Sterile liposome-containing compositions and articles

Abstract

Described herein is a sterile composition comprising an aqueous carrier and liposomes, wherein the mean size and / or zeta potential of the liposomes change by no more than 20% over a period of 300 days, and a method of preparing the composition by exposing the aqueous composition comprising an aqueous carrier and liposomes to a temperature greater than 100° C. Also described is a method of preparing a sterile lipid-attached article of manufacture by contacting the article of manufacture with an aqueous composition comprising an aqueous carrier and liposomes and further exposing the article to a temperature greater than 100° C., as well as a sterile article of manufacture prepared according to the methods described herein. The liposomes comprise a bilayer-forming lipid and a polymeric compound having the formula: [Formula 1] TIFF2024530360000023.tif33120In the above formula, m, n, L, X, Y, and Z are as defined herein.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 238,831, filed August 31, 2021, U.S. Provisional Patent Application No. 63 / 278,123, filed November 11, 2021, and U.S. Provisional Patent Application No. 63 / 353,657, filed June 20, 2022, the contents of which are incorporated by reference in their entireties herein.

[0002] The present invention in some embodiments thereof relates to therapy, and more particularly, but not exclusively, to sterile liposomal compositions that can be used in the treatment of joint disorders, such as osteoarthritis. [Background technology]

[0003] Osteoarthritis, the most common form of arthritis, is a degenerative joint disease caused by the destruction of articular cartilage and the underlying bone, the most common symptoms of which are joint pain and stiffness. Conventional treatments include painkillers and anti-inflammatory drugs, as well as surgery such as bone fusion (e.g., in ankle arthritis) and artificial joint replacement.

[0004] In early osteoarthritis, there is no obvious cartilage lesion or complex abnormality that requires surgical management. For patients who do not have obvious signs of osteoarthritis but are considered to be at a stage that defines early osteoarthritis, several treatments have been proposed and are currently used in clinical practice [Luyten et al., Knee Surg Sports Traumatol Arthrosc 2012, 20:401-406]. Non-surgical treatments available for the management of early osteoarthritis include non-pharmacological therapies such as lifestyle modification, exercise, and physical therapy, nutritional supplements, and the use of pharmacological therapies such as analgesics, anti-inflammatory drugs, or slow-acting drugs, as well as the local administration of various substances by minimally invasive injection [Kon et al., Knee Surg Sports Traumatol Arthrosc 2012, 20:436-449].

[0005] Viscosupplementation involves intra-articular injection of hyaluronic acid (HA), a glycosaminoglycan that lubricates joints, absorbs shock, and acts as a scaffold for the proteoglycans of the extracellular matrix. Normal adult knees have HA concentrations of 2.5-4.0 mg / mL, whereas osteoarthritis reduces HA concentrations by 33-50% [Kon et al., Knee Surg Sports Traumatol Arthrosc 2012, 20:436-449]. However, there is no clear evidence that viscosupplementation affects the natural progression of osteoarthritis. Some reports have shown changes in serum and urinary biomarkers, but not in the structural composition of cartilage [Conrozier et al., J Orthop Res 2012, 30:679-685].

[0006] WO 2015 / 193888 describes a method for coating a surface with amphiphilic lipids by attaching a water-soluble polymer to the surface and contacting the water-soluble polymer with liposomes to reduce the coefficient of friction of the surface, as well as a method for treating synovial joint disorders associated with increased joint friction.

[0007] Injectable pharmaceutical compositions generally must be sterilized for use in the body. Steam sterilization (e.g., at 121-134°C under pressure) is commonly used because it is non-toxic, reliable, and inexpensive, but is not suitable for heat- and / or moisture-sensitive materials. Ethylene oxide gas is used to sterilize heat- and moisture-sensitive materials. Microfiltration with pore sizes of 0.22 μm can remove microorganisms, but smaller pore sizes (e.g., 20-50 nm) are required to remove viruses. Gamma (γ) radiation is highly penetrating and useful for sterilization, but has safety issues. Ultraviolet light is safer but has low penetrating properties, making it suitable for sterilizing surfaces and some transparent objects, and can damage some plastics.

[0008] Toh & Chiu [Asian J Pharm Sci 2013, 8:88-95] discuss sterilization of liposome compositions and disclose that filtration can be useful for sterilization, but is costly and laborious, and is only applicable to liposome systems with diameters less than 200 nm, and that ultraviolet irradiation, gamma irradiation, and steam sterilization can degrade liposomes.

[0009] Steam sterilization is also used to sterilize packaged contact lenses during their manufacture and during reuse.

[0010] WO 2015 / 193887 describes a formulation for rinsing and / or soaking contact lenses and / or for use in treating ocular discomfort (e.g., ocular discomfort associated with contact lenses), which formulation comprises at least one water-soluble polymer, liposomes, and an aqueous carrier.

[0011] WO 2017 / 109784 describes polymeric compounds comprising lipid and ionic polymeric moieties, such as pMPC (poly(O-(2-methacryloyloxyethyl)phosphorylcholine)) moieties, as well as bilayers and liposomes comprising such polymeric compounds in combination with bilayer-forming lipids. Bilayers and / or liposomes comprising such polymeric compounds are described as being useful for reducing the coefficient of friction of surfaces and / or inhibiting biofilm formation.

[0012] Further background art includes WO 2016 / 051413 and WO 2018 / 150429. Summary of the Invention

[0013] According to one aspect of some embodiments of the present invention, there is provided a sterile composition comprising an aqueous carrier and liposomes, the liposomes exhibiting a mean diameter and / or zeta potential of no more than 20% over a period of 300 days, and the liposomes are a) at least one bilayer-forming lipid, and b) a polymeric compound having the following general formula I: Includes. [ka] In the above formula, m is zero or a positive integer; n is an integer that is at least 1, and if X does not contain a phosphate group, then n is at least 2; X is a lipid moiety; Y is a backbone unit forming the polymer backbone; L is absent or a linking moiety; and Z has the general formula II, [ka] In the above formula, A is a substituted or unsubstituted hydrocarbon; B is an oxygen atom or is absent; and R 1 ~R 3 is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl, and heteroaryl.

[0014] According to an aspect of some embodiments of the present invention, there is provided a method of preparing a sterile composition according to any corresponding embodiment described herein, the method comprising: (i) providing an aqueous composition comprising an aqueous carrier and a liposome comprising at least one bilayer-forming lipid and a polymeric compound according to any corresponding embodiment described herein; (ii) exposing the aqueous composition to a temperature of greater than 100° C., thereby obtaining a sterile composition. Includes.

[0015] According to an aspect of some embodiments of the present invention there is provided a method of preparing a sterile article of manufacture having lipid attached to at least a portion of its surface, the method comprising: (i) contacting at least a portion of a surface of an article of manufacture with an aqueous composition comprising an aqueous carrier and liposomes, thereby obtaining an article of manufacture having lipids attached to at least a portion of its surface, the liposomes comprising: a) at least one bilayer-forming lipid, and b) A polymeric compound having the general formula I and (ii) exposing the article of manufacture having lipid attached to at least a portion of its surface to a temperature of greater than 100° C., thereby obtaining a sterile article of manufacture having lipid attached to at least a portion of its surface; Includes. [ka] In the above formula, m is zero or a positive integer; n is an integer that is at least 1, and if X does not contain a phosphate group, then n is at least 2; X is a lipid moiety; Y is a backbone unit forming the polymer backbone; L is absent or a linking moiety; and Z has the general formula II, [ka] In the above formula, A is a substituted or unsubstituted hydrocarbon; B is an oxygen atom or is absent; and R 1 ~R 3 is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl, and heteroaryl.

[0016] According to an aspect of some embodiments of the present invention there is provided a sterile article of manufacture prepared according to a method described herein according to any corresponding embodiment.

[0017] According to some of the corresponding embodiments of any of the present invention, the polydispersity index of the liposomes in the sterile composition is less than or equal to 0.2.

[0018] According to some of the optional embodiments of the present invention, the zeta potential of the liposomes is in the range of -40 to 40 mV or -10 to 10 mV.

[0019] According to some optional embodiments of the present invention, the molar ratio of bilayer-forming lipid to polymeric compound is in the range of 5:1 to 5,000:1.

[0020] According to some optional embodiments of the present invention, Y is a substituted or unsubstituted alkylene unit.

[0021] According to some optional embodiments of the present invention, Y is a substituted or unsubstituted ethylene unit.

[0022] According to some optional embodiments of the present invention, Y is of the formula -CR 4 R 5 -CR 6 D- has: If Y is a backbone unit that is not bound to L or Z, then D is R 7 and; When Y is a backbone unit bonded to L or Z, D is a covalent bond or linking group bonding Y to L or Z, the linking group being selected from the group consisting of -O-, -S-, alkylene, arylene, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, and amino; and R 4 ~R 7are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azido, azo, phosphate, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, and amino.

[0023] According to some optional embodiments of the present invention, B is an oxygen atom.

[0024] According to some optional embodiments of the present invention, A is a substituted or unsubstituted hydrocarbon that is 1 to 4 carbon atoms in length.

[0025] According to some of the optional embodiments of the present invention, R 1 ~R 3 are each independently hydrogen or C 1-4 -alkyl.

[0026] According to some optional embodiments of the present invention, n is at least 3.

[0027] According to some optional embodiments of the present invention, n is in the range of 5-150, or 5-100, or 5-50, and m is in the range of 0-50.

[0028] According to some of the optional embodiments of the present invention, the lipid moiety is selected from the group consisting of a fatty acid moiety, a monoglyceride moiety, a diglyceride moiety, a triglyceride moiety, a glycerophospholipid moiety, a sphingolipid moiety, and a sterol moiety.

[0029] According to some of the optional embodiments of the present invention, the lipid moiety comprises at least one fatty acid moiety selected from the group consisting of lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0030] According to some optional embodiments of the present invention, X has the general formula III: [ka] In the above formula, W 1 and W 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and acyl; W 1 and W 2 at least one of is not hydrogen; J is -P(=O)(OH)-O- or absent; K is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length, or is absent; M is a linking group selected from the group consisting of -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, and sulfonamido, or is absent; and Q is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length; If M is not present, then K is also not present.

[0031] According to some optional embodiments of the invention relating to formula III, J is -P(=O)(OH)-O- and K is selected from the group consisting of an ethanolamine moiety, a serine moiety, a glycerol moiety, and an inositol moiety.

[0032] According to some of the optional embodiments of the present invention relating to formula III, M is an amide.

[0033] According to some optional embodiments of the present invention relating to formula III, J and K are absent and M is carbonyl.

[0034] According to some of the optional embodiments of the invention relating to formula III, Q is dimethylmethylene (-C(CH 3 ) 2 -).

[0035] According to some of the optional embodiments of the present invention relating to formula III, W 1 and W 2 At least one of is an alkyl, alkenyl, alkynyl, or acyl having a length of 10 to 30 carbon atoms.

[0036] According to some of the optional embodiments of the present invention relating to a sterile composition, the sterile composition is for rinsing, cleaning, and / or soaking contact lenses.

[0037] According to some of the optional embodiments of the present invention directed to sterile compositions, the aqueous carrier is an ophthalmically acceptable carrier.

[0038] According to some of the optional embodiments of the present invention relating to a sterile composition, the sterile composition includes an article of manufacture immersed therein.

[0039] According to some of the optional embodiments of the present invention relating to an article of manufacture, the article of manufacture comprises a contact lens.

[0040] According to some of the optional embodiments of the present invention relating to a sterile composition, the sterile composition is capable of ameliorating pathological changes in knee tissue following intra-articular injection of the composition in an animal model of osteoarthritis.

[0041] According to some of these embodiments, the model is a rat medial meniscus destabilization model.

[0042] According to some of the optional embodiments of the invention relating to the sterile composition, the sterile composition is for use in the treatment of a synovial joint disorder, the treatment comprising intra-articular administration of the composition.

[0043] According to some of the optional embodiments of the present invention relating to the treatment of a synovial joint disorder, the synovial joint disorder is osteoarthritis.

[0044] According to some of the optional embodiments of the invention relating to the treatment of synovial joint disorders, the treatment is characterized by an improvement in joint physiology as measured by at least one of the Kellgren-Lawrence scale of radiological severity, range of motion, physical activity, and quality of life.

[0045] According to some of the optional embodiments of the present invention directed to the treatment of synovial joint disorders, the treatment is characterized by a reduction in pain.

[0046] According to some of the optional embodiments of the method, the temperature is in the range of 121-134°C.

[0047] The aqueous composition comprising an aqueous carrier and liposomes according to any of the embodiments of the invention relating to methods of preparing a sterile composition further comprises an article of manufacture immersed therein, such that upon exposure of the aqueous composition to a temperature above 100°C, the article of manufacture immersed in the aqueous composition becomes sterile.

[0048] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used to carry out or test embodiments of the present invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will prevail. Furthermore, the materials, methods, and examples are illustrative only and are not necessarily intended to be limiting.

[0049] Some embodiments of the present invention are herein described, by way of example only, with reference to the accompanying drawings. Reference will now be made specifically in detail to the drawings, and it will be emphasized that the specific details shown are by way of example and are for the purpose of illustrating embodiments of the invention. In this regard, the description taken together with the drawings will make apparent to those skilled in the art how embodiments of the invention may be practiced. [Brief description of the drawings]

[0050] [Figure 1] FIG. 1 is a graph showing the size distribution of liposomes in an exemplary composition (each of the three lines represents an individual measurement). [Diagram 2] Figure 2, A and B, show cryo-tunneling electron microscopy images of liposomes in an exemplary composition. [Diagram 3] FIG. 3 is a graph showing the zeta potential of liposomes in an exemplary composition as a function of time (black lines indicate initial value ±10%). [Figure 4] FIG. 4 is a graph showing the polydispersity index (PDI) of liposomes in an exemplary composition as a function of time (black line indicates PDI=15%). [Diagram 5] 5 is a graph showing the coefficient of friction in a simulated knee joint when tested in a pin-on-disk format for 500,000 cycles in the presence of an exemplary liposome-containing composition (Lipo 100%), calf calf serum (BCS 100%), or a mixture thereof containing 50% liposome-containing composition (50 / 50) or 25% liposome-containing composition (Lipo 25%). BCS 100% and 50 / 50 were tested in duplicate. The average value for all samples is also shown. [Figure 6] 6 is a graph showing the dynamic weight-bearing difference (side to side) at the indicated postoperative time points in a rat medial meniscus destabilization model of osteoarthritis. Rats were treated with intra-articular (IA) injections of AqueousJoint, Synvisc® (a commercially available HA injectable), or saline (vehicle control) on days 7, 21, 35, and 49 postoperatively. [Figure 7]7 is a graph showing the gait score in a rat medial meniscus destabilization model of osteoarthritis on postoperative day 10. Rats were treated with intra-articular (IA) injections of AqueousJoint, Synvisc® (a commercially available HA injectable), or saline (vehicle control) on postoperative day 7. [Figure 8] Figures 8A and B are graphs showing the change in friction response when fresh cartilage (Figure 8A) and frozen cartilage (Figure 8B) are exposed to two test solutions, synthetic lipid and hyaluronic acid, respectively. The same samples were alternately exposed to either the control (buffer) or the test solutions (control-test solution-control-test solution-control). The results show that the addition of synthetic lipid reduced the friction force to a greater extent than that observed with hyaluronic acid. [Figure 9] 9 is a graph showing wear tests performed using a pin-on-disk setup to demonstrate the wear-reducing performance of the AqueousJoint formulation described herein compared to a control calf serum standard solution. The results show that after 2 million cycles, the AqueousJoint formulation reduced wear by 5-fold compared to the control solution. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] The present invention in some embodiments thereof relates to therapy, and more particularly, but not exclusively, to sterile liposomal compositions that can be used in the treatment of joint disorders, such as osteoarthritis.

[0052] Before describing at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or illustrated by way of examples, as the invention is capable of other embodiments or of being practiced or carried out in various ways.

[0053] During the course of their investigations into liposome-containing solutions, the present inventors have serendipitously discovered that compositions comprising liposomes having lipid-derived polymeric compounds formed with a backbone consisting of backbone units containing both phosphate and ammonium ion groups are surprisingly stable to stabilization by, for example, heat treatment, which normally promotes liposome instability, characterized by liposome fusion and / or aggregation and / or a significant increase in liposome size.

[0054] As shown in the Examples section below, the present inventors have demonstrated that compositions containing liposomes containing such polymeric compounds show little change in liposome properties during sterilization and for approximately one year thereafter.

[0055] Thus, embodiments of the present invention relate to sterile compositions comprising liposomes and the preparation of such sterile compositions, as well as the use of such sterile compositions in a variety of applications, particularly applications where sterility is an important feature, such as the treatment of synovial joint disorders (e.g., osteoarthritis) involving intra-articular administration of the composition, and in contact lens solutions and the treatment of contact lens surfaces.

[0056] Sterile composition: According to an aspect of some embodiments of the present invention, there is provided a sterile composition comprising an aqueous carrier and a liposome, the liposome comprising at least one bilayer-forming lipid and a polymeric compound according to any corresponding embodiment described herein.

