Lipid analogs, liposomes containing the same and uses thereof

Abstract

Disclosed are novel polymeric compounds (lipid-polymer conjugates) that can be used to form lipid bilayers and liposomes containing the same, the lipid bilayers and liposomes formed thereby, and uses thereof. Also disclosed are novel methods for preparing the polymeric compounds (lipid-polymer conjugates).

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Patent Application No. 63 / 402,097, filed August 30, 2022, and U.S. Patent Application No. 63 / 427,943, filed November 25, 2022, the contents of which are incorporated herein by reference in their entireties.

[0002] The present invention, in some embodiments thereof, relates to materials science, and more particularly, but not exclusively, to novel polymeric compounds that can be used to form liposomes and the use of such liposomes, for example, in biomedical applications. [Background technology]

[0003] Phosphatidylcholine (PC) liposomes are known to be extremely good lubricants when placed on surfaces, even under high pressure (Goldberg et al., Adv Materials 2011, 23:3517-3521; Goldberg et al., Biophys J 2011, 100:2403-2411; Sorkin et al., Biomaterials 2014, 34:5465-5475).

[0004] Liposome aggregation into macroscopic aggregates can hinder the use of liposomes in a variety of ways. Larger aggregates can cause precipitation and sedimentation from the dispersion, rendering the dispersion unusable. Aggregates larger than about 200-300 nm can scatter visible light, causing turbidity and hindering the use of liposomes in applications where transparency is important. Furthermore, when large aggregates are injected into the body, they are more susceptible to protein adsorption and attack and removal by macrophages [Moghimi & Szebeni, Prog Lipid Res 2003, 42:463-478].

[0005] PEGylated PC small unilamellar vesicles (SUVs) have been used for drug delivery; they incorporate PEG brushes into the membrane bilayer, which extend from the SUV surface and sterically stabilize it against aggregation [Harris & Chess, Nat Rev Drug Discov 2003, 2:214-221]. However, PEG chains are not highly hydrated and do not form a good lubricant by themselves under high pressure, so PEGylation has been reported to reduce the efficiency of SUVs for lubrication purposes under high pressure (such as in joints) [Goldberg et al., Adv Materials 2011, 23:3517-3521].

[0006] U.S. Pat. No. 8,617,592 describes block copolymers and conjugates containing zwitterionic poly(carboxybetaine), poly(sulfobetaine), or poly(phosphobetaine) blocks and hydrophobic blocks that self-assemble into particles and the use of such particles for the delivery of therapeutic and diagnostic agents.

[0007] Chen et al. [Science 2009, 323:1698-1702] described effective lubrication by poly[2-(methacryloyloxy)ethylphosphorylcholine] (PMPC) brushes and attributed this phenomenon to the strong hydration of the zwitterionic monomer.

[0008] WO 2017 / 109784 describes the design and preparation of polymeric compounds carrying phosphocholine analogues as pendant groups and conjugated to lipid moieties. It further describes liposomes containing such compounds that exhibit enhanced stability in aqueous environments.

[0009] WO 2018 / 150429 describes the use of lipid-derived polymeric compounds, as described in WO 2017 / 109784, in the delivery of therapeutically active agents to a body site of a subject, and associated use in the treatment of a medical condition treatable by the therapeutically active agent.

[0010] Further background art includes Goldberg & Klein [Chem Phys Lipids 2012, 165:374-381], WO 2011 / 158237, WO 2015 / 001564, WO 2015 / 193887, WO 2015 / 193888, WO 2016 / 051413 and WO 2018 / 150429. Summary of the Invention

[0011] According to an aspect of some embodiments of the present invention, there is provided a polymeric compound represented by Formula I: [ka] (In the formula, m is zero or a positive integer; n is an integer of at least 2, at least 5, preferably at least 10 (e.g., from 10 to 200); Y is a backbone unit that forms the polymer backbone of the polymer compound, L is absent or a linking moiety, and Z has the general formula II: [ka] (In the formula, The dashed (wavy) lines represent the points of attachment to the respective Y backbone unit or to the linking moiety L, if present; A is a substituted or unsubstituted hydrocarbon; B is an oxygen atom or is absent; R1 to R3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl, and heteroaryl. and X is a lipid moiety represented by formula IV. [ka] (In the formula, The dashed (wavy) lines represent points of attachment to the polymer backbone; F1, F2, F3, and F4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, acyl, alkoxy, thioalkoxy, carboxy, and thiocarboxy, and at least one of F1, F2, F3, and F4 is not hydrogen and is at least 10 carbon atoms in length; J is -OP(=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 or is absent; When M is not present, Q is not present, and when J is not present, M is not present; provided that when J is -OP(=O)(OH)-O-, then M is other than an amide and / or Q includes an aryl moiety.

[0012] According to some of the optional embodiments described herein, at least one of F1, F2, F3, and F4 is an alkoxy, thioalkoxy, acyl, or carboxy at least 10 carbon atoms in length.

[0013] According to some of the optional embodiments described herein, at least one of F1, F2, F3, and F4 is derived from a fatty acid selected from the group consisting of lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0014] According to some of the embodiments described herein, M is carboxy.

[0015] According to some of the embodiments described herein, K is alkyl.

[0016] According to some of the embodiments described herein, J is -P(=O)(OH)-O-, M is an amide, and Q is a hydrocarbon substituted with at least one aryl (e.g., phenyl).

[0017] According to some of the embodiments described herein, Q is methylene substituted with at least one aryl.

[0018] According to some of the optional embodiments described herein, J is absent.

[0019] According to some of the optional embodiments described herein, J and K are each absent.

[0020] According to some of the embodiments described herein, J and K are each absent and M is carboxy.

[0021] According to some of the embodiments described herein, at least one or at least two of F1, F2, F3, and F4 are each independently thioalkoxy.

[0022] According to some of the embodiments described herein, at least one or at least two of F1, F2, F3, and F4 are each independently carboxy.

[0023] According to some of the optional embodiments described herein, at least one or both of F1 and F2 is carboxy, and at least one of F3 and F4 is alkyl.

[0024] According to some of the embodiments described herein, Q is —C(CH 3 ) 2 —.

[0025] According to some of the optional embodiments described herein, Y is a substituted or unsubstituted alkylene unit.

[0026] According to some of the optional embodiments described herein, Y is a substituted or unsubstituted ethylene unit.

[0027] According to some of the embodiments described herein, Y has the formula -CR4R5-CR6D-; When Y is a backbone unit that is not attached to L or Z, D is R7; When Y is a backbone unit attached to L or Z, D is a covalent bond or linking group attaching 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 R4-R7 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.

[0028] According to some of the optional embodiments described herein, R4-R7 are each independently selected from hydrogen and alkyl.

[0029] According to some of the embodiments described herein, R4 and R5 are each hydrogen.

[0030] According to some of the embodiments described herein, R6 is hydrogen.

[0031] According to some of the optional embodiments described herein, the linking group is selected from the group consisting of -O-, -C(=O)O-, -C(=O)NH-, and phenylene.

[0032] According to some of the embodiments described herein, the linking group is -C(=O)O-.

[0033] According to some of the optional embodiments described herein, L is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length.

[0034] According to some of the optional embodiments described herein, L is a substituted or unsubstituted ethylene group.

[0035] According to some of the embodiments described herein, B is an oxygen atom.

[0036] According to some of the optional embodiments described herein, A is a substituted or unsubstituted hydrocarbon of 1 to 4 carbon atoms in length.

[0037] According to some of the optional embodiments described herein, A is a substituted or unsubstituted ethylene group.

[0038] According to some of the embodiments described herein, R1-R3 are each independently hydrogen or C 1~4 - alkyl.

[0039] According to some of the optional embodiments described herein, R1-R3 are each methyl.

[0040] According to some of the optional embodiments described herein, n is in the range of 10-200.

[0041] According to some of the embodiments described herein, n is at least 30.

[0042] According to some of the optional embodiments described herein, n is in the range of 30-70.

[0043] According to some of the embodiments described herein, n is at least 50 or at least 60.

[0044] According to some of the optional embodiments described herein, n is in the range of 50-150 or 50-80.

[0045] According to some of the embodiments described herein, n is at least 80.

[0046] According to some of the optional embodiments described herein, n is in the range of 80-120.

[0047] According to some of the optional embodiments described herein, n is in the range of 10-50.

[0048] According to some of the optional embodiments described herein, m is in the range of 0-50.

[0049] According to some of the optional embodiments described herein, at least some of the backbone units Y, L and / or Z comprise at least one targeting moiety as described herein.

[0050] According to an aspect of some embodiments of the present invention, there is provided a lipid bilayer comprising at least one bilayer-forming lipid and a polymeric compound as described herein for any corresponding embodiment and any combination thereof.

[0051] According to some of the embodiments described herein, the molar ratio of at least one bilayer-forming lipid to polymeric compound is in the range of 5:1 to 5,000:1, or 10:1 to 1,000:1, or 10:1 to 100:1, or 10:1 to 50:1 (e.g., 30:1 to 40:1), or 100:1 to 200:1.

