Long-acting liposomal compositions for the treatment of pain in joint disorders - Patent Application 20070122997

Abstract

The present invention provides a long-acting liposomal composition for use in treating joint pain or inflammation in subjects with joint disease, particularly osteoarthritis, which contains a phosphatidylcholine lipid as the sole active ingredient and provides pain relief with a single dose or multiple doses administered once every 4 to 12 months.

Description

[Technical Field]

[0001] The present invention relates to a liposomal pharmaceutical composition for use in the treatment of pain in joint disorders. [Background technology]

[0002] Osteoarthritis (OA) is the most common joint disease and is characterized by articular cartilage degradation, osteophyte formation, bone remodeling, joint space narrowing, and arthritis. The etiology of OA is unknown but is thought to be multifactorial, including genetic, metabolic, mechanical, and inflammatory causes. Knee osteoarthritis is more prevalent than other joints. Clinical symptoms of knee OA include intra- and peri-articular pain, particularly during weight bearing, 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, which imposes a significant economic burden on individuals and society. OA diagnosis is based on signs and symptoms and is often confirmed by excluding concurrent inflammatory causes using imaging or clinical tests. Because the pathophysiology of OA is unknown, current recommendations for OA management focus on relieving pain and stiffness and improving physical function as key treatment goals. Non-surgical treatment of OA focuses on reducing joint overload, physical therapy, and relief of pain and inflammation, usually through topical, systemic, or intra-articular (IA) medication.

[0003] Currently, medication regimens available for most OA patients include non-opioid analgesics. This is primarily because long-term use of opioids for OA is generally discouraged due to a lack of information regarding their benefits as well as the risk of addiction and other side effects. Therefore, medications such as acetaminophen / paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), anti-irritants, glucosamine or chondroitin, corticosteroids, and injectable hyaluronic acid are commonly used. While these medications provide highly effective temporary 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 failure. Topical NSAIDs and cyclooxygenase II (COXII) inhibitors are considered somewhat safer than other NSAIDs in terms of gastrointestinal side effects, although COXII 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; 26:3 55-369; Glyn-Jones et al., Lancet. 2015; 386: 376-387). Corticosteroid injections reduce inflammation and relieve pain more quickly than NSAIDs, but the relief is temporary. Corticosteroid injections are typically given every 3 months, and the number of injections is typically limited to four in the same joint. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Mehta et al., Statistics in Medicine. 2011; 30(28): 3267-3284 [Non-patent document 2] Zhang et al., Clin Geriatr Med. 2010; 26:3 55-369 [Non-patent document 3] Glyn-Jones et al., Lancet. 2015; 386: 376-387 Summary of the Invention [Problem to be solved by the invention]

[0005] Due to the high incidence of side effects associated with long-term NSAID and corticosteroid therapy, effective and safer alternative treatments for OA are urgently needed.

[0006] Hyaluronic acid (HA) injections are typically administered once weekly for 3 to 5 weeks. While HA injections have been shown to be safe when used long-term, various studies have reported minimal benefit. Furthermore, injectable HA compositions are known to have a variety of side effects, including impaired mobility, muscle pain and stiffness, joint pain, and joint swelling and redness.

[0007] The lubrication of cartilage within synovial joints involves a complex interplay of several mechanical and molecular factors, resulting in reduced friction between opposing surfaces of articular cartilage. In healthy, weight-bearing joints, a layer of lubricating molecules coats the surface of the articular cartilage, acting as a boundary lubricant and enabling nearly frictionless joint movement. The lubricating components of synovial fluid (SF) include, among others, hyaluronic acid or hyaluronan, lubricin, and surface-active phospholipids. Various studies have been conducted to evaluate the efficiency of phospholipids in joint lubrication.

[0008] US Patent No. 6,800,298 discloses dextran-based hydrogel compositions containing lipids, particularly phospholipids, for lubrication of mammalian joints.

[0009] US Patent Application 2005 / 0123593 relates to a composition comprising glycosaminoglycans encapsulated in a liposomal delivery system for intra-articular administration for the treatment of osteoarthritis.

[0010] US Patent No. 8,895,054 relates to a method for lubricating joints and / or preventing cartilage wear using liposomes consisting essentially of phospholipid membranes having a phase transition temperature in the range of about 20°C to about 39°C.

[0011] International patent application WO2019 / 038763 relates to a pharmaceutical composition for lubricating joints, comprising a non-ionic tonicity agent comprising a polyol and glycerophospholipid- or sphingomyelin-based liposomes having a phase transition temperature below the temperature of the joint.

[0012] International Patent Application WO 2003 / 000191 relates to compositions and methods for treating arthritis comprising one or more glycosaminoglycans in combination with one or more hyaluronidase inhibitors, wherein the hyaluronidase inhibitors can be selected from heparan sulfate, dextran sulfate, and xylose sulfate, and the hyaluronic acid can be encapsulated together with the hyaluronidase inhibitor within a liposome.

[0013] There remains an unmet need for therapeutically effective pharmaceutical compositions for joint lubrication that would provide long-term efficacy while reducing the probability of side effects associated with frequent intra-articular administration. [Means for solving the problem]

[0014] The present invention provides a liposome formulation for use in treating pain or inflammation in the joints of subjects with arthropathy. The formulation of the present invention contains, as an active ingredient, a liposome comprising a phospholipid membrane with 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). Therefore, the liposome is in the liquid-disordered (LD) phase when administered to a synovial joint.

[0015] This is the first time that a single intra-articular injection of a liposomal pharmaceutical composition according to the principles of the present invention has been shown to provide pain relief in subjects, with the relief lasting for six months. In particular, nominally significant reductions in pain scores were achieved using the WOMACA pain score, and statistically significant reductions in pain scores were achieved using the VAS average daily knee pain score and the patient's global assessment. Pain relief was also evidenced by a reduction in the use of rescue medications for pain relief. Furthermore, the liposomal composition was found to be safe and well tolerated. Thus, administering the liposomal composition once or more every three months is beneficial for the treatment of joint disorders, particularly osteoarthritis.

[0016] According to one aspect, the present invention provides a liposome composition for use in a method for treating pain or inflammation in a joint in a subject with a joint disorder, the method comprising administering, via intra-articular injection once or once every 4 to 12 months, a liposome composition comprising, as the sole active ingredient, a phosphatidylcholine (PC) selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythroC16, and combinations thereof.

[0017] According to another aspect, the present invention provides a method for treating pain or inflammation in a joint in a subject with a joint disorder, the method comprising administering via intra-articular injection once or once every 4 to 12 months a liposome composition comprising, as the sole active ingredient, a phosphatidylcholine (PC) selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythroC16, and combinations thereof.

[0018] In yet another aspect, the present invention provides use of a liposome composition comprising a phosphatidylcholine (PC) selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythroC16, and combinations thereof, as a single active ingredient for the manufacture of a medicament for use in a method for treating pain or inflammation in a joint in a subject with a joint disorder, the method comprising administering a single intra-articular injection of the liposome composition once or every 4 to 12 months.

[0019] In one embodiment, treating pain or inflammation in a joint in a subject with a joint disorder comprises a decrease, compared to baseline or untreated controls, in at least one of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) B stiffness score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) C disability score, Patient Global Assessment of Disease Activity (PtGA) by visual analog scale (VAS), weekly mean daily global pain score by visual analog scale (VAS), weekly mean daily joint pain score by visual analog scale (VAS), cumulative amount of rescue medication used for pain relief, and urinary C-terminal cross-linked telopeptide of collagen (CTX) type II levels. Each possibility represents a separate embodiment.

[0020] In another embodiment, the decrease is at least a 5% decrease compared to baseline or an untreated control. In yet another embodiment, the decrease is at least a 10% decrease compared to baseline or an untreated control. In an additional embodiment, the decrease is at least a 15% decrease compared to baseline or an untreated control. In a further embodiment, the decrease is at least a 20% decrease compared to baseline or an untreated control. In certain embodiments, the decrease is at least a 25% decrease compared to baseline or an untreated control. In various embodiments, the decrease is at least a 30% decrease compared to baseline or an untreated control. In certain embodiments, the decrease is at least a 40% decrease compared to baseline or an untreated control. In an exemplary embodiment, the decrease is at least a 50% decrease compared to baseline or an untreated control.

[0021] In some embodiments, the subject has a baseline WOMAC A pain score of ≧2 and a reduction in the WOMAC A pain score of at least 0.5 points. In other embodiments, the subject has a baseline WOMAC A pain score of ≧2 and a reduction in the WOMAC A pain score of at least 0.75 points. In further embodiments, the subject has a baseline WOMAC A pain score of ≧2 and a reduction in the WOMAC A pain score of at least 1 point.

[0022] In certain embodiments, the subject has a baseline weekly mean daily joint pain score by VAS of ≥ 50 mm and a reduction in the baseline weekly mean daily joint pain score by at least 5. In various embodiments, the subject has a baseline weekly mean daily joint pain score by VAS of ≥ 50 mm and a reduction in the baseline weekly mean daily joint pain score by VAS of at least 10. In additional embodiments, the subject has a baseline weekly mean daily joint pain score by VAS of ≥ 50 mm and a reduction in the baseline weekly mean daily joint pain score by VAS of at least 15. In other embodiments, the subject has a baseline weekly mean daily joint pain score by VAS of ≥ 50 mm and a reduction in the baseline weekly mean daily joint pain score by VAS of at least 20. In further embodiments, the subject has a baseline weekly mean daily joint pain score by VAS ranging from 50 mm to 90 mm, including each value within the specified range.

[0023] In one embodiment, the liposome composition is administered once. In an alternative embodiment, the liposome composition is administered once every four months. In a further alternative embodiment, the liposome composition is administered once every six months. In an additional embodiment, the liposome composition is administered once every 26 weeks. According to some embodiments, administration of the liposome composition provides pain relief to the subject for three months or more after administration. According to further embodiments, administration of the liposome composition provides pain relief to the subject for at least six months after administration.

[0024] In various embodiments, the liposome composition comprises a plurality of liposomes having a phosphatidylcholine concentration of about 50 mM to about 300 mM, including values ​​within the specified range. In certain embodiments, the liposome composition comprises a plurality of liposomes having a phosphatidylcholine concentration of about 100 mM to about 200 mM, including values ​​within the specified range.

[0025] 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 certain embodiments, the liposome composition comprises DMPC and DPPC in a molar ratio of 25:75 to 70:30, including all ratio values ​​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 all ratio values ​​within the specified range. In certain embodiments, the molar ratio of DMPC to DPPC is about 45:55. In further embodiments, the liposome composition comprises a weight percentage of DMPC ranging from about 1% (w / w) to about 10% (w / w) and a weight percentage of DPPC ranging from about 2% (w / w) to about 12% (w / w), each within the specified range. In additional embodiments, the liposome composition comprises about 20 mg to about 700 mg of DMPC and about 30 mg to about 900 mg of DPPC, each within the specified range. In certain embodiments, the liposome composition comprises about 45 mg to about 300 mg of DMPC and about 60 mg to about 400 mg of DPPC, each within the specified range.

[0026] According to some embodiments, the liposome composition is administered in a volume of about 0.5 mL to about 10 mL, including any value within the range specified. In specific embodiments, the liposome composition is administered in a volume of about 1 mL to about 6 mL, including any value within the range specified. In more specific embodiments, the liposome composition is administered in a volume of about 3 mL.

