinical laboratory evaluations, vital signs, electrocardiograms, and physical examinations. During the study, a total of 526 treatment-emergent AEs were recorded in 253 subjects as follows: 73.5% in Group A, 57.0% in Group B, 66.2% in Group C, 53.6% in Group D, 59.0% in Group E, and 67.9% in Group F. Most AEs (>95%) were mild or moderate. During the study, a total of 15 treatment-emergent serious adverse events (SAEs) occurred in 11 subjects. All SAEs were single patients in each treatment group, except for 2 SAEs of osteoarthritis in 2 subjects in Group E. All SAEs were assessed as unrelated to this study.

[0237] There were no clinically significant overall changes in hematology, chemistry, lipids, urinalysis, vital signs, and electrocardiogram measurements. No differences in clinically significant abnormalities were observed between the liposome and control groups in the individual safety laboratory assessments post-dose. Few observations on physical examination were assessed as abnormal and clinically significant, and no differences in frequency were observed between the liposome and placebo groups.

[0238] Thus, in the WOMAC A pain score (primary endpoint), no statistically significant differences were measured in any of the active substance groups using the p-value adjusted for multiplicity. However, when using the unadjusted p-value, a statistically significant reduction was measured when subjects were treated with 3 mL of the liposomal suspension. In the WOMAC C disability score, no statistically significant differences were observed in any of the active substance groups.

[0239] In both active substance groups containing 1 mL and 3 mL of liposomal suspension, the weekly mean of daily knee pain scores showed a statistically significant decrease early (week 6). The decrease continued until week 25. A statistically significant decrease in patient global assessment was observed at week 26 when treated with 3 mL of liposomal suspension. All three dose levels of the liposomal composition showed a trend toward reduced rescue medication use, indicating that the subjects receiving treatment had reduced pain. From week 8 onwards, rescue medication use was observed to be lower with 1 mL of liposomal suspension than with 3 mL of placebo (P<0.05). For changes in urinary CTX II compared to baseline, a trend of decrease over time was observed in the 3 mL liposomal group, with a difference observed at week 12, compared to which an increase was observed with 3 mL of placebo (P=0.041). Pharmacokinetic results showed that there was no increase in systemic exposure to endogenous DMPC and DPPC after IA injection of the liposomal suspension. Finally, the liposomal suspension was shown to be well tolerated, with similar incidence of AEs across groups, no treatment-emergent deaths, and no AEs of special interest reported. The incidence of SAEs was low and similar across groups, and none was related to the study drug.

[0240] Example 2 - Phase III, randomized, double-blind, placebo-controlled, single-dose study

[0241] A Phase III clinical trial was conducted to evaluate the safety and efficacy of a single administration of liposomes containing 46.1 mg / ml DMPC and 60.2 mg / ml DPPC (at a concentration of 150 mM, suspended in a liquid medium containing mannitol and histidine buffer) in subjects with symptomatic knee osteoarthritis (OA). As a control, a placebo sample containing the liquid medium without liposomes was used.

[0242] Subject inclusion criteria:

[0243] 1. Male or female aged ≥40 years.

[0244] 2. OA of the index knee according to the American College of Rheumatology (ACR) criteria (clinical and radiological).

[0245] 3. Presence of Kellgren Lawrence (KL) grade 2 or 3 disease in the index knee.

[0246] 4. Index knee pain present for at least 6 months prior to screening and present for >15 days in the last month prior to screening.

[0247] 5. WOMAC A pain score of index knee ≥2 at screening and baseline.

[0248] 6. VAS pain score of the index knee ≥50 mm and ≤90 mm for at least 5 days in the 7 days before baseline.

[0249] 7. Able and willing to use only protocol-permitted rescue medications for OA knee pain, including acetaminophen / paracetamol, up to a maximum permitted dose of 4 g / day, throughout the study, except during the last 24 hours prior to the planned study efficacy assessment.

[0250] 8. Discontinue oral nonsteroidal anti-inflammatory drugs (NSAIDs) from the time of screening and during the study.

[0251] 9. Discontinue application of topical therapy (eg, NSAIDs, capsaicin, lidocaine patch, etc.) to the index knee from the time of screening and for the duration of the study.

[0252] 10. Any IA treatment / intervention on either knee was prohibited during the study period.

[0253] Primary endpoint:

[0254] - Change in weekly ADP scores from baseline to week 12.

[0255] Secondary endpoints:

[0256] - Change in WOMAC A pain score from baseline to week 12.