[0052] According to some of the embodiments described herein, the at least one bilayer-forming lipid comprises at least one zwitterionic glycerophospholipid.

[0053] According to some of any of the embodiments described herein, the at least one bilayer-forming lipid further comprises a negatively charged bilayer-forming lipid (eg, DPPG).

[0054] According to some of the optional embodiments described herein, the amount of negatively charged bilayer-forming lipid is in the range of 0.1 to 40, or 1 to 40, or 1 to 20 mole % of the lipid bilayer.

[0055] According to some of the embodiments described herein, n is at least 50.

[0056] According to an aspect of some embodiments of the present invention there is provided a liposome comprising at least one lipid bilayer as described herein for any corresponding embodiment and any combination thereof.

[0057] According to some of the optional embodiments described herein, the liposome further comprises at least one functional moiety or agent attached to the surface of the liposome and / or present in the lipid bilayer and / or core of the liposome.

[0058] According to some of the embodiments described herein, the functional moiety or agent is a therapeutically active agent or portion thereof, a labeling moiety or agent, and / or a targeting moiety or agent.

[0059] According to an aspect of some embodiments of the present invention there is provided a composition comprising a liposome as described herein for any corresponding embodiment and any combination thereof, and a carrier, preferably an aqueous carrier.

[0060] According to some of the embodiments of any of the compositions described herein, the compositions are sterile compositions.

[0061] According to some of the optional embodiments described herein, the composition is a lubricant composition.

[0062] According to some of the optional embodiments described herein, the lubricant composition further comprises a water-soluble polymer.

[0063] According to some of the optional embodiments described herein, the lubricant composition is for lubricating a physiological surface and the carrier is a physiologically acceptable carrier.

[0064] According to an aspect of some embodiments of the present invention there is provided a method of reducing the coefficient of friction of a surface, the method comprising contacting the surface with a liposome as described herein for any corresponding embodiment and any combination thereof.

[0065] According to some of the optional embodiments described herein, the method includes contacting the surface with a composition comprising liposomes and a carrier, preferably an aqueous carrier.

[0066] According to some of the optional embodiments described herein, the method further comprises contacting the surface with a water-soluble polymer.

[0067] According to some of any of the embodiments described herein, the surface is a hydrogel surface.

[0068] According to some of the optional embodiments described herein, the surface is a surface of a contact lens.

[0069] According to some of any of the embodiments described herein, the surface is a physiological surface and the carrier is a physiologically acceptable carrier.

[0070] According to some of any of the embodiments described herein, the surface is an articular surface of a synovial joint.

[0071] According to an aspect of some embodiments of the present invention there is provided a liposome as described herein with respect to any corresponding embodiment, and any combination thereof, for the treatment of a synovial joint disorder associated with an increased coefficient of friction of the articular surfaces in a synovial joint.

[0072] According to an aspect of some embodiments of the present invention, there is provided a method of inhibiting biofilm formation on a surface of a substrate, the method comprising contacting the substrate with a composition comprising a liposome as described herein for any corresponding embodiment and any combination thereof.

[0073] According to an aspect of some embodiments of the present invention, there is provided an article of manufacture comprising a composition, the composition comprising a substrate having at least a portion of its surface coated with a lipid bilayer or liposome as described herein for any corresponding embodiment and any combination thereof.

[0074] According to an aspect of some embodiments of the present invention there is provided a lipid bilayer, a liposome or a composition comprising same, as described herein for any corresponding embodiment, and any combination thereof, for use in treating a synovial joint disorder.

[0075] According to some of any of the embodiments described herein, the treatment comprises intra-articular administration of a lipid bilayer, liposome or composition.

[0076] According to an aspect of some embodiments of the present invention, there is provided a liposome or a composition comprising same, as described herein with respect to any corresponding embodiment and any combination thereof, wherein the liposome has a therapeutically active agent associated therewith, and wherein the liposome or composition is for use in delivery of the therapeutically active agent to a body site of a subject.

[0077] According to some of the embodiments of any of the methods described herein, the liposome or composition is for the treatment of a medical condition in a subject that is treatable by a therapeutically active agent.

[0078] According to an aspect of some embodiments of the present invention, there is provided a method for preparing a polymeric compound as described herein for any corresponding embodiment and any combination thereof, comprising reacting an initiator compound having formula V with a compound selected from the group consisting of -[YLZ] n -[Y] m - contacting a plurality of monomers that form the polymer backbone under conditions that promote atom transfer radical polymerization (ATRP). [ka] (In the formula, F1, F2, F3, F4, J, K, M, and Q are as defined for formula IV; Ri is an electron transfer functional group.

[0079] According to some of the optional embodiments described herein, the ATRP is an ARGET-ATRP.

[0080] According to some of the optional embodiments described herein, the method further comprises isolating the polymeric compound.

[0081] According to some of the embodiments of any of the methods described herein, the isolating is by precipitation.

[0082] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this invention, exemplary methods and / or materials are described below. In case of conflict, the present patent specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0083] 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 describing 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 explanation of the drawings]

[0084] [Figure 1] FIG. 1 is a scheme (prior art) presenting the preparation of the lipid-containing polymeric compound (LPC) DSPE-pMPC from the phospholipid distearoylphosphatidylethanolamine (DSPE) and phosphocholine-derivatized MPC (O-(2-methacryloyloxyethyl)phosphorylcholine) via brominated derivatized DSPE (DSPE-Br), as described in WO 2017 / 109784. [Figure 2] 1 is a scheme presenting an exemplary two-step synthesis of LPC DPPE-dm-pMPC. Synthesis of a DPPE-dm-Br initiator and polymerization of MPC via atom transfer radical polymerization (ATRP) using the DPPE-dm-Br initiator provides LPC DPPE-dm-pMPC. [Figure 3]A general scheme presenting the catalytic process of activators regenerated by electron transfer-atom transfer radical polymerization (ARGET-ATRP, Figure 3A) and a GPC chromatogram (Figure 3B) showing an overlay of DPPE-dm-pMPC batch LS1 (Procedure 1) polymerized by ATRP using DPPE-dm-Br and DPPE-dm-pMPC30 (Procedure 2) polymerized by ARGET-ATRP using DPPE-dm-Br are presented. [Figure 4-1] FIG. 4A is a scheme presenting an exemplary two-step procedure (Procedure 2) for preparing a phenylated, brominated, derivatized DPPE initiator (DPPE-Ph-Br, FIG. 4A), and a scheme presenting polymerization of MPC from the DPPE-Ph-Br initiator via ARGET-ATRP to provide the LPC DPPE-Ph-pMPC (FIG. 4B). [Figure 4-2] Figure 4C shows a GPC chromatogram overlaying DPPE-Ph-pMPC prepared by ARGET-ATRP using DPPE-Ph-Br (Procedure 2, Batch 1056, dashed plot) with DPPE-dm-pMPC30 polymerized by ARGET-ATRP using DPPE-dm-Br (Procedure 2, dotted plot). Figure 4D also shows a GPC chromatogram overlaying DPPE-Ph-pMPC prepared by ARGET-ATRP using DPPE-Ph-Br (Procedure 2, Batch 1056, dashed plot) with DPPE-dm-pMPC batch LS1 polymerized by ATRP using DPPE-dm-Br (Procedure 1, LS1, solid plot). [Figure 5] FIG. 5A is a scheme presenting an exemplary two-step synthesis of a bis-thiolated brominated initiator (2C16S-Prop-Br) from propargyl alcohol (FIG. 5A) and the resulting LPC 2C16S-Prop-pMPC (FIG. 5B) after polymerization of MPC using the exemplary 2C16S-Prop-Br initiator. [Figure 6]FIG. 6A is a scheme presenting an exemplary two-step synthesis of a bis-palmitoyl brominated initiator (2C16-TMP-Br) from trimethylolpropane (TMP), and FIG. 6B is a scheme presenting the LPC 2C16-TMP-pMPC obtained after polymerization of MPC using the exemplary 2C16-TMP-Br initiator. [Figure 7-1] DSC thermograms of a series of liposomes are presented, including a 0.7% exemplary liposome sample containing long-chain (_L) and short-chain (_S) LPC (DPPE-dm-pMPC(DM), DPPE-Ph-pMPC(Ph), 2C16S-Prop-pMPC(Prop), 2C16-TMP-pMPC(TMP), Figure 7A), propargyl-based polymers of different lengths (Prop_S and Prop_L, Figure 7B), and TMP-based polymers of different lengths (TMP_S and TMP_L, Figure 7C). All liposomes were prepared by Procedure 2 as described herein. [Figure 7-2] Same as above [Figure 8] Images from CryoTEM analysis of exemplary liposome samples of 3.5% DPPE-Ph-pMPC_S (Figure 8A, scale bar is 100 nm), DPPE-Ph-pMPC_L (Figure 8B, scale bar is 0.2 μm), 2C16-TMP-pMPC_S (Figure 8C, scale bar is 0.2 μm), and 2C16-TMP-pMPC_L (Figure 8D, scale bar is 0.2 μm). [Figure 9] 1 is a bar graph showing the percent viability of L929 mouse cells after 72 hours of incubation with exemplary liposome samples containing long-chain (_L) and short-chain (_S) LPC (DPPE-dm-pMPC(DM), DPPE-Ph-pMPC(Ph), 2C16S-Prop-pMPC(Prop), 2C16-TMP-pMPC(TMP)) in a cytotoxicity assay, compared with two 0.7% short-chain DPPE-dm-pMPC (0.7%DM_S) samples after one year of storage (labeled 1-year storage A and B). The horizontal line represents 70% viability. [Figure 10]1 is a bar graph showing C activation by liposomes containing different types of LPC. [Figure 11] A comparative plot showing the zeta potential (ZP) of pMPC as a function of pH is presented. The zeta potential was measured for liposomes composed of DSPC, zwitterionic lipids, and LPC (blue circles) and for water-soluble pMPC polymers (orange squares). [Figure 12] A comparative plot is presented showing the zeta potential of liposome formulations in low salt solutions. These curves reflect both increasing LPC membrane content and a dependence on LPC particle size. [Figure 13] A comparative plot showing zeta potential as a function of total ion concentration for liposome formulations incorporating short-chain LPC (FIG. 13A) and long-chain LPC (FIG. 13B) is presented. For formulations with long-chain LPC, ZP decayed very rapidly with salt, making ZP measurements at high salt concentrations irrelevant. The dashed line is the fit of a linear equation. The slope is the LPC layer thickness. [Figure 14] A comparative plot is presented showing the average LPC layer thickness as a function of LPC length over a range of concentrations. The rate of increase in layer thickness for short-chain LPC is less than that for long-chain LPC. The long-chain LPC layer thickness is three times that of the short-chain LPC. [Figure 15] Comparative plots are presented showing the correlation between liposome surface properties and immunogenic response as determined by complement activation-associated pseudoallergy (CARPA) for short-chain LPC (Figure 15A) and long-chain LPC (Figure 15B). DETAILED DESCRIPTION OF THE INVENTION