[0027] In some embodiments, the liposome composition comprises a plurality of liposomes selected from the group consisting of small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), giant unilamellar vesicles (GUVs), oligolamellar vesicles (OLVs), multilamellar vesicles (MLVs), multivesicular liposomes (MVLs), and mixtures or combinations thereof. Each possibility represents a separate embodiment. In one embodiment, the liposomes are multilamellar vesicles (MLVs).

[0028] In certain embodiments, the liposome size ranges from about 0.3 μm to about 50 μm, including each value within the specified range, while in other embodiments, the liposome size ranges from about 0.5 μm to about 10 μm, including each value within the specified range.

[0029] According to some embodiments, the liposome composition comprises a fluid medium comprising water or a buffer. In other embodiments, the buffer is a histidine buffer. According to additional embodiments, the fluid medium further comprises a tonicity agent selected from a low molecular weight polyol and a sugar alcohol. In one embodiment, the tonicity agent is a polyol. In another embodiment, the polyol is a linear polyol. In a further embodiment, the polyol is selected from the group consisting of mannitol, sorbitol, glycerol, lactitol, maltitol, dextrose, lactose, trehalose, and combinations thereof. Each possibility represents a separate embodiment. According to certain embodiments, the polyol is mannitol. According to various embodiments, multiple liposomes may be used in combination, including all ratio values ​​within the range specified. In further embodiments, the weight ratio of polyol to polyol ranges from about 6:1 to about 2:1, and the specified polyols are present in the liposome composition at weight percentages ranging from about 0.05% (w / w) to about 10% (w / w), including each value within the specified range.

[0030] According to certain embodiments, the liposome composition has a pH ranging from about 5 to about 8, including each value within the specified range.

[0031] In some embodiments, the composition is used to reduce knee joint pain in patients with osteoarthritis.

[0032] Further embodiments and the full scope of applicability of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are intended for purposes of illustration only, as various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. [Brief explanation of the drawings]

[0033] [Figure 1] FIG. 1 shows a schematic of the Phase IIb study design. [Figure 2] FIG. 1 shows the disposition of subjects enrolled in the study. [Figure 3] Figure 1 shows WOMAC A pain results over the 26 week study. *: p<0.05 without adjustment for multiplicity. [Figure 4] FIG. 1 shows WOMAC C physical function over the 26-week study. [Figure 5] FIG. 1 shows weekly average daily knee pain over the 26-week study. [Figure 6] FIG. 1 shows patients' global assessment of disease activity over the 26-week study. [Figure 7] FIG. 1 shows weekly average daily overall pain over the 26-week study. [Figure 8] FIG. 1 shows the cumulative weekly amounts (mg) of rescue medication used over the 26-week study. [Figure 9] FIG. 1 shows the change from baseline in urinary collagen C-terminal cross-linked telopeptide type II (CTX) (μg / mol) versus time over the 12-week study. [Figure 10A] FIG. 1 shows mean baseline-adjusted plasma DMPC concentrations (ng / mL). [Figure 10B] FIG. 1 shows mean baseline-adjusted plasma DPPC concentrations (ng / mL). DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention provides a liposomal formulation for use in treating joint pain or inflammation in a mammal, which provides pain relief for more than three months, preferably at least six months, after a single administration. Thus, the liposomal formulation of the present invention is a long-acting composition with improved efficacy and reduced side effects due to frequent administration.

[0035] Previously known drugs for relieving OA-related pain typically require repeated administration to achieve long-term efficacy. For example, intra-articularly injected HA, widely used to treat lower limb osteoarthritis, is rapidly degraded by reactive oxygen species (ROS), limiting its intra-articular residence time (Conrozier et al., Rheumatol Ther. 2014;1(1):45-54).

[0036] In another study, 40 patients with unilateral knee arthritis were randomized into two groups and received a single injection of either an aqueous dispersion of multilamellar vesicles (MLVs) composed of DMPC and DPPC or hyaluronic acid. The MLV composition provided earlier pain relief compared with HA, but did not demonstrate long-term efficacy. Specifically, the MLV composition was most effective within 14 days of administration, with a steady decrease in relative pain from days 14 to 90 (Kandel et al., Meeting: 2014 ACR / ARHP Annual Meetings). It was concluded that the pain-reducing effect was more rapid than that of HA and lasted for up to 3 months. Therefore, it was entirely unexpected that a single intra-articular injection of a liposomal composition combining DMPC and DPPC in MLV form could reduce joint pain and improve function in OA patients for more than 3 months. Furthermore, a 3 mL dose of the liposomal composition demonstrated unexpected efficacy compared with a 6 mL dose. Furthermore, when the aforementioned efficacy of the compositions of the present invention is compared with the published efficacy of a commercially available composition containing a corticosteroid active ingredient (Zilretta®) in a Phase III study, the former has been found to exhibit superior efficacy. Finally, reduced dosing frequency improves patient compliance.

[0037] Thus, the present invention provides a long-acting liposomal composition comprising a plurality of liposomes useful for treating patients with joint disorders, the composition being administered in a single treatment regimen or once every 4 to 12 months, each within a specified time period.

[0038] As used herein, the term "long-acting" refers to a composition that provides a sustained or prolonged effect at a local site of action in a subject, or a composition that provides a sustained or prolonged duration of action in a subject. Thus, therapeutic benefit may be achieved over a period of 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer. Each possibility represents a separate embodiment. Surprisingly, effective treatment at the local site of action is achieved essentially without systemic effects, as evidenced by plasma levels indicative of endogenous lipid concentrations.

[0039] As used herein, the term "liposome" refers to a vesicle characterized by an internal aqueous core surrounded by a lipid membrane, typically comprising 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 a separate embodiment. Suitable phosphatidylcholines within the scope of the present invention include, but are 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 a separate embodiment. Suitable phosphatidylethanolamines include, but are not limited to, 1,2-dilauroyl-L-phosphatidylethanolamine (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 a separate 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 a separate embodiment.

[0040] According to some embodiments, liposomes suitable for use in the pharmaceutical compositions of the present invention do not contain membrane active sterols, such as cholesterol, in their bilayer.

[0041] In some aspects and embodiments, the liposome is composed of a phosphatidylcholine (PC) selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythroC16, and combinations thereof. Each possibility represents a separate embodiment.

[0042] According to some embodiments of the present invention, the total concentration of phosphatidylcholine in a pharmaceutical composition ranges from about 20 mM to about 500 mM, inclusive. In further embodiments, the concentration ranges from about 50 mM to about 300 mM, inclusive. In yet further embodiments, the concentration ranges from about 100 mM to about 200 mM, inclusive. In yet further embodiments, the concentration ranges from about 130 mM to about 170 mM, inclusive. In certain embodiments, the total concentration of DMPC and DPPC is about 150 mM.

[0043] Preferably, the liposomes comprise a combination of DMPC and DPPC as the only active ingredients. In some embodiments, the liposomes consist essentially of DMPC and DPPC. In other embodiments, the molar percentage ratio of DMPC:DPPC ranges from about 25:75 to about 70:30, including all ratio values ​​within the specified range. In further embodiments, the molar percentage ratio of DMPC:DPPC ranges from about 30:70 to about 65:25, from about 35:65 to about 60:30, or from about 40:60 to about 55:45, including all ratio values ​​within the specified range. Each possibility represents a separate embodiment. In certain embodiments, the molar percentage ratio of DMPC:DPPC is about 45:55. In additional embodiments, the molar percentage ratio of DMPC:DPPC is about 25:75.

[0044] In some embodiments, the combined DMPC and DPPC concentration ranges from about 10 mg / mL to about 500 mg / mL, including each value within the specified range. In further embodiments, the concentration ranges from about 30 mg / mL to about 300 mg / mL, including each value within the specified range. In yet further embodiments, the concentration ranges from about 50 mg / mL to about 200 mg / mL, including each value within the specified range. In certain embodiments, the combined DMPC and DPPC concentration is about 100 mg / mL.

[0045] In some embodiments, the concentration of DMPC ranges from about 1 mg / mL to about 250 mg / mL, including each value within the specified range. In further embodiments, the concentration of DMPC ranges from about 10 mg / mL to about 100 mg / mL, including each value within the specified range. In still further embodiments, the concentration of DMPC ranges from 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.

[0046] In some embodiments, the concentration of DPPC ranges from about 5 mg / mL to about 300 mg / mL, including each value within the specified range. In further embodiments, the concentration of DPPC ranges from about 20 mg / mL to about 200 mg / mL, including each value within the specified range. In still further embodiments, the concentration of DPPC ranges from about 30 mg / mL to about 90 mg / mL, including each value within the specified range. In certain embodiments, the concentration of DPPC is about 60 mg / mL.

[0047] In some embodiments, the combination of DMPC and DPPC is present in the pharmaceutical composition at a weight percentage ranging from 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).

[0048] In accordance with 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 any 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 any value within the specified range. According to further embodiments, the composition comprises about 40 mg to about 300 mg of DMPC and about 50 mg to about 500 mg of DPPC, including any value within the specified range. According to yet 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 any 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 additional embodiments, each dose of the pharmaceutical composition comprises about 365 mg of DPPC. In certain embodiments, 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 of DMPC. In a specific embodiment, each dose of the pharmaceutical composition comprises about 275 mg of DMPC.

[0049] It should be emphasized that the liposomes used in the liposome compositions of the present invention are used as active ingredients themselves, not as carriers of pharmaceutically active agents. According to some embodiments, the DMPC and DPPC phospholipids are used as the sole active ingredients in the pharmaceutical compositions of the present invention. Thus, pharmaceutical compositions according to the principles of the present invention are essentially free of additional pharmaceutically active agents. As used herein, the term "essentially free of additional pharmaceutically active agents" refers, in some embodiments, to pharmaceutical compositions containing less than a therapeutically effective amount of a pharmaceutically active agent known for use in joint lubrication, treatment of joint dysfunction, relief of joint pain, irritation, and / or wear, or any combination thereof. As used herein, the term "known for use" refers, in some embodiments, to a pharmaceutically active agent that is approved for a specified use at the time of the present invention. In further embodiments, the term "known for use" refers to a pharmaceutically active agent that is referenced in scientific literature and / or patents as being suitable for a specified use.

[0050] In some embodiments, the liposome compositions of the present invention are free of a pharmaceutically active agent that is a lubricant, such as, inter alia, a glycosaminoglycan or a pharmaceutically acceptable salt, ester, or derivative thereof. In certain embodiments, the glycosaminoglycan is hyaluronic acid or a hyaluronic acid-containing salt or ester. In certain embodiments, the hyaluronic acid is not encapsulated within the liposome. Additionally, or alternatively, the hyaluronic acid is not dispersed in the fluid medium. In some currently preferred embodiments, the liposome composition is essentially free of hyaluronic acid or a pharmaceutically acceptable salt or ester thereof. When used in reference to hyaluronic acid, the term "essentially free" in some embodiments refers to a composition containing less than a therapeutically effective amount of hyaluronic acid or a salt or ester thereof. In additional embodiments, the term "essentially free" refers to a composition containing less than a detectable amount of hyaluronic acid or a salt or ester thereof.

[0051] In some embodiments, the liposome compositions of the present invention do not include a pharmaceutically active agent that is a lubricant selected from superficial zone protein (SZP), proteoglycan 4, and analogs and derivatives thereof.