[0257] In addition, other secondary endpoints included:

[0258] - Change in weekly ADP score from baseline to Weeks 4, 8, 16, 20, 26, 30, 38, 46, and 52.

[0259] - Change in WOMAC A pain score from baseline to Weeks 4, 8, 16, 20, 26, 30, 38, 46, and 52.

[0260] - Percentage of patients demonstrating a 30% and 50% improvement in weekly ADP scores from baseline to Weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0261] - Percentage of patients demonstrating 30% and 50% improvement in WOMAC A pain score from baseline to Weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0262] - Change in WOMAC B stiffness score from baseline to Weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0263] - Change in WOMAC C physical function score from baseline to weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0264] - Change in PtGA of disease activity from baseline to Weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0265] - Change in weekly cumulative rescue medication use from baseline to Weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0266] Safety endpoints:

[0267] Safety and tolerability were assessed by medical history, physical examination (including vital signs), and clinical laboratory tests. The nature, frequency, and severity of adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) were evaluated.

[0268] Exploratory endpoints:

[0269] - Change in urinary CTX-II compared with baseline over time.

[0270] Study design and statistics:

[0271] After screening, eligible subjects were randomized (2:1) to receive 3 mL of the liposomal composition of the invention or placebo in their index knee on Day 1 (baseline). The primary efficacy assessment was conducted at Week 12. Efficacy and safety were assessed until Week 52, which represented the end of the study (EoS).

[0272] Efficacy evaluation:

[0273] The primary analysis population constituted the full analysis set (FAS), including all randomized subjects who received a dose of 3 mL of the liposome composition of the invention or placebo. According to the intention-to-treat principle, subjects were analyzed according to their randomly assigned treatment, regardless of the actual treatment received.

[0274] WOMAC A, B, and C scores were measured using a 5-point Likert scale, weekly ADP scores were measured using a 100-mm visual analog scale [VAS], and PtGA was measured using a 100-mm VAS scale.

[0275] Example 3 - Phase III, randomized, double-blind, placebo-controlled, repeated administration study

[0276] A Phase III clinical trial was conducted to evaluate the safety and efficacy of repeated administration of liposomes containing 46.1 mg / ml DMPC and 60.2 mg / ml DPPC (at a concentration of 150 mM, suspended in a liquid medium containing mannitol and histidine buffer) in subjects with symptomatic knee osteoarthritis (OA). As a control, a placebo sample containing the liquid medium without liposomes was used.

[0277] Subject inclusion criteria:

[0278] 1. Male or female aged ≥40 years.

[0279] 2. OA of the index knee according to the American College of Rheumatology (ACR) criteria (clinical and radiological).

[0280] 3. Presence of Kellgren Lawrence (KL) grade 2 or 3 disease in the index knee.

[0281] 4. Index knee pain present for at least 6 months prior to screening and present for >15 days in the last month prior to screening.

[0282] 5. WOMAC A pain score of index knee ≥2 at screening and baseline.

[0283] 6. VAS pain score of the index knee ≥50 mm and ≤90 mm for at least 5 days in the 7 days before baseline.

[0284] 7. Able and willing to use only protocol-permitted rescue medications for OA knee pain, including acetaminophen / paracetamol, up to a maximum permitted dose of 4 g / day, throughout the study, except during the last 24 hours prior to the planned study efficacy assessment.

[0285] 8. Discontinue oral nonsteroidal anti-inflammatory drugs (NSAIDs) from the time of screening and during the study.

[0286] 9. Discontinue application of topical therapy (eg, NSAIDs, capsaicin, lidocaine patch, etc.) to the index knee from the time of screening and for the duration of the study.

[0287] 10. Any IA treatment / intervention on either knee was prohibited during the study period.

[0288] 11. In the case of physical therapy for OA, it must be stable for at least 4 weeks before IP administration and throughout the study.

[0289] 12. In the case of oral glucosamine, chondroitin or other nutraceuticals used to treat OA, this must be stable for at least 4 weeks prior to IP administration and throughout the study.

[0290] Primary endpoint:

[0291] - Change in weekly ADP scores from baseline to week 12.

[0292] Secondary endpoints:

[0293] - Change in WOMAC A pain score from baseline to week 12.

[0294] In addition, other secondary endpoints included:

[0295] - Change in weekly ADP scores from baseline to Weeks 4, 8, 16, 20, and 26 for the first dose administration and Weeks 30, 38, 46, and 52 for the second dose administration.

[0296] - Change in WOMAC A pain score from baseline to Weeks 4, 8, 16, 20, and 26 for the first dose administration and Weeks 30, 38, 46, and 52 for the second dose administration.