[0085] The present invention, in some embodiments thereof, relates to materials science and more particularly, but not exclusively, to novel polymeric compounds that can be used to form liposomes and the use of such liposomes, for example, in biomedical applications.

[0086] Before describing at least one embodiment of the present 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 the examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

[0087] As discussed above, WO 2017 / 109784 describes the design and preparation of polymeric compounds carrying phosphocholine analogues as pendant groups and conjugated to lipid moieties.

[0088] These polymeric compounds have the ability to stabilize lipid layers, such as those of liposomes, while exhibiting significantly enhanced stability and effective lubrication between sliding surfaces, particularly in saline environments (e.g., physiological environments) and / or under high pressure.

[0089] In light of the highly advantageous properties of these lipid-containing polymeric compounds, also referred to herein as lipid-polymer conjugates (LPCs), the present inventors sought to improve the methodology for preparing such LPCs. As will be discussed in more detail in the Examples section below, the present inventors have designed and successfully prepared a novel synthetic method for preparing LPCs and a novel LPC prepared thereby. More specifically, the present inventors have designed and successfully implemented both a novel synthetic methodology used to prepare LPCs that provides improved control over the polymer moiety of the LPCs, a newly designed lipid-containing compound, and an LPC characterized by improved performance.

[0090] Accordingly, embodiments of the present invention relate to newly designed polymeric compounds bearing phosphocholine analogs as pendant groups and conjugated to lipid (e.g., phospholipid) moieties. An exemplary such polymeric compound is represented by Formula I. Such polymeric compounds are also referred to herein as "lipid-containing polymeric compounds" or simply "polymeric compounds," or as "lipid-polymer conjugates," or by the abbreviation "LPC."

[0091] The lipid-containing polymeric compounds disclosed herein have the ability to stabilize liposomes used in various applications (including in vivo applications) against aggregation and fusion, thereby increasing shelf life, while preserving and even enhancing surface-associated properties of liposomes and other phospholipid layers, such as biocompatibility and lubricating activity (e.g., through hydration lubrication). The disclosed polymeric compounds also have the ability to form stable micelles in aqueous environments, which can be used as stable alternatives to liposomes in various applications (including in vivo applications), such as lubrication, including interfacial lubrication with physiological surfaces. The disclosed polymeric compounds and / or liposomes formed therewith can also be used as drug delivery vehicles in ophthalmic and other applications, as described herein.

[0092] The present inventors have demonstrated that liposomes made from newly designed polymeric compounds exhibit substantially reduced immunogenicity even when formed from negatively charged bilayer-forming lipids.

[0093] The inventors have further demonstrated that lipid bilayers (e.g., in the form of liposomes) comprising newly designed polymeric compounds as described herein and, optionally, negatively charged bilayer-forming lipids and / or sterols such as cholesterol, can be used efficiently to deliver therapeutically active agents to a body site of a subject.

[0094] High molecular compound (LPC): According to an aspect of some embodiments of the present invention, there are provided polymeric compounds generally represented by Formula I, as described in more detail herein below. [ka] (In the formula, m is zero or a positive integer; n is an integer of at least 2, at least 5, preferably at least 10 (e.g., from 10 to 200); Y is a backbone unit that forms the polymer backbone of the polymer compound, X is a lipid moiety as described herein in any corresponding embodiment; L is absent or a linking moiety, and Z has the general formula II: [ka] (In the formula, The dashed (wavy) lines represent the points of attachment to the respective Y backbone unit or to the linking moiety L, if present; A is a substituted or unsubstituted hydrocarbon; B is an oxygen atom or is absent, and R1 to R3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl, and heteroaryl.

[0095] Formula I is referred to herein simply as: X-[Y(-LZ)] n [Y] m - which should be considered interchangeable with the schematic diagram above, where X is -[Y(-LZ)] n [Y] m - a lipid moiety conjugated to a polymer moiety.

[0096] Polymer part: As used herein, the term "polymer" refers to a compound having at least two repeat units (and more preferably at least three repeat units), where the repeat units are identical or similar. It should be 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 of the backbone units represented by Y.

[0097] 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 with respect to general formula I). [ka] wherein m, n, Y, L, and Z are as defined herein for general formula I, and the dashed (wavy) line represents the point of attachment to the X lipid moiety.

[0098] Formula Ia is referred to herein simply as: -[Y(-LZ)] n [Y] m - and this should be considered as being interchangeable with the above schematic diagram.

[0099] As used herein, the phrase "polymeric compound" further encompasses compounds having a "polymer portion" as described herein having at least one unit (e.g., according to Formula Ia, where n is at least 1), provided that the lipid portion (e.g., the lipid portion represented by X) as described herein has a similar unit. For example, if the lipid portion contains a phosphate group (e.g., the lipid portion is a glycerophospholipid portion) and a single unit of the polymer portion has a phosphate group, the two phosphate groups can be considered a repeating unit.

[0100] However, in preferred embodiments, n is at least 2, so that the polymeric portion itself has at least 2 units. In some embodiments, n is at least 3.

[0101] 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. Multiple linked repeating units are themselves also referred to herein as a "polymer backbone." A polymer segment as described herein may include multiple repeating backbone units that are identical to one another, thereby forming a homopolymer segment, or alternatively, may include two or more types of repeating backbone units that are linked to one another randomly or in a certain order (e.g., in two or more blocks or alternating sequences), thereby forming a copolymer segment.

[0102] As shown in Formulas I and Ia, L and Z together form a pendant group of at least a portion of the backbone unit, which for brevity will be referred to herein simply as the "pendant group."

[0103] 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 having no pendant group (the number of which is represented by the variable m) are also referred to herein as "monomer units."

[0104] The backbone unit can optionally be a polymerizable monomer or a polymerizable portion of a monomer. A variety of polymerizable monomers and moieties will be known to those skilled in the art, and the structures of such monomeric units (e.g., monomer units) that result upon polymerization will also be known to those skilled in the art.

[0105] "Unit of polymerizable monomer" refers to a modified form of a polymerizable monomer and / or a portion of a polymerizable monomer that remains after polymerization.

[0106] Some of the polymerizable monomers 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), are replaced with a covalent bond with another polymerizable monomer.

[0107] Modified forms of polymerizable monomers can be formed, for example, by ring opening (where the covalent bond between two atoms in the ring is broken and each of the two atoms is optionally bonded to another polymerizable monomer) and / or by addition to an unsaturated bond, where the 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 each bonded to another polymerizable monomer.

[0108] Modified forms of polymerizable monomers can consist essentially of the same atoms as the original monomer, e.g., differing only in rearrangements of covalent bonds, or can alternatively have a different atomic composition, e.g., polymerization involves a condensation reaction (e.g., as described herein).

[0109] 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 alkylenediamines, such as paraphenylenediamine and 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 moieties (which may form polysaccharide backbones).