[0052] 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 salsalate, diflunisal, ibuprofen, fenoprofen, fenamate, ketoprofen, nabumetone, naproxen, diclofenac, indomethacin, sulindac, tolmetin, etodolac, ketorolac, oxaprozin, celecoxib, meclofenamate, mefenamic acid, oxyphenbutazone, phenylbutazone, salicylate, or a phytosphingosine-type drug.

[0053] 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 virazole. 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.

[0054] In some embodiments, the liposomal compositions of the present invention do not include pharmaceutically active agents that are antibiotics, such as antibiotics belonging to the families of penicillins, cephalosporins, aminoglycosides, macrolides, carbapenems and penems, beta-lactam monocyclics, beta-lactamase inhibitors, tetracyclines, polypeptide antibiotics, chloramphenicol and derivatives, polyether ionophores, and quinolones. Examples of such antibiotics include ampicillin, dapsone, chloramphenicol, neomycin, cefaclor, cefadroxil, cephalexin, cephradine, erythromycin, clindamycin, lincomycin, amoxicillin, ampicillin, bacampicillin, carbenicillin, dicloxacillin, cyclacillin, picloxacillin, hetacillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, ticarcillin, rifampicin, tetracycline, fusidic acid, lincomycin, novobiocin, and spectinomycin.

[0055] In some embodiments, the liposome compositions of the present invention do not include pharmaceutically active agents that are steroids. As used herein, the term "steroid" refers to natural steroids and their derivatives, as well as synthetic or semi-synthetic steroid analogs that have steroid-like activity. Steroids can be glucocorticoids or corticosteroids. Examples of specific natural and synthetic steroids include aldosterone, beclomethasone, betamethasone, budesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluchlorone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, tixocortol, or triamcinolone, and their respective pharmaceutically acceptable salts or derivatives.

[0056] 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.

[0057] In accordance with the principles of the present invention, the liposomes have the structure or are in the form of small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), giant unilamellar vesicles (GUVs), oligolamellar vesicles (OLVs), multilamellar vesicles (MLVs), multivesicular liposomes (MVLs), and mixtures or combinations thereof. Each possibility represents a separate embodiment. The liposomes may be unilamellar or, according to some embodiments, multivesicular (MLV) liposomes. According to other embodiments, the liposomes may be giant multivesicular vesicles (LMVs) or dehydrated rehydrated vesicles (DRVs).

[0058] In some currently preferred embodiments, the liposomes are in the form of multilamellar vesicles (MLVs). In certain such embodiments, the liposomes have multiple membranes.

[0059] According to some embodiments, the average diameter of the liposomes is 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 a separate embodiment. The average diameter of the liposomes can be less than about 10 μm, less than 8 μm, less than 7 μm, less than 6 μm, or less than 5 μm. Each possibility represents a separate embodiment. According to some embodiments, the average diameter of the liposomes is in the range of about 0.3 μm to about 10 μm, including each value within the specified range. According to further embodiments, the average diameter of the liposomes is in the range of about 0.5 μm to about 9 μm, including each value within the specified range. According to yet further embodiments, the average diameter of the liposomes is in the range of about 1 μm to about 8 μm, including each value within the specified range. According to yet other embodiments, the average diameter of the liposomes is in the range of about 3 μm to about 5 μm, including each value within the specified range.

[0060] As used herein, the terms "mean diameter" and "mean particle size" are used interchangeably and, in some embodiments, refer to the mean diameter of liposomes obtained from a particle size distribution based on a number distribution model. In some embodiments, the term refers to the mean diameter of liposomes obtained from a particle size distribution based on a volume distribution model. In additional embodiments, the term refers to the mean diameter of liposomes obtained from a particle size distribution based on a surface area distribution model. Particle size distribution can be determined by laser light diffraction and / or Coulter counter methods, among others.

[0061] According to one embodiment, MLVs are defined by an average diameter ranging from 0.3 μm to 10 μm, inclusive of each value within the specified range. According to another embodiment, MLVs are defined by an average diameter ranging from 0.5 μm to 9 μm, inclusive of each value within the specified range. According to yet another embodiment, MLVs are defined by an average diameter ranging from 1 μm to 8 μm, inclusive of each value within the specified range. According to yet another embodiment, MLVs are defined by an average diameter ranging from 3 μm to 5 μm, inclusive of each value within the specified range.

[0062] Within the scope of the present invention are liposome compositions having a defined phase transition temperature of the liposome membrane, said temperature being lower than the temperature of the joint. As used herein, the term "phase transition temperature" refers, in some embodiments, to the temperature at which the phase transition of the liposome from an ordered solid phase (SO) to a liquid disordered phase (LD) occurs. The phase transition temperature of the liposome can be evaluated by differential scanning calorimetry (DSC). Various parameters of the DSC thermogram that can be examined to evaluate the phase transition temperature include T, which represents the temperature at which the SO-LD phase transition begins; on and T, which represents the temperature at which the SO-LD phase transition ends during the heating scan. off and pre-metastasis (T p ) and main transition (T m ) the temperature T at which the maximum change in heat capacity occurs p and T m In some embodiments, the term "phase transition temperature" refers to T mIn 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 ranging from about 20°C to about 39°C, including each value within the specified range. In some embodiments, the phase transition temperature of liposomes ranges from about 33°C to about 37°C, including each value within the specified range. In some embodiments, DMPC and DPPC form lipid bilayers that become highly hydrated and vesiculated above the SO to LD phase transition temperature, forming lipid vesicles (liposomes). The liposome bilayer can be in either a solid-ordered (SO) or liquid-disordered (LD) phase. The conversion from the SO phase to the LD phase involves an endothermic, first-order phase transition, referred to as the main phase transition. T m is the temperature at which the change in heat capacity is maximum during the SO phase to LD phase transition.

[0063] In accordance with the principles of the present invention, liposomes are suspended or dispersed in a fluid medium. The fluid medium can be selected from a buffer solution and water. Each possibility represents a separate embodiment. In some embodiments, the fluid medium comprises a buffer solution. In certain embodiments, the buffer solution comprises a histidine buffer solution. The concentration of the histidine buffer solution can range from about 0.5 mg / mL to about 10 mg / mL, including each value within the specified range. In certain embodiments, the concentration of the histidine buffer solution is about 2 mg / mL. In some embodiments, the concentration of the histidine buffer solution ranges from about 1 mM to about 50 mM, including each value within the specified range. In certain embodiments, the concentration of the histidine buffer solution is about 10 mM. Histidine can be present in the composition in the form of a dissolved hydrochloride or acetate salt. In certain embodiments, the liposome composition further comprises a trace amount of an inorganic acid, such as hydrochloric acid.

[0064] In additional embodiments, the liposome composition includes a tonicity agent. As used herein, the term "tonicity agent" refers to an agent used in some embodiments to reduce local irritation by preventing osmotic shock at the application site. As shown in WO2019 / 038763 (the contents of which are incorporated herein by reference in their entirety), the addition of a polyol-based nonionic tonicity agent to a pharmaceutical composition containing glycerophospholipid-based liposomes having a phase transition temperature below the joint temperature reduced the cartilage friction coefficient compared to a liposome composition that did not contain a polyol.

[0065] In accordance with the principles of the present invention, the polyol can be selected from low molecular weight polyols and sugar alcohols. Each possibility represents a separate embodiment. In some embodiments, the polyol is a linear polyol. In other embodiments, the polyol is a cyclic polyol. Non-limiting examples of polyols suitable for use in the liposome compositions of the present invention include mannitol, sorbitol, glycerol, dextrose, lactose, trehalose, lactitol, and maltitol. Each possibility represents a separate embodiment. In some currently preferred embodiments, the polyol is mannitol.

[0066] In some embodiments, the liposome composition includes a combination of polyols, such as a combination of mannitol and glycerol. The liposome composition can further include a combination of a polyol and an additional tonicity agent. In some embodiments, the polyol does not include xylitol.

[0067] It should be emphasized that, according to some currently preferred embodiments, the tonicity agent is not encapsulated within the liposome. As used herein, the term "encapsulation" refers, in some embodiments, to a concentration of the tonicity agent inside the liposome that is substantially higher than the medium outside the liposome. The term "inside the liposome" should be understood to include at least one internal aqueous phase of the liposome. The term "concentration" can include osmotic concentration. As used herein, the term "substantially high" refers, in some embodiments, to a concentration difference of at least about 90%. In some embodiments, the polyol is not encapsulated within the liposome. In further embodiments, the mannitol is not encapsulated within the liposome.

[0068] According to further embodiments, the concentration of polyol within the liposome is essentially the same as the concentration of polyol in the medium outside the liposome. According to yet further embodiments, the concentration of mannitol within the liposome is essentially the same as the concentration of mannitol in the medium outside the liposome. As used herein, the term "essentially the same" refers, in some embodiments, to a concentration difference of less than about 15%. In further embodiments, the term "essentially 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%, with each possibility representing a separate embodiment.

[0069] In some embodiments, the liposomes are not lyophilized. In further embodiments, the liposomes are not lyophilized and / or thawed prior to administration to the joint.

[0070] In some embodiments, the concentration of the polyol in the liposome composition ranges from about 0.5 to about 100 mg / mL, including each value within the specified range. In further embodiments, the concentration of the polyol ranges from about 1 to about 70 mg / mL, including each value within the specified range. In even further embodiments, the concentration of the polyol ranges from about 2.5 to about 60 mg / mL, including each value within the specified range. In still further embodiments, the concentration of the polyol ranges from about 5 to about 50 mg / mL, including each value within the specified range. In still further embodiments, the concentration of the polyol ranges from about 30 to about 50 mg / mL, including each value within the specified range. In specific embodiments, the concentration of the polyol ranges from about 5 to about 30 mg / mL, including each value within the specified range.

[0071] In some embodiments, the concentration of mannitol in the liposome composition ranges from about 1 mg / mL to about 70 mg / mL, including each value within the specified range. In further embodiments, the concentration of mannitol ranges from about 10 mg / mL to about 70 mg / mL, including each value within the specified range. In still further embodiments, the concentration of mannitol ranges from about 10 mg / mL to about 50 mg / mL, including each value within the specified range. In certain embodiments, the concentration of mannitol is about 40 mg / mL. In additional embodiments, the concentration of mannitol is about 20 mg / mL.

[0072] In some embodiments, the concentration of glycerol in the liposome composition ranges from about 0.5 mg / mL to about 50 mg / mL, including each value within the specified range. In further embodiments, the concentration of glycerol ranges from about 1 mg / mL to about 40 mg / mL, including each value within the specified range. In still further embodiments, the concentration of glycerol ranges from about 5 mg / mL to about 30 mg / mL, including each value within the specified range. In certain embodiments, the concentration of glycerol is about 20 mg / mL. In additional embodiments, the concentration of glycerol is about 10 mg / mL.

[0073] In some embodiments, the concentration of the polyol in the liposome composition ranges from about 50 to about 500 mM, including each value within the specified range. In further embodiments, the concentration of the polyol ranges from about 100 to about 400 mM, including each value within the specified range. In still further embodiments, the concentration of the polyol ranges from about 200 to about 300 mM, including each value within the specified range. The polyol can be selected from mannitol and glycerol.

[0074] In some embodiments, the polyol is present in the liposome composition at a weight percent ranging from 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 percent of the polyol is about 4% (w / w). In additional embodiments, the weight percent of the polyol is about 2% (w / w).