[0297] - The percentage of patients demonstrating a 30% and 50% improvement in weekly ADP scores from baseline to Weeks 4, 8, 12, 16, 20 and 26 for the first dose administration and Weeks 30, 38, 46 and 52 for the second dose administration.

[0298] - The percentage of patients demonstrating a 30% and 50% improvement in WOMAC A pain score from baseline to Weeks 4, 8, 12, 16, 20 and 26 for the first dose administration and Weeks 30, 38, 46 and 52 for the second dose administration.

[0299] - Change in WOMAC B stiffness score from baseline to Weeks 4, 8, 12, 16, 20, and 26 for the first dose administration and Weeks 30, 38, 46, and 52 for the second dose administration.

[0300] - Change in WOMAC C physical function score from baseline to Weeks 4, 8, 12, 16, 20, and 26 for the first dose administration and Weeks 30, 38, 46, and 52 for the second dose administration.

[0301] - Change in PtGA of disease activity from baseline to Weeks 4, 8, 12, 16, 20 and 26 for the first dose administration and Weeks 30, 38, 46 and 52 for the second dose administration.

[0302] - Change in SF-36 from baseline to Weeks 4, 8, 12, 16, 20, and 26 for the first dose administration and Weeks 30, 38, 46, and 52 for the second dose administration.

[0303] - Change in weekly cumulative amount of rescue medication use from baseline to Weeks 4, 8, 12, 16, 20, and 26 for the first dose administration and Weeks 30, 38, 46, and 52 for the second dose administration.

[0304] Safety endpoints:

[0305] Safety and tolerability were assessed by medical history, physical examination (including vital signs), and clinical laboratory tests. The nature, frequency, and severity of adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) were evaluated.

[0306] Exploratory endpoints:

[0307] - Change in urinary CTX-II compared with baseline over time.

[0308] Study design and statistics:

[0309] After screening, eligible subjects were randomized (2:1) to receive 3 mL of the liposomal composition of the invention or placebo in their index knee at day 1 (baseline, first dose) and week 26 (second dose according to the original randomization). The primary efficacy assessments were conducted at weeks 12 and 26. Efficacy and safety were assessed until week 52, which represented the end of the study (EoS).

[0310] Example 4 - Pharmacokinetic Studies

[0311] A pK study was performed to assess the systemic exposure of liposomes containing 46.1 mg / ml DMPC and 60.2 mg / ml DPPC (at a concentration of 150 mM, suspended in a liquid medium containing mannitol and histidine buffer) after a single intra-articular (IA) knee injection in subjects with symptomatic knee OA and to characterize the time-concentration curve. As a control, a placebo sample containing the liquid medium without liposomes was used.

[0312] Subject inclusion criteria:

[0313] 1. Index knee pain present for at least 6 months prior to screening and present for >15 days in the last month prior to screening.

[0314] 2. Stop oral or topical nonsteroidal anti-inflammatory drugs (NSAIDs) 48 hours before the planned knee injection.

[0315] 3. WOMAC A pain score ≥2 in the index knee at screening and baseline.

[0316] 4. VAS pain score of the index knee ≥50 mm and ≤90 mm for at least 5 days in the 7 days before baseline.

[0317] 5. Able and willing to use only protocol-permitted rescue medications for OA knee pain, including acetaminophen / paracetamol, up to a maximum permitted dose of 4 g / day, throughout the study, except during the last 24 hours prior to the planned study efficacy assessment.

[0318] 6. Discontinue oral nonsteroidal anti-inflammatory drugs (NSAIDs) from the time of screening and during the study.

[0319] 7. Discontinue topical therapy (eg, NSAIDs, capsaicin, lidocaine patch, etc.) on the index knee prior to baseline.

[0320] 8. Any IA treatment / intervention on either knee was prohibited during the study period.

[0321] Primary endpoint:

[0322] PK characteristics, such as systemic levels and C, of ​​the liposomes following a single IA knee injection in subjects with symptomatic knee OA max .

[0323] Secondary endpoints:

[0324] Safety and tolerability of liposomes following a single IA knee injection in subjects with symptomatic knee OA.

[0325] Study design and statistics:

[0326] After screening, eligible subjects were randomized (2:1) to receive 3 mL of a liposomal composition of the invention or placebo in their index knee on Day 1 (baseline).