[0057] The term "sterile" as used herein refers to no observed microbial growth when the composition is subjected to conditions (e.g., medium, incubation temperature) for an appropriate period of time, for example according to any standard protocol for testing sterility. Optionally, the composition is sterile when sterility is tested in liquid thioglycolate medium, for example at a temperature ranging from 30 to 35°C for up to 3 days, and / or in soybean casein digest medium (also known as trypticase soy broth or trypticase soy agar), for example at a temperature ranging from 20 to 25°C for up to 5 days, for example, whereby no microbial growth is observed in either medium. The contents of the liquid thioglycolate medium and / or the soybean casein digest medium and / or the sterility testing procedures may optionally be as described in the United States Pharmacopeia Chapter 71, the contents of which are incorporated herein by reference.

[0058] In some of the embodiments described herein, the sterile composition is further characterized by a bacterial endotoxin concentration below an acceptable threshold, for example below a threshold of 35 endotoxin units (EU) / mL (for example, endotoxin units are defined according to the United States Pharmacopeia standard). Bacterial endotoxin levels can be determined by any suitable test known in the art, for example, by comparison with a commercially available reference sample containing endotoxin, for example, using a Limulus amebocyte lysate (for example, according to the United States Pharmacopeia Chapter 85, the contents of which are incorporated herein by reference).

[0059] In some of the embodiments described herein, the polydispersity index (PDI) of the liposomes in the sterile composition is 0.2 or less, optionally 0.15 or less, or 0.1 or less, or even 0.05 or less.

[0060] In some of the embodiments described herein, the average diameter of the liposomes ranges from 20 to 1000 nm, optionally from 50 to 300 nm.

[0061] In some embodiments of any of the embodiments described herein, the liposomes have an average diameter of at least 100 nm, e.g., 100-1000 nm, or 100-300 nm. In some embodiments, the liposomes have an average diameter of at least 125 nm, e.g., 125-1000 nm, or 125-300 nm. In some embodiments, the liposomes have an average diameter of at least 150 nm, e.g., 150-1000 nm, or 150-300 nm.

[0062] Without being bound to a particular theory, it is believed that a liposome diameter of at least about 100 nm provides increased residence time in vivo and is therefore particularly suitable for sterile compositions intended for in vivo use (according to any corresponding embodiment described herein).

[0063] In some of the embodiments described herein, the change in mean diameter of the liposomes in the sterile composition is no more than 20% over 300 days (e.g., at room temperature), and optionally no more than 15%, or no more than 10%, or even no more than 5% over 300 days (e.g., at room temperature).

[0064] The mean diameter according to any corresponding embodiment described herein may optionally be the arithmetic mean (ratio of the sum of values ​​to the number of values) or the Z-average as this term is defined in the art of dynamic light scattering (simply put, the intensity-weighted harmonic mean). In an exemplary embodiment, the mean diameter is the Z-average diameter determined by dynamic light scattering.

[0065] The polydispersity index (PDI) and / or mean diameter of the liposomes in the composition may optionally be determined (e.g., using commercially available equipment) by dynamic light scattering using a two-parameter fit to the data (e.g., according to ISO 13321 and ISO 22412 standards) to determine PDI and Z-average diameter.

[0066] In some of the embodiments described herein, the zeta potential of the liposomes in the sterile composition is at least -3 mV (ie, -3 mV or lower), optionally at least -3.5 mV, and optionally at least -4 mV.

[0067] In some of the embodiments described herein, the zeta potential of the liposomes in the sterile composition is in the range of 40 to -40 mV, or 30 to -30 mV, or 20 to -20 mV, or 15 to -15 mV, or 10 to -10 mV (e.g., 5 to -5 mV), optionally in the range of 0 to -10 mV (e.g., 0 to -5 mV, or -3 to -5 mV).

[0068] Without being bound by any particular theory, it is believed that liposomes in the indicated range, e.g., a zeta potential in the range of 10 to −10 mV, are typically particularly susceptible to instability (e.g., liposomes that do not contain a polymeric compound as described herein), and therefore the stability of liposomes having such a zeta potential according to embodiments of the present invention (e.g., upon sterilization) is particularly noteworthy, and is difficult to achieve with other liposomes having such a zeta potential.

[0069] In some of the embodiments described herein, the change in zeta potential of the liposomes in the sterile composition is 20% or less over 300 days (e.g., at room temperature or optionally at a lower temperature), and optionally 15% or less, or 10% or less, or even 5% or less over 300 days (e.g., at room temperature or optionally at a lower temperature). In some such embodiments, the change in the average diameter of the liposomes in the sterile composition is 20% or less over 300 days (e.g., at room temperature or optionally at a lower temperature) (according to any of the corresponding embodiments described herein). In some embodiments, the change in zeta potential shown over 300 days refers to room temperature. In some embodiments, the change in zeta potential shown over 300 days refers to 4°C.

[0070] The zeta potential can be determined using any suitable technique known in the art, such as electrophoretic light scattering, optionally using a commercially available device. The zeta potential of liposomes can be determined by diluting the liposomes with an aqueous salt (e.g., NaCl) solution of a given salt concentration (e.g., 10 μM).

[0071] As described herein, liposomes according to embodiments include, inter alia, at least one bilayer-forming lipid.

[0072] As used herein, the term "bilayer-forming lipid" encompasses any compound that can form a bilayer from a pure aqueous solution of the compound, the bilayer comprising two parallel layers of molecules of the compound (called "lipids").

[0073] Typically, a bilayer (e.g., in a liposome according to some of the embodiments described herein) comprises relatively polar portions of lipids at the two surfaces of the bilayer, which may optionally include an interface with an aqueous solution and / or an interface with a solid surface, and relatively hydrophobic portions of lipids in the interior of the bilayer, which is the interface between the two layers of lipid molecules that form the bilayer.

[0074] Examples of bilayer-forming lipids include glycerophospholipids. Suitable examples of glycerophospholipids include, but are not limited to, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, and phosphatidylinositol.

[0075] It is to be understood that the polymeric compound included in the liposome (according to any corresponding embodiment described herein) may optionally be a bilayer-forming lipid capable of forming a bilayer by itself or in combination with one or more additional bilayer-forming lipids.

[0076] In some embodiments of any one of the embodiments described herein, the bilayer-forming lipids comprise at least one charged group (e.g., one or more negatively charged groups and / or one or more positively charged groups).

[0077] In some embodiments, the bilayer-forming lipids are zwitterionic and contain (eg, equal numbers of) both negatively charged groups and positively charged groups (eg, one of each).

[0078] In some embodiments of any of the embodiments described herein, the molar ratio of bilayer-forming lipids (included in addition to the polymeric compound) to polymeric compound (according to any corresponding embodiment described herein) in the liposome is in the range of 5:1 to 5,000:1 (bilayer-forming lipids:polymeric compound), optionally in the range of 10:1 to 2,500:1, optionally in the range of 25:1 to 1,000:1, and optionally in the range of 50:1 to 500:1.

[0079] Liposomes may optionally comprise a single bilayer (e.g., unilamellar vesicles) or multiple bilayers (e.g., multilamellar vesicles), including, for example, concentric bilayer vesicles and / or multiple separate bilayer vesicles contained within the same bilayer vesicle, each bilayer optionally forming an independently closed vesicle.

[0080] Liposomes according to any corresponding embodiment described herein may be approximately spherical, or may have any alternative shape, such as elongated tubes and / or flattened (e.g., sheet-like) shapes.

[0081] In some of any of the embodiments described herein, the liposomes, and optionally the entire sterile composition, do not include a therapeutically active agent.

[0082] In some of the embodiments of any of the present invention, the sterile composition comprises a therapeutically active agent, which is optionally incorporated into and / or on the surface of the liposome. In some such embodiments, the therapeutically active agent is a therapeutically active agent described in WO 2018 / 150429, which is incorporated herein by reference.

[0083] As used herein, the phrase "therapeutically active agent" refers to any agent (e.g., a compound) having a therapeutic effect, provided that the compound is not a bilayer-forming lipid or polymeric compound contained in a liposome (according to any corresponding embodiment described herein), and refers to any portion of an agent (e.g., a portion of a compound) that includes a bilayer-forming lipid or polymeric compound, which upon release (e.g., upon cleavage of one or more covalent bonds) produces an agent having a therapeutic effect. Thus, bilayer-forming lipids and polymeric compounds themselves are excluded from the definition of a therapeutically active agent, but the bilayer-forming lipids and / or polymeric compounds may optionally produce a therapeutically active agent upon release, in which case the portion of the bilayer-forming lipid and / or polymeric compound that produces the therapeutically active agent is also considered to be a therapeutically active agent as defined herein.

[0084] When present, the therapeutically active agent in the sterile composition may be either associated with liposomes and / or not associated with liposomes (e.g., dissolved in a carrier). When associated with liposomes, the therapeutically active agent may be bound to the liposomes (e.g., the outer and / or inner surface of the liposomal membrane) optionally by covalent or non-covalent bonds (e.g., electrostatic and / or hydrophobic bonds), incorporated within the liposomal membrane (e.g., a lipophilic agent stably partitioned in the lipid phase of the liposome), and / or contained within the liposomal core (e.g., a hydrophilic agent in the aqueous compartment of the liposome). The therapeutically active agent may optionally be a moiety covalently bound to the liposome (e.g., bound to a lipid to form a lipid derivative containing the moiety). Such binding may be achieved in some embodiments using techniques known in the art (e.g., amide bond formation).

[0085] In some of any corresponding embodiments, the sterile composition includes an article of manufacture immersed therein (that is part of the sterile composition and is also sterile), such as a solid or semi-solid article of manufacture that is typically packaged with the liposome-containing aqueous composition. In some embodiments, the article of manufacture is a contact lens, e.g., the aqueous carrier and liposomes are a contact lens storage solution.

[0086] The sterile composition according to any corresponding embodiment described herein may optionally be prepared according to the method described herein according to any corresponding embodiment.

[0087] method: According to one aspect of some embodiments of the present invention, there is provided a method of preparing a sterile composition comprising an aqueous carrier (e.g., according to any corresponding embodiment described herein) and a liposome (e.g., according to any corresponding embodiment described herein), the method comprising providing an aqueous composition comprising an aqueous carrier and a liposome comprising at least one bilayer-forming lipid (e.g., according to any corresponding embodiment described herein) and a polymeric compound (e.g., according to any corresponding embodiment described herein); and exposing the aqueous composition to a temperature of greater than 100°C.

[0088] The sterile composition obtained according to the method may optionally be a sterile composition according to any corresponding embodiment described herein.

[0089] In some of the corresponding embodiments described herein, the aqueous composition comprising the aqueous carrier and the liposomes further comprises an article of manufacture (e.g., according to any corresponding embodiment described herein) immersed therein, such that upon exposure of the aqueous composition to a temperature of greater than 100° C., the article of manufacture immersed in the aqueous composition becomes sterile. In some exemplary embodiments, the article of manufacture comprises a contact lens. Such a method may allow for efficient and relatively inexpensive simultaneous sterilization of a solid or semi-solid article of manufacture and one or more contact lenses immersed in (e.g., commonly packaged together) a liposome-containing aqueous composition, e.g., a liposome-containing contact lens solution (e.g., a contact lens storage solution).

[0090] According to another aspect of some embodiments of the present invention, there is provided a method for preparing a sterile article of manufacture having lipid attached to at least a portion of its surface, the method comprising contacting at least a portion of the surface of the article of manufacture with an aqueous composition comprising an aqueous carrier (e.g., according to any corresponding embodiment described herein) and a liposome (e.g., according to any corresponding embodiment described herein), thereby obtaining an article of manufacture having lipid attached to at least a portion of its surface; and exposing the article of manufacture having lipid attached to at least a portion of its surface to a temperature of greater than 100°C. The liposome comprises at least one bilayer-forming lipid (e.g., according to any corresponding embodiment described herein) and a polymeric compound (e.g., according to any corresponding embodiment described herein). In some exemplary embodiments, the article of manufacture comprises a contact lens.

[0091] According to this embodiment, it is understood that the lipid attached to at least a portion of the surface may be in the form of liposomes and / or another form, such as an open bilayer (i.e., a bilayer with no volume), obtained, for example, by "bursting" the liposomes upon contact with the surface. Optionally, at least a portion of the lipid attached to the surface may be in a different form before and after application of a temperature above 100°C, for example, in the form of liposomes before sterilization by heat and in a different form (e.g., open bilayer) after sterilization by heat. Alternatively or additionally, the form of the lipid changes gradually (e.g., from liposomes to another form) when the article of manufacture is incubated in an aqueous composition following sterilization by heat (e.g., for at least one hour, or at least one day, or even at least one month).

[0092] Such methods may allow for efficient and relatively inexpensive sterilization of a solid or semi-solid article of manufacture having lipid attached to at least a portion of its surface, such as one or more lipid-coated contact lenses.

[0093] In some of the corresponding embodiments described herein, the temperature to which the aqueous composition according to any of the aspects described herein is exposed is 150°C or less, e.g., 110-150°C, or 115-150°C, or 121-150°C, or 130-150°C.

[0094] In some of the corresponding embodiments described herein, the temperature to which the aqueous composition is exposed is 140°C or less, such as 110-140°C, or 115-140°C, or 121-140°C, or 130-140°C.

[0095] In some of the corresponding embodiments described herein, the temperature to which the aqueous composition is exposed is 134°C or less, such as 110-134°C, or 115-134°C, or 121-134°C.

[0096] In some of the corresponding embodiments described herein, the temperature to which the aqueous composition is exposed is 130°C or less, such as 110-130°C, or 115-130°C, or 121-130°C.

[0097] In some of the corresponding embodiments described herein, the temperature to which the aqueous composition is exposed is 125°C or less, such as 110-125°C, or 115-125°C, or 121-125°C.

[0098] In some of the corresponding embodiments described herein, exposing the aqueous composition to a temperature of more than 100° C. is performed at high pressure, i.e., at a pressure higher than ambient pressure. Such pressure may be obtained, for example, by heating the aqueous composition in a closed vessel such that water vapor formed by heating contributes to the increase in pressure. In some such embodiments, the pressure is such that the boiling point of the aqueous composition at that pressure is equal to or near (e.g., ±10° C. or ±5° C.) the temperature to which the composition is exposed (according to any of the corresponding embodiments described herein).

[0099] Exposing a composition according to any corresponding embodiment described herein to elevated temperatures (and optionally, elevated pressures) may optionally be carried out using commercially available equipment configured for such use, such as an autoclave.

[0100] Polymer compounds: According to some embodiments of any of the embodiments described herein, the polymeric compound contained in the liposome (according to any corresponding embodiment described herein) has the general formula I: [ka] In the above formula, m is zero or a positive integer; n is an integer that is at least 1; X is a lipid moiety, and if X does not contain a phosphate group, n is at least 2; Y is a backbone unit forming the polymer backbone; L is absent or a linking moiety; and Z has the general formula II, [ka] In the above formula, A is a substituted or unsubstituted hydrocarbon; B is an oxygen atom or is absent; and R 1 ~R 3 are each independently hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl, or heteroaryl; Details will be described later.

[0101] As used herein, formula I may be written in the following abbreviated form: X-[Y(-LZ)]n[Y]m This may be considered as an alternative to the schematic formula above.

[0102] As used herein, the term "polymer" refers to a compound having at least two repeat units (more preferably at least three repeat units), which are identical or similar. It is understood that a compound of general formula I is by definition a polymer when n is at least 2, since it contains at least two backbone units represented by Y.

[0103] As used herein, the phrase "polymeric moiety" refers to a portion of a polymeric compound having general formula Ia (according to any of the embodiments described herein for general formula I). [ka] In the above formula, m, n, Y, L, and Z are as defined herein for general formula I.

[0104] As used herein, formula Ia may be written in the following abbreviated form: [Y(-LZ)]n[Y]m This may be considered as an alternative to the schematic formula above.

[0105] When m is a positive integer, the backbone units [Y(-LZ)] and [Y] can be arranged in any order to form the polymer backbone.

[0106] As used herein, the phrase "polymeric compound" further includes compounds having a "polymer moiety" as described herein having one unit (e.g., according to formula Ia, where n is 1), provided that the lipid moiety as described herein (e.g., a lipid moiety represented by X) has a similar unit. For example, if the lipid moiety has a phosphate group because it contains a phosphate group (e.g., the lipid moiety is a glycerophospholipid moiety), and a single unit of the polymer moiety has a phosphate group, the two phosphate groups can be considered as a repeat unit.

[0107] However, in preferred embodiments, n is at least 2, so that the polymer segment itself has at least 2 units.

[0108] As used herein, the term "backbone unit" refers to a repeating unit, where the linking (e.g., sequential linking) of multiple repeating units forms a polymer backbone. The linked repeating units themselves are also referred to herein as the "polymer backbone."

[0109] As shown in Formulas I and Ia, L and Z together form at least a portion of a pendant group of a backbone unit, which for brevity is referred to herein simply as the "pendant group."

[0110] Each skeletal unit Y having a pendant group (i.e., a unit represented by Y(-LZ), the number of which is represented by the variable n) and each skeletal unit Y not having a pendant group (the number of which is represented by the variable m) are also referred to herein as "monomer units."

[0111] The backbone unit can optionally be the residue of a polymerizable monomer or the polymerizable portion of a monomer. A wide variety of polymerizable monomers and moieties will be known to those of skill in the art, as will the structures of the residues of such monomers (e.g., monomer units) that result upon polymerization.