[0110] In some embodiments of any of the embodiments described herein, Y is a substituted or unsubstituted alkylene unit.

[0111] In some embodiments, Y is a substituted or unsubstituted ethylene unit, ie, an alkylene unit two atoms in length.

[0112] The polymer backbone in which Y is a substituted or unsubstituted ethylene unit may optionally be such a polymer backbone formed by polymerizing ethylene (CH=CH) and / or its substituted derivatives (also referred to herein as "vinyl monomers"). Such polymerizations are well-studied procedures, and those skilled in the art will be aware of many techniques for carrying out such polymerizations.

[0113] 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 other type of polymerization).

[0114] As is well known in the art, the unsaturated bonds of ethylene and substituted ethylene derivatives become saturated upon polymerization, and therefore the backbone unit of the polymer backbone formed by polymerization is saturated, but it can also be referred to as a unit of the unsaturated compound it resembles (e.g., a "vinyl monomer" or an "olefin monomer").

[0115] Polymers that can be formed from unsaturated monomers such as vinyl and olefin monomers are also referred to by the terms "polyvinyl" and "polyolefin," respectively.

[0116] 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 (represented as (-LZ)) discussed herein. That is, an alkylene unit attached to said pendant group is considered unsubstituted when there are no substituents elsewhere on the alkylene unit.

[0117] In some embodiments of any of the embodiments described herein, Y has the formula -CR4R5-CR6D-.

[0118] When Y is a backbone unit that is not attached to L or Z (i.e., a pendant group as described herein), D is R7 (a terminal group as defined herein), and when Y is a backbone unit that is attached to L or Z, D is a covalent bond or linking group that attaches 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.

[0119] R4 to R7 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.

[0120] Throughout this specification, the phrase "linking group" refers to a group (eg, a substituent) that joins two or more moieties in a compound.

[0121] Throughout this specification, the phrase "terminal group" refers to a group (eg, a substituent) that is attached to a single moiety in a compound through one atom of the group.

[0122] When each of R4-R6 is hydrogen and D is a covalent bond or linking group, Y is an unsubstituted ethylene group attached (through D) to a pendant group described herein.

[0123] When each of R4 through R7 is hydrogen (and D is R7), Y is an unsubstituted ethylene group that is not attached to a pendant group as described herein.

[0124] In some embodiments of any of the embodiments described herein, R4 and R5 are each hydrogen. Such embodiments include polymer backbones formed from many 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, acrylamides), and methacrylates and their derivatives (e.g., methacrylate esters, methacrylamides).

[0125] In some embodiments of any of the embodiments described herein, R6 is hydrogen. In some such embodiments, R4 and R5 are each hydrogen.

[0126] In some embodiments of any embodiment described herein, R6 is methyl. In some such embodiments, R4 and R5 are each hydrogen. In some such embodiments, the backbone units are methacrylate units or derivatives thereof (e.g., methacrylate esters, methacrylamides).

[0127] In some embodiments of any of the embodiments described herein, the linking group represented by variable D is -O-, -C(=O)O-, -C(=O)NH-, or phenylene. In an exemplary embodiment, D is -C(=O)O-.

[0128] For example, the backbone unit may 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.

[0129] In some embodiments of any of the embodiments described herein, L is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length. In some embodiments, the hydrocarbon is unsubstituted. In some embodiments, the hydrocarbon is -(CH) i - (wherein i is an integer of 1 to 10).

[0130] In some embodiments of any of the embodiments described herein, L is a substituted or unsubstituted ethylene group. In some embodiments, L is an unsubstituted ethylene group (—CH2CH2—).

[0131] In some embodiments of any 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 absent), and Z is a phosphate group attached to L.

[0132] In some embodiments of any 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 absent), and Z is a phosphonate group bonded to L. In some embodiments, L is also absent, and thus the phosphorus atom of formula II is bonded directly to Y.

[0133] In some embodiments of any of the embodiments described herein, A is a substituted or unsubstituted hydrocarbon of 1 to 4 carbon atoms in length.

[0134] In some embodiments of any of the embodiments described herein, A is an unsubstituted hydrocarbon. In some such embodiments, the unsubstituted hydrocarbon is 1 to 4 carbon atoms in length. In some embodiments, the hydrocarbon is a straight chain unsubstituted hydrocarbon, i.e., -(CH2) j - (wherein j is an integer of 1 to 4).

[0135] In some embodiments of any of the embodiments described herein, A is a substituted or unsubstituted ethylene group.

[0136] In some embodiments of any of the embodiments described herein, A is an unsubstituted ethylene group (-CHCH-). In such embodiments, the moiety having general formula II (represented by 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., phosphatidylcholines, phosphatidylethanolamines).

[0137] In some embodiments of any of the embodiments 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 depicted in Formula II (rather than the carbon atom attached to the oxygen atom depicted). In such embodiments, the moiety having general formula II (represented by variable Z) is similar to or identical to a phosphoserine moiety. Phosphopserine occurs in many naturally occurring compounds (e.g., phosphatidylserines).

[0138] Without being bound to any particular theory, it is believed that moieties similar to or identical to naturally occurring moieties such as phosphocholine, phosphoethanolamine and / or phosphoserine may be particularly biocompatible.

[0139] In some embodiments of any of the embodiments described herein, R1-R3 (the substituents of the nitrogen atom depicted in general formula II) are each independently hydrogen or C 1~4 -alkyl. In some embodiments, R1-R3 are each independently hydrogen or methyl. In some embodiments, R1-R3 are each methyl. In some such embodiments, R1-R3 are each hydrogen.

[0140] The variable n can be considered to represent the number of backbone units (represented by variable Y) that are substituted with pendant groups represented by (-LZ), and the variable m can be considered to represent the number of backbone units that are not substituted with such pendant groups. The sum n+m can be considered to represent the total number of backbone units in the polymer backbone. The ratio n / (n+m) can be considered to represent the percentage of backbone units that are substituted with pendant groups represented by (-LZ).

[0141] In some embodiments of any of the embodiments 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%.

[0142] In some embodiments of any of the embodiments described herein, m is 0, and therefore each of the backbone units (represented by the variable Y) is substituted with a pendant group represented by (-LZ).

[0143] In some embodiments of any of the embodiments described herein, n is at least 5. In some embodiments, n is at least 10. In some embodiments, n is at least 15.

[0144] In some embodiments of any of the embodiments described herein, n is in the range of 2 to 1,000, including any intermediate values ​​and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 2 to 500, including any intermediate values ​​and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 2 to 200, including any intermediate values ​​and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 2 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 2 to 50, including any intermediate values ​​and subranges therebetween. In some such embodiments, m is 0.

[0145] In some embodiments of any of the embodiments described herein, n is in the range of 3 to 1,000, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 3 to 500, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 3 to 200, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 3 to 100, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 3 to 50, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 5 to 50, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 10 to 50, including any intermediate value and subrange 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, and in some such embodiments, m is 0.

[0146] In some embodiments of any of the embodiments described herein, n is in the range of 10 to 200, 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 180, 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 150, 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 120, including any intermediate values ​​and subranges therebetween. In some such embodiments, m is 0.

[0147] In some embodiments of any of the embodiments described herein, n is at least 30.

[0148] In some embodiments of any of the embodiments described herein, n is in the range of 30 to 200, 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 180, 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 150, 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 120, including any intermediate values ​​and subranges therebetween. In some such embodiments, m is 0.

[0149] In some embodiments of any of the embodiments described herein, n is in the range of 30 to 70, including any intermediate values ​​and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 35 to 65, including any intermediate values ​​and subranges therebetween. In some such embodiments, m is 0.

[0150] In some embodiments of any of the embodiments described herein, n is at least 50, or at least 60, or at least 80.

[0151] In some embodiments of any of the embodiments described herein, n is in the range of 50 to 200, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 50 to 180, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 50 to 150, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 50 to 120, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 80 to 120, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 50 to 100, including any intermediate value and subrange therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 50 to 80, including any intermediate value and subrange therebetween. In some such embodiments, m is 0.

[0152] In some embodiments of any embodiment described herein, when n is less than 80, or less than 70, or less than 50, or less than 30, or in the ranges of 10-50, or 30-60, or 30-80, or 30-70, or 50-80, as described herein in any corresponding embodiment, the polymeric compound is referred to herein as "short chain" or "S."

[0153] In some embodiments of any embodiment described herein, when n is greater than 80, or greater than 100, or in the range of 50-150, or 50-120, or 80-150, or 80-120, as described herein in any corresponding embodiment, the polymeric compound is referred to herein as "long chain" or "L."

[0154] In some embodiments of any of the embodiments described herein, n is in the range of 10 to 50, including any intermediate values ​​and subranges therebetween, and in some such embodiments, m is 0.

[0155] In some embodiments of any of the embodiments described herein, n is in the range of 50 to 80, including any intermediate values ​​and subranges therebetween, and in some such embodiments, m is 0.