[0075] In some embodiments, mannitol is present in the liposome composition at a weight percent 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 percent of mannitol is about 4% (w / w).

[0076] In some embodiments, glycerol is present in the liposome composition at a weight percent ranging from about 0.05% (w / w) to about 5% (w / w) of the total weight of the liposome composition, or from about 0.5% (w / w) to about 5% (w / w), including each value within the specified range. In certain embodiments, the weight percent of glycerol is about 2% (w / w).

[0077] In some embodiments, the liposome composition administered to a subject comprises about 10 mg to about 700 mg of polyol, including any value within the specified range. In some embodiments, the liposome composition comprises about 20 mg to about 500 mg of polyol, including any value within the specified range. In additional embodiments, the liposome composition comprises about 20 mg to about 350 mg of polyol, including any value within the specified range. In further embodiments, the liposome composition comprises about 40 mg to about 250 mg of polyol, including any value within the specified range. In some embodiments, the liposome composition comprises about 10 mg to about 175 mg of polyol, including any value within the specified range. In further embodiments, the liposome composition comprises about 20 mg to about 125 mg of polyol, including any value within the specified range. In some embodiments, the liposome composition comprises about 40 mg to about 700 mg of polyol, including any value within the specified range. In further embodiments, the liposome composition comprises about 100 mg to about 500 mg of polyol, including any value within the specified range.

[0078] In some embodiments, the liposome composition comprises about 20 mg to about 350 mg of mannitol, including each value within the specified range. In some embodiments, the liposome composition comprises about 40 mg to about 250 mg of mannitol, including each value within the specified range. In certain embodiments, the liposome composition comprises about 120 mg of mannitol. In other embodiments, the liposome composition comprises about 40 mg of mannitol. In additional embodiments, the liposome composition comprises about 250 mg of mannitol.

[0079] In some embodiments, the liposome composition has an osmolality ranging from about 200 to about 600 mOsm, including each value within the specified range. In further embodiments, the liposome composition has an osmolality ranging from about 250 to about 500 mOsm, including each value within the specified range. In further embodiments, the liposome composition has an osmolality ranging from about 250 to about 400 mOsm, including each value within the specified range. In certain embodiments, the liposome composition has an osmolality of about 300 mOsm. In certain such embodiments, the liposome composition is isotonic.

[0080] In some embodiments, the weight ratio of liposomes to polyol ranges from about 30:1 to about 1:2, including all ratio values ​​within the specified range. In further embodiments, the weight ratio of liposomes to polyol ranges from about 15:1 to about 2:1, including all ratio values ​​within the specified range. In still further embodiments, the weight ratio of liposomes to polyol ranges from about 10:1 to about 2:1, including all ratio values ​​within the specified range. In still further embodiments, the weight ratio of liposomes to polyol ranges from about 6:1 to about 2:1, including all ratio values ​​within the specified range. In additional embodiments, the weight ratio of liposomes to polyol ranges from about 10:1 to about 6:1, including all ratio values ​​within the specified range.

[0081] In some embodiments, the weight ratio of liposomes to mannitol ranges from about 10:1 to about 1:1, including all ratio values ​​within the specified range. In further embodiments, the weight ratio of liposomes to mannitol ranges from about 6:1 to about 2:1, including all ratio values ​​within the specified range. In certain embodiments, the weight ratio of liposomes to mannitol is about 4:1.

[0082] In some embodiments, the weight ratio of liposomes to glycerol ranges from about 15:1 to about 2:1, including all ratio values ​​within the specified range. In further embodiments, the weight ratio of liposomes to glycerol ranges from about 12:1 to about 2:1, including all ratio values ​​within the specified range. In still further embodiments, the weight ratio of liposomes to glycerol ranges from about 10:1 to about 6:1, including all ratio values ​​within the specified range.

[0083] The pH of the liposome composition can range from about 5 to about 8, including each value within the specified range. In some embodiments, the pH ranges from about 6 to about 7, including each value within the specified range. In certain embodiments, the pH of the liposome composition is about 6.5.

[0084] In some embodiments, the pH of the liposome composition can be adjusted by the use of an inorganic acid or an inorganic base. Non-limiting examples of suitable inorganic acids include hydrochloric acid and sulfuric acid. Each possibility represents a separate embodiment. Non-limiting examples of suitable inorganic bases include sodium hydroxide and potassium hydroxide. Each possibility represents a separate embodiment.

[0085] According to some embodiments, the liposome composition consists essentially of a non-ionic tonicity agent, including a polyol, liposomes, and a fluid medium in which the liposomes are suspended, as described herein. In some embodiments, the term "consisting essentially of" refers to a composition in which the only active ingredient is the specified active ingredient (i.e., liposomes), although other substances may be included to stabilize, preserve, or control the osmolality, viscosity, and / or pH of the formulation, but which are not directly involved in the therapeutic effect of the liposomes and / or phospholipids. In some embodiments, the term "consisting of" refers to a composition comprising liposomes, a tonicity agent, a fluid medium, and a pharmaceutically acceptable excipient.

[0086] The liposome compositions according to various embodiments of the present invention can be sterilized and, if desired, mixed with auxiliary substances that do not adversely react with the liposomes, such as preservatives, stabilizers, wetting agents, synthetic emulsifiers, additional salts that affect osmotic pressure, coloring agents, and / or fragrances.

[0087] In accordance with the principles of the present invention, the liposome compositions disclosed herein are useful in a method for treating pain or inflammation in a joint in a subject with an arthropathy, the method comprising administering the liposome composition into 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. As used herein, the term "single dose" means that one dose of the liposome composition effectively relieves pain or inflammation in a subject's joint for an extended period of time. As used herein, the term "long-term" refers, in some embodiments, to a period of more than 3 months. In a further embodiment, the term "long-term" refers to a period of at least 4 months. In yet a further embodiment, the term "long-term" refers to a period of at least 5 months. In yet a further embodiment, the term "long-term" refers to a period of at least 6 months. In yet a further embodiment, the term "long-term" refers to a period of at least 26 weeks. In yet a further embodiment, the term "long-term" refers to a period of at least 7 months. In yet a further embodiment, the term "long-term" refers to a period of at least 8 months. In yet a further embodiment, the term "long-term" refers to a period of at least 9 months. In yet further embodiments, the term "long-term" refers to a period of at least 10 months. In yet further embodiments, the term "long-term" refers to a period of at least 11 months. In yet further embodiments, the term "long-term" refers to a period of at least 12 months. According to some embodiments, the single dose provides pain relief to a subject for at least 4 months after administration. According to further embodiments, the single dose provides pain relief to a subject for at least 5 months after administration. According to still further embodiments, the single dose provides pain relief to a subject for at least 6 months after administration. According to yet other embodiments, the single dose provides pain relief to a subject for at least 7 months after administration. According to still further embodiments, the single dose provides pain relief to a subject for at least 8 months after administration.According to additional embodiments, the single dose provides pain relief to the subject for at least 9 months after administration. According to some embodiments, the single dose provides pain relief to the subject for at least 10 months after administration. According to further embodiments, the single dose provides pain relief to the subject for at least 11 months after administration. According to yet further embodiments, the single dose provides pain relief to the subject for at least 12 months after administration. According to some embodiments, the liposome composition and single dose are administered no more frequently than once every 6 months. According to some embodiments, the liposome composition and single dose are administered no more frequently than once every 8 months. According to certain embodiments, the method does not include administering an additional dose of liposome composition to the joint cavity. In some embodiments, the liposome composition and single dose provides perceptible pain relief to the subject.

[0088] In other embodiments, the composition is administered once every 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more. Each possibility represents a separate embodiment. In accordance with the principles of the present invention, the benefit (i.e., pain relief) provided by the composition persists for a period of at least 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more. Each possibility represents a separate embodiment.

[0089] In accordance with the principles of the present invention, the liposome composition provides treatment for subjects with joint disorders. As used herein, the term "joint disorder" should be considered to mean any affliction (congenital, autoimmune, or otherwise), injury, or disease of the joint area that causes joint degeneration, pain, decreased mobility, inflammation, irritation, or physiological destruction and dysfunction. This disorder may be associated with decreased joint secretion and lubrication and may result from complications of knee or hip replacement surgery. As used herein, the term "treat" is intended to encompass pain relief.

[0090] Specific joint disorders within the scope of the present invention include, but are not limited to, deficiencies in joint secretion and / or lubrication due to arthritis such as joint erosion conditions in rheumatoid arthritis, osteoarthritis, osteoarthritis in rheumatoid arthritis patients, traumatic joint injuries (including sports injuries), joint immobilization (such as in the temporomandibular joint (TMJ)), post-arthrocentesis conditions, arthroscopic surgery, open joint surgery such as knee or hip replacement in mammals, preferably humans, etc. In certain embodiments, the joint disorder is osteoarthritis.

[0091] In some embodiments, the liposome compositions are useful for reducing knee joint pain in patients with osteoarthritis.

[0092] In accordance with the principles of the present invention, treatment of joint pain or inflammation includes a reduction in at least one of the following, compared to baseline or untreated controls: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) B stiffness score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) C disability score, Patient Global Assessment of Disease Activity (PtGA) by visual analog scale (VAS), weekly mean daily global pain score by visual analog scale (VAS), weekly mean daily joint pain score by visual analog scale (VAS), cumulative amount of rescue medication used for pain relief, and urinary collagen C-terminal cross-linked telopeptide (CTX) type II levels. Each possibility represents a separate embodiment. Pain relief can be further assessed by various pain assessment methods known in the art, including, but not limited to, the OMERACT OARSI response criteria and the Patient Acceptable Symptom Status (PASS). Each possibility represents a separate embodiment.

[0093] As used herein, the term "baseline" refers to the period of time before treatment with a liposomal composition of the present invention is initiated. In certain embodiments, the term "baseline" as used herein refers to the period of time before treatment with a liposomal composition of the present invention is initiated, e.g., 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 a separate embodiment.

[0094] 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 is 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 a separate embodiment.

[0095] According to other aspects and embodiments, the subject has a weekly mean baseline daily VAS joint pain score of ≥ 50 mm. According to further aspects and embodiments, the subject has a weekly mean baseline daily VAS joint pain score of ≥ 50 mm to ≤ 90 mm, including each value within the specified range. For example, the weekly mean baseline daily VAS joint pain score is about 55 mm, about 60 mm, about 65 mm, about 70 mm, about 75 mm, about 80 mm, about 85 mm, or about 90 mm. Each possibility represents a separate embodiment.

[0096] In certain embodiments, the therapeutic effect is compared with an untreated control.As used herein, the term "control" refers to a subject with untreated joint disorders.In one embodiment, the subject with joint disorders is not treated with the composition of the present invention.In another embodiment, the subject with joint disorders is not treated with a therapy known to be used for joint disorders.

[0097] According to some embodiments, the subject's BMI is about 40 kg / m2 In another embodiment, the subject's BMI is about 35 kg / m 2 In yet another embodiment, the subject's BMI is about 35 kg / m 2 In additional embodiments, the subject's BMI is less than about 30 kg / m 2 According to a further embodiment, the subject's BMI is about 30 kg / m 2 In other embodiments, the subject's BMI is less than about 29 kg / m 2 In a further embodiment, the subject's BMI is less than about 28 kg / m 2 In additional embodiments, the subject's BMI is less than about 27 kg / m 2 In yet other embodiments, the subject's BMI is less than about 26 kg / m 2 In certain embodiments, the subject's BMI is less than about 25 kg / m 2 In various embodiments, the subject's BMI is about 18.5 to about 30 kg / m 2 In another embodiment, the subject's BMI is between about 18.5 and about 25 kg / m 2 In yet another embodiment, the subject's BMI is in the range of about 30 to about 35 kg / m 2 The range is inclusive of each value in the specified range.