[0112] "Residue of a polymerizable monomer" refers to a modified form of a polymerizable monomer and / or the portion of a polymerizable monomer that remains after polymerization.

[0113] A portion of the polymerizable monomer may be formed, for example, by a condensation reaction in which at least one atom or group in the monomer (e.g., a hydrogen atom or a hydroxyl group), and optionally at least two atoms or groups in the monomer (e.g., a hydrogen atom and a hydroxyl group), is replaced with a covalent bond with another polymerizable monomer.

[0114] Modified forms of polymerizable monomers can be formed, for example, by ring opening (where a covalent bond between two atoms in a ring is broken and the two atoms are optionally bonded to each other polymerizable monomer) and / or by addition to an unsaturated bond, where an unsaturated bond between two adjacent atoms is broken (e.g., conversion of an unsaturated double bond to a saturated bond, or conversion of an unsaturated triple bond to an unsaturated double bond) and the two atoms are optionally bonded to each other polymerizable monomer.

[0115] Modified forms of polymerizable monomers may consist essentially of the same atoms as the original monomer, e.g., differing only in rearrangements of covalent bonds, or alternatively may have a different atomic composition, e.g., where the polymerization involves a condensation reaction (e.g., as described herein).

[0116] Examples of backbone units include, but are not limited to, substituted or unsubstituted hydrocarbons, such as alkylene units (which may form substituted or unsubstituted hydrocarbon backbones); hydroxycarboxylic acid units, such as glycolate, lactate, hydroxybutyrate, hydroxyvalerate, hydroxycaproate, and hydroxybenzoate units (which may form polyester backbones); dicarboxylic acid units, such as adipate, succinate, terephthalate, and naphthalenedicarboxylic acid units (which may be combined with diols to form polyester backbones and / or with diamines to form polyamides); diol units, such as ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, and bisphenol A units (which may form polyether backbones or may be combined with dicarboxylic acids to form polyester backbones); diamine units, such as paraphenylenediamine, and alkylenediamines, such as hexylenediamine (which may be combined with dicarboxylic acids to form polyamide backbones); carbamate units (which may form polyurethane backbones); amino acid residues (which may form polypeptide backbones); and sugar residues (which may form polysaccharide backbones).

[0117] In some embodiments of any of the corresponding embodiments described herein, Y is a substituted or unsubstituted alkylene unit.

[0118] In some embodiments, Y is a substituted or unsubstituted ethylene unit, ie, an alkylene unit that is two atoms in length.

[0119] The polymer backbone, where Y is a substituted or unsubstituted ethylene unit, is optionally ethylene (CH 2 =CH 2 ) and / or their substituted derivatives (also referred to herein as "vinyl monomers"). Such polymerization is a very well-studied procedure and those skilled in the art will be aware of numerous techniques for carrying out such polymerizations.

[0120] Any embodiment described herein that refers to a polymer backbone formed by polymerization should be understood to encompass any polymer backbone having a structure that can be formed by such polymerization, regardless of whether the polymer backbone is actually formed by such polymerization (or any other type of polymerization).

[0121] As is well known in the art, the unsaturated bonds in ethylene and substituted ethylene derivatives become saturated bonds upon polymerization, and therefore the backbone units of the polymer backbone are saturated, but may be referred to as units of analogous unsaturated compounds (e.g., "vinyl monomers" or "olefin monomers").

[0122] Polymers that can be formed from unsaturated monomers, such as vinyl and olefin monomers, are also referred to by the terms "polyvinyl" and "polyolefin."

[0123] As used herein, an "unsubstituted" alkylene unit (e.g., an ethylene unit) refers to an alkylene unit that has no substituents other than the pendant group discussed herein (represented as (-LZ)). That is, an alkylene unit bonded to said pendant group is considered unsubstituted when there are no substituents at other positions on the alkylene unit.

[0124] In some embodiments of any of the corresponding embodiments described herein, Y is a group of formula -CR 4 R 5 -CR 6 Has D-.

[0125] When Y is a backbone unit that is not attached to L or Z (i.e., to a pendant group as described herein), D is R 7 (an end group as defined herein) and Y is a backbone unit attached to L or Z, then D is a covalent bond or linking group attaching Y to L or Z. The linking group can optionally be -O-, -S-, arylene, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, or amino.

[0126] R 4 ~R 7 are each independently hydrogen, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azido, azo, phosphate, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, or amino.

[0127] As used herein, the phrase "linking group" refers to a group (eg, a substituent) that is attached to two or more moieties in a compound.

[0128] As used herein, the phrase "terminal group" refers to a group (eg, a substituent) that is attached to a moiety in a compound through an atom thereof.

[0129] R 4 ~R 6 is hydrogen and D is a covalent bond or a linking group, then Y is an unsubstituted ethylene group attached (through D) to a pendant group described herein.

[0130] R 4 ~R 7 are hydrogen (and D is R 7 When Y is 1, Y is an unsubstituted ethylene group that is not attached to a pendant group as described herein.

[0131] In some embodiments of any of the corresponding embodiments described herein, R 4 and R 5 and each are hydrogen. Such embodiments include polymer backbones formed from many of the commonly used vinyl monomers (including ethylene), including, for example, olefins (e.g., ethylene, propylene, 1-butylene, isobutylene, 4-methyl-1-pentene), vinyl chloride, styrene, vinyl acetate, acrylonitrile, acrylates and their derivatives (e.g., acrylate esters, acrylamide), and methacrylates and their derivatives (e.g., methacrylic acid esters, methacrylamide).

[0132] In some embodiments of any of the corresponding embodiments described herein, R 6 is hydrogen. In some such embodiments, R 4 and R 5 are hydrogen.

[0133] In some embodiments of any of the corresponding embodiments described herein, R6 is methyl. In some such embodiments, R 4 and R 5 are each hydrogen. In some such embodiments, the backbone units are units of methacrylate or a derivative thereof (e.g., methacrylic acid ester, methacrylamide).

[0134] In some embodiments of any of the corresponding embodiments described herein, the linking group represented by the variable D is -O-, -C(=O)O-, -C(=O)NH-, or phenylene. In an exemplary embodiment, D is -C(=O)O-.

[0135] For example, the backbone unit can optionally be a vinyl alcohol derivative (e.g., an ester or ether of a vinyl alcohol unit) when D is -O-; an acrylate or methacrylate derivative (e.g., an ester of an acrylate or methacrylate unit) when D is -C(=O)O-; an acrylamide or methacrylamide unit when D is -C(=O)NH-; and / or a styrene derivative (e.g., a substituted styrene unit) when D is phenylene.

[0136] In some embodiments of any of the corresponding embodiments described herein, L is a substituted or unsubstituted hydrocarbon having a length of 1-10 carbon atoms. In some embodiments, the hydrocarbon is unsubstituted. In some embodiments, the hydrocarbon is a straight chain unsubstituted hydrocarbon, i.e., -(CH 2 ) i where i is an integer from 1 to 10.

[0137] In some embodiments of any of the corresponding embodiments described herein, L is a substituted or unsubstituted ethylene group. In some embodiments, L is an unsubstituted ethylene group (-CH 2 CH 2 -).

[0138] In some embodiments of any corresponding embodiment described herein, B is an oxygen atom. In some such embodiments, L is a hydrocarbon according to any corresponding embodiment described herein (i.e., L is present) and Z is a phosphate group bonded to L.

[0139] In some embodiments of any corresponding embodiment described herein, B is absent. In some such embodiments, L is a hydrocarbon according to any corresponding embodiment described herein (i.e., L is present) and Z is a phosphonic acid group bonded to L. In some embodiments, L is also absent, such that the phosphorus atom of formula II is bonded directly to Y.

[0140] In some embodiments of any of the corresponding embodiments described herein, A is a substituted or unsubstituted hydrocarbon of 1 to 4 carbon atoms in length.

[0141] In some embodiments of any of the corresponding embodiments described herein, A is an unsubstituted hydrocarbon. In some such embodiments, the unsubstituted hydrocarbon is 1-4 carbon atoms in length. In some embodiments, the hydrocarbon is a straight chain unsubstituted hydrocarbon, i.e., -(CH 2 ) j -, and j is an integer from 1 to 4.

[0142] In some embodiments of any of the corresponding embodiments described herein, A is a substituted or unsubstituted ethylene group.

[0143] In some embodiments of any of the corresponding embodiments described herein, A is an unsubstituted ethylene group (-CH 2 CH 2 In such embodiments, the moiety having general formula II (represented by the variable Z) is similar to or identical to a phosphoethanolamine or phosphocholine moiety. Phosphoethanolamine and phosphocholine moieties are present in many naturally occurring compounds (e.g., phosphatidylcholine, phosphatidylethanolamine).

[0144] In some embodiments of any corresponding embodiment described herein, A is an ethylene group substituted with a C-carboxy group. In some embodiments, the C-carboxy is attached to the carbon atom adjacent to the nitrogen atom shown in formula II (not the carbon atom attached to the oxygen atom shown). In such embodiments, the moiety having general formula II (represented by the variable Z) is similar or identical to a phosphoserine moiety. Phosphopserine is present in many naturally occurring compounds (e.g., phosphatidylserine).

[0145] Without being bound to a particular theory, moieties similar or identical to naturally occurring moieties such as phosphocholine, phosphoethanolamine, and / or phosphoserine are believed to be particularly biocompatible.

[0146] In some embodiments of any of the corresponding embodiments described herein, R 1 ~R 3 (the substituents of the nitrogen atom shown in general formula II) are each independently hydrogen or C 1-4 -alkyl. In some embodiments, R 1 ~R 3 are each independently hydrogen or methyl. In some embodiments, R 1 ~R 3 Each is methyl. In some such embodiments, R 1 ~R 3 are hydrogen.

[0147] The variable n may be considered to represent the number of backbone units (represented by the variable Y) that are substituted with pendant groups represented by (-LZ), and the variable m may be considered to represent the number of backbone units that are not substituted with such pendant groups. The sum of n+m may be considered to represent the total number of backbone units in the polymer backbone. The ratio of n / (n+m) may be considered to represent the percentage of backbone units that are substituted with pendant groups represented by (-LZ).

[0148] The backbone units Y that are substituted with pendant groups can be the same as or different from the backbone units Y that are not substituted with pendant groups (eg, when m is at least 1).

[0149] The multiple backbone units Y substituted with pendant groups (denoted by the variable n) may be the same or different from each other.

[0150] In addition, the pendant groups (-LZ) attached to the backbone units Y (represented by the variable n) may be the same or different from each other (e.g., A, B, R 1 , R 2 , R 3 , and the identity of any one or more of L may be different).

[0151] In any of the embodiments described herein in which more than one backbone unit Y is not substituted with a pendant group as described herein (i.e., m is greater than 1), the backbone units Y substituted with a pendant group (denoted by the variable m) can be the same or different from one another.

[0152] The number of types of backbone units substituted with pendant groups, the number of types of backbone units not substituted with pendant groups (if such units are present), and / or the number of types of pendant groups in the polymer moiety can each independently be any number (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more).

[0153] In some embodiments of any of the embodiments described herein, the polymeric portion is a copolymer portion, i.e., the polymeric portion comprises at least two types of monomeric units. The difference in the types of monomeric units can be the difference in the inclusion or absence of a pendant group (-LZ) according to any of the corresponding embodiments described herein (e.g., when m is at least 1), the difference in the type of backbone unit Y, and / or the difference in the type of pendant group (-LZ).

[0154] For example, in some embodiments of any corresponding embodiment described herein, the backbone unit Y in each of the Y(-LZ) units may optionally be the same or different, while the L and Z moieties are the same among the Y(-LZ) units. In some such embodiments, the backbone units that are not substituted with pendant groups (if such units are present) may optionally be the same as the backbone unit Y in each of the Y(-LZ) units. Alternatively, the backbone units that are not substituted with pendant groups (if such units are present) may optionally be different from the backbone unit Y in each of the Y(-LZ) units (while optionally being the same among all backbone units that are not substituted with pendant groups).

[0155] In some embodiments of any corresponding embodiment described herein, the L moieties in each of the Y(-LZ) units may optionally be the same or different, while the backbone units Y and Z moieties are the same among the Y(-LZ) units. In some such embodiments, the backbone units that are not substituted with pendant groups (if such units are present) may optionally be the same as the backbone units Y in each of the Y(-LZ) units. Alternatively, the backbone units that are not substituted with pendant groups (if such units are present) may optionally be different from the backbone units Y in each of the Y(-LZ) units (while optionally being the same among all backbone units that are not substituted with pendant groups).

[0156] In some embodiments of any corresponding embodiment described herein, the Z moieties in each of the Y(-LZ) units may optionally be the same or different, while the backbone units Y and Z moieties are the same among the Y(-LZ) units. In some such embodiments, the backbone units that are not substituted with pendant groups (if such units are present) may optionally be the same as the backbone units Y in each of the Y(-LZ) units. Alternatively, the backbone units that are not substituted with pendant groups (if such units are present) may optionally be different from the backbone units Y in each of the Y(-LZ) units (while optionally being the same among all backbone units that are not substituted with pendant groups).

[0157] In any of the embodiments described herein where the polymer moiety is a copolymer moiety, any two or more different types of monomer units may be randomly or non-randomly distributed throughout the polymer moiety. When the different types of monomer units are non-randomly distributed, the copolymer may be characterized by any non-random distribution, such as, for example, an alternating copolymer, a periodic copolymer, and / or a block copolymer.

[0158] In some embodiments of any of the embodiments described herein, at least a portion of the monomeric units of the polymeric portion comprise a targeting moiety (according to any of the embodiments described herein relating to targeting moieties). In some embodiments, the targeting moiety, the monomeric unit comprising a targeting moiety, and / or the polymeric compound comprising a targeting moiety may optionally comprise any of the targeting moieties, monomeric units comprising a targeting moiety, and / or polymeric compounds comprising a targeting moiety described in WO 2018 / 150429, each of which is incorporated herein by reference.

[0159] As used herein, a "targeting moiety" refers to a moiety that is capable of bringing a compound (e.g., a compound according to some embodiments of the present invention) into proximity with a selected substance and / or material (referred to herein as a "target"). The target is optionally a cell (e.g., a proliferating cell associated with a proliferative disease or disorder), and the proximity facilitates the targeting moiety to attach and / or internalize the compound into the target cell, whereby the compound may exert a therapeutic effect.

[0160] The targeting moiety may optionally be included in the backbone unit Y according to any corresponding embodiment described herein, the linking moiety L according to any corresponding embodiment described herein, and / or the moiety Z according to any corresponding embodiment described herein, e.g., a substituent according to any corresponding embodiment described herein comprises (and optionally consists of) a targeting moiety. For example, at least a portion of the backbone unit Y (as described herein in any of the corresponding embodiments) is of the formula -CR 4 R 5 -CR 6 In some embodiments having D-, R 4 ~R 6 and D (optionally D is R as described herein). 7 any one or more of which comprises a targeting moiety according to any corresponding embodiment described herein (e.g., R 4 ~R 6 and any one or more of D are substituents, including substituents that are targeting moieties, and optionally, R 4 ~R 6 and D are targeting moieties. However, many other structures of monomeric units that include a substituent that includes (and optionally consists of) a targeting moiety are also encompassed by embodiments of the invention.

[0161] When Y is a backbone unit that is not attached to L or Z (i.e., a pendant group as described herein), D is R 7(end group as defined herein); and if Y is a backbone unit attached to L or Z, then D is a covalent bond or linking group attaching Y to L or Z. The linking group can optionally be -O-, -S-, arylene, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, or amino.

[0162] R 4 ~R 7 are each independently hydrogen, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azido, azo, phosphate, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, or amino.

[0163] In some embodiments, the polymer portion is a copolymer portion, where at least one type of monomer unit comprises a target moiety (according to any corresponding embodiment described herein) and at least one type of monomer unit does not comprise such a target moiety. The distribution of monomer units that comprise a target moiety may follow any distribution described herein of monomer units in the copolymer portion (e.g., random, alternating, periodic copolymers, and / or block copolymers).

[0164] In some embodiments of any of the embodiments described herein in which some of the monomer units include a targeting moiety, the monomer units that include the targeting moiety are, on average, closer to the end of the polymer moiety that is distal to the lipid moiety, e.g., the average distance (measured in atoms or backbone units along the backbone of the polymer moiety) from the lipid moiety to the monomer units that include the targeting moiety is greater than the average distance from the lipid moiety to the other monomer units.

[0165] In some embodiments, at least a portion (and optionally all) of the monomer units comprising the targeting moiety form a block (of one or more monomer units) near (and optionally at) the end of the polymer portion distal to the lipid portion. In some such embodiments, the copolymer portion comprises a single monomer unit comprising the targeting moiety, and the monomer unit is at the end of the polymer portion distal to the lipid portion.

[0166] Without being bound to a particular theory, it is postulated that a targeting moiety that is located distal to a lipid moiety may be more effective as a targeting moiety (e.g., more effective at binding to a target) because, for example, the targeting moiety is less sterically shielded (e.g., by the surface to which the lipid moiety is associated) and therefore more likely to be exposed to the target in an aqueous environment and therefore better able to contact the target.