[0156] In some embodiments of any of the embodiments described herein, n is in the range of 80 to 120, including any intermediate values ​​and subranges therebetween, and in some such embodiments, m is 0.

[0157] In some embodiments of any of the embodiments described herein, m is in the range of 0 to 1,000, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 2 to 1,000 (including any intermediate value and subrange therebetween), and therefore the total number of backbone units is in the range of 2 to 2,000, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 3 to 1,000, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 500, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 200, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 100, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 5 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 10 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 50 to 80, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 80 to 120, including any intermediate value and subrange therebetween.

[0158] In some embodiments of any of the embodiments described herein, m is in the range of 0 to 500, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 2 to 1,000, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 3 to 1,000, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 500, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 200, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 100, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 5 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 10 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 50 to 80, including any intermediate value and subrange therebetween, hi some embodiments, n is in the range of 80 to 120, including any intermediate value and subrange therebetween.

[0159] In some embodiments of any of the embodiments described herein, m is in the range of 0 to 200, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 2 to 1,000, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 3 to 1,000, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 500, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 200, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 100, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 5 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 10 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 50 to 80, including any intermediate value and subrange therebetween, hi some embodiments, n is in the range of 80 to 120, including any intermediate value and subrange therebetween.

[0160] In some embodiments of any of the embodiments described herein, m is in the range of 0 to 100, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 2 to 1,000, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 3 to 1,000, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 500. In some embodiments, n is in the range of 3 to 200, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 100, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 50. In some embodiments, n is in the range of 5 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 10 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 50 to 80, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 80 to 120, including any intermediate value and subrange therebetween.

[0161] In some embodiments of any of the embodiments described herein, m is in the range of 0 to 50, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 2 to 1,000, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 3 to 1,000, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 500, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 200, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 100, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 5 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 10 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 50 to 80, including any intermediate value and subrange therebetween, hi some embodiments, n is in the range of 80 to 120, including any intermediate value and subrange therebetween.

[0162] In some embodiments of any of the embodiments described herein, m is in the range of 0 to 20, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 2 to 1,000, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 3 to 1,000, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 500, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 200, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 100, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 5 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 10 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 50 to 80, including any intermediate value and subrange therebetween, hi some embodiments, n is in the range of 80 to 120, including any intermediate value and subrange therebetween.

[0163] In some embodiments of any of the embodiments described herein, m is in the range of 0 to 10, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 2 to 1,000, including any intermediate value and subrange therebetween. In some such embodiments, n is in the range of 3 to 1,000, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 500, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 200, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 100, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 3 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 5 to 50, including any intermediate value and subrange therebetween. In some embodiments, n is in the range of 10 to 50, including any intermediate value and subrange therebetween. In some of any of the embodiments described herein for m, n is in the range of 30 to 70, as described herein in any corresponding embodiment, or represents a short chain polymer moiety as described herein. In some such embodiments, n is in the range of 50 to 80, including any intermediate values ​​and subranges therebetween.

[0164] In some of any of the embodiments described herein for m, n is in the range of 80 to 120, as described herein in any corresponding embodiment, or represents a long chain polymer moiety, as described herein.

[0165] In some embodiments of any of the embodiments described herein, the backbone units Y substituted with pendant groups represented by (-LZ) are the same as the backbone units Y that are not substituted with pendant groups (e.g., when m is at least 1). In alternative embodiments, at least a portion of the backbone units Y substituted with pendant groups are different from a portion of the backbone units Y that are not substituted with pendant groups (e.g., when m is at least 1).

[0166] In some embodiments of any of the embodiments described herein, the plurality of backbone units Y (as indicated by variable n) substituted with pendant groups represented by (-LZ) are the same as one another. In alternative embodiments, at least a portion of the plurality of backbone units Y substituted with pendant groups represented by (-LZ) is different from a second portion of the plurality of backbone units Y substituted with pendant groups.

[0167] In some embodiments of any of the embodiments described herein, the pendant groups (-LZ) attached to the backbone units Y are the same as one another (as indicated by the variable n). In alternative embodiments, at least some of the pendant groups (-LZ) attached to the backbone units Y are different from one another (e.g., differing in the identity of any one or more of A, B, R1, R2, R3, and L).

[0168] In any embodiment described herein where two or more backbone units Y are not substituted with pendant groups described herein (i.e., when m is greater than 1), the plurality of backbone units Y (as indicated by variable m) that are not substituted with pendant groups are identical to one another. In alternative embodiments where m is greater than 1, at least some of the backbone units Y that are not substituted with pendant groups described herein are different from at least a second portion of the plurality of backbone units Y that are not substituted with pendant groups.

[0169] The number of types of backbone units substituted with pendant groups, the number of types of backbone units not substituted with pendant groups (if any 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, 10, or more).

[0170] In some embodiments of any embodiment described herein, the polymeric segment is a copolymer segment, i.e., the polymeric segment comprises at least two different types of monomeric units. In some such embodiments, the different types of monomeric units differ in whether they comprise a pendant group (-LZ) according to any corresponding embodiment described herein (e.g., when m is at least 1), and / or the different types of monomeric units differ in the type of backbone unit Y, and / or the different types of monomeric units differ in the type of pendant group (-LZ).

[0171] For example, in some embodiments of any of the embodiments described herein, the backbone units Y in each of the Y(-LZ) units can optionally be the same or different, while the L and Z moieties are the same between the Y(-LZ) units. In some such embodiments, the backbone units not substituted with pendant groups (if any such units are present) can optionally be the same as the backbone units Y in each of the Y(-LZ) units. Alternatively, the backbone units not substituted with pendant groups (if any such units are present) can optionally be different from the backbone units Y in each of the Y(-LZ) units (while optionally being the same between all of the backbone units not substituted with pendant groups).

[0172] In some embodiments of any of the embodiments described herein, the L moieties in each of the Y(-LZ) units can 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 not substituted with pendant groups (if any such units are present) can optionally be the same as the backbone units Y in each of the Y(-LZ) units. Alternatively, the backbone units not substituted with pendant groups (if any such units are present) can optionally be different from the backbone units Y in each of the Y(-LZ) units (while optionally being the same among all of the backbone units not substituted with pendant groups).

[0173] In some embodiments of any of the embodiments described herein, the Z moieties in each of the Y(-LZ) units can 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 not substituted with pendant groups (if any such units are present) can optionally be the same as the backbone units Y in each of the Y(-LZ) units. Alternatively, the backbone units not substituted with pendant groups (if any such units are present) can optionally be different from the backbone units Y in each of the Y(-LZ) units (while optionally being the same among all of the backbone units not substituted with pendant groups).

[0174] In any embodiment described herein in which the polymeric portion is a copolymeric portion, any two or more different types of monomeric units can be randomly or non-randomly distributed throughout the polymeric portion. When the different types of monomeric units are non-randomly distributed, the copolymer can be any one characterized by a non-random distribution, such as an alternating copolymer, a periodic copolymer, and / or a block copolymer.

[0175] In some of the embodiments described herein, the polymer moiety that is attached at one of its ends to a lipid moiety X may have a different terminal group at the other end (i.e., at the end closest to the backbone unit Y that does not have a pendant group, if m is at least 1; or at the other end closest to the backbone unit Y that includes a pendant group, if m is 0).

[0176] The end groups may be inherent end groups from the monomers used to form the polymeric compound and / or from the method used to polymerize the monomers, or may otherwise be conjugated to or generated within the terminus of the polymeric moiety. For example, the end groups may be hydrogen, halo, alkyl, hydroxy, carboxy, etc., or may be targeted moieties as described in more detail below. In some of the embodiments described herein, the end groups are hydrogen or halo. In some of the embodiments described herein, the end groups are derived from the initiators used to form the polymeric compound as described in any corresponding embodiment herein and exemplified in the Examples section below; in some of these embodiments, the end groups are halo (e.g., chloro or bromo).

[0177] In some of any of the embodiments described herein, the terminal group is a functional group suitable for electron transfer radical polymerization, such as variable Ri in Formula V as described herein in any corresponding embodiment.

[0178] Lipid part: A lipid moiety according to any embodiment of this section (represented by variable X in Formula I herein) may be attached to a polymer moiety according to any of the embodiments described herein in this section with respect to polymer moieties.

[0179] 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 a lipid can optionally involve 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).

[0180] In some embodiments of any of the embodiments 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 as described herein (e.g., rather than a backbone unit that is not substituted with a pendant group).

[0181] Alternatively or additionally, in some embodiments of any embodiment described herein, where m is at least 1, the lipid moiety (according to any corresponding embodiment described herein) may optionally be attached to a backbone unit (Y) that is not substituted with 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 portion may optionally be a copolymer in which the identity of the backbone unit attached to the lipid moiety varies randomly between molecules. Thus, the depiction in Formula I that X 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.

[0182] In some embodiments of any of the embodiments described herein, the lipid moiety is a portion of a lipid that is a fatty acid, a monoglyceride, a diglyceride, a triglyceride, a glycerophospholipid, a sphingolipid, or a sterol, hi some embodiments, the lipid is a glycerophospholipid.