[0327] Systemic exposure and PK measurements were performed at designated time points (baseline, 1, 2, 3, 4, 6, 8, 12, 16, 24, 32, 36, 40, 44, 48, 72, and 168 hours post-dose). PK measurements and safety assessments were determined until Day 7 post-dose, which represented the end of the study (EoS). On the day of injection, the subject could receive analgesics until 8 hours after IP injection.

[0328] Those skilled in the art will appreciate that the present invention is not limited by what is specifically shown and described above. On the contrary, the scope of the present invention includes combinations and sub-combinations of the various features described above as well as variations and modifications. Therefore, the present invention should not be construed as being limited to the specifically described embodiments, and the scope and concept of the present invention will be more easily understood by reference to the following claims.< / l>

Claims

1. A liposomal composition for treating pain or irritation in the joints of a subject with a joint disorder, the treatment comprising a single intra-articular injection of a liposomal composition administered once or every 4 to 12 months, the liposomal composition comprising a phosphatidylcholine (PC) selected from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-pentacosanoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythro-C16 and combinations thereof as the only active ingredient.

2. The liposome composition for use according to claim 1, wherein treating pain or irritation in the joints of a subject with a joint disorder comprises reducing at least one of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A pain score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) B stiffness score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) C disability score, the patient global assessment of disease activity (PtGA) by visual analog scale (VAS), the weekly average of daily overall pain scores obtained by visual analog scale (VAS), the weekly average of daily joint pain scores obtained by visual analog scale (VAS), the cumulative amount of rescue medication used for pain relief, and the urinary collagen C-terminal cross-linked telopeptide (CTX) type II level as compared to baseline or untreated controls.

3. The liposome composition for use according to claim 1 or 2, wherein the liposome composition is administered once.

4. The liposome composition for use according to claim 1 or 2, wherein the liposome composition is administered once every four months.

5. The liposome composition for use according to claim 1 or 2, wherein the liposome composition is administered once every six months.

6. The liposome composition for use according to claim 1 or 2, wherein the liposome composition is administered once every 26 weeks.

7. The liposome composition for use according to claim 2, wherein the reduction is at least 5% compared to a baseline or untreated control.

8. The liposome composition for use according to claim 7, wherein the reduction is at least 10% compared to a baseline or untreated control.

9. The liposome composition for use according to claim 8, wherein the reduction is at least 15% compared to a baseline or untreated control.

10. The liposome composition for use according to claim 9, wherein the reduction is at least 20% compared to a baseline or untreated control.

11. The liposome composition for use according to claim 10, wherein the reduction is at least 25% compared to a baseline or untreated control.

12. The liposome composition for use according to claim 11, wherein the reduction is at least 30% compared to a baseline or untreated control.

13. The liposome composition for use according to claim 12, wherein the reduction is at least 40% compared to a baseline or untreated control.

14. The liposome composition for use according to claim 13, wherein the reduction is at least 50% compared to a baseline or untreated control.

15. The liposome composition for use according to claim 2, wherein the subject has a baseline WOMAC A pain score of ≥ 2, and the WOMAC A pain score is reduced by at least 0.5 points.

16. The liposome composition for use according to claim 15, wherein the subject has a baseline WOMAC A pain score of ≥ 2, and the WOMAC A pain score is reduced by at least 0.75 points.

17. The liposome composition for use according to claim 16, wherein the subject has a baseline WOMAC A pain score of ≥ 2, and the WOMAC A pain score is reduced by at least 1 point.

18. The liposome composition for use according to claim 2, wherein the baseline weekly average of the daily joint pain score obtained by VAS of the subject is ≥50 mm, and the weekly average of the daily joint pain score obtained by VAS is reduced by at least 5.

19. The liposome composition for use according to claim 18, wherein the baseline weekly average of the daily joint pain score obtained by VAS of the subject is ≥50 mm, and the weekly average of the daily joint pain score obtained by VAS is reduced by at least 10.

20. The liposome composition for use according to claim 19, wherein the baseline weekly average of the daily joint pain score obtained by VAS of the subject is ≥50 mm, and the weekly average of the daily joint pain score obtained by VAS is reduced by at least 15.

21. The liposome composition for use according to claim 20, wherein the baseline weekly average of the daily joint pain score obtained by VAS of the subject is ≥50 mm, and the weekly average of the daily joint pain score obtained by VAS is reduced by at least 20.

22. The liposomal composition for use according to any one of claims 18 to 21, wherein the weekly average of the daily joint pain score obtained by VAS at baseline of the subject is in the range of 50 mm to 90 mm.

23. The liposome composition for use according to any one of claims 1 to 22, wherein the PC concentration is from about 50 mM to about 300 mM.