[0167] In any of the embodiments described herein where m is at least 1, the polymeric portion comprises a monomeric unit that comprises a targeting moiety, the monomeric unit being at the end of the polymeric portion distal to the lipid portion. In such embodiments, the compound represented by general formula I has formula Ib. [ka] In the above formula, T is a monomeric unit comprising a targeting moiety (according to any corresponding embodiment described herein); X and T are attached to the distal ends of a moiety represented by [Y(-LZ)][Y]; and X, Y, L, Z, n, and m are defined according to any of the embodiments described herein for general formula I, where m is at least 1.

[0168] It should be understood that T in formula Ib is one type of monomeric unit represented by Y in formulas I and Ia (i.e., not having a pendant group represented by (-LZ)), and the number of monomeric units represented by Y other than T (i.e., not having a pendant group represented by (-LZ)) is represented by the value m-1, and thus the total number of monomeric units not having a pendant group represented by (-LZ), including T, is represented by the variable m as in formulas I and Ia.

[0169] In some embodiments, m is 1, such that m-1 is zero, and the compound of formula Ib has the formula X-[Y(-LZ)]T, where L, T, X, Y, Z, and n are defined according to any of the embodiments described herein.

[0170] A monomeric unit comprising a targeting moiety according to any corresponding embodiment described herein may be prepared, optionally using any suitable technique known in the art, including but not limited to linking techniques, by preparing a monomer comprising a targeting moiety and using that monomer to prepare a polymeric portion described herein (e.g., by polymerization of a monomer according to any corresponding embodiment described herein), and / or by modifying a monomeric unit in the polymeric portion subsequent to preparation of the polymeric portion (e.g., by polymerization of a monomer according to any corresponding embodiment described herein).

[0171] In alternative embodiments, the polymeric portion does not include a targeting moiety according to any corresponding embodiment described herein.

[0172] In some embodiments of any corresponding embodiment described herein, the percentage of skeletal units (represented by the variable Y) substituted with pendant groups represented by (-LZ) (represented by the formula: 100%*n / (n+m)) is at least 20%. In some embodiments, the percentage of skeletal units substituted with said pendant groups is at least 30%. In some embodiments, the percentage of skeletal units substituted with said pendant groups is at least 40%. In some embodiments, the percentage of skeletal units substituted with said pendant groups is at least 50%. In some embodiments, the percentage of skeletal units substituted with said pendant groups is at least 60%. In some embodiments, the percentage of skeletal units substituted with said pendant groups is at least 70%. In some embodiments, the percentage of skeletal units substituted with said pendant groups is at least 80%. In some embodiments, the percentage of skeletal units substituted with said pendant groups is at least 90%. In some embodiments, the percentage of skeletal units substituted with said pendant groups is at least 95%. In some embodiments, the percentage of skeletal units substituted with said pendant groups is at least 98%.

[0173] In some embodiments of any of the corresponding embodiments described herein, m is 0, such that each of the backbone units (represented by the variable Y) is substituted with a pendant group represented by (-LZ).

[0174] In some embodiments of any corresponding embodiment described herein, n is at least 5. In some embodiments, n is at least 10. In some embodiments, n is at least 15.

[0175] In some embodiments of any corresponding embodiment described herein, n is in the range of 2 to 1,000, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 2 to 500, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 2 to 200, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 2 to 100, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 2 to 50, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 10 to 100, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 10 to 50, including any intermediate values ​​and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 50 to 100, including any intermediate values ​​and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 30 to 100, including any intermediate values ​​and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 20 to 120, including any intermediate values ​​and subranges therebetween. In some such embodiments, m is 0.

[0176] In some embodiments of any corresponding embodiment described herein, n is in the range of 3 to 1,000, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 3 to 500, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 3 to 200, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 3 to 100, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 3 to 50, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 5 to 50, including any intermediate values ​​and subranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 10 to 50, including any intermediate values ​​and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 10 to 25, including any intermediate values ​​and subranges therebetween. In some such embodiments, m is 0.

[0177] In some embodiments of any corresponding embodiment described herein, m is in the range of 0 to 1,000, including any intermediate values ​​and subranges therebetween. In some such embodiments, n is in the range of 2 to 1,000, such that the total number of backbone units is in the range of 2 to 2,000. In some such embodiments, n is in the range of 3 to 1,000. In some embodiments, n is in the range of 3 to 500. In some embodiments, n is in the range of 3 to 200. In some embodiments, n is in the range of 3 to 100. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 5 to 50. In some embodiments, n is in the range of 10 to 50.

[0178] In some embodiments of any corresponding embodiment described herein, m is in the range of 0 to 500, including any intermediate values ​​and subranges therebetween. In some such embodiments, n is in the range of 2 to 1,000. In some such embodiments, n is in the range of 3 to 1,000. In some embodiments, n is in the range of 3 to 500. In some embodiments, n is in the range of 3 to 200. In some embodiments, n is in the range of 3 to 100. In some embodiments, n is in the range of 10 to 100. In some embodiments, n is in the range of 30 to 100. In some embodiments, n is in the range of 50 to 100. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 10 to 50. In some embodiments, n is in the range of 5 to 50. In some embodiments, n is in the range of 10 to 50.

[0179] In some embodiments of any corresponding embodiment described herein, m is in the range of 0 to 200, including any intermediate values ​​and subranges therebetween. In some such embodiments, n is in the range of 2 to 1,000. In some such embodiments, n is in the range of 3 to 1,000. In some embodiments, n is in the range of 3 to 500. In some embodiments, n is in the range of 3 to 200. In some embodiments, n is in the range of 3 to 100. In some embodiments, n is in the range of 10 to 100. In some embodiments, n is in the range of 30 to 100. In some embodiments, n is in the range of 50 to 100. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 10 to 50. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 10 to 50. In some embodiments, n is in the range of 5 to 50. In some embodiments, n is in the range of 10 to 50.

[0180] In some embodiments of any corresponding embodiment described herein, m is in the range of 0 to 100, including any intermediate values ​​and subranges therebetween. In some such embodiments, n is in the range of 2 to 1,000. In some such embodiments, n is in the range of 3 to 1,000. In some embodiments, n is in the range of 3 to 500. In some embodiments, n is in the range of 3 to 200. In some embodiments, n is in the range of 3 to 100. In some embodiments, n is in the range of 10 to 100. In some embodiments, n is in the range of 30 to 100. In some embodiments, n is in the range of 50 to 100. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 10 to 50. In some embodiments, n is in the range of 10 to 50. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 5 to 50. In some embodiments, n is in the range of 10 to 50.

[0181] In some embodiments of any corresponding embodiment described herein, m is in the range of 0 to 50, including any intermediate values ​​and subranges therebetween. In some such embodiments, n is in the range of 2 to 1,000. In some such embodiments, n is in the range of 3 to 1,000. In some embodiments, n is in the range of 3 to 500. In some embodiments, n is in the range of 3 to 200. In some embodiments, n is in the range of 3 to 100. In some embodiments, n is in the range of 10 to 100. In some embodiments, n is in the range of 30 to 100. In some embodiments, n is in the range of 50 to 100. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 10 to 50. In some embodiments, n is in the range of 10 to 50. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 5 to 50. In some embodiments, n is in the range of 10 to 50.

[0182] In some embodiments of any corresponding embodiment described herein, m is in the range of 0 to 20, including any intermediate values ​​and subranges therebetween. In some such embodiments, n is in the range of 2 to 1,000. In some such embodiments, n is in the range of 3 to 1,000. In some embodiments, n is in the range of 3 to 500. In some embodiments, n is in the range of 3 to 200. In some embodiments, n is in the range of 3 to 100. In some embodiments, n is in the range of 10 to 100. In some embodiments, n is in the range of 30 to 100. In some embodiments, n is in the range of 50 to 100. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 10 to 50. In some embodiments, n is in the range of 10 to 50. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 5 to 50. In some embodiments, n is in the range of 10 to 50.

[0183] In some embodiments of any corresponding embodiment described herein, m is in the range of 0 to 10, including any intermediate values ​​and subranges therebetween. In some such embodiments, n is in the range of 2 to 1,000. In some such embodiments, n is in the range of 3 to 1,000. In some embodiments, n is in the range of 3 to 500. In some embodiments, n is in the range of 3 to 200. In some embodiments, n is in the range of 3 to 100. In some embodiments, n is in the range of 10 to 100. In some embodiments, n is in the range of 30 to 100. In some embodiments, n is in the range of 50 to 100. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 10 to 50. In some embodiments, n is in the range of 10 to 50. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 5 to 50. In some embodiments, n is in the range of 10 to 50.

[0184] A lipid moiety (represented by the variable X in formula I herein) according to any corresponding embodiment herein may be attached to a polymer moiety according to any of the embodiments described herein with respect to the polymer moiety.

[0185] The lipid moiety can be optionally derived from any lipid known in the art, including, but not limited to, naturally occurring lipids. The derivation of the lipid moiety from the lipid can optionally consist of replacing a hydrogen atom at any position of the lipid with a polymer moiety represented by [Y(-LZ)]n[Y]m in general formula I (i.e., a polymer moiety represented by general formula Ia).

[0186] In some embodiments of any of the embodiments described herein, the polymer moiety in the liposome, in addition to the polymer moiety (according to any corresponding embodiment described herein), includes a lipid moiety that includes a residue of a bilayer-forming lipid (e.g., a glycerophospholipid) included in the liposome, or a lipid moiety that is closely related to such a bilayer-forming lipid included in the liposome (e.g., a lipid moiety represented by variable X of Formula I, according to any corresponding embodiment described herein); for example, the lipid moiety includes a glycerophospholipid residue and the liposome includes another glycerophospholipid as a bilayer-forming lipid (e.g., optionally, the fatty acid residue in the glycerophospholipid residue has approximately the same length as the fatty acid residue in the bilayer-forming lipid, and optionally, the fatty acid residue in the glycerophospholipid residue is substantially the same as the fatty acid residue in the bilayer-forming lipid).

[0187] Without being bound to a particular theory, it is believed that the similarity of the lipid portion of the polymer moiety to the bilayer-forming lipids facilitates immobilization of the lipid portion of the polymer moiety in liposomes that contain bilayer-forming lipids.

[0188] In some embodiments of any corresponding embodiment described herein, the lipid moiety (according to any corresponding embodiment described herein) is attached to a Y(-LZ) unit (according to any of the embodiments described herein for Y, L, and / or Z), i.e., a backbone unit substituted with a pendant group described herein (e.g., rather than a backbone unit that is not substituted with a pendant group).

[0189] Alternatively or additionally, in some embodiments of any corresponding embodiment described herein where m is at least 1, the lipid moiety (according to any corresponding embodiment described herein) may be optionally attached to a backbone unit (Y) that is not substituted by a pendant group as described herein (e.g., rather than being attached to a backbone unit substituted with a pendant group). For example, the polymer moiety may be optionally a copolymer in which the identity of the backbone unit attached to the lipid moiety varies randomly between molecules. Thus, the depiction that X in formula I is attached to a backbone unit substituted with a pendant group (i.e., Y-(LZ)) rather than to an unsubstituted backbone unit Y is arbitrary and not intended to be limiting.

[0190] In some embodiments of any of the corresponding embodiments described herein, the lipid moiety is a lipid moiety that is a fatty acid, a monoglyceride, a diglyceride, a triglyceride, a glycerophospholipid, a sphingolipid, or a sterol. In some embodiments, the lipid is a glycerophospholipid, such as phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, and / or phosphatidylinositol.

[0191] In some embodiments of any corresponding embodiment described herein, the lipid moiety comprises at least one fatty acid moiety (e.g., an acyl group derived from a fatty acid). The fatty acid moiety can be derived from a saturated or unsaturated fatty acid. For example, the lipid moiety can consist of a fatty acid moiety, or can be a monoglyceride moiety containing one fatty acid moiety, a diglyceride moiety containing two fatty acid moieties, or a triglyceride moiety containing three fatty acid moieties.

[0192] Examples of fatty acid moieties that may optionally be included in the lipid moiety include, but are not limited to, lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0193] In some embodiments of any of the embodiments described herein, the lipid moiety represented by the variable X has the general formula III. [ka] W 1 and W 2 are each independently hydrogen, alkyl, alkenyl, alkynyl, or acyl; W 1 and W 2 at least one of is not hydrogen; J is -P(=O)(OH)-O- or J is absent (so K is directly bonded to the oxygen atom shown in the glycerol moiety); K is a substituted or unsubstituted hydrocarbon of 1-10 carbon atoms in length, or K is absent (so that M is directly bonded to J, or, if J is absent, M is directly bonded to the oxygen atom shown in the glycerol moiety); M is a linking group which is -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, or sulfonamide, or M is absent; Q is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length and is attached to a polymer backbone unit according to any corresponding embodiment described herein.

[0194] If M is absent, then K is also absent and Q is directly attached to J, or if J is absent, Q is directly attached to the oxygen atom shown in the glycerol moiety.

[0195] In some embodiments of any of the embodiments described herein, W 1 and W 2 One of the is hydrogen and the other is not hydrogen.

[0196] In some embodiments of any of the embodiments described herein, W 1 and W 2 None of these are hydrogen.

[0197] In some embodiments of any of the embodiments described herein, W 1 and W 2 At least one of W is an alkyl, alkenyl, alkynyl, or acyl having a length of 10 to 30 carbon atoms. 1 and W 2 are each between 10 and 30 carbon atoms long.

[0198] Optionally, independently W 1 and / or W 2 Examples of acyl groups that can function as include, but are not limited to, lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0199] In some embodiments of any of the embodiments described herein, J is -P(=O)(OH)-O- (e.g., the lipid moiety is a glycerophospholipid).

[0200] As used herein, the length of the hydrocarbon, represented by the variable K, refers to the number of atoms separating J and M (ie, along the shortest path between J and M), as shown in Formula III.

[0201] When K is a substituted hydrocarbon, M may be attached to a carbon atom of the hydrocarbon itself or to a substituent of the hydrocarbon.

[0202] In some embodiments of any of the embodiments described herein, K is an ethanolamine moiety (e.g., -CH 2 -CH 2 -NH- or -CH attached to a nitrogen atom 2 -CH 2 -), serine moiety (e.g., -CH 2 -CH(CO 2 H) -NH- or -CH bonded to a nitrogen atom 2 -CH(CO 2 H)-), glycerol moieties (e.g., -CH(OH)-CH(OH)-CH-O-), and inositol moieties (e.g., -cyclohexyl(OH) 4 In some embodiments, J is -P(=O)(OH)-O-.

[0203] In some embodiments of any of the embodiments described herein, M is an amide, optionally -C(=O)NH-.

[0204] In some embodiments, the nitrogen atom of the amide is bonded to K. In some such embodiments, K is an ethanolamine or serine moiety as described herein.

[0205] In some embodiments of any of the embodiments described herein, J is absent (e.g., the lipid moiety is a glycerolipid moiety that is not a glycerophospholipid moiety). In some such embodiments, K is also absent, such that M is directly attached to the oxygen atom depicted in the glycerol moiety, or, if M is also absent, Q is directly attached to the oxygen atom depicted in the glycerol moiety (e.g., the glycerolipid is a monoacylglycerol derivative or a diacylglycerol derivative). In some embodiments, M is a carbonyl linking group, such that the attachment of M to said oxygen atom of the glycerol moiety is via an ester bond.

[0206] In some embodiments of any of the embodiments described herein, Q is a substituted or unsubstituted methylene group. In some such embodiments, M comprises a carbonyl (i.e., C(=O)) linking group. In some embodiments, M is an amide (comprising a carbonyl and a nitrogen atom). In some embodiments, the C(=O) (e.g., of the amide) is bonded to Q. In some embodiments, M comprises a carbonyl linking group.

[0207] In some embodiments of any of the embodiments described herein, Q is a methylene group substituted with one or two substituents. In some embodiments, the methylene group is substituted with one or two alkyl groups (e.g., C 1-4 -alkyl).

[0208] In some embodiments of any of the embodiments described herein, Q is a methylene group substituted with two substituents. In some embodiments, the methylene group is substituted with two alkyl groups (e.g., C 1-4 In some embodiments, the alkyl group is methyl, such that Q is dimethylmethylene (-C(CH 3 ) 2 -).

[0209] As illustrated in the Examples section herein, substituted methylenes (e.g., disubstituted methylenes), represented by the variable Q, are particularly suitable for participating in polymerization reactions (e.g., as initiators) because free radicals and / or ions on the methylene can be stabilized by their substituent(s).

[0210] As further exemplified herein, formation of an amide group (represented by the variable M) can serve as a convenient method of attaching the above-described substituted methylene to a lipid (e.g., a naturally occurring lipid), such as phosphatidylethanolamine or phosphatidylserine.

[0211] As further exemplified herein, formation of an ester bond between a carbonyl (e.g., contained in M) and an oxygen atom of a lipid (e.g., an oxygen atom of a glycerol moiety) can serve as a convenient method of attaching the above-mentioned substituted methylenes to lipids (e.g., naturally occurring lipids), such as monoacylglycerol, diacylglycerol, phosphatidylglycerol, or phosphatidylinositol.

[0212] Manufactured articles: As discussed herein, a sterile composition according to any corresponding embodiment described herein may optionally include an article of manufacture immersed therein, and a sterile article of manufacture may optionally be obtained according to each method described herein (e.g., immersed in a liposome-containing composition and / or having lipid attached to at least a portion of its surface).