[0183] In some embodiments of any of the embodiments 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.

[0184] 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.

[0185] Suitable examples of glycerophospholipids include, without limitation, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, and phosphatidylinositol.

[0186] In some embodiments of any of the embodiments described herein, the lipid moiety represented by variable X has the general formula I and is represented by formula IV: [ka] (In the formula, The dashed (wavy) lines represent points of attachment to the polymer backbone (i.e., via the respective Y backbone units); F1, F2, F3, and F4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, acyl, alkoxy, thioalkoxy, carboxy, and thiocarboxy, and at least one of F1, F2, F3, and F4 is not hydrogen and is at least 10 carbon atoms in length; J is -OP(=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 or is absent; When M does not exist, Q does not exist either.)

[0187] Q is attached to a backbone unit of the polymer backbone according to any corresponding embodiment described herein, or alternatively, when Q is absent, M is attached to said backbone unit.

[0188] When M is absent, Q is also absent and K is attached to a backbone unit of the polymer backbone according to any corresponding embodiment described herein.

[0189] In some embodiments of any of the embodiments described herein for Formula IV, when J is absent, M is absent.

[0190] In some embodiments of any of the embodiments described herein for Formula IV, when J is -OP(=O)(OH)-O-, M is other than an amide and / or Q includes an aryl moiety.

[0191] In some embodiments of any of the embodiments described herein for Formula IV, at least one of F1, F2, F3, and F4 is preferably an alkoxy, thioalkoxy, acyl, or carboxy group at least 10 carbon atoms in length, e.g., from 8 to 40, or from 10 to 40, or from 10 to 30 carbon atoms in length.

[0192] In some such embodiments, the alkoxy, thioalkoxy, acyl, and / or carboxy have alkyl moieties derived from fatty acyl as described herein, such as lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0193] In some embodiments of any of the embodiments described herein for Formula IV, at least one or at least two of F1, F2, F3, and F4 are each independently a thioalkoxy. In some of these embodiments, the thioalkoxy is at least 10 carbon atoms in length, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms in length. In an exemplary embodiment, the alkyl is 15 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the thioalkoxy has an alkyl group that is that of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, each of F1 and F2 is independently a thioalkoxy as described herein and can be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0194] In some embodiments of any of the embodiments described herein, at least one or at least two of F1, F2, F3, and F4 are each independently carboxy. In some of these embodiments, carboxy is at least 10 carbon atoms in length, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms in length. In an exemplary embodiment, carboxy is 16 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, carboxy has an alkyl group that is that of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, at least one or both of F1 and F2 are carboxy as described herein in any corresponding embodiment. In some of these embodiments, both F1 and F2 are carboxy as described herein in any corresponding embodiment, and they can be the same or different, preferably the same. In some of these embodiments, at least one of F3 and F4 is alkyl, which can be the same or different. In some such embodiments, alkyl is a short-chain alkyl of 1 to 6 or 1 to 4 carbon atoms in length, e.g., methyl. Alternatively, each of F3 and F4 is hydrogen.

[0195] According to some of the embodiments described herein, M is other than an amide.

[0196] According to some of the embodiments described herein, M is carboxy.

[0197] According to some of the embodiments described herein, M is carboxy, and at least one or at least two of F1, F2, F3, and F4 are each independently a thioalkoxy. In some of these embodiments, the thioalkoxy is at least 10 carbon atoms in length, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms in length. In an exemplary embodiment, the alkyl is 15 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the thioalkoxy has an alkyl group that is that of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, each of F1 and F2 is each independently a thioalkoxy as described herein and can be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0198] According to some of the embodiments described herein, M is carboxy, and at least one or at least two of F1, F2, F3, and F4 are each independently carboxy. In some of these embodiments, carboxy is at least 10 carbon atoms in length, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms in length. In an exemplary embodiment, carboxy is 16 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, carboxy has an alkyl group that is that of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, at least one or both of F1 and F2 are carboxy, as described herein in any corresponding embodiment. In some of these embodiments, both F1 and F2 are carboxy, as described herein in any corresponding embodiment, and they can be the same or different, preferably the same. In some of these embodiments, at least one of F3 and F4 is alkyl, which can be the same or different. In some such embodiments, the alkyl is a short chain alkyl of 1 to 6 or 1 to 4 carbon atoms in length, such as methyl. Alternatively, each of F3 and F4 is hydrogen.

[0199] According to some of the embodiments described herein, J is absent.

[0200] According to some of the embodiments described herein, J is absent and M is other than amide.

[0201] According to some of the embodiments described herein, J is absent and M is carboxy.

[0202] According to some of the embodiments described herein, J is absent and at least one or at least two of F1, F2, F3, and F4 are each independently a thioalkoxy. In some of these embodiments, the thioalkoxy is at least 10 carbon atoms in length, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms in length. In an exemplary embodiment, the alkyl is 15 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the thioalkoxy has an alkyl group that is that of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, each of F1 and F2 is each independently a thioalkoxy as described herein and can be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0203] According to some of the embodiments described herein, J is absent, M is carboxy, and at least one or at least two of F1, F2, F3, and F4 are each independently a thioalkoxy. In some of these embodiments, the thioalkoxy is at least 10 carbon atoms in length, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms in length. In an exemplary embodiment, the alkyl is 15 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the thioalkoxy has an alkyl group that is that of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, each of F1 and F2 is each independently a thioalkoxy as described herein and can be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0204] According to some of the embodiments described herein, J is absent and at least one or at least two of F1, F2, F3, and F4 are each independently carboxy. In some of these embodiments, carboxy is at least 10 carbon atoms in length, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms in length. In an exemplary embodiment, carboxy is 16 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, carboxy has an alkyl group that is that of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, at least one or both of F1 and F2 are carboxy as described herein in any corresponding embodiment. In some of these embodiments, both F1 and F2 are carboxy as described herein in any corresponding embodiment, and they may be the same or different, preferably the same. In some of these embodiments, at least one of F3 and F4 is alkyl, which may be the same or different. In some such embodiments, the alkyl is a short chain alkyl of 1 to 6 or 1 to 4 carbon atoms in length, such as methyl. Alternatively, each of F3 and F4 is hydrogen.

[0205] According to some of the embodiments described herein, J is absent, M is carboxy, and at least one or at least two of F1, F2, F3, and F4 are each independently carboxy. In some of these embodiments, carboxy is at least 10 carbon atoms in length, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms in length. In an exemplary embodiment, carboxy is 16 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, carboxy has an alkyl group that is that of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, at least one or both of F1 and F2 are carboxy as described herein in any corresponding embodiment. In some of these embodiments, both F1 and F2 are carboxy as described herein in any corresponding embodiment, and they may be the same or different, preferably the same. In some of these embodiments, at least one of F3 and F4 is alkyl, which may be the same or different. In some such embodiments, the alkyl is a short chain alkyl of 1 to 6 or 1 to 4 carbon atoms in length, such as methyl. Alternatively, each of F3 and F4 is hydrogen.

[0206] According to some of the embodiments described herein for Formula IV, when J is absent, Q is -C(CH3)2-.

[0207] According to some of the embodiments described herein for Formula IV, when J is absent, M is carboxy and Q is -C(CH3)2-.

[0208] As used herein, the hydrocarbon length represented by the variable K refers to the number of atoms separating J and M (i.e., along the shortest path between J and M) as depicted in Formula IV when J is not present, or the number of atoms separating M and the lipid backbone formed by F1, F2, F3, and F4.

[0209] When K is a substituted hydrocarbon, M may be attached to a carbon atom of the hydrocarbon itself or to a substituent on the hydrocarbon.

[0210] In some embodiments, K is an all-carbon hydrocarbon.

[0211] In some embodiments, K is an unsubstituted hydrocarbon.

[0212] In some embodiments, K is an unsubstituted all-carbon hydrocarbon.

[0213] In some of these optional embodiments, K is an alkyl (alkylene chain or linking group), preferably an unsubstituted, short chain alkyl or alkylene, optionally 1 to 6, or 1 to 4, or 1 to 2 carbon atoms in length.

[0214] According to some of the embodiments described herein, K is absent.

[0215] According to some of any of the embodiments described herein, J is absent and K is absent, as described herein in any corresponding embodiment. In some of these embodiments, M is carboxy.

[0216] According to some of the embodiments described herein, Q is a hydrocarbon substituted with at least one aryl (eg, phenyl).

[0217] In some of these embodiments, Q is a hydrocarbon that is an all-carbon hydrocarbon, and in some of these embodiments, the hydrocarbon is an alkyl (alkylene linking group) substituted with at least one aryl (e.g., phenyl), preferably a short chain alkyl (or alkylene) of 1 to 6 or 1 to 4, preferably 1 or 2 carbon atoms in length.

[0218] According to some of the embodiments described herein, Q is methylene substituted with at least one aryl (eg, phenyl).