[0098] According to some embodiments, pain relief is represented by a relative change from baseline, i.e., a decrease in at least one of the scores detailed above. In some embodiments, pain relief is represented by a decrease in all of the aforementioned scores. For example, a joint disorder is considered treatable when at least one of the following decreases: joint pain VAS, total body pain VAS, WOMAC pain score, WOMAC stiffness score, WOMAC disability score, WOMAC composite score, PGA, rescue medication consumption, and urinary CTXII level by at least 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. Each possibility represents a separate embodiment.

[0099] According to certain embodiments, pain relief is represented by a reduction of at least 0.5 points from baseline or an untreated control as measured by the WOMAC pain score. According to other embodiments, pain relief is represented by a reduction of at least 0.75 points from baseline or an untreated control as measured by the WOMAC pain score. According to still other embodiments, pain relief is represented by a reduction of at least 1 point from baseline or an untreated control as measured by the WOMAC pain score. According to various embodiments, pain relief is represented by a reduction of at least 1 point from baseline or an untreated control as measured by the WOMAC pain score achieved at about 10 weeks to about 26 weeks after administration, including each value within the specified range. According to further embodiments, pain relief is represented by a reduction of at least 1 point from baseline or an untreated control as measured by the WOMAC pain score achieved at about 12 weeks after administration. According to additional embodiments, pain relief is represented by at least a 1-point reduction from baseline or untreated control as measured by the WOMAC pain score achieved at about 26 weeks after administration.

[0100] According to some embodiments, pain relief is represented by at least a one-point reduction from baseline or an untreated control, as determined by a WOMAC disability score achieved at about 10 weeks to about 26 weeks after administration, including each value within the specified range. According to certain embodiments, pain relief is represented by at least a one-point reduction from baseline or an untreated control, as determined by a WOMAC disability score achieved at about 12 weeks after administration. According to other embodiments, pain relief is represented by at least a one-point reduction from baseline or an untreated control, as determined by a WOMAC disability score achieved at about 26 weeks after administration.

[0101] According to various embodiments, pain relief is represented by at least a 5 mm reduction from baseline or an untreated control in the weekly average daily VAS joint pain score. According to certain embodiments, pain relief is represented by at least a 10 mm reduction from baseline or an untreated control in the weekly average daily VAS joint pain score. According to further embodiments, pain relief is represented by at least a 15 mm reduction from baseline or an untreated control in the weekly average daily VAS joint pain score. According to other embodiments, pain relief is represented by at least a 20 mm reduction from baseline or an untreated control in the weekly average daily VAS joint pain score. According to certain embodiments, pain relief is represented by at least a 30 mm reduction from baseline or an untreated control in the weekly average daily VAS joint pain score achieved from about 10 weeks to about 26 weeks after administration, including each value within the specified range. According to additional embodiments, pain relief is represented by at least a 30 mm reduction from baseline or an untreated control in daily joint pain scores measured by weekly average VAS, achieved at about 12 weeks after administration. According to further embodiments, pain relief is represented by at least a 30 mm reduction from baseline or an untreated control in daily joint pain scores measured by weekly average VAS, achieved at about 20 weeks after administration.

[0102] According to certain embodiments, pain relief is represented by a reduction of at least 30 from baseline or an untreated control as determined by patient global assessment achieved at about 10 weeks to about 26 weeks after administration, including each value within the specified range. According to some embodiments, pain relief is represented by a reduction of at least 30 from baseline or an untreated control as determined by patient global assessment achieved at about 12 weeks after administration. According to other embodiments, pain relief is represented by a reduction of at least 30 from baseline or an untreated control as determined by patient global assessment achieved at about 26 weeks after administration.

[0103] According to various embodiments, pain relief is represented by at least a 15-point decrease from baseline or untreated controls, measured as a weekly average of global pain, achieved at about 10 weeks to about 26 weeks after administration, including each value within the specified range. According to further embodiments, pain relief is represented by at least a 15-point decrease from baseline or untreated controls, measured as a weekly average of global pain, achieved at about 12 weeks after administration. According to additional embodiments, pain relief is represented by at least a 15-point decrease from baseline or untreated controls, measured as a weekly average of global pain, achieved at about 26 weeks after administration.

[0104] According to further embodiments, pain relief is manifested by a reduction in rescue medication consumption, including a reduction in oral administration of systemic analgesics such as, but not limited to, acetaminophen / paracetamol, NSAIDs, opioids, etc.

[0105] According to some embodiments, onset of pain relief is achieved from about 1 day to about 2 weeks after administration, including values ​​within the specified ranges. According to other embodiments, onset of pain relief is achieved from about 3 days to about 2 weeks after administration, including values ​​within the specified ranges. According to still other embodiments, onset of pain relief is achieved from about 4 days to about 1.5 weeks after administration, including values ​​within the specified ranges. According to specific embodiments, onset of pain relief is achieved about 1 week after administration.

[0106] According to various embodiments, maximum pain relief is achieved between about 3 weeks and about 26 weeks after administration, including values ​​within the specified ranges. According to other embodiments, maximum pain relief is achieved between about 4 weeks and about 26 weeks after administration, including values ​​within the specified ranges. According to additional embodiments, maximum pain relief is achieved between about 5 weeks and about 26 weeks after administration, including values ​​within the specified ranges. According to further embodiments, maximum pain relief is achieved between about 6 weeks and about 26 weeks after administration, including values ​​within the specified ranges. According to yet other embodiments, maximum pain relief is achieved between about 7 weeks and about 26 weeks after administration, including values ​​within the specified ranges. According to specific embodiments, maximum pain relief is achieved between about 6 and 7 weeks after administration, and the pain relief effect persists for at least 26 weeks.

[0107] In some embodiments, the liposome compositions disclosed herein result in a response rate of at least 30%, 40%, or 50% in subjects administered the liposome composition. Each possibility represents a separate embodiment. In certain embodiments, the liposome compositions disclosed herein result in a response rate of about 30% to about 50% in subjects administered the liposome composition, including each value within the specified range.

[0108] A joint according to the principles of the present invention may be any of the following: knee, hip, ankle, shoulder, elbow, tarsal, carpal, interphalangeal, and intervertebral. Each possibility represents a separate embodiment. In a specific embodiment, the joint is a knee joint.

[0109] In some embodiments, the liposome composition is in a form suitable for parenteral administration. Parenteral administration of the liposome composition of the present invention into a patient's joint cavity can be by a method selected from the group consisting of intra-articular injection, arthroscopic administration, and surgical administration. Each possibility represents a separate embodiment. Thus, in some embodiments, the liposome composition is formulated in a form suitable for administration by a route selected from intra-articular injection, arthroscopic administration, and surgical administration. Each possibility represents a separate embodiment. In some currently preferred embodiments, the liposome composition is administered by intra-articular injection.

[0110] The liposome compositions according to various embodiments of the present invention can be administered in a volume of about 0.5 mL to about 10 mL, including values ​​within the specified ranges. In further embodiments, the liposome compositions are administered in a volume of about 1 mL to about 6 mL, including values ​​within the specified ranges. In certain embodiments, the liposome compositions are administered in a volume of about 3 mL. In other embodiments, the liposome compositions are administered in a volume of about 1 mL. In additional embodiments, the liposome compositions are administered in a volume of about 6 mL. The compositions can be dispensed in vials or single injections or in any other manner suitable for practical use. The compositions can also be provided in prefilled syringes.

[0111] Subjects contemplated for administration of the liposome compositions of the present invention include mammals such as, but not limited to, humans and other primates.

[0112] In some embodiments, the therapeutic methods of the present invention provide therapeutic efficacy comparable to or greater than commercially available compositions, while reducing the incidence and / or 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, mobility impairment, muscle pain or stiffness, joint pain, and joint swelling or redness. Administration of the liposome compositions of the present invention in a single dose or once every 4-12 months reduces the incidence or severity of these side effects. In some embodiments, these side effects are completely avoided.

[0113] Thus, the present invention provides a method for improving tolerability of treatment in a subject with a joint disorder, 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 tolerability includes reducing the number of injections. In other embodiments, improving tolerability includes reducing the number of injection site reactions. In yet other embodiments, improving tolerability includes improving patient compliance.

[0114] Throughout the description and claims, the singular forms "a," "an," and "the" include the plural 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, plural words include reference to the singular unless the context clearly dictates otherwise. It should be noted that the term "and" or "or" is generally used in its sense to include "and / or" unless the context clearly dictates otherwise.

[0115] Throughout the description and claims of this specification, the words "comprise" and "contain," as well as variations of these words, such as "comprising" and "containing," mean "including but not limited to," and are not intended to exclude (or not exclude) other moieties, adjuncts, components, integers, or steps.

[0116] As used herein, the term "about," when referring to a measurable value such as an amount, time period, etc., is meant to encompass a variation of ±10%, more preferably ±5%, and even more preferably ±1% from the specified value, as such variations are appropriate in practicing the disclosed methods.

[0117] The following examples are presented to more fully illustrate some embodiments of the present invention. However, they should in no way be construed as limiting the broad scope of the invention. Those skilled in the art will be able to readily devise numerous variations and modifications of the principles disclosed herein without departing from the scope of the present invention. [Example]

[0118] Example 1 - Phase IIb Randomized Double-Blind Placebo-Controlled Single-Administration Multiple-Dose Study A phase IIb clinical trial was conducted to evaluate the safety and efficacy of a single intra-articular (IA) injection of a liposomal 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 liquid vehicle of the suspension contained a histidine buffer and a mannitol tonicity agent. A placebo sample containing the liquid vehicle without any liposomes served as a control.

[0119] Subject selection criteria: 1. Male or female, aged 40 years or older at the time of screening.

[0120] 2. Radiographic evidence of knee OA in a standing AP view in conjunction with a fixed flexion frame (e.g., Synaflexor) confirmed by Kellgren-Lawrence KL grade 2 or 3 of the index knee on an x-ray taken within the past 12 months.

[0121] 3. Chronic OA of the index knee confirmed by American College of Rheumatology (ACR) criteria (clinical and radiological) at screening.

[0122] 4. Presence of index knee pain for at least 6 months prior to screening.

[0123] 5. WOMAC pain (index knee) severity (range 0-4, average of five questions) pain score ≥ 2 in the last 24 hours prior to screening and baseline.

[0124] 6. Pain severity (index knee) with a VAS pain score of 50 mm or more and 90 mm or less for at least 5 of the 7 days prior to baseline.

[0125] 7. Index knee pain for more than 15 days in the month prior to screening.

[0126] 8. Previous inadequate response or intolerance to acetaminophen / paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs).

[0127] 9. Ability and willingness to use only acetaminophen / paracetamol (no more than 4 grams daily) as rescue analgesic for knee pain.

[0128] 10. Non-pharmacological treatments, if applicable, given at regular intervals from 4 weeks prior to IP initiation through the end of the study.