[0213] According to an aspect of some embodiments of the present invention there is provided a sterile article of manufacture prepared according to a method according to any of the embodiments described herein relating to a method for obtaining a sterile article of manufacture.

[0214] As used herein, the term "article of manufacture" refers to an article that is made from materials in a manner that results in a new shape, property, characteristic, or combination of materials and does not include any human parts. It should be understood that this definition is not necessarily the same as the standard legal definition of the term.

[0215] An article of manufacture according to any corresponding embodiment described herein preferably includes one or more substances in a form that does not occur in nature, which may optionally include naturally occurring combinations of natural substances that do not occur in nature and / or may optionally include one or more substances that do not occur in nature.

[0216] In some of the corresponding embodiments described herein, the article of manufacture has lipids non-covalently attached to at least a portion of its surface, e.g., at least a portion of the lipids are in the form of a lipid bilayer (i.e., two parallel layers of lipid molecules). In some such embodiments, at least a portion of the lipid molecules (e.g., in the bilayer) are oriented such that their polar groups (e.g., charged groups) face outward at the surface of the article of manufacture.

[0217] As used herein, the phrase "facing outward at the surface" refers to a group in a molecule (e.g., a lipid) on the surface of a substrate (e.g., the surface of an article of manufacture to which the lipid is attached) that is closer to the external environment than the center of mass of the molecule is to the external environment, and farther from the substrate than the center of mass of the molecule is from the substrate.

[0218] Without being bound to a particular theory, it is believed that the outwardly facing polar groups (e.g., charged groups) according to some embodiments of the present invention provide highly effective lubrication and / or inhibition of adhesion, biofouling, and / or biofilm formation due at least in part to the properties of hydrated polar groups (e.g., hydrated lubrication), particularly hydrated charged groups.

[0219] In any of the embodiments described herein, the portion of the article of manufacture to which the lipid is attached may comprise any type of material, or a combination of different types of materials, including inorganic and / or organic materials in crystalline, amorphous, and / or gel (e.g., hydrogel) form, such as metals, minerals, ceramics, glasses, polymers (e.g., synthetic polymers, biopolymers), plant and / or animal biomass (e.g., wood or leather), and combinations thereof.

[0220] In some embodiments of any embodiment described herein, the article of manufacture is a medical device, for example, a medical device having lipid attached to at least a portion of its surface.In some embodiments, the medical device is a device designed to contact parts of the body that are susceptible to infection, such as the inside of the body, mucous membranes, and / or the surface of the eye.Examples of such medical devices include, but are not limited to, surgical tools and implants (which contact the inside of the body), and contact lenses (which contact the surface of the eye).

[0221] The phrase "medical device" as used throughout this specification includes any material or device used on, in, or through the body of a subject, for example, in the course of medical treatment (e.g., of a disease or injury). The subject may be a human or a non-human animal, so the phrase "medical device" also includes veterinary devices. Medical devices include, but are not limited to, medical implants (including permanent and temporary implants), wound treatment devices, medical devices for drug delivery, contact lenses, and body cavity and personal protection devices. Medical implants include, but are not limited to, catheters (e.g., urinary catheters, intravascular catheters), injection ports, intubation devices, dialysis shunts, wound drainage tubes, skin sutures, vascular grafts, implantable meshes, intraocular devices, heart valves, and the like. Wound treatment devices include, but are not limited to, general wound dressings, biological implants, tape closures and dressings, and surgical incise drapes. Medical devices for drug delivery include, but are not limited to, injection needles, drug delivery skin patches, drug delivery mucosal patches, and medical sponges. Body cavity and personal protection devices include, but are not limited to, tampons, sponges, surgical and examination gloves, and toothbrushes. Contraceptive devices include, but are not limited to, intrauterine devices (IUDs), diaphragms, and condoms.

[0222] In the context of medical devices, it is understood that the macroscopic medical device is coated with the bilayer described herein.

[0223] Examples of suitable articles of manufacture include, but are not limited to, the following: Medical devices (e.g., contact lenses, pacemakers, heart valves, artificial joints, catheters, catheter access ports, dialysis tubing, gastric bands, shunts, screw plates, artificial spinal discs, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, implantable cardiac monitors, mitral annular repair devices, left ventricular assist devices (LVADs), artificial hearts, implantable infusion pumps, implantable insulin pumps, stents, implantable neurostimulators, maxillofacial implants, dental implants, etc.); Packaging or containers, such as packaging or containers for food and / or beverages (e.g., packaging for meat and / or dairy products and / or containers for storing or transporting meat and / or dairy products, such as storage tanks, milk holding equipment, conveyor belts for milk processing operations, pipe walls, gaskets, rubber seals, stainless steel coupons, piping systems, filling machines, silo tanks, heat exchangers, post-pasteurization equipment, pumps, valves, separators, and spraying equipment), medical device packaging, agricultural packaging and containers (for pesticides), packaging and containers for biological samples such as blood samples, and any other packaging or containers for a variety of goods; and Water treatment system components (eg, for containing and / or transporting and / or treating aqueous media or water), equipment, vessels, filters, pipes, solutions, gases, and the like.

[0224] In some of any one of the embodiments described herein, the article of manufacture includes, for example, a hydrogel surface having lipid attached to at least a portion thereof.

[0225] A contact lens is an exemplary article of manufacture that includes a hydrogel surface. In some embodiments, the contact lens includes a hydrogel surface and a hard center. In some embodiments, the contact lens consists essentially of hydrogel.

[0226] The hydrogel can include any material known in the art for use in hydrogel contact lenses. Examples of such hydrogel materials include, but are not limited to, alphafilcon A, asmofilcon A, balafilcon A, bufilcon A, comfilcon A, clofilcon, deltafilcon A, dimefilcon, droxifilcon A, enfilcon A, etafilcon A, galyfilcon A, hefilcon A, hefilcon B, hilafilcon A, hilafilcon B, hyoxifilcon A, hyoxifilcon D, isofilcon, lidofilcon A, lidofilcon B, lotrafilcon B, mafilcon, metafilcon A, metafilcon B, narafilcon A, narafilcon B, ocfilcon A, ocfilcon B, ofilcon A, omafilcon A, perfilcon, femfilcon A, polymacon, scafilcon A, senofilcon A, sarfilcon, tefilcon, tetrafilcon A, tetrafilcon B, bifilcon A, and xylofilcon A.

[0227] In some embodiments of any one of the embodiments described herein, the hydrogel comprises a polymer comprised of poly(2-hydroxyethyl methacrylate) and / or silicone. In some embodiments, the polymer comprises silicone. Such polymers may optionally contain small amounts of additional monomers (e.g., cross-linking monomers) copolymerized with the 2-hydroxyethyl methacrylate or silicone monomers. For example, 2-hydroxyethyl methacrylate may optionally be copolymerized in a hydrogel contact lens with vinylpyrrolidone, methyl methacrylate, methacrylic acid (anionic monomers), ethylene glycol dimethacrylate (cross-linking monomers), and / or 3-(ethyldimethyl-ammonium)propyl methacrylamide (cationic monomers).

[0228] Use of the composition: The composition according to any of the embodiments described herein may be useful for use in physiological environments, such as internal physiological environments or ophthalmic environments, in view of its sterility.Accordingly, the aqueous carrier according to any of the corresponding embodiments described herein may be selected from, for example, physiologically acceptable carriers and / or ophthalmologically acceptable carriers according to intended use.

[0229] Throughout this specification, the term "physiologically acceptable carrier" refers to a carrier or diluent that, when administered in the intended manner, does not cause significant irritation to a subject and does not impair the activity and properties of the composition (e.g., the ability of the liposomes therein to treat a condition and / or reduce the coefficient of friction of a surface, as described herein in any one of the corresponding embodiments). Without being limiting, examples of suitable aqueous carriers include saline, and emulsions and / or mixtures of organic solvents and water (or saline).

[0230] As used herein, the phrase "ophthalmologically acceptable carrier" refers to a carrier or diluent that, when contacted with a subject's eye (e.g., the cornea and / or sclera), does not cause significant irritation to the subject and does not impair the activity and properties of the composition (e.g., the ability of the liposomes therein to reduce the coefficient of friction of a contact lens surface and / or the ocular surface).

[0231] Use in a physiological environment may optionally be for reducing the coefficient of friction (also referred to herein as "lubrication", "lubricating", and variations thereof) of physiological surfaces (e.g., articular or ocular surfaces) and / or non-physiological surfaces (e.g., contact lens surfaces), for example in the treatment of a disease or disorder associated with an increased coefficient of friction of the surface. Reduction of the coefficient of friction of the surface may optionally be achieved by any one or more compounds present in the liposome (according to any corresponding embodiment described herein), including bilayer-forming lipids and / or polymeric compounds according to any corresponding embodiment described herein.

[0232] In some of the optional embodiments described herein, the sterile composition is for rinsing, cleaning, and / or soaking in a contact lens. In some such embodiments, the sterile composition includes an ophthalmically acceptable carrier and may optionally remain on the contact lens after rinsing, cleaning, and / or soaking in the solution, since the residual solution is not harmful to the eye when the contact lens is placed on the eye. In some alternative embodiments, the aqueous carrier is not an ophthalmically acceptable carrier (e.g., the carrier includes an ophthalmically unacceptable preservative and / or an ophthalmically unacceptable concentration of a preservative), and the sterile composition (e.g., a composition having a sterile contact lens soaked therein according to any of the corresponding embodiments described herein) may optionally be for reducing the risk of bacterial growth in the solution while the contact lens is soaked for an extended period of time (e.g., when the contact lens is not being used, such as at night) and / or while it is stored for an extended period of time (e.g., between the manufacture and first use of the contact lens). For example, such a composition is rinsed with an ophthalmically acceptable solution (e.g., water, saline) before the contact lens is placed on the eye.

[0233] In some of the optional embodiments described herein relating to contact lenses, the sterile composition is for soaking a contact lens therein (e.g., to keep the contact lens hydrated and optionally also to reduce the coefficient of friction of the contact lens). In some such embodiments, the carrier of the sterile composition includes additional ingredients suitable for cleaning, such as preservatives. Such a composition may optionally be provided as a single product with the contact lens soaked therein, e.g., the sterile contact lens and the sterile composition are packaged together. The sterile composition may optionally be intended to be rinsed with a more ophthalmically acceptable composition before insertion into the eye.

[0234] In some of the optional embodiments described herein relating to contact lenses, the sterile composition is for rinsing the contact lenses (e.g., to remove other compositions, such as ophthalmically unacceptable liquids, from the contact lenses and / or to reduce the coefficient of friction of the contact lenses). Such compositions may optionally be provided as a separate product from the contact lenses. In some such embodiments, the carrier of the sterile composition is an ophthalmically acceptable carrier.

[0235] In some of the optional embodiments described herein relating to contact lenses, the sterile composition is for cleaning used and / or new contact lenses (e.g., to remove bacteria and / or other impurities and optionally also reduce the coefficient of friction of the contact lenses). In some such embodiments, the carrier of the sterile composition includes additional components suitable for performing the cleaning, e.g., antimicrobial agents (e.g., peroxides and / or other oxidizing agents) and / or cleaning agents for removing impurities are ophthalmically acceptable carriers. Such compositions may optionally be provided as a separate product from the contact lenses and may be intended to be rinsed with a more ophthalmically acceptable composition before insertion into the eye.

[0236] In some of any of the embodiments, the sterile composition according to any of the corresponding embodiments described herein is for use in treating a synovial joint disorder, for example, the treatment comprises intra-articular administration of the composition.

[0237] According to an aspect of some embodiments of the present invention there is provided a use of a sterile composition according to any corresponding embodiment described herein in the manufacture of a medicament for the treatment of a synovial joint disorder, e.g., wherein the treatment comprises intra-articular administration of the composition.

[0238] According to an aspect of some embodiments of the present invention there is provided a method of treating a synovial joint disorder in a subject in need thereof, the method comprising administering to the subject a sterile composition according to any corresponding embodiment described herein, e.g., by intra-articular administration.

[0239] Examples of synovial joint disorders treatable according to embodiments of the various aspects of the invention include, but are not limited to, arthritis (e.g., osteoarthritis, rheumatoid arthritis, and / or psoriatic arthritis), bursitis, carpal tunnel syndrome, fibromyositis, gout, joint locking (optionally associated with osteochondritis dissecans and / or synovial osteochondromatosis), tendonitis, traumatic joint injury (optionally resulting directly from trauma, e.g., from previous trauma, such as post-traumatic injury sustained at the time of trauma and / or occurring some time after trauma), and joint injury associated with surgery (optionally surgery that directly damages the joint surface, such as by incision, and / or surgery that only indirectly damages the joint surface; e.g., surgery that repairs or otherwise affects tissues near the joint, such as ligaments and / or menisci, may involve joint injury due to changes in joint mechanics). Osteoarthritis is an exemplary synovial joint disorder treatable according to some embodiments of the invention.

[0240] In some of any corresponding embodiments, treatment of synovial joint disorders (eg, osteoarthritis) is characterized by, for example, reduced pain during movement, at night, and / or at rest.

[0241] In such embodiments, the reduction in pain may be determined by any suitable technique known in the art. Examples of suitable techniques for determining the reduction in pain include, but are not limited to, a short pain questionnaire (e.g., a shortened version), a physical activity test (e.g., Timed Up&Go), a VAS (visual analog scale) questionnaire for assessing pain (no pain to unbearable pain), the WOMAC (Western Ontario-McMaster University) scale, and / or the KOOS (Knee Injury-Osteoarthritis Outcome Score).

[0242] In some of any corresponding embodiments, treatment of synovial joint disorders (eg, osteoarthritis) is characterized by improvement in joint physiology.

[0243] In some of the corresponding embodiments, the improvement in joint physiology is determined by the Kellgren-Lawrence scale of radiological severity, e.g., the improvement is characterized by a reduction in severity. In some such embodiments, the treatment is further characterized by a reduction in pain (e.g., according to any of the corresponding embodiments described herein).

[0244] In some of any corresponding embodiments, the improvement in joint physiology is determined by the range of motion of the affected joint (e.g., the improvement is characterized by an increase in the range of motion of the joint), optionally in addition to being characterized by a reduction in severity according to the Kellgren-Lawrence scale. In some such embodiments, the treatment is further characterized by a reduction in pain (e.g., according to any corresponding embodiment described herein).

[0245] In some of any corresponding embodiments, the improvement in joint physiology is characterized by increased physical activity (e.g., activity involving the affected joint), optionally in addition to being characterized by reduced severity and / or increased range of motion according to the Kellgren-Lawrence scale (e.g., according to any corresponding embodiment described herein). In some such embodiments, the treatment is further characterized by reduced pain (e.g., according to any corresponding embodiment described herein).

[0246] In some of the corresponding embodiments, the improvement in joint physiology is characterized by an increase in quality of life in addition to being characterized by a reduction in severity according to the Kellgren-Lawrence scale, an increase in range of motion, and / or an increase in physical activity (e.g., according to any corresponding embodiment described herein). In some such embodiments, the treatment is further characterized by a reduction in pain (e.g., according to any corresponding embodiment described herein).

[0247] In some of the corresponding embodiments, the improvement in joint physiology is determined by at least one, or at least two, or at least three, or all four of the Kellgren-Lawrence scale of radiological severity, range of motion, physical activity, and quality of life (e.g., according to any corresponding embodiment described herein). In some such embodiments, the treatment is further characterized by a reduction in pain (e.g., according to any corresponding embodiment described herein).

[0248] In some of the corresponding embodiments, the sterile composition according to any of the embodiments described herein can improve the pathological changes of knee tissues after intra-articular injection of the composition in an animal model of osteoarthritis. Any suitable animal model of osteoarthritis known in the art can be used. Examples of suitable animal models include, but are not limited to, the Hartley guinea pig model and the rat medial meniscus destabilization model (optionally performed as described in the Examples section herein). In some embodiments, the animal model is a rat animal model, for example, the rat medial meniscus destabilization model (optionally performed as described in the Examples section herein).

[0249] The composition for use in treating synovial joint disorders (e.g., osteoarthritis) according to any corresponding embodiment described herein may optionally include one or more therapeutically active agents (e.g., according to any corresponding embodiment described herein). Examples of therapeutically active agents suitable for compositions for treating synovial joint disorders include, but are not limited to, analgesics and anti-inflammatory agents.

[0250] Examples of suitable analgesics include, but are not limited to, allylprodine, alpha methylfentanyl, AP-237, bezitramide, butorphanol, buprenorphine, carfentanil, clonidine, codeine, desmethylprodine, dextromoramide, dexocin, difenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, diphenoxylate, dipipanone, eluxadoline, ethylmorphine, etorphine, fentanyl, heterocodeine, hydrocone, hydromorphone, ketamine ... In some embodiments, the medicaments include azetidine, ketobemidone, lefetamine, levomethadyl (e.g., levomethadyl acetate), levomethorphan, levorphanol, loperamide, meptazinol, methadone, mexiletine, mitragynine, morphine, nalbuphine, omefentanyl, oxycodone, oxymorphone, paracetamol, pentazocine, pethidine, phenethylphenylacetoxypiperidine, piritramide, prozine, promedol, propoxyphene, remifentanil, sulfentanyl, tapentadol, tilidine, and tramadol.