[0219] According to some of the embodiments described herein, J is -P(=O)(OH)-O-, M is an amide, and Q is a hydrocarbon substituted with at least one aryl (e.g., phenyl), as described herein for any corresponding embodiment and any combination thereof.

[0220] According to some of the embodiments described herein, J is -P(=O)(OH)-O-, M is amide, and Q is methylene substituted with at least one aryl (e.g., phenyl).

[0221] In some embodiments of any of the embodiments described herein for Formula I, the lipid moiety represented by variable X has the general formula III. [ka] (In the formula, The dashed lines (wavy lines) represent the points of attachment to the corresponding Y backbone units, W1 and W2 are each independently hydrogen, alkyl, alkenyl, alkynyl, or acyl, and at least one of W1 and W2 is not hydrogen; J is -P(=O)(OH)-O- or J is absent (thus K is bonded directly to the oxygen atom of the depicted glycerol moiety); K is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length; M is a linking group that is -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, or sulfonamido, or M is absent (thus, K is directly bonded to Q), and Q is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length, or Q is absent.

[0222] Q is attached to a backbone unit of the polymer backbone according to any corresponding embodiment described herein, or alternatively, when Q is absent, M is attached to said backbone unit.

[0223] When M is absent, Q is also absent and K is attached to a backbone unit of the polymer backbone according to any corresponding embodiment described herein.

[0224] In some embodiments of any of the embodiments described herein for Formula III, one of W1 and W2 is hydrogen and the other is not hydrogen.

[0225] In some embodiments of any of the embodiments described herein for Formula III, neither W1 nor W2 is hydrogen.

[0226] In some embodiments of any of the embodiments described herein for Formula III, at least one of W1 and W2 is alkyl, alkenyl, alkynyl, or acyl that is 10 to 30 carbon atoms in length. In some embodiments, W1 and W2 are each 10 to 30 carbon atoms in length.

[0227] Examples of acyl groups which may optionally function independently as W1 and / or W2 include, but are not limited to, lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0228] In some embodiments of any of the embodiments described herein for Formula III, J is -P(=O)(OH)-O- (e.g., the lipid moiety is a glycerophospholipid).

[0229] As used herein, the length of a hydrocarbon, represented by the variable K, refers to the number of atoms separating J and M (i.e., along the shortest path between J and M), as shown in Formula III.

[0230] 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.

[0231] In some embodiments of any of the embodiments described herein for Formula III, K is an acyl moiety (e.g., -C(=O)-C(CH3)2-). In some such embodiments, J is absent, and thus K is directly attached to the oxygen atom of the depicted glycerol moiety. In some such embodiments, K comprises a carbonyl linking group (-C(=O)-) attached to the oxygen atom of the glycerol moiety via an ester bond.

[0232] In some embodiments of any of the embodiments described herein for Formula III, K is an ethanolamine moiety (e.g., -CH-CH-NH- or -CH-CH- attached to the nitrogen atom), a serine moiety (e.g., -CH-CH(COH)-NH- or -CH-CH(COH)- attached to the nitrogen atom), a glycerol moiety (e.g., -CH(OH)-CH(OH)-CH-O-), and an inositol moiety (e.g., -cyclohexyl(OH)-O-). In some embodiments, J is -P(=O)(OH)-O-.

[0233] In some embodiments of any of the embodiments described herein for Formula III, M is an amide, optionally -C(=O)NH-.

[0234] In some embodiments, the nitrogen atom of the amide is bound to K. In some such embodiments, K is an ethanolamine or serine moiety described herein.

[0235] In some embodiments of any of the embodiments described herein for Formula III, Q is a substituted alkylene (e.g., 1 to 6, or 1 to 4, or 1 to 2 carbon atoms in length, e.g., a methylene group). In some such embodiments, M is amido or carboxy. In some embodiments, the C(=O) of the amido or carboxy is bonded to Q.

[0236] In some embodiments of any of the embodiments described herein for Formula III, Q is an alkylene group, as described herein, where the methylene group is substituted with one or two substituents, at least one of which is or includes aryl (e.g., phenyl). In some such embodiments, M is an amide. In some embodiments, the C(=O) of the amide is bonded to Q. Alternatively, M is carboxy, where the C(=O) of the carboxy is bonded to Q.

[0237] In some embodiments of any of the embodiments described herein for Formula III, Q is a methylene group substituted with two substituents, at least one of which is or includes an aryl (e.g., phenyl), and the other of which can be, for example, an aryl (e.g., phenyl) or an alkyl (e.g., 1 to 6 or 1 to 4 carbon atoms in length). In some embodiments, the methylene group is substituted with an alkyl group (e.g., C 1~4 -alkyl) and aryl (e.g., phenyl). In some such embodiments, M is amide. In some such embodiments, M is carboxy.

[0238] In some embodiments of any of the embodiments described herein for Formula III, Q is a substituted alkylene (e.g., 1 to 6, or 1 to 4, or 1 to 2 carbon atoms in length, e.g., a methylene group). In some such embodiments, M is amido or carboxy. In some embodiments, the C(=O) of the amido or carboxy is bonded to Q.

[0239] In some embodiments of any of the embodiments described herein for Formula III, Q is an alkylene group as described herein, wherein the methylene group is 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). In some such embodiments, M is other than amido. In some such embodiments, M is carboxy.

[0240] In some embodiments of any of the embodiments described herein for Formula III, Q is a methylene group substituted by two substituents. In some embodiments, the methylene group is substituted with two alkyl groups (e.g., C 1~4 In some such embodiments, M is other than amide. In some such embodiments, M is carboxy.

[0241] According to some of the embodiments described herein for Formula III, when M is an amide, Q is an alkylene substituted with at least one aryl as described herein in any corresponding embodiment.

[0242] According to some of the embodiments described herein, M is other than amide, and Q is as described herein in any corresponding embodiment.

[0243] In some embodiments of any embodiment described herein for Formula III, M and Q are each absent, and K is a terminally substituted or unsubstituted methylene group, such as a methylene group substituted by two substituents (e.g., dimethylmethylene (-C(CH)-), according to any corresponding embodiment described herein related to Q. In some embodiments, K further comprises a carbonyl group, according to any corresponding embodiment described herein.

[0244] In some embodiments of any of the embodiments described herein, J, M, and Q are each absent. In some such embodiments, K comprises a carbonyl linking group (-C(=O)-) bonded directly (via an ester bond) to an oxygen atom of the depicted glycerol moiety and further comprises a substituted or unsubstituted methylene group (e.g., dimethylmethylene). In some embodiments, K consists of a carbonyl linking group and a substituted or unsubstituted methylene group bonded directly (via an ester bond) to an oxygen atom of the depicted glycerol moiety, e.g., K is -C(=O)-C(CH3)2-.

[0245] According to some of the embodiments described herein for Formula IV, F1 is as described herein for OW1. According to some of these embodiments, F3 and F4 are each hydrogen. According to some of these embodiments, J is absent. According to some of these embodiments, M is other than amide.

[0246] According to some of the embodiments described herein for Formula IV, F2 is as described herein for OW2. According to some of these embodiments, F3 and F4 are each hydrogen. According to some of these embodiments, J is absent. According to some of these embodiments, M is other than an amide.

[0247] According to some of the embodiments described herein for Formula IV, F1 is as described herein for OW1 and F2 is as described herein for OW2. According to some of these embodiments, F3 and F4 are each hydrogen. According to some of these embodiments, J is absent. According to some of these embodiments, M is other than an amide.

[0248] According to some of any of the embodiments described herein, the lipid moiety does not include a moiety of formula III, as described herein.

[0249] According to some of the embodiments described herein, the lipid moiety has a moiety of formula III, as described herein, except that M is other than amide (e.g., M is carboxy), and / or Q includes an aryl substituent, as described herein.

[0250] According to some of the optional embodiments described herein for Formula IV, polymeric compounds in which the lipid moiety X is as described in WO 2017 / 109784 are excluded from the scope of the present embodiments.

[0251] Target part: In some embodiments of any of the embodiments described herein, at least a portion of the monomer units of the polymer segment comprise a targeting moiety (according to any of the embodiments described herein with respect to the targeting moiety).

[0252] As used herein, a "targeting moiety" refers to a moiety that has the ability to bring a compound (e.g., a compound according to some embodiments of the present invention) into proximity with a selected substance and / or material (which is 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 is such that the targeting moiety facilitates binding and / or internalization of the compound into the target cell so that the compound can exert its therapeutic effect.

[0253] In some of any of the embodiments described herein, the targeting moiety comprises a backbone unit Y according to any corresponding embodiment described herein, and optionally a linking moiety L according to any corresponding embodiment described herein and / or a 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.

[0254] For example, in some embodiments in which at least a portion of the backbone units Y have the formula -CR4R5-CR6D- (as described herein in any corresponding embodiment), any one or more of R4-R6 and D (optionally, D is R7 as described herein) comprise a targeting moiety according to any corresponding embodiment described herein (e.g., any one or more of R4-R6 and D are substituents that include a substituent that is a targeting moiety), and optionally, any one or more of R4-R6 and D are targeting moieties. However, many other monomer unit structures that include substituents that include (and optionally consist of) targeting moieties are also encompassed by embodiments of the invention.