[0129] 11. Use of topical analgesics (excluding index knee) and nasal or inhaled corticosteroids, if applicable, at a stable dose and regimen for at least 2 months prior to enrollment and continued throughout the study period.

[0130] Primary endpoint: Change from baseline in WOMAC A pain score at week 12 to determine the dosage of the liposomal composition.

[0131] Secondary endpoints Secondary efficacy endpoints were the change from baseline in the following:

[0132] - WOMAC A pain score at week 26 and over time.

[0133] - WOMAC stiffness and disability subscores at weeks 12, 26, and over time.

[0134] - Weekly mean daily VAS knee pain scores at Weeks 12, 26, and over time.

[0135] - Weekly mean VAS daily global pain score at Weeks 12, 26, and over time.

[0136] PtGA of disease activity at Week 12, Week 26, and over time.

[0137] - Cumulative weekly use of rescue medications (acetaminophen / paracetamol) at Week 12, Week 26, and over time.

[0138] Exploratory Endpoints : - 30% and 50% improvement in WOMAC A pain score from baseline.

[0139] - Pharmacokinetic endpoints.

[0140] Test Design and Statistics: Subjects were randomly assigned to arms A to F according to the following criteria: 1) BMI < 30 kg / m 2 , 30 kg / m 2 BMI < 35 kg / m 2 , and BMI ≥ 35 kg / m 2 BMI ≥ 40 kg / m 2Subjects with 1) were limited to 10% of the total number of subjects; and 2) index knee pain VAS ≦74, baseline VAS ≧75. BL WOMAC A pain score >2.0; SD=0.59. The change from baseline in WOMAC A pain scores of 0.80 for liposome suspension and 0.52 for placebo yielded a difference of 0.28 between groups. Power=80%, α=0.05. Approximately 72 subjects were assigned to each arm (Arms A, B, C, and E).

[0141] Subjects received a single IA joint injection of liposome suspension or placebo at the doses outlined below.

[0142] Arm A: single IA joint injection of liposome suspension (1 mL); Arm B: single IA joint injection of liposome suspension (3 mL); Arm C: single IA joint injection of liposome suspension (6 mL); Arm D: single IA joint injection of placebo (1 mL); Arm E: A single IA joint injection of placebo (3 mL); and Arm F: single IA joint injection of placebo (6 mL).

[0143] The primary efficacy endpoint was analyzed using a mixed-effects model (MMRM) with fixed effects for treatment group, study visit, treatment-visit interaction, center, and baseline covariates. Treatment differences were estimated for all active arms (A, B, C) versus placebo 3 mL (arm E) estimated by least-squares means from the analytical model, along with 95% confidence intervals and associated two-sided p-values. The study design is shown schematically in Figure 1.

[0144] Efficacy assessment: Knee joint examination A blinded investigator performed knee evaluations of both knees at screening, baseline, and follow-up. At screening and baseline, the index knee was inspected for deformity, bruising, open wounds (i.e., abrasions), or surgical scars suggestive of prior knee surgery, such as reconstructive surgery or total knee arthroplasty. The index knee was palpated to determine erythema or the amount of knee joint fluid. Erythema or moderate (or excessive) knee joint fluid suggested conditions such as inflammatory arthropathy, and the subject was excluded from the study.

[0145] Patients underwent radiography and WOMAC pain assessment at screening. Selection of the index knee was based on screening and baseline pain reports (WOMAC and daily pain over the past 7 days) and KL grade. If eligible based on radiography, daily pain scores over the past 7 days, and other knee-specific criteria, the knee with the highest baseline WOMAC pain score was selected as the index knee. If the knee with the highest baseline pain score did not meet the KL or daily pain criteria, exclusion criterion 1 (moderate / severe pain in the non-target knee) was applied, and the subject failed screening, regardless of the eligibility of the other knees.

[0146] WOMAC assessment of knee osteoarthritis The WOMAC survey consists of 24 items divided into three subscales: pain (5 items), stiffness (2 items), and physical function (17 items). Participants were asked a wide range of questions about their knee pain, knee stiffness, and ability to perform daily activities such as using stairs, rising from a sitting position, lying in bed, and performing light or heavy household chores. All items were rated on a scale of 0 to 4 (lower scores indicated lower levels of symptoms or disability). Values ​​were summed as a composite WOMAC score (WOMAC total score) or subscores (e.g., WOMAC A pain score), and means were calculated for the total and subscores on a 0 to 4 scale. Higher scores indicated greater levels of pain, stiffness, and functional limitation.

[0147] Weekly average daily knee pain measured by VAS Subjects were asked, "By tapping the line, please indicate how much pain you have had in your <left / right> knee on average over the past 24 hours." Subjects answered the question on a VAS scale (0-100), with lower numbers on the scale indicating less knee pain experienced.

[0148] Weekly average of daily overall pain scores by VAS Subjects were asked, "Tap the line to indicate the average overall pain level experienced over the past 24 hours." Subjects answered the question on a VAS scale (0-100), with lower numbers indicating less overall pain experienced.

[0149] Patient Global Assessment of Disease Activity Subjects rated their current overall status of symptomatic knee OA using a VAS ("Taking into account all the effects that knee osteoarthritis has had on you, please tap the line to indicate how you have been doing over the past 24 hours, on average.").

[0150] Exploratory Biomarkers To assess osteoarthritis biomarkers, blood samples were collected and analyzed to measure serum levels of MMPs, ADAMTS-4, ADAMTS-5, and huARGS, and urine samples were collected to measure fasting urinary levels of CTXI and CTXII.

[0151] Pharmacokinetic evaluation Pharmacokinetic (DMPC and DPPC) sampling was performed at selected centers. Subjects underwent additional blood draws for pharmacokinetic measurements before IP (baseline) and at 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.

[0152] Safety rating: Adverse events (AEs) were determined using clinical laboratory assessments, including blood chemistry, hematology, and urinalysis, electrocardiogram evaluations including computerized 12-lead ECG recordings, physical examinations, and vital signs. Any relevant observations made at screening and baseline visits (including screening laboratory results and up to the single dose of IP) were recorded in the AE eCRF but were not considered treatment-emergent AEs (TEAEs) and were reported separately. Any relevant observations after the single dose of IP were recorded as AEs in the subject's AE eCRF. AEs related to pre-existing conditions were recorded only if the pre-existing condition worsened during the study, based on its nature, severity, or frequency. AE severity was characterized as follows: mild—if the AE was easily tolerated; moderate—if the AE was so bothersome that it interfered with daily activities; severe—if the AE interfered with normal daily activities; life-threatening—if the subject was at risk of death when the AE occurred; and death—if death was related to the AE.

[0153] result: Similarities were observed among the six study arms. Discontinuation rates were low and comparable across arms. The 6 mL liposomal suspension arm (Arm C) and the 3 mL placebo arm (Arm E) had relatively high discontinuation rates. However, discontinuations were not due to AEs. Figure 2 shows the distribution of treated subjects according to randomized treatment, where N indicates the number of subjects. Table 1 shows baseline disease characteristics. Groups were comparable for baseline disease parameters. For WOMAC A pain scores, most arms had a higher number of subjects in the ≤2.40 score group, except for Arms C and F, where the distribution of WOMAC pain groups was similar.

[0154] Table 1 [Table 1]

[0155] Table 2 shows the analysis of the change in WOMAC A (pain) from baseline to week 12. The unadjusted p-values ​​showed a statistically significant reduction in Arm B (3 mL liposome suspension) compared to placebo (Figure 3).

[0156] Table 2 [Table 2]

[0157] Table 3 shows the analysis of changes in WOMAC C (physical function) from baseline to weeks 12 and 26. No statistically significant differences were observed between any of the active and placebo groups, but there were minimal numerical differences between arms A and B (1 mL and 3 mL liposome suspension) (Figure 4).

[0158] Table 3 [Table 3]

[0159] Table 4 shows the time course analysis of the change from baseline in the weekly average daily knee pain score. There were minimal numerical differences between Arm A and Arm B. However, both arms containing 1 mL and 3 mL of liposome suspension showed statistically significant reductions early (from week 6) that were consistently maintained through week 25. At week 26, only Arm B showed a statistically significant reduction (Figure 5).

[0160] Table 4 [Table 4]

[0161] Table 5 shows an analysis of the change from baseline in Patient Global Assessment of Disease Activity to Weeks 12 and 26. No statistically significant reduction was observed in any of the active arms at Week 12, but a statistically significant reduction was observed in Arm B, which contained 3 mL of liposome suspension, at Week 26 (Figure 6).

[0162] Table 5 [Table 5]

[0163] Weekly mean overall pain showed a strong benefit in arms A and B compared with placebo (Figure 7).

[0164] Table 6 shows the analysis of the change in weekly cumulative amount (mg) of rescue medication use from baseline to weeks 12 and 26. Both the 1 mL and 3 mL liposome groups showed a trend toward an overall decrease in rescue medication use. This decrease was greater in Arm A (1 mL group), which was statistically significant at weeks 12 and 26. Furthermore, this arm showed a statistically significant decrease as early as week 8, which was consistently maintained through week 26 (Figure 8).

[0165] Table 6 [Table 6]

[0166] Table 7 shows a summary of safety. The incidence of AEs and discontinuations due to AEs were similar in all groups. The incidence of study drug-related AEs was higher in the 6 mL active agent arm and the placebo arm (Arms C and F, respectively). The incidence of study procedure-related AEs was higher in Arms B and C. No treatment-related deaths or AESIs were reported. The incidence of SAEs was low and similar in all groups, and none were considered related to the study drug. Most AEs were mild to moderate in intensity.

[0167] Table 7 [Table 7]

[0168] Figure 9 shows the change in urinary biomarker CTX-II. The decrease in CTX-II observed in Arm B indicates a reduction in disease severity.

[0169] The liposomal suspension of the present invention was compared with published efficacy data for Zilretta®, a sustained-release corticosteroid composition approved for the treatment of osteoarthritic knee pain. Tables 8 and 9 show the change from baseline to week 12 in WOMAC A (pain) and WOMAC C (physical function), respectively. The reduction from baseline was greater with the liposomal suspension compared to Zilretta®. However, the liposomal composition placebo group showed a greater reduction in scores compared to Zilretta®.

[0170] Table 8 [Table 8]

[0171] Table 9 [Table 9]

[0172] No significant changes were observed in any of the biomarkers evaluated, with the exception of change from baseline in urinary CTX II levels, which showed a trend toward a decrease over time in the 3 mL liposome arm compared with placebo, reaching statistical significance at week 12 (P=0.041).

[0173] Table 10 shows the absolute number and percentage of subjects who achieved a 30% or greater and a 50% or greater reduction in WOMAC A pain scores. A higher 30% or greater response rate was observed in Arm A compared to Arm E at weeks 12, 16, and 20 (P<0.05), and in Arm B compared to Arm E at weeks 8 and 20 (P<0.05). A higher 50% or greater response rate was observed in Arm A compared to Arm E at weeks 1, 8, 16, 20, and 26 (P<0.05), in Arm B compared to Arm E at weeks 8, 16, 20, and 26 (P<0.05), and in Arm C compared to Arm E at weeks 1, 2, and 48 (P<0.05). Thus, a trend toward a 50% or greater response rate was observed for both 1 mL and 3 mL of the liposome suspension of the present invention, beginning at week 8 and continuing through week 26, demonstrating a higher response rate than treatment with 3 mL placebo. These values ​​were numerically higher in the 3 mL arm compared to the 1 mL arm of the liposomal suspension of the present invention at most time points.