[0251] Steroidal as well as nonsteroidal anti-inflammatory drugs (eg, the nonsteroidal anti-inflammatory drugs described herein) may be used as analgesics.

[0252] Examples of suitable anti-inflammatory drugs include, but are not limited to, alclofenac; alclometasone (e.g., alclometasone dipropionate); algestone (e.g., algestone acetonide); alpha amylase; amcinafal; amcinafide; amfenac (e.g., amfenac sodium); amiprilose (e.g., amiprilose hydrochloride); anakinra; anilorac; anitrazafen; apazone; aspirin; balsalazide disodium; bendazac; benoxaprofen; benzydamine (e.g., benzydamine hydrochloride); bromelain; broperamol. ;Budesonide;Carprofen;Cycloprofen;Synthazone;Cliprofen;Clobetasol (e.g., clobetasol propionate, clobetasone butyrate);Clopirac;Cloticasone (cloticasone propionate);Cormetsone (cormethasone acetate);Cortoxone;Deflazacort;Desonide;Desoximetasone;Dexamethasone (e.g., dexamethasone dipropionate);Diclofenac (e.g., diclofenac potassium, diclofenac sodium);Diflorasone (e.g., diflorasone diacetate);Diflumidone (e.g., diflu midone sodium); diflunisal; difluprednate; diphthalone; drocinonide; endrisone; enlimomab; enolicam (e.g., enolicam sodium); epirizole; etodolac; etofenamate; felbinac; fenamol; fenbufen; fenclofenac; fenclorac; fendosal; fenpiparone; fentiazac; furazarone; fluazacort; flufenamic acid; flumisole; flunisolide (e.g., flunisolide acetate); flunixin (e.g., flunixin meglumine); fluocortin (e.g., flu Occortin butyl; Fluorometholone (e.g., Fluorometholone acetate); Flucasone; Flurbiprofen; Fluretofen; Fluticasone (e.g., Fluticasone propionate); Furaprofen; Flobufen; Halcinonide; Halobetasol (e.g., Halobetasol propionate); Halopredone (e.g., Halopredone acetate); Ibufenac; Ibuprofen (e.g., Ibuprofen aluminum, Ibuprofen piconol); Ilonidap; Indomethacin (e.g., Indomethacin sodium); Indoprofen; Indoxol;Intrazol;Isoflupredone (e.g., Isoflupredone acetate);Isoxepac;Isoxicam;Ketoprofen;Lofemizole (e.g., Lofemizole hydrochloride);Lomoxicam;Loteprednol (e.g., Loteprednol etabonate);Meclofenamate (e.g., Meclofenamate sodium, Meclofenamic acid);Meclorizone (e.g., Meclorizone dibutyrate);Mefenamic acid;Mesalamine;Meseclazone;Methylprednisolone (e.g., Methylprednisolone suleptanate);Momiflumate;Nabumetone;Naproxen (e.g., Naproxen sodium);Naproxol;Nimazone;Olsalazine (e.g., Olsalazine sodium);Orgotein;Orpanoxin;Oxaprozin;Oxyphenbutazone;Paranyline (e.g., Paranyline hydrochloride);Pentosan polysulfate (e.g., Pentosan polysulfate sodium);Phenbutazone (e.g., Phenbutazone sodium muglicerate;pirfenidone;piroxicam (e.g., piroxicam cinnamate, piroxicam olamine);pirprofen;prednazate;priferon;prodolic acid;proquazone;proxazole (e.g., proxazole citrate);rimexolone;romazarit;sarcolex;salicylates (e.g., salicylic acid);salnacedin;salsalate;sanguinarium (e.g., sanguinarium chloride);seclazone;selmetacin;s Doxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap (e.g., tenidap sodium); Tenoxicam; Tesicam; Tesimide; Tetridamine; Tiopinac; Tixocortol (e.g., tixocortol pivalate); Tolmetin (e.g., tolmetin sodium); Triclonide; Triflumidate; Zidometacin; and Zomepirac (e.g., Zomepirac sodium).

[0253] Examples of other therapeutically active agents suitable for compositions for treating synovial joint disorders include, but are not limited to, cannabinoids (eg, cannabidiol) and other cannabis-derived substances.

[0254] Techniques for formulating and administering compounds may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., latest edition, which is incorporated herein by reference.

[0255] Sterile compositions (eg, solutions) according to any one of the embodiments of the present invention may be prepared by methods well known in the art, eg, conventional mixing or dissolving methods.

[0256] Thus, sterile compositions (e.g., solutions) for use in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers that facilitate processing of the liposomes (and, optionally, other components of the compositions described herein) into a pharma- ceutically usable preparation. Appropriate formulations will depend on the chosen route of administration.

[0257] For injection, sterile compositions may be formulated using suitable aqueous carriers, preferably physiologically compatible buffers such as Hank's solution, Ringer's solution, histidine buffer, or physiological saline buffer, with or without organic solvents, such as propylene glycol, polyethylene glycol, and the like.

[0258] The sterile compositions described herein may be formulated for parenteral administration, for example, by bolus injection or continuous infusion. Preparations for injection may be provided in unit dosage form, for example in ampoules or in multi-dose containers, optionally with the addition of preservatives. The compositions may be formulated as suspensions, solutions, or emulsions (e.g., in aqueous carriers as described herein), and may contain formulatory agents, such as suspending, stabilizing, and / or dispersing agents.

[0259] Sterile compositions may be formulated as aqueous solutions per se. Furthermore, sterile compositions may be in the form of suspensions and / or emulsions (e.g., water-in-oil, oil-in-water, or water-in-oil-in-oil emulsions), for example, to increase the viscosity of the formulation. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, suspensions may contain suitable stabilizers or agents that increase the solubility and / or stability of the liposomes described herein, for example, to allow the formulation of highly concentrated solutions.

[0260] Sterile compositions may be formulated so that the liposomes are contained in an amount effective to achieve the intended purpose, for example, an amount effective to prevent, alleviate, or ameliorate symptoms of a disorder in a subject being treated.

[0261] The dosage may vary depending on the dosage form employed, the route of administration utilized, and the site of administration (eg, the volume and / or surface of the site in contact with the liposome).

[0262] The amount of composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0263] Sterile compositions (e.g., solutions) according to embodiments of the invention may be provided in a pack or dispenser device, such as an FDA (United States Food and Drug Administration) approved kit, if desired, which may contain one or more unit dosage forms containing the active ingredient(s) (e.g., liposomes as described herein). The pack may, for example, include, but is not limited to, a blister pack, metal or plastic foil. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also include a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the government agency of the form of the composition for administration to humans or animals. Such notice may be, for example, a label approved by the United States Food and Drug Administration for prescription drugs, or an approved product insert. Sterile compositions comprising liposomes as described herein in any one of the corresponding embodiments formulated in a physiologically acceptable carrier may also be prepared, placed in an appropriate container, and further labeled for the treatment of the indicated condition or diagnosis, as detailed herein.

[0264] Other definitions: The term "hydrocarbon" as used herein refers to an organic moiety that contains as its backbone a chain of carbon atoms substituted primarily with hydrogen atoms. The hydrocarbon can be saturated or unsaturated, can consist of an aliphatic, alicyclic, or aromatic moiety, and can be optionally substituted with one or more substituents (other than hydrogen). The substituted hydrocarbon can have one or more substituents, whereby each substituent can independently be, for example, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, oxo, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The hydrocarbon can be a terminal group or a linking group (as these terms are defined herein). The hydrocarbon moiety is optionally interrupted with one or more heteroatoms, including, but not limited to, one or more oxygen, nitrogen, and / or sulfur atoms. In some embodiments of any of the embodiments described herein relating to a hydrocarbon, the hydrocarbon is not interrupted by any heteroatoms.

[0265] Preferably, and unless otherwise defined, the hydrocarbon moiety has 1 to 20 carbon atoms. Whenever a numerical range is given herein, such as "1 to 20," it means that the group (in this case an alkyl group) can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms.

[0266] As used herein, the term "alkyl" refers to any saturated aliphatic hydrocarbon, including straight and branched chain groups. Preferably, the alkyl group has 1-20 carbon atoms. More preferably, the alkyl is a medium size alkyl having 1-10 carbon atoms. Most preferably, unless otherwise defined, the alkyl is a lower alkyl having 1-4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent can be, for example, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein.

[0267] As used herein, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon containing at least one carbon-carbon double bond, including straight-chain and branched-chain groups. Preferably, the alkenyl group has 2-20 carbon atoms. More preferably, the alkenyl is a medium size alkenyl having 2-10 carbon atoms. Most preferably, unless otherwise defined, the alkenyl is a lower alkenyl having 2-4 carbon atoms. The alkenyl group may be substituted or unsubstituted. A substituted alkenyl can have one or more substituents, whereby each substituent can independently be, for example, alkynyl, cycloalkyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy, sulfonamide, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino.

[0268] The term "alkynyl" as used herein refers to an unsaturated aliphatic hydrocarbon containing at least one carbon-carbon triple bond, including straight-chain and branched-chain groups. Preferably, the alkynyl group has 2-20 carbon atoms. More preferably, the alkynyl is a medium size alkynyl having 2-10 carbon atoms. Most preferably, unless otherwise defined, the alkynyl is a lower alkynyl having 2-4 carbon atoms. The alkynyl group may be substituted or unsubstituted. A substituted alkynyl can have one or more substituents, whereby each substituent can independently be, for example, cycloalkyl, alkenyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy, sulfonamide, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino.

[0269] The term "alkylene" refers to a saturated or unsaturated aliphatic hydrocarbon linking group, as that term is defined herein, which differs from an alkyl group (if saturated) or an alkenyl or alkynyl group (if unsaturated), as defined herein, only in that alkylene is a linking group rather than a terminal group.

[0270] A "cycloalkyl" group refers to a saturated or unsaturated all-carbon monocyclic or fused ring (i.e., rings sharing an adjacent pair of carbon atoms) group in which one or more rings do not have a completely conjugated pi-electron system. Examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane. Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein. If the cycloalkyl group is unsaturated, it can contain at least one carbon-carbon double bond and / or at least one carbon-carbon triple bond. A cycloalkyl group may be a terminal group (as this term is defined herein) attached to a single adjacent atom, or a linking group (as this term is defined herein) joining two or more moieties.

[0271] An "aryl" group refers to the terminal group of an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) having a completely conjugated pi-electron system. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, and anthracenyl. Aryl groups can be substituted or unsubstituted. When substituted, the substituent can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein.

[0272] A "heteroaryl" group refers to a monocyclic or fused ring terminal group (i.e., rings that share adjacent pairs of atoms) having one or more atoms, such as nitrogen, oxygen, and sulfur, in the ring(s) and further having a completely conjugated pi-electron system. Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, and purine. Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituent can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein.

[0273] The term "arylene" refers to a monocyclic or fused ring polycyclic linking group, as that term is defined herein, and includes linking groups that differ from aryl or heteroaryl groups, as these groups are defined herein, only in that the arylene is a linking group rather than a terminal group.

[0274] A "heteroalicyclic" group refers to a monocyclic or fused ring group having one or more atoms such as nitrogen, oxygen, and sulfur in the ring(s). The ring may also have one or more double bonds. However, the ring does not have a completely conjugated pi-electron system. Heteroalicyclics can be substituted or unsubstituted. When substituted, the substituent may be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy, sulfonamide, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino (as these terms are defined herein). Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine, and the like. Heteroalicyclic groups may be terminal groups (as this term is defined herein) attached to a single adjacent atom, or linking groups (as this term is defined herein) connecting two or more moieties.

[0275] As used herein, the terms "amine" and "amino" refer to the -NR'R'' group or -N +refers to any of the groups R'R''R''', where R', R'', and R''' are each hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic (linked to the amine nitrogen through a ring carbon thereof), aryl, or heteroaryl (linked to the amine nitrogen through a ring carbon thereof) as defined herein. Optionally R', R'', and R''' are hydrogen or an alkyl containing 1 to 4 carbon atoms. Optionally R' and R'' (and R''', if present) are hydrogen. If substituted, the carbon atom of the R', R'', or R''' hydrocarbon portion that is bonded to the nitrogen atom of the amine is not substituted with oxo (unless otherwise expressly stated) such that R', R'', and R''' are not (for example) carbonyl, C-carboxy, or amido (as these groups are defined herein).

[0276] The "azide" group is -N=N + =N - Refers to the end group.

[0277] An "alkoxy" group refers to any of the -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, and -O-heteroalicyclic end groups, as defined herein, or any of the -O-alkylene, -O-cycloalkyl-, and -O-heteroalicyclic linking groups, as defined herein.

[0278] An "aryloxy" group refers to both an --O-aryl and an --O-heteroaryl group, or an --O-arylene, as defined herein.

[0279] A "hydroxy" group refers to an --OH group.

[0280] A "thiohydroxy" or "thiol" group refers to a --SH group.

[0281] A "thioalkoxy" group refers to any of the -S-alkyl, -S-alkenyl, -S-alkynyl, -S-cycloalkyl, and -S-heteroalicyclic end groups, as defined herein, or any of the -S-alkylene-, -S-cycloalkyl-, and -S-heteroalicyclic linking groups, as defined herein.

[0282] A "thioaryloxy" group refers to both an --S-aryl and an --S-heteroaryl group, or an --S-arylene, as defined herein.

[0283] A "carbonyl" or "acyl" group refers to a -C(=O)-R' terminal group, where R' is defined above, or to a -C(=O)- linking group.

[0284] A "thiocarbonyl" group refers to a -C(=S)-R' terminal group, where R' is as defined herein, or to a -C(=S)- linking group.

[0285] A "carboxy", "carboxyl", "carboxylic acid", or "carboxylate" group refers to both the "C-carboxy" and "O-carboxy" terminal groups as defined herein, and to a carboxy linking group as defined herein.

[0286] A "C-carboxy" group refers to a -C(=O)-O-R' group, with R' as defined herein.

[0287] An "O-carboxy" group refers to an R'C(=O)-O- group, with R' as defined herein.

[0288] A "carboxy linking group" refers to a -C(=O)-O- linking group.

[0289] An "oxo" group refers to the =O terminal group.

[0290] An "imine" group refers to a =N-R' terminal group, where R' is as defined herein, or to a =N-linking group.

[0291] An "oxime" group refers to a =N-OH terminal group.

[0292] A "hydrazone" group refers to a ═N-NR'R'' terminal group, where R' and R'' are each as defined herein, or to a ═N-NR'- linking group, where R' is as defined herein.

[0293] A "halo" group refers to a fluorine, chlorine, bromine, or iodine.

[0294] A "sulfinyl" group refers to an -S(=O)-R' terminal group, where R' is as defined herein, or to an -S(=O)- linking group.

[0295] The "sulfonyl" group is -S(=O). 2 -R' refers to an end group, where R' is as defined herein, or -S(=O) 2 -refers to a linking group.

[0296] The "sulfonate" group is -S(=O). 2 refers to an -O-R' terminal group, where R' is as defined herein, or -S(=O) 2 Refers to the -O- linking group.

[0297] The "sulfate" group is -OS(=O). 2 refers to an -O-R' terminal group, where R' is as defined herein, or -OS(=O) 2 Refers to the -O- linking group.

[0298] A "sulfonamide" or "sulfonamido" group includes both the S-sulfonamido and N-sulfonamido end groups, as defined herein, and a sulfonamide linking group, as defined herein.

[0299] The "S-sulfonamide" group is -S(=O). 2 refers to an --NR'R'' end group, where R' and R'' are each as defined herein.

[0300] The "N-sulfonamide" group is R'S(=O). 2 refers to the -NR''- terminal group, where R' and R'' are each as defined herein.

[0301] "Sulfonamide linking group" is -S(=O) 2 refers to the --NR'-- linking group, where R' is as defined herein.

[0302] A "carbamyl" group includes both O-carbamyl and N-carbamyl end groups, as defined herein, and a carbamyl linking group, as defined herein.

[0303] An "O-carbamyl" group refers to an -OC(=O)-NR'R'' terminal group, with R' and R'' as defined herein.

[0304] An "N-carbamyl" group refers to an R'OC(=O)-NR''- terminal group, where R' and R'' are as defined herein.

[0305] A "carbamyl linking group" refers to an -OC(=O)-NR'- linking group, where R' is as defined herein.

[0306] "Thiocarbamyl" groups include O-, S-, and N-thiocarbamyl end groups, as defined herein, and thiocarbamyl linking groups, as defined herein.

[0307] An "O-thiocarbamyl" group refers to an -OC(=S)-NR'R'' terminal group, with R' and R'' as defined herein.

[0308] An "N-thiocarbamyl" group refers to an R'OC(=S)NR''- terminal group, where R' and R'' are as defined herein.

[0309] An "S-thiocarbamyl" group refers to a -SC(=O)-NR'R'' terminal group, with R' and R'' as defined herein.

[0310] A "thiocarbamyl linking group" refers to an -OC(=S)-NR'- or -SC(=O)-NR'- linking group, where R' is as defined herein.

[0311] An "amide" or "amido" group includes C-amide and N-amide terminal groups, as defined herein, and an amide linking group, as defined herein.

[0312] A "C-amido" group refers to a -C(=O)-NR'R'' terminal group, with R' and R'' as defined herein.