24. A liposome composition for use according to any one of claims 1 to 23, wherein the liposome composition comprises 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) as the only active ingredients.

25. The liposome composition for use according to claim 24, wherein the liposome composition comprises DMPC and DPPC in a molar ratio of 40:60 to 50:

50.

26. The liposome composition for use according to claim 24, wherein the liposome composition comprises DMPC in a weight percentage range of about 1% (w / w) to about 10% (w / w) and DPPC in a weight percentage range of about 2% (w / w) to about 12% (w / w).

27. The liposome composition for use according to claim 24, wherein the liposome composition comprises about 20 mg to about 700 mg of DMPC and about 30 mg to about 900 mg of DPPC.

28. The liposome composition for use according to any one of claims 1 to 27, wherein the liposome composition is administered in a volume between about 0.5 ml and about 10 ml.

29. The liposome composition for use according to claim 28, wherein the liposome composition is administered in a volume between about 1 ml and about 6 ml.

30. The liposome composition for use according to claim 29, wherein the liposome composition is administered in a volume of about 3 ml.

31. A liposome composition for use according to any one of claims 1 to 30, wherein the liposome composition comprises a plurality of liposomes selected from the group consisting of small unilamellar vesicles (SUV), large unilamellar vesicles (LUV), giant unilamellar vesicles (GUV), oligolamellar vesicles (OLV), multilamellar vesicles (MLV), multivesicular liposomes (MVL), and mixtures or combinations thereof.

32. The liposome composition for use according to claim 31, wherein the plurality of liposomes are multilamellar vesicles (MLVs).

33. The liposome composition for use according to claim 31 or 32, wherein the plurality of liposomes have a size ranging from about 0.5 μm to about 10 μm.

34. The liposome composition for use according to any one of claims 1 to 33, wherein the liposome composition comprises a fluid medium comprising water or a buffer.

35. The liposome composition for use according to claim 34, wherein the buffer is a histidine buffer.

36. The liposome composition for use according to claim 34 or 35, wherein the fluid medium further comprises a tonicity agent selected from the group consisting of low molecular weight polyols and sugar alcohols.

37. The liposome composition for use according to claim 36, wherein the polyol is selected from the group consisting of mannitol, sorbitol, glycerol, lactitol, maltitol, dextrose, lactose, trehalose and combinations thereof.

38. The liposome composition for use according to claim 37, wherein the weight ratio between the plurality of liposomes and the polyol is in the range of about 6:1 to about 2:

1.

39. The liposome composition for use according to any one of claims 1 to 38, wherein the liposome composition has a pH in the range of about 5 to about 8.

40. A liposomal composition for use according to any one of claims 1 to 39, wherein the joint disorder is osteoarthritis.

41. A method for treating pain or irritation in the joints of a subject with a joint disorder, the method comprising administering a single intra-articular injection of a liposome composition once or every 4 to 12 months, the liposome composition comprising a phosphatidylcholine (PC) selected from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-pentacosanoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythro-C16 and combinations thereof as the only active ingredient.

42. The method of claim 41, wherein treating pain or irritation in a joint of a subject with a joint disorder comprises reducing at least one of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A pain score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) B stiffness score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) C disability score, the Patient Global Assessment of Disease Activity (PtGA) by a visual analog scale (VAS), the weekly average of daily overall pain scores by a visual analog scale (VAS), the weekly average of daily joint pain scores by a visual analog scale (VAS), the cumulative amount of rescue medication used for pain relief, and urinary collagen C-terminal cross-linked telopeptide (CTX) type II levels, compared to baseline or an untreated control.

43. Use of a liposome composition comprising a phosphatidylcholine (PC) selected from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-pentacoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythro-C16 and combinations thereof as the only active ingredient for the preparation of a medicament for a method of treating pain or irritation in the joints of a subject suffering from a joint disorder, the method comprising administering a single intra-articular injection of the liposome composition once or every 4 to 12 months.

44. Use of a liposome composition according to claim 43, wherein treating pain or irritation in a joint of a subject with a joint disorder comprises reducing at least one of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A pain score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) B stiffness score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) C disability score, the Patient Global Assessment of Disease Activity (PtGA) by a visual analog scale (VAS), the weekly average of daily overall pain scores by a visual analog scale (VAS), the weekly average of daily joint pain scores by a visual analog scale (VAS), the cumulative amount of rescue medication used for pain relief, and urinary collagen C-terminal cross-linked telopeptide (CTX) type II levels, compared to baseline or untreated controls.

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