[0174] Table 10 [Table 10]

[0175] TIFF2026503349000011.tif76168

[0176] Figures 10A-10B show mean baseline-adjusted plasma DMPC and DPPC concentrations up to 168 hours after IP administration based on modified pharmacokinetic analysis. Quantifiable levels of DMPC and DPPC were observed in pre-dose samples, suggesting that DMPC and DPPC are endogenous in the systemic circulation. There were no significant changes in plasma DMPC and DPPC concentrations from pre-dose to post-dose time points. Furthermore, baseline-adjusted DMPC and DPPC concentrations and exposures appeared comparable between the liposomal suspension of the present invention (arms A-C) and the corresponding placebo groups (arms D-F).

[0177] In summary, both arms A and B showed a trend toward a decrease in WOMAC A pain scores compared with arm E, with arm B showing a numerically greater decrease.

[0178] The unmultiplicity-adjusted P values ​​for the comparison with arm E at week 12 were arm B (P = 0.047) and arm A (P = 0.152). Sensitivity analysis of the primary efficacy endpoint based on the pooling of FAS and arms D, E, and F revealed that the baseline-adjusted WOMAC A pain score at week 12 was numerically lower in arm B than in arm E: -0.28 (-0.484, -0.068), P = 0.018 (multiplicity-adjusted), P = 0.009 (unadjusted).

[0179] Regarding changes in WOMAC A pain scores over time, both Arms A and B showed a trend toward a decrease compared with Arm E. The estimated treatment differences between Arms B and 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 values ​​unadjusted for multiplicity). Furthermore, comparing Arms B and E, numerical reductions were also observed at week 8 that persisted through weeks 12, 16, and 20 (P = 0.055, P = 0.051, P = 0.022, and P = 0.041, respectively). The reductions in Arms A and C were numerically lower than those in Arm B, and no differences were observed between Arms C and E.

[0180] Changes from baseline in WOMAC B stiffness scores did not differ between arms A, B, C, and E at any time point, except for a worsening (i.e., increase) score in arm C versus arm E at week 26 [0.28 (0.028, 0.535), P = 0.030].

[0181] There was a trend toward a decrease in the change from baseline in WOMAC C disability score in both Arms A and B compared with Arm E. At week 20, there was a numerically greater improvement (i.e., decrease) in score in Arm A compared with Arm E [-0.22 (-0.437, -0.010), P = 0.040].

[0182] For the change from baseline in weekly mean daily knee pain VAS scores, both Arms A and B showed an early and sustained trend toward a decrease over time compared with Arm E. Reductions in Arm A compared with Arm E were observed at weeks 3 and 4 and from weeks 6 to 25 [Week 25: -9.1 (-17.16, -1.02), P = 0.027]. Reductions in Arm B compared with Arm E were observed 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 Arm B compared with Arm A at most time points.

[0183] For the change from baseline in the weekly mean daily global pain VAS score, both Arms A and B tended to decrease over time compared with Arm E. Reductions in Arm A compared with Arm E were observed at Week 4, Weeks 6 to 17, and Weeks 20 to 26 [Week 26: -8.8 (-17.37, -0.30), P = 0.042]. Reductions in Arm B compared with Arm E were observed 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 in Arm C compared with Arm E were observed from Weeks 4 to 7 [Week 7: -8.2 (-16.14, -0.16), P = 0.046].

[0184] For the change from baseline in PtGA, both arms A and B showed a trend toward a decrease compared with arm E. The estimated treatment difference for arm B compared with arm E was -9.4 (-17.72, -1.08) at week 16, P = 0.027, and -9.1 (-17.63, -0.57) at week 26, P = 0.037.

[0185] WOMAC C disability scores tended to decrease from week 8 onwards in arms A, B and C compared with arm E.

[0186] The weekly cumulative use of rescue medications tended to be lower in Arms A, B, and C compared with Arm E. The largest difference in Arm A compared with Arm E was observed after Week 8 [Week 26: -1109.4 mg (-1855.37, -363.48), P = 0.004].

[0187] Changes from baseline in MMP-1, MMP-2, MMP-9, ADAMTS-4, ADAMTS-5, huARGS, and urinary CTX I concentrations were not different in arms A, B, or C compared with arm E at any time point (weeks 1, 2, or 4). The exceptions were: (1) the decrease in MMP-9 observed in arm A at week 2 was different from the increase observed in arm E [-41.90 μg / L (-79.065, -4.735), P = 0.027]; (2) the increase in ADAMTS-4 observed in arm B at week 1 was different from the decrease observed in arm E [895.4 pmol / mL (21.33, 1769.56), P = 0.045]; and (3) a decrease in CTX I observed in arm B at week 4 was different from the increase observed in arm E [-0.115 mg / mol (-0.2135, -0.0172), P = 0.021].

[0188] Regarding the change from baseline in urinary CTX II levels, a decreasing trend was observed over time in Arms B and E, with a difference of -96.1 mg / mol (-188.40, -3.89), P = 0.041, observed at Week 12.

[0189] The response rate of 30% or more was higher in Arm A compared with Arm 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 higher in Arm B compared with Arm E at week 8 (77.2% vs. 62.2%, P = 0.048) and week 20 (77.2% vs. 61.1%, P = 0.036).

[0190] For response rates of 50% or greater, starting at week 8 and continuing through week 26, there was a trend toward higher response rates in both arms A and B compared with arm E. These figures were numerically higher in arm B than in arm A at most time points. Compared with arm E, rates were higher in arm A 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). Compared with Arm E, higher rates were observed in Arm B 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). Compared with Arm E, higher rates were observed in Arm C 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).

[0191] Quantifiable levels of DMPC and DPPC were observed in pre-dose samples from all arms, suggesting that DMPC and DPPC are endogenous compounds in the systemic circulation. Baseline-adjusted pharmacokinetic parameters (C max and AUC) were comparable to or lower than those in the corresponding arms D, E, and F, suggesting that intra-articular administration of liposomes did not increase the systemic exposure of endogenous DMPC and DPPC levels.

[0192] The liposomes were safe and well-tolerated, with no differences in safety compared with placebo as assessed by adverse events (AEs), clinical laboratory assessments, vital signs, electrocardiograms, and physical examinations. A total of 526 treatment-related AEs were recorded in 253 subjects during the study period, with the following breakdown: 73.5% in Arm A, 57.0% in Arm B, 66.2% in Arm C, 53.6% in Arm D, 59.0% in Arm E, and 67.9% in Arm F. The majority of adverse events (>95%) were mild or moderate. A total of 15 treatment-related serious adverse events (SAEs) occurred in 11 subjects during the study period. All SAEs were isolated within each treatment group, except for two osteoarthritis SAEs in two subjects in Arm E. All SAEs were assessed as unrelated to the study.

[0193] No clinically significant overall changes occurred in hematology, chemistry, lipids, urinalysis, vital signs, or electrocardiograms. No differences were observed between the liposome and control arms in clinically significant abnormalities among individual post-dose safety clinical assessments. Observations rated as abnormal on physical examination were few and clinically significant, but did not differ in frequency between the liposome and placebo groups.

[0194] Thus, for the WOMAC A pain score (primary endpoint), no statistically significant difference was measured in any of the active arms using a multiplicity-adjusted p-value. However, using unadjusted p-values, a statistically significant reduction was measured when subjects were treated with 3 mL of liposome suspension. For the WOMAC C disability score, no statistically significant difference was observed in any of the active arms.

[0195] Weekly mean daily knee pain scores showed a statistically significant decrease early (week 6) in both active-agent arms receiving 1 mL and 3 mL liposome suspension. This decrease was maintained through week 25. A statistically significant decrease in patient global assessment was observed with 3 mL liposome suspension treatment at week 26. All three dose levels of the liposome composition showed a trend toward decreased rescue medication use, suggesting pain relief in treated subjects. Rescue medication use was observed to be lower for 1 mL liposome suspension than for 3 mL placebo from week 8 onward (P<0.05). Changes from baseline in urinary CTX II showed a trend toward a decrease over time in the 3 mL liposome arm, with a difference observed at week 12 compared with an increase in the 3 mL placebo arm (P=0.041). Pharmacokinetic results indicated that intravenous injection of liposome suspension did not increase systemic exposure of endogenous DMPC and DPPC. Finally, the liposomal suspension was shown to be well tolerated, with similar rates of AEs across arms, no treatment-emergent deaths, and no AEs of note reported. The incidence of significant adverse events (SAEs) was low and similar across arms, and none were related to the study drug.

[0196] Example 2 - Phase III Randomized, Double-Blind, Placebo-Controlled, Single-Dose Study A phase 3 clinical trial will be conducted to evaluate the safety and efficacy of a single dose 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 patients with symptomatic knee arthritis (OA). A placebo sample containing a liquid medium without liposomes will be used as a control.

[0197] Subject selection criteria: 1. Men or women aged 40 or over.

[0198] 2. OA of the index knee according to the American College of Rheumatology (ACR) criteria (clinical and radiological).

[0199] 3. The index knee has Kellgren-Lawrence (KL) grade 2 or 3 disease.

[0200] 4. Knee pain has been present for at least 6 months prior to screening and for more than 15 days in the last month prior to screening.

[0201] 5. Index knee WOMAC A pain score ≥ 2 at screening and baseline.

[0202] 6. Knee VAS pain score of 50mm or more and 90mm or less for at least 5 of the 7 days before baseline.

[0203] 7. Ability and willingness to use only rescue medications permitted by protocol, such as acetaminophen / paracetamol at a maximum tolerated dose of 4 g / day, for OA knee pain during the study period, except for the last 24 hours prior to scheduled study efficacy assessments.

[0204] 8. Discontinue oral nonsteroidal anti-inflammatory drugs (NSAIDs) at screening and throughout the study.

[0205] 9. Discontinue topical therapy (e.g., NSAIDs, capsaicin, lidocaine patches, etc.) applied to the index knee at screening and during the study period.

[0206] 10. Refrain from IA treatment / intervention in either knee during the study period.

[0207] Primary endpoint: - Change in weekly ADP score from baseline to Week 12.

[0208] Secondary endpoints: - Change in WOMAC A pain score from baseline to week 12.

[0209] In addition, other secondary endpoints include:

[0210] - Change in weekly ADP score from baseline to Weeks 4, 8, 16, 20, 26, 30, 38, 46, and 52.

[0211] - Change in WOMAC A pain score from baseline to weeks 4, 8, 16, 20, 26, 30, 38, 46, and 52.

[0212] - Percentage of patients with a 30% and 50% improvement in weekly ADP scores from baseline to weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0213] - Percentage of patients with a 30% and 50% improvement in WOMAC A pain score from baseline to Weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0214] - Change in WOMACB stiffness score from baseline to weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0215] - Change in WOMACC physical function score from baseline to weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0216] - Change in PtGA of disease activity from baseline to weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0217] Change in weekly cumulative rescue medication use from baseline to weeks 4, 8, 12, 16, 20, 26, 30, 38, 46, and 52.

[0218] Safety Endpoints: Safety and tolerability will be assessed through medical history, physical examination (including vital signs), and laboratory tests. The nature, frequency, and severity of adverse events (AEs), treatment-related adverse events (TEAEs), and serious adverse events (SAEs).

[0219] Exploratory endpoints: -Change from baseline in urinary CTX-II over time.