[0313] An "N-amido" group refers to an R'C(=O)-NR''- terminal group, where R' and R'' are as defined herein.

[0314] An "amide linker" refers to a -C(=O)-NR'- linker, where R' is as defined herein.

[0315] "Urea group" refers to the -N(R')-C(=O)-NR''R''' terminal group, where R', R'', and R'' are each as defined herein, or to the -N(R')-C(=O)-NR''- linking group, where R' and R'' are each as defined herein.

[0316] A "thiourea group" refers to the -N(R')-C(=S)-NR''R''' terminal group, where R', R'', and R'' are each as defined herein, or to the -N(R')-C(=S)-NR''- linking group, where R' and R'' are each as defined herein.

[0317] The "nitro" group is -NO 2 Refers to the base.

[0318] A "cyano" group refers to a -C≡N group.

[0319] The term "phosphonyl" or "phosphonate" refers to the group -P(=O)(OR')(OR''), where R' and R'' are as defined herein, or to the linking group -P(=O)(OR')-O-, where R' is as defined herein.

[0320] The term "phosphate" refers to an -OP(=O)(OR')(OR'') terminal group, where R' and R'' are each as defined herein, or to an -OP(=O)(OR')-O- linking group, where R' is as defined herein.

[0321] The term "phosphinyl" refers to a -PR'R'' terminal group, where R' and R'' are each as defined herein, or to a -PR'- linking group, where R' is as defined herein.

[0322] The term "hydrazine" refers to an -NR'-NR''R''' terminal group, where R', R'', and R''' are as defined herein, or to an -NR'-NR''- linking group, where R' and R'' are as defined herein.

[0323] The term "hydrazide" as used herein refers to a -C(=O)-NR'NR''R''' terminal group, where R', R'', and R''' are as defined herein, or to a -C(=O)-NR'NR''- linking group, where R' and R'' are as defined herein.

[0324] As used herein, the term "thiohydrazide" refers to a -C(=S)-NR'NR''R''' terminal group, where R', R'', and R''' are as defined herein, or a -C(=S)-NR'NR''- linking group, where R' and R'' are as defined herein.

[0325] A "guanidinyl" group refers to a -RaNC(=NRd)-NRbRc terminal group, where Ra, Rb, Rc, and Rd can be as defined herein for R' and R'', respectively, or represents a -R'NC(=NR'')-NR'''- linking group, where R', R'', and R''' are as defined herein.

[0326] A "guanyl" or "guanine" group refers to an R"R"NC(=NR')-terminated group, where R', R", and R" are as defined herein, or to a -R"NC(=NR')- linking group, where R' and R" are as defined herein.

[0327] For any of the embodiments described herein, the compounds described herein may be in the form of a salt, for example a pharma- ceutically acceptable salt.

[0328] As used herein, the phrase "pharmaceutically acceptable salt" refers to a charged species of the parent compound and its counterion, which is usually used to modify the solubility characteristics of the parent compound and / or reduce any significant irritation of the parent compound to an organism, but does not impair the biological activity and properties of the administered compound. Pharmaceutically acceptable salts of the compounds described herein may alternatively be formed during the synthesis of the compounds, for example, during the process of isolating the compounds from a reaction mixture or during the process of recrystallizing the compounds.

[0329] In some contexts of the present embodiments, pharma- ceutically acceptable salts of the compounds described herein may optionally be acid addition salts and / or base addition salts.

[0330] An acid addition salt comprises at least one basic (e.g., amine and / or guanidinyl) group of a compound in positively charged form (e.g., the basic group is protonated) in combination with at least one counterion derived from a selected acid to form a pharma- ceutically acceptable salt.Accordingly, an acid addition salt of a compound described herein may be a complex formed between one or more basic groups of the compound and one or more equivalents of an acid.

[0331] A base addition salt comprises a combination of at least one acidic (e.g., carboxylic acid) group of a compound in negatively charged form (e.g., the acidic group is deprotonated) with at least one counterion derived from a selected base to form a pharma- ceutically acceptable salt. Thus, a base addition salt of a compound described herein may be a complex formed between one or more acidic groups of the compound and one or more equivalents of a base.

[0332] Depending on the stoichiometric ratio of the charged group(s) in the compound and the counter ions in the salt, the acid and / or base addition salts can be either mono- or poly-addition salts.

[0333] As used herein, the phrase "mono-addition salt" refers to a salt that has a 1:1 stoichiometric ratio of counterion to the charged form of the compound, such that the addition salt contains one molar equivalent of counterion per molar equivalent of compound.

[0334] As used herein, the phrase "polyaddition salt" refers to salts in which the stoichiometric ratio of counterion to charged form of the compound is greater than 1:1, e.g., 2:1, 3:1, 4:1, etc., such that the addition salt contains more than one molar equivalent of counterion per molar equivalent of compound.

[0335] Examples of pharma- ceutically acceptable salts include, but are not limited to, ammonium or guanidinium cations and their acid addition salts, and / or carboxylate anions and their base addition salts.

[0336] Base addition salts may include cationic counter ions such as sodium, potassium, ammonium, calcium, magnesium, etc., which form pharma- ceutically acceptable salts.

[0337] The acid addition salts may be from a variety of organic and inorganic acids, including, but not limited to, hydrochloric acid forming a hydrochloric acid addition salt, hydrobromic acid forming a hydrobromic acid addition salt, acetic acid forming an acetic acid addition salt, ascorbic acid forming an ascorbic acid addition salt, benzenesulfonic acid forming a besylic acid addition salt, camphorsulfonic acid forming a camphorsulfonic acid addition salt, citric acid forming a citric acid addition salt, maleic acid forming a maleic acid addition salt, malic acid forming a malic acid addition salt, methanesulfonic acid forming a methanesulfonic acid (mesylic acid) addition salt, naphthalenesulfonic acid forming a naphthalenesulfonic acid addition salt, oxalic acid forming an oxalic acid addition salt, phosphoric acid forming a phosphoric acid addition salt, toluenesulfonic acid forming a p-toluenesulfonic acid addition salt, succinic acid forming a succinic acid addition salt, sulfuric acid forming a sulfuric acid addition salt, tartaric acid forming a tartrate addition salt, and trifluoroacetic acid forming a trifluoroacetic acid addition salt. Each of these acid addition salts may be either a mono- or poly-addition salt (as these terms are defined herein).

[0338] Furthermore, each of the compounds described herein, including the salts thereof, may be in the form of a solvate or hydrate thereof.

[0339] The term "solvate" refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, etc.) formed with a solute (a heterocyclic compound as described herein) and a solvent whereby the solvent does not interfere with the intended activity of the solute.

[0340] The term "hydrate" refers to a solvate as defined above where the solvent is water.

[0341] The compounds described herein are available as polymorphs, and the present embodiments further encompass any isomorphic form of the compounds and any combination thereof.

[0342] The compounds and structures described herein encompass any stereoisomers, including enantiomers and diastereomers, of the compounds described herein, unless a particular stereoisomer is specifically indicated.

[0343] The term "enantiomer" as used herein refers to a stereoisomer of a compound that is superimposable on its counterpart only when completely inverted / reflected (mirror image) with respect to each other. Enantiomers are said to have "handedness" because they face each other like right and left hands. Enantiomers have identical chemical and physical properties except when they are present in an environment that itself has handedness, e.g., all living systems. In the context of the present embodiment, a compound may exhibit one or more chiral centers, each of which exhibits the (R) or (S) form, and any combination, and compounds according to some embodiments of the present invention may exhibit the (R) or (S) form at any of their chiral centers.

[0344] The term "diastereomers" as used herein refers to stereoisomers that are not enantiomers of each other. Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more, but not all, corresponding (related) stereocenters and are not mirror images of each other. If two diastereoisomers differ from each other only at one stereocenter, they are epimers. Each stereocenter (chiral center) gives rise to two different configurations and thus two different stereoisomers. In the context of the present invention, the embodiments of the present invention encompass compounds with multiple chiral centers that occur in any combination of configurations, i.e., any diastereomers.

[0345] As used herein, the term "about" refers to ±10%, and optionally ±5%.

[0346] The terms "comprises," "comprising," "includes," "including," "having," and their conjugations mean "including but not limited to."

[0347] The term "consisting of" means "including and limited to."

[0348] The term "consisting essentially of" means that a composition, method, or structure may include additional components, steps, and / or moieties, but only if the additional components, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0349] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0350] Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation of the scope of the invention. Thus, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1-6 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, etc. as well as individual numerical values ​​within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0351] Whenever a numerical range is given herein, it is meant to include any recited numbers (fractional or integer) within the given range. As used herein, the phrases "ranging from" a first indicated value and a second indicated value, and "ranging from" a first indicated value to a second indicated value, are used interchangeably and are meant to include the first and second indicated values ​​and all fractional and integer numbers therebetween.

[0352] As used herein, the term "method" refers to manners, means, techniques, and procedures for accomplishing a given task, including but not limited to manners, means, techniques, and procedures known or readily developed from known manners, means, techniques, and procedures to practitioners of chemistry, pharmacology, biology, biochemistry, and medicine.

[0353] As used herein, the term "treating" includes inhibiting, substantially arresting, slowing, or reversing the progression of a condition, substantially ameliorating the clinical or cosmetic symptoms of a condition, or substantially preventing the appearance of clinical or cosmetic symptoms of a condition.

[0354] It will be understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination, or as suitable in any other embodiment described in the present invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperable without those elements.

[0355] The various embodiments and aspects of the present invention as delineated hereinabove and claimed in the claims section below find experimental confirmation in the following examples. EXAMPLES

[0356] Reference is now made to the following examples which, together with the above description, illustrate, by way of non-limiting example, certain embodiments of the present invention.

[0357] material and method Synthesis and properties of DPPE-Br (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-2'-bromoisobutyrate) DPPE-Br (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-2'-bromoisobutyrate) was prepared according to the procedure described by Li et al. [J Controlled Release 2014, 176:104-114]. DPPE lipid was mixed with dichloromethane (DCM) in a flask and shaken by hand to obtain a white suspension. Triethylamine was added to the flask and the mixture was stirred until thoroughly mixed. α-Bromoisobutyryl bromide was then carefully added to the suspension. The solution was then washed with HCl using a separatory funnel. The organic phase was separated using Na 2 SO 4 The target solution was dried at 40° C. and the volume of the target solution was reduced using a rotary evaporator. The final product was isolated by adding the DCM solution to cold methanol. It was precipitated in a freezer overnight. The white powder of DPPE-Br was filtered and dried in a desiccator for 3 days. The final product showed the following characteristics: 1 H NMR (300 MHz, CDCl 3 ): δ = 5.25 (-OCHCH 2 OP-); δ=4.45(-CH 2 COOCH 2 -);δ=4.30(-P-OCH 2 CH 2 -);δ=4.14(-P-OCH 2 CH-);δ=3.57(-OCH 2 CH 2 N-); δ=2.30(-COCH 2 CH 2 -);δ=1.95(-BrCCH 3 CH 3 );δ=1.60(-COCH 2 CH 2 -);δ=1.25(-(CH 2 )14 -);δ=0.88(-CH 2 CH 3 ).

[0358] Synthesis and properties of DPPE-pMPC (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-poly(2-(methacryloyloxy)ethyl phosphorylcholine) The general scheme for the synthesis of lipid-conjugated polymer DPPE-pMPC is as described in Lin et al. [Langmuir 2019, 35:6048-6054]. DPPE-Br initiator was mixed with MPC monomer in ethanol, and then PMDETA (N,N,N′,N′′,N′′-pentamethyldiethylenetriamine) ligand was added to the flask. Atom transfer radical polymerization was triggered by adding catalyst CuBr. After the polymerization was completed, the reaction mixture was precipitated in cold diethyl ether, and the blue solid intermediate was filtered and redissolved in ethanol. The ethanol solution was added dropwise to water with stirring, and then hydrochloric acid was added to obtain a colorless and transparent solution. TFF (tangential flow filtration) cassette washing was performed to eliminate small molecular weight compounds. After lyophilization, the final product was obtained. The lipid-conjugated polymer showed the following characteristics: 1 H NMR (300 MHz, CDCl 3 :CD 3 OD 1:1): δ = 5.25 (-OCHCH 2 OP-); δ=4.32(-N-CH 2 CH 2 O-); δ = 4.22 (-CO-OCH 2 CH 2 -);δ=4.07(-OCH 2 CH 2 OP-); δ=3.75(-(CH 3 ) 3 N + -CH 2 CH 2 -);δ=3.34(-(CH 3 ) 3 N + -);δ=1.9(-(CH 2 ) n -, active center);δ=1.28(-(CH 2 )12 -);δ=0.88(-CH 2 CH 3 The molecular weight was determined by integration of the peaks at chemical shifts δ = 1.28 and δ = 3.75, which correspond to the relative amounts of hydrogen atoms in the lipid and monomeric moieties.

[0359] Further data regarding the preparation and characterization of lipid-conjugated polymers such as DPPE-pMPC can be found in WO 2017 / 109784.

[0360] Example 1 Preparation of sterile liposome compositions Liposomes were prepared by hydration-extrusion according to the procedure described in Cao et al. [Langmuir 2012, 28:11625-11632]. Phosphatidylcholine and DPPE-pMPC were dissolved in heated organic solvent. The solvent was removed using a rotary evaporator to obtain a dry homogeneous lipid mixture. The resulting lipid powder was dissolved in ethanol. Multilamellar vesicles (MLVs) were formed by filtering the ethanol solution through a 0.2 μm filter and directly pouring it into hot aqueous medium. The liposome suspension was stirred at 65 °C for at least 25 min. To reduce the vesicle size, the MLVs were passed through membrane filters with defined pore sizes of 400 nm and 200 nm. Repeated extrusion yielded small unilamellar vesicles (SUVs).

[0361] A TFF system was used to remove low molecular weight fractions.

[0362] The liposome solution was filled into 5 mL sterile glass vials, and each vial was closed with a rubber stopper and sealed with an aluminum cap. The primary packaged liposome product was steam sterilized at 121°C for 20 minutes. The effectiveness of this sterilization procedure was confirmed by the absence of microbial growth according to the sterility test results, and the presence of endotoxins less than 25EU / mL (the pass criterion for bacterial endotoxin testing is less than 35EU / mL).

[0363] The osmolality of the liposome solution was measured with a micro-osmometer (stand-alone type) to be 289 mOsm / kg, which is consistent with the small unilamellar vesicles not being osmotically active.

[0364] The size distribution and zeta potential of liposomes in sterile solutions were determined by dynamic light scattering using a Zetasizer® Nano ZS instrument (Malvern). Zeta potential was measured by diluting the samples with 10 μM saline.

[0365] The particle size distribution and zeta potential data are shown in FIG. 1 and Table 1 below.

[0366] [Table 1]

[0367] To visualize the liposomes and characterize their size and shape, exemplary liposome compositions on carbon grids were flash frozen and subjected to cryo-tunneling electron microscopy.

[0368] As shown in Figures 2A and 2B, the liposomes were generally spherical, contained unilamellar and multilamellar structures, and had a heterogeneous size distribution ranging from 50 to 200 nm in diameter as measured by cryo-tunneling electron microscopy.

[0369] As shown in Figures 3 and 4, the Z-average of liposome diameter (Figure 3) and polydispersity index (Figure 4) of the sterile liposome solution were stable over a period of 350 days (storage at room temperature) as measured by dynamic light scattering.

[0370] These results indicate that the sterile liposome solution is highly stable after steam sterilization, even though steam sterilization may induce hydrolysis of the liposomes [Toh & Chiu, Asian J Pharm Sci 2013, 8:88-95]. This is advantageous because steam sterilization is usually cheaper, more convenient, and safer than alternative sterilization procedures such as gamma irradiation, ethylene oxide, and ultraviolet sterilization.

[0371] Example 2 Effect of Exemplary Sterile Liposomal Compositions on Lubrication in a Simulated Knee Joint Model The effect of the exemplary sterile composition prepared as described in Example 1 on the lubrication of a simulated knee joint was measured over 500,000 cycles using a pin-on-disk test with duration, load, and waveform parameters according to the ASTM F732 standard. The coefficient of friction was measured over 500,000 cycles, and the wear rate was evaluated by measuring the weight loss of the pin after 500,000 cycles. The effect of the exemplary composition as a lubricant was compared to a bovine calf serum (BCS)-based lubricant (mimicking human synovial fluid), as well as 50:50 and 25:75 mixtures of the exemplary composition and BCS.

[0372] As shown in Table 2 below and in FIG. 5, the exemplary compositions (by themselves and in admixtures with BCS) had lower average and maximum coefficients of friction than BCS.

[0373] Additionally, as shown in Table 2, the exemplary compositions significantly reduced the extent of wear (pin weight loss) after 500,000 cycles in a dose-dependent manner compared to BCS.

[0374] These results indicate that the sterile compositions described herein are suitable for increasing joint lubrication.

[0375] [Table 2]

[0376] Example 3 Effect of Exemplary Sterile Liposomal Compositions on Cartilage Lubrication The effect of an exemplary composition prepared as described in Example 1 on the lubricity of cartilage surfaces was evaluated in vitro. Fresh articular cartilage from the knees of 1-year-old calves is cut into disks. The mechanical properties of the samples are measured by indentation testing, optionally with a pin-on-disc setup, and the maximum experimental contact pressure is calculated. Tribological measurements are performed for 1 hour at a speed representative of physiological joint motion, e.g. 1 mm / sec. The coefficient of friction is calculated by dividing the measured lateral force by the normal force applied during shear. Control measurements are performed, e.g., with a PBS solution. The results are compared with the results of corresponding measurements performed with, e.g., polymeric hyaluronic acid or a commercially available hyaluronic acid intra-articular injection, such as the Synvisc® composition.

[0377] Example 4 Efficacy of Exemplary Sterile Liposomal Compositions in Treating Osteoarthritis in Animal Models Light microscopy studies have shown that Hartley guinea pigs develop moderate to severe cartilage destruction and subchondral bone sclerosis between 6 and 12 months of age, mainly in the central part of the medial tibial plateau, and the changes usually progress to severe osteoarthritis (OA) in old age [de Bri et al., J Orthop Res 1995, 13:769-776; de Bri et al., Acta Orthop Scan 1996, 67:498-504]. This is a typical change that mimics the human disease [Bendele & Hulman, Arthritis Rheum 1988, 31:561-565]. Therefore, Dunkin Hartley guinea pigs were selected as a model of spontaneous age-related osteoarthritis, and an in vivo preclinical study of the effect of an exemplary composition prepared as described in Example 1 on knee joint lubrication by intra-articular administration was performed.

[0378] After the animals are acclimated for one week, the test composition is administered via intra-articular injection. The animals are then observed for 3-6 months to evaluate the effect of the test composition. Histological analysis mainly deals with tissue lesions and eventual tissue regeneration. All stained slides are scanned using a NanoZoomer® digital slide scanner (Hamamatsu) and converted to digital format for subsequent analysis and OA scoring.

[0379] In another test, rat medial meniscus destabilization model of osteoarthritis is used.Rats are randomly assigned to each group, anesthetized with isoflurane, and surgically induced osteoarthritis is performed on the right knee.The effect of intra-articular administration of test composition on the pathological changes (e.g., cartilage cell death, cartilage degeneration) and pain of knee tissue 56 days after surgery is evaluated.

[0380] It is determined whether one or more of the symptoms of the disease described above are alleviated.

[0381] Example 5 Efficacy of Exemplary Sterile Liposomal Compositions in Treating Osteoarthritis in Humans A Phase I, open-label study will be conducted in volunteers with osteoarthritis (ages 18-85 (optional, ages 40-80), body mass index 18.5-35) who have pain in the test knee with a mean VAS (visual analog scale) score (valid) of >5 in the week prior to screening and who have degenerative changes in the test knee that can be classified as grade III-IV (Kellgren-Lawrence) based on upright posteroanterior and lateral x-rays of the knee [Kellgren & Lawrence, Ann Rheum Dis 1957, 16:494-502].

[0382] Subjects were given a 2-5 day washout period off pain medication and NSAIDs depending on the medication, after which they were administered 4 mL of the exemplary composition (also referred to herein as "AqueousJoint") prepared as described in Example 1 via a single intra-articular injection into the target knee (the injection volume was based on the volume of a standard sodium hyaluronate formulation, which is typically injected multiple times at weekly intervals) in conjunction with standard conservative treatment (e.g., 500 mg paracetamol for mild pain, 1 g paracetamol for more severe pain). The patient was placed supine with eyes closed, the knee flexed approximately 60 degrees, and a sterilely prepared 21-gauge needle (0.8 x 50 mm) was inserted into the joint capsule. Follow-up visits were conducted at 4, 8, 12, and 24 weeks after administration.

[0383] Safety of intra-articular injections in subjects for up to 6 months will be assessed by examining injection-related side effects such as adverse reactions related to the injected material, injection site reactions, erythema, swelling, injection site pain, and pruritus. Additionally, the effects of treatment on range of motion, functionality, quality of life, and analgesic consumption may optionally be evaluated.

[0384] Diagnostic techniques to assess the subject's condition include MRI analysis of the treated knee (e.g., at 4 and / or 24 weeks after treatment); diagnostic grading; e.g., bowed / valgus knee, etiology of osteoarthritis (knee malalignment or anterior cruciate ligament injury), and / or physical evaluation of the major compartments of the affected knee (patellofemoral and medial, tibiofemoral and lateral tibiofemoral); radiographic severity according to the Kellgren-Lawrence scale; range of motion (prone knee flexion and extension test using a universal goniometer); pain assessment (e.g., measured with the Brief Pain Questionnaire (short version)); and / or physical activity testing (e.g., Timed Up&Go); record of analgesics and / or anti-inflammatory medications; record of adverse events and serious adverse events (i.e. need for or prolonged hospitalization, persistent or significant disability or incapacity, or life-threatening or death); and / or completion by the subject of questionnaires, such as a VAS to assess pain (from no pain to intolerable pain) during movement, at night, and at rest; the WOMAC (Western Ontario-McMaster Universities) scale to assess pain, stiffness, and physical activity; the KOOS (Knee Injury and Osteoarthritis Outcome Score) to assess pain, other symptoms, function in daily living, function in sports and recreation, and knee-related quality of life; and / or the SF12 questionnaire (to assess health-related quality of life).

[0385] It is determined whether one or more of the symptoms of the disease described above are alleviated.

[0386] A summary of the studies is shown in Table 3 below.

[0387] [Table 3] TIFF2024530360000015.tif162163

[0388] Example 6 Efficacy of Exemplary Sterile Liposomal Compositions in Treating Osteoarthritis in a Rat Animal Model method: Rats were randomly assigned to groups of 15 rats. On study day 0, animals were anesthetized with isoflurane and underwent medial meniscus destabilization (DMM) surgery on the right knee. 50 μL of the exemplary composition prepared as described in Example 1 (also referred to herein as "AqueousJoint"), Synvisc® (a commercially available HA injection), or saline (as vehicle) was locally injected intra-articularly (IA) on days 7, 21, 35, and 49 after surgery in each group. Animals were euthanized on day 56 after surgery. Dynamic weight-bearing was analyzed in all rats over a 56-day postoperative period, comparing the difference in force between the operated and non-treated legs. Meloxicam (1 mg / kg) was administered orally between 30 and 60 minutes before surgery for the purpose of rapid pain management, with an additional dose administered 24 hours after surgery. Clinical parameters, dynamic weight bearing (DWB, assessing nociceptive pain (inflammatory hyperalgesia / mechanical allodynia)), and gait (mobility) were assessed over the course of the study. Gait was scored as follows: 0=normal, 1=slight, 2=mild, 3=moderate, 4=marked, 5=severe, 6=hopping. Histopathological evaluation of the knees was performed to assess joint damage. All animals survived to the end of the study.

[0389] result: The rat medial meniscus destabilization model of osteoarthritis was used as an in vivo preclinical model to examine the efficacy of an exemplary composition prepared as described in Example 1 to treat osteoarthritis by restoring the natural lubricating properties of cartilage to facilitate articulation within the affected joint. Without being bound by theory, the formulation acts as a long-lasting liposomal, highly hydrated boundary lubricant on the cartilage surface, and the unique lipid-polyphosphocholine conjugate incorporated into the liposome prevents aggregation and acts as a highly efficient lubricating element, allowing protection from wear and tear.

[0390] As shown in Figure 6 on day 7, rats in all groups showed clear differences in weight bearing between the operated and non-operated legs after the surgical procedure. Although administration of Synvisc® showed beneficial effects on postoperative day 28, treatment with AqueousJoint was significantly better in terms of efficacy, with weight bearing on both legs being nearly equivalent (Figure 6 and Table 4 below). The effect of AqueousJoint on postoperative day 56 remained stable, while the effect of Synvisc® reverted to the weight bearing characteristics of the vehicle group (Figure 6). As shown in Figure 7 and Table 4 below, the mobility of rats treated with AqueousJoint was significantly better compared to rats treated with Synvisc® or vehicle control, as judged by the gait score on postoperative day 10. Furthermore, the group treated with Synvisc® showed a significant increase in synovitis score compared to the vehicle group (Table 4 below).

[0391] In summary, treatment with AqueousJoint in osteoarthritis rat models was superior to the current market standard of care.

[0392] [Table 4]

[0393] Example 7 Tribological Measurements method: The measurements were performed using a microtribometer. The evaluation was performed according to a standard procedure based on the work published by Roba et al. [Tribology Letters 2011, 44, 387-397]. Briefly, under the assumption of a linear dependence between Fn and Ft, the values ​​of the lateral force and the experimentally determined normal force were calculated by averaging 20 data points at a distance of about 1.5 mm and then plotted on a graph. The trace and retrace curves thus obtained were averaged and the coefficient of friction was determined from the slope of the linear regression of the selected points. The contact pressure was calculated using the Hertzian model and was found to be 5.6 MPa.

[0394] Comparative measurements were performed at a speed of 1 mm / s in a five-step sequence: (i) PBS-baseline, (ii) HA solution, (iii) PBS rinse, (iv) solution of an exemplary composition prepared as described in Example 1 (also referred to herein as "synthetic lipid solution"), and (v) PBS rinse. After each step, the system was rinsed at least three times with fresh PBS, and before step (iii), the rinse was repeated at least six times and the solution was allowed to stand for 1 hour. In steps (ii) and (iv), the two surfaces were immersed in the solution without contact for 30 minutes before starting the friction measurements. For each of the five steps, tribological experiments (i.e., force gradients) were performed twice. For better visibility, the two values ​​for a given sample and condition were averaged and plotted ("internal average").

[0395] result: Changes in the friction response of fresh and frozen cartilage exposed to two test solutions of synthetic lipids and hyaluronic acid, respectively, were investigated within a comparative protocol in which the same samples were alternately exposed to control (buffer) or test solutions (control-test solution-control-test solution-control).

[0396] In general, the CoF in the synthetic lipid solutions was lower than that measured for HA (Figure 8).

[0397] Taken together, the results suggest that the addition of synthetic lipids results in a greater reduction in frictional forces than does hyaluronic acid.

[0398] Example 8 Wear measurement method: Pin-on-disk (POD) testing to evaluate the wear performance of polyethylene (PE) test pins with an exemplary sterile composition (also referred to herein as "AqueousJoint") prepared as described in Example 1. Three stations contained the sterile composition diluted 1:1 with calf serum lubricant. Three stations, used as controls, contained only calf serum lubricant. Testing was performed for 2 million cycles (Mc) and all test pins reported observable damage after testing. Testing was performed in accordance with ASTM F732-00 and OIC test protocol 21091-P01 Rev A. Prior to testing, all pins and discs were marked with unique identification numbers. Discs were labeled 1-6 and mounted in their corresponding station numbers. Prior to testing, all discs were polished to an average roughness (Ra) of ≤ 0.05 ± 0.006 μm. Three scans were performed per disc, yielding an average value of 8.1, confirming compliance with the average roughness specification. Digital images were taken of the pin and disc articular surfaces. After completion of the test, digital images were taken of the pin and disc surfaces to compare the pre- and post-test surfaces. A qualitative macroscopic analysis was performed on all components to determine the characteristics of damage present. Microscopic images were taken of the PE pin surfaces to characterize the damage characteristics present.

[0399] result: The station with AqueousJoint had an average wear of 5.487 ± 0.693 mg after 2.0 Mc, while the standard calf serum lubricant had an average wear of 25.732 ± 0.361 mg after 2.0 Mc (Figure 9). No visible difference was observed in pin damage after the test.

[0400] While the present invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, the present invention is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0401] It is the intention of the applicant(s) that all publications, patents, and patent applications referenced herein are incorporated herein by reference in their entirety as if each individual publication, patent, or patent application was specifically and individually referred to when referenced. Furthermore, citation or identification of any reference in this application should not be construed as an admission that the reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting. Additionally, the priority document(s) of this application are incorporated herein by reference in their entirety.

Claims

1. A sterile composition comprising an aqueous carrier and liposomes, The change in mean diameter and / or zeta potential of the liposomes is 20% or less over 300 days, and the liposomes are a) at least one bilayer-forming lipid, and b) a polymeric compound having the following general formula I: Including, The composition, wherein the polydispersity index of the liposome is 0.2 or less, and the zeta potential of the liposome is in the range of -40 mV to 40 mV or -10 mV to 10 mV. 【Chemical 1】 In the above formula, m is zero or a positive integer; n is an integer that is at least 1, and if X does not contain a phosphate group, then n is at least 2; X is a lipid moiety; Y is a backbone unit that forms the polymer backbone; L is absent or a linking moiety; and Z has the general formula II: 【Chemistry 2】 In the above formula, A is a substituted or unsubstituted hydrocarbon; B is an oxygen atom or is absent; and R １ ~R ３ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl, and heteroaryl.

2. wherein Y is of the formula -CR ４ R ５ -CR ６ has D-, When the Y is a skeletal unit that is not bonded to the L or the Z, D is R ７ and When Y is a backbone unit bonded to L or Z, D is a covalent bond or linking group that bonds Y to L or Z, and the linking group is selected from the group consisting of -O-, -S-, alkylene, arylene, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, and amino; R ４ ~R ７ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azido, azo, phosphate, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, and amino; The composition of claim 1.

3. The composition of claim 1 wherein X has the general formula III. 【Chemistry 3】 In the above formula, W １ and W ２ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and acyl; W １ and W ２ at least one of which is not hydrogen; J is —P(═O)(OH)—O— or absent; K is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length or is absent; M is a linking group selected from the group consisting of -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, and sulfonamido, or is absent; Q is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length; If M does not exist, then K does not exist either.

4. 4. The composition of claim 3, wherein J is -P(=O)(OH)-O- and K is selected from the group consisting of an ethanolamine moiety, a serine moiety, a glycerol moiety, and an inositol moiety.

5. The composition of claim 3 wherein M is an amide.

6. The composition of claim 4, wherein M is an amide.

7. The Q is dimethylmethylene (-C(CH ３ ) ２ The composition according to claim 3, wherein 8. The composition according to claim 6, wherein Q is dimethylmethylene (-C(CH 3 ) 2 -).

9. The W １ and the W ２ 4. The composition of claim 3, wherein at least one of is an alkyl, alkenyl, alkynyl, or acyl having a length of 10 to 30 carbon atoms.

10. The composition of claim 2, wherein X has the general formula III. 【Chemistry 4】 In the above formula, W 1 and W 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and acyl, provided that at least one of W 1 and W 2 is not hydrogen; J is —P(═O)(OH)—O— or absent; K is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length or is absent; M is a linking group selected from the group consisting of -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, and sulfonamido, or is absent; Q is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length; If M does not exist, then K does not exist either.

11. The composition of claim 10, wherein at least one of W 1 and W 2 is an alkyl, alkenyl, alkynyl, or acyl having a length of 10 to 30 carbon atoms.

12. The composition of claim 11, wherein J is -P(=O)(OH)-O- and K is selected from the group consisting of an ethanolamine moiety, a serine moiety, a glycerol moiety, and an inositol moiety.

13. The composition of claim 12, wherein M is an amide.

14. The composition according to claim 13, wherein Q is dimethylmethylene (-C(CH 3 ) 2 -).

15. The composition according to any one of claims 1 to 14, which is for treating a synovial joint disorder and is a formulation for intra-articular administration.

16. The composition of any one of claims 1 to 14, comprising an article of manufacture immersed in the composition.

17. 17. The composition of claim 16, wherein the article of manufacture comprises a contact lens.

18. A method for preparing a sterile composition according to any one of claims 1 to 14, comprising: (i) providing an aqueous composition comprising an aqueous carrier and a liposome comprising at least one bilayer-forming lipid and a polymeric compound; (ii) exposing said aqueous composition to a temperature greater than 100°C, thereby obtaining a sterile composition. A method comprising:

19. 1. A method for preparing a sterile article of manufacture having lipid attached to at least a portion of its surface, comprising: (i) contacting at least a portion of the surface of the article of manufacture with an aqueous composition comprising an aqueous carrier and liposomes, thereby obtaining an article of manufacture having lipids attached to at least a portion of its surface, wherein the liposomes comprise: a) at least one bilayer-forming lipid, and b) a polymeric compound having the following general formula I: and (ii) exposing the article of manufacture having lipids attached to at least a portion of its surface to a temperature greater than 100°C, thereby obtaining an article of manufacture having lipids attached to at least a portion of its surface that is sterile; A method comprising: 【Chemistry 5】 In the above formula, m is zero or a positive integer; n is an integer that is at least 1, and if X does not contain a phosphate group, then n is at least 2; X is a lipid moiety; Y is a backbone unit that forms the polymer backbone; L is absent or a linking moiety; and Z has the general formula II: 【Chemistry 6】 In the above formula, A is a substituted or unsubstituted hydrocarbon; B is an oxygen atom or is absent; and R １ ~R ３ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl, and heteroaryl.

20. 20. The method of claim 19, wherein Y is a substituted or unsubstituted alkylene unit.

21. 20. The method of claim 19, wherein X has the general formula III. 【Chemistry 7】 In the above formula, W １ and W ２ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and acyl; W １ and W ２ at least one of which is not hydrogen; J is —P(═O)(OH)—O— or absent; K is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length or is absent; M is a linking group selected from the group consisting of -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, and sulfonamido, or is absent; and Q is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length; If M does not exist, then K does not exist either.

22. 20. The method of claim 19, wherein the article of manufacture comprises a contact lens.

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