[0220] Study Design and Statistics: After screening, eligible subjects will be randomized (2:1) to receive either 3 mL of the liposomal composition of the present invention or placebo in the index knee on Day 1 (baseline). The primary efficacy assessment will be performed at Week 12. Efficacy and safety will be evaluated through Week 52, which represents the end of study (EoS).

[0221] Efficacy assessment: The primary analysis population constitutes the full analysis set (FAS), which includes all randomized subjects who received a single 3 mL dose of the liposome composition of the present invention or placebo. Following the intention-to-treat principle, subjects are analyzed based on the treatment to which they were randomized, regardless of the treatment they actually received.

[0222] WOMAC A, B, and C are measured using a 5-point Likert scale, weekly ADP scores are measured using a 100mm visual analog scale [VAS], and PtGA is measured using a 100mm VAS scale.

[0223] Example 3 - Phase III Randomized, Double-Blind, Placebo-Controlled, Continuous-Dose Study A phase 3 clinical trial will be conducted to evaluate the safety and efficacy of sequential 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 patients with symptomatic knee arthritis (OA). A placebo sample containing a liquid medium without liposomes will be used as a control.

[0224] Subject selection criteria: 1. Men or women aged 40 or over.

[0225] 2. OA of the index knee according to the American College of Rheumatology (ACR) criteria (clinical and radiological).

[0226] 3. The index knee has Kellgren-Lawrence (KL) grade 2 or 3 disease.

[0227] 4. Knee pain has been present for at least 6 months prior to screening and for more than 15 days in the last month prior to screening.

[0228] 5. Index knee WOMAC A pain score ≥ 2 at screening and baseline.

[0229] 6. Knee VAS pain score of 50mm or more and 90mm or less for at least 5 of the 7 days before baseline.

[0230] 7. Ability and willingness to use only rescue medications permitted by protocol, such as acetaminophen / paracetamol at a maximum tolerated dose of 4 g / day, for OA knee pain during the study period, except for the last 24 hours prior to scheduled study efficacy assessments.

[0231] 8. Discontinue oral nonsteroidal anti-inflammatory drugs (NSAIDs) at screening and throughout the study.

[0232] 9. Discontinue topical therapy (e.g., NSAIDs, capsaicin, lidocaine patches, etc.) applied to the index knee at screening and during the study period.

[0233] 10. Refrain from IA treatment / intervention in either knee during the study period.

[0234] 11. Physical therapy for OA must be stable for at least 4 weeks before IP administration and throughout the trial.

[0235] 12. If OA is treated with oral glucosamine, chondroitin, or other nutritional supplements, this must be stable for at least 4 weeks before IP administration and throughout the study.

[0236] Primary endpoint: - Change in weekly ADP score from baseline to Week 12.

[0237] Secondary endpoints: - Change in WOMAC A pain score from baseline to week 12.

[0238] In addition, other secondary endpoints include:

[0239] - Change in weekly ADP score from baseline to weeks 4, 8, 16, 20, and 26 for the first dose, and to weeks 30, 38, 46, and 52 for the second dose.

[0240] - Change in WOMAC A pain score from baseline to weeks 4, 8, 16, 20, and 26 for the first dose, and to weeks 30, 38, 46, and 52 for the second dose.

[0241] -Percentage of patients with a 30% and 50% improvement from baseline in weekly ADP scores through weeks 4, 8, 12, 16, 20, and 26 for the first dose, and through weeks 30, 38, 46, and 52 for the second dose.

[0242] - Percentage of patients with 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, and to weeks 30, 38, 46, and 52 for the second dose.

[0243] - Change in WOMAC B stiffness score from baseline to weeks 4, 8, 12, 16, 20, and 26 for the first dose, and to weeks 30, 38, 46, and 52 for the second dose.

[0244] - Change in WOMAC C physical function score from baseline to weeks 4, 8, 12, 16, 20, and 26 for the first dose, and to weeks 30, 38, 46, and 52 for the second dose.

[0245] - Change in PtGA of disease activity from baseline to weeks 4, 8, 12, 16, 20, and 26 for the first dose, and to weeks 30, 38, 46, and 52 for the second dose.

[0246] - Change in SF-36 from baseline to weeks 4, 8, 12, 16, 20, and 26 for the first dose, and to weeks 30, 38, 46, and 52 for the second dose.

[0247] - Change in weekly cumulative rescue medication use from baseline to weeks 4, 8, 12, 16, 20, and 26 for the first dose, and to weeks 30, 38, 46, and 52 for the second dose.

[0248] Safety Endpoints: Safety and tolerability will be assessed through medical history, physical examination (including vital signs), and laboratory tests. The nature, frequency, and severity of adverse events (AEs), treatment-related adverse events (TEAEs), and serious adverse events (SAEs).

[0249] Exploratory endpoints: -Change from baseline in urinary CTX-II over time.

[0250] Study Design and Statistics: After screening, eligible subjects are randomized (2:1) to receive an intra-articular (IA) injection of either 3 mL of the liposome composition of the present invention or placebo into the index knee on Day 1 (baseline, first dose) and Week 26 (second dose, per original randomization). Primary efficacy assessments are conducted at Weeks 12 and 26. Efficacy and safety are evaluated through Week 52, which represents the end of study (EoS).

[0251] Example 4 - Pharmacokinetic Study A pK study was performed to assess the systemic exposure and characterize the time-concentration curve in patients with symptomatic knee OA after a single intra-articular (IA) knee joint injection of liposomes containing 46.1 mg / mL DMPC and 60.2 mg / mL DPPC at 150 mM concentration suspended in a liquid medium containing mannitol and histidine buffer. A placebo sample containing a liquid medium without liposomes served as a control.

[0252] Subject selection criteria: 1. Knee pain has been present for at least 6 months prior to screening and for more than 15 days in the last month prior to screening.

[0253] 2. Discontinue oral or topical nonsteroidal anti-inflammatory drugs (NSAIDs) 48 hours prior to the scheduled knee joint injection.

[0254] 3. Index knee WOMAC A pain score ≥ 2 at screening and baseline.

[0255] 4. Knee VAS pain score of 50mm or more and 90mm or less for at least 5 of the 7 days before baseline.

[0256] 5. Ability and willingness to use only protocol-allowed rescue medications, such as acetaminophen / paracetamol at a maximum tolerated dose of 4 g / day, for OA knee pain during the study period, except for the last 24 hours prior to scheduled study efficacy assessments.

[0257] 6. Discontinue oral nonsteroidal anti-inflammatory drugs (NSAIDs) at screening and throughout the study.

[0258] 7. Discontinue any topical therapies (e.g., NSAIDs, capsaicin, lidocaine patches, etc.) applied to the index knee before baseline.

[0259] 8. Abstain from IA treatment / intervention in any joint during the trial.

[0260] Primary endpoint: Systemic levels and C in subjects with symptomatic knee OA after a single intra-articular injection of liposomes max PK characteristics such as:

[0261] Secondary endpoints: Safety and tolerability of liposomes in subjects with symptomatic knee OA after a single IA knee joint injection of liposomes.

[0262] Study Design and Statistics: After screening, eligible subjects are randomized (2:1) to receive either 3 mL of a liposome composition of the present invention or placebo in the index knee on Day 1 (baseline).

[0263] Systemic exposure and PK measurements will be performed at specified 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 will be performed until day 7 post-dose, which marks the end of study (EoS). On the day of injection, subjects may receive analgesics for up to 8 hours after IP injection.

[0264] It will be appreciated by those skilled in the art that the present invention is not limited to what has been particularly shown and described above. Rather, the scope of the present invention includes both combinations and subcombinations 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 particularly described embodiments, and the scope and spirit of the present invention will be more readily understood by reference to the following claims.

Claims

1. 1. A liposome composition for use in treating pain or inflammation in a joint of a subject with an arthropathy, the liposome composition comprising, as the sole active ingredient, a phosphatidylcholine (PC) selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythroC16, and combinations thereof, administered by intra-articular injection once or once every 4 to 12 months.

2. 2. The liposome composition for use according to claim 1, wherein the treatment of pain or inflammation in a joint in a subject with a joint disorder comprises a reduction in at least one of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) B stiffness score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) C disability score, Patient Global Assessment of Disease Activity (PtGA) by visual analogue scale (VAS), weekly mean daily global pain score by visual analogue scale (VAS), weekly mean daily joint pain score by visual analogue scale (VAS), 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.

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

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

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

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

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

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

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

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

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

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

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

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

18. 3. The liposome composition for use according to claim 2, wherein the subject has a baseline weekly mean daily joint pain score by VAS of ≧50 mm and a reduction in weekly mean daily joint pain score by VAS of at least 5.

19. 19. The liposome composition for use according to claim 18, wherein the subject has a baseline weekly mean daily joint pain score by VAS of ≧50 mm and a reduction in weekly mean daily joint pain score by VAS of at least 10.

20. 20. The liposome composition for use according to claim 19, wherein the subject has a baseline weekly mean daily joint pain score by VAS of ≧50 mm and a reduction in weekly mean daily joint pain score by VAS of at least 15.

21. 21. The liposome composition for use according to claim 20, wherein the subject has a baseline weekly mean daily joint pain score by VAS of ≧50 mm and a reduction in weekly mean daily joint pain score by VAS of at least 20.

22. 22. The liposome composition for use according to any one of claims 18 to 21, wherein the subject has a baseline weekly mean daily joint pain score by VAS 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. The 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. 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. 25. The liposome composition for use according to claim 24, wherein the liposome composition comprises DMPC at a weight percentage ranging from about 1% to about 10% by weight and DPPC at a weight percentage ranging from about 2% to about 12% by weight.

27. 25. 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 of about 0.5 mL to about 10 mL.

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

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

31. 31. The 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 (SUVs), large unilamellar vesicles (LUVs), giant unilamellar vesicles (GUVs), oligolamellar vesicles (OLVs), multilamellar vesicles (MLVs), multivesicular liposomes (MVLs), and mixtures or combinations thereof.

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

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

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

37. 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. 38. The liposome composition for use according to claim 37, wherein the weight ratio of said plurality of liposomes to said polyol ranges from about 6:1 to about 2:

1.

39. 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. The liposome composition for use according to any one of claims 1 to 39, wherein the joint disorder is osteoarthritis.

41. 1. A method for treating pain or inflammation in a joint in a subject with a joint disorder, the method comprising administering by intra-articular injection once or once every 4 to 12 months a liposome composition comprising, as the sole active ingredient, a phosphatidylcholine (PC) selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythroC16, and combinations thereof.

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

43. 1. Use of a liposome composition comprising, as the sole active ingredient, a phosphatidylcholine (PC) selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (C15), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), D-erythroC16, and combinations thereof, for the manufacture of a medicament for use in a method for treating pain or inflammation in a joint in a subject with a joint disorder, wherein the method comprises administering a single intra-articular injection of the liposome composition once or once every 4 to 12 months.

44. 44. The use of the liposome composition of claim 43, wherein the treatment of pain or inflammation in a joint in a subject with a joint disorder comprises a reduction in at least one of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) B stiffness score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) C disability score, Patient Global Assessment of Disease Activity (PtGA) by visual analog scale (VAS), weekly mean daily global pain score by visual analog scale (VAS), weekly mean daily joint pain score by visual analog scale (VAS), cumulative amount of rescue medications 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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