[0255] In some embodiments, the polymeric portion is a copolymer portion as described herein in any corresponding embodiment, wherein at least one monomeric unit as described herein comprises a target moiety (according to any corresponding embodiment described herein), and at least one other monomeric unit does not comprise such a target moiety. The distribution of the monomeric units comprising the target moiety can be according to any distribution of monomeric units in the copolymer portion as described herein (e.g., random, alternating, periodic copolymer, and / or block copolymer). In any embodiment described herein where m is at least 1, at least some of the monomeric units comprise a target moiety according to any corresponding embodiment described herein. In some such embodiments, at least some of the monomeric units comprising a target moiety according to any corresponding embodiment described herein are monomeric units that do not comprise a pendant group represented by (-LZ) as described herein in any corresponding embodiment. In some such embodiments, the number of monomeric units comprising a target moiety according to any corresponding embodiment is represented by the variable m according to any corresponding embodiment described herein. In some such embodiments, none of the monomeric units comprising a pendant group represented by (-LZ) comprise such a target moiety.

[0256] In any embodiment described herein where m is at least 1, each of the monomeric units (the number of which is represented by variable m) that do not contain a pendant group represented by (-LZ) comprises a target moiety (according to any corresponding embodiment described herein). In some such embodiments, each of the monomeric units that contain a target moiety (according to any corresponding embodiment described herein) is a monomeric unit that does not contain a pendant group represented by (-LZ), i.e., none of the monomeric units that contain a pendant group represented by (-LZ) contain said target moiety, and each of the monomeric units that do not contain a pendant group represented by (-LZ) contain said target moiety.

[0257] In any embodiment described herein where m is at least 1, the monomeric unit comprising a targeting moiety may consist essentially of a backbone unit Y (according to any corresponding embodiment described herein) substituted with one or more targeting moieties (according to any corresponding embodiment described herein).

[0258] In some of the embodiments described herein, at least a portion of the monomeric units comprising a target moiety according to any corresponding embodiment described herein are monomeric units comprising a pendant group represented by (-LZ) as described herein in any corresponding embodiment. In some such embodiments, the number of monomeric units comprising a target moiety according to any corresponding embodiment is represented by the variable n according to any corresponding embodiment described herein (i.e., each of the monomeric units comprising a target moiety according to any corresponding embodiment described herein is a monomeric unit comprising a pendant group). In some such embodiments, none of the monomeric units that do not comprise a pendant group represented by (-LZ) comprise such a target moiety.

[0259] In some of the embodiments described herein, a monomeric unit comprising a targeting moiety may optionally differ (optionally significantly differ) in structure (i.e., in the structure of Y and / or L and / or Z, if present, as defined in any embodiment described herein) from another monomeric unit comprising a targeting moiety. For example, the backbone unit Y of a monomeric unit comprising a targeting moiety may optionally differ in structure from the backbone unit Y of other monomeric units in the polymer portion (according to any corresponding embodiment described herein).

[0260] In any embodiment described herein where m is at least 1, the polymeric portion comprises a monomeric unit comprising a targeting moiety, the monomeric unit being at the end of the polymeric portion distal to the lipid portion. In such an embodiment, the compound represented by general formula I has formula Ib. [ka] (In the formula, T is a monomeric unit comprising a targeting moiety (according to any corresponding embodiment described herein); X and T are [Y(-LZ)] n [Y] m -1, and X, Y, L, Z, n, and m are defined as in any embodiment described herein for Formula I, with the proviso that m is at least 1.

[0261] T in Formula Ib is a monomeric unit of the type represented by Y in Formula I and Formula Ia (i.e., lacking a pendant group represented by (-LZ)), and the number of monomeric units represented by Y other than T (i.e., lacking a pendant group represented by (-LZ)) is represented by the value m-1. Thus, it should be understood that the total number of monomeric units (lacking a pendant group represented by (-LZ)), including T, is represented by the variable m as in Formula I and Formula Ia.

[0262] In some embodiments, m is 1, and thus m-1 is 0, and the compound represented by formula Ib has the formula: X-[Y(-LZ)]T, where L, T, X, Y, Z, and n are defined as in any embodiment described herein.

[0263] Preparation of a monomeric unit comprising a targeting moiety according to any corresponding embodiment described herein may optionally be carried out by preparing a monomer comprising the targeting moiety and using that monomer to prepare a polymeric moiety described herein (e.g., by polymerization of a monomer according to any corresponding embodiment described herein), and / or by modifying the monomeric unit in the polymeric moiety using any suitable technique known in the art, including but not limited to conjugation techniques, and then subsequently preparing a polymeric moiety (e.g., by polymerization of a monomer according to any corresponding embodiment described herein).

[0264] In some embodiments of any embodiment described herein with respect to a targeting moiety, the targeting moiety does not include a moiety having general formula II (according to any corresponding embodiment described herein). For example, it should be understood that even if a moiety represented by formula II has the ability to form a bond with a target as described herein, the phrase "targeting moiety" in some embodiments relates to a moiety that is distinct from the moiety represented by variable Z (having general formula II).

[0265] In some embodiments of any one of the embodiments described herein, the pendant group represented by (-LZ) is selected so as not to form a bond with the target and / or so as not to include the structure and / or properties of the targeting moiety as described herein in any one of the corresponding embodiments. For example, in embodiments in which a targeting moiety including a nucleophilic group, e.g., an amine group (according to any corresponding embodiment described herein), is capable of forming a bond (e.g., a covalent bond) with the target, variable Z (having general formula II) is optionally selected so that the depicted amine / ammonium group is a tertiary amine / ammonium (i.e., no more than two of R1-R3 are hydrogen) or a quaternary ammonium (i.e., none of R1-R3 are hydrogen), preferably a quaternary ammonium (e.g., containing a trimethylamino group, as in phosphocholine). Tertiary amine groups, and particularly quaternary ammonium groups, can be significantly less reactive nucleophiles than primary and secondary amine groups.

[0266] In some embodiments of any of the embodiments described herein with respect to a targeting moiety, the targeting moiety comprises (and optionally consists of) at least one functional group capable of forming a covalent or non-covalent bond (preferably a selective non-covalent bond) with a substance and / or material (which is referred to herein as a "target"), for example, to the surface of the target (e.g., the surface of a cell and / or tissue).

[0267] As used herein, the phrase "functional group" encompasses chemical groups and moieties of any size and any functionality described herein (e.g., any functionality capable of forming a covalent or non-covalent bond with a target).

[0268] Non-covalent binding according to any corresponding embodiment described herein may optionally be achieved by non-covalent interactions such as, without limitation, electrostatic attraction, hydrophobic bonding, hydrogen bonding, and aromatic interactions.

[0269] In some embodiments, the targeting moiety comprises a functional group capable of forming a selective non-covalent bond with a target, e.g., the affinity of the targeting moiety and / or functional group for the target (e.g., as determined based on the dissociation constant) is higher than the affinity of the targeting moiety and / or functional group for most (or all) other compounds capable of forming non-covalent bonds with the targeting moiety.

[0270] In some embodiments of any one of the embodiments described herein, the one or more functional groups are capable of forming covalent bonds with one or more specific functional groups (e.g., hydroxy, amine, thiohydroxy, and / or oxo groups) present on a target (e.g., on a target according to any corresponding embodiment described herein).

[0271] Examples of functional groups (on the targeting moiety) capable of forming covalent bonds with targets (according to any corresponding embodiment described herein) and the types of covalent bonds that the functional groups are capable of forming include, without limitation: For example, nucleophilic groups such as thiohydroxy, amines (e.g., primary or secondary amines) and hydroxy, which can form covalent bonds with nucleophilic leaving groups (e.g., any nucleophilic group described herein) on the target, Michael acceptors (e.g., any Michael acceptors described herein), acyl halides, isocyanates and / or isothiocyanates (e.g., as described herein); Nucleophilic leaving groups such as, for example, halo, azido (-N3), sulfate, phosphate, sulfonyl (e.g., mesyl, tosyl), N-hydroxysuccinimide (NHS) (e.g., NHS ester), sulfo-N-hydroxysuccinimide, and anhydrides, which can form covalent bonds with nucleophilic groups (e.g., as described herein) on a target; For example, Michael acceptors such as enones (e.g., maleimide, acrylate, methacrylate, acrylamide, methacrylamide), nitro groups, and vinyl sulfones, which can form covalent bonds with nucleophilic groups (e.g., as described herein) on the target, optionally thiohydroxy; For example, a dihydroxyphenyl group (according to any corresponding embodiment described herein) that can form a covalent bond with a nucleophilic group (e.g., as described herein) and / or a substituted or unsubstituted phenyl group (e.g., another dihydroxyphenyl group) on a target as described herein; For example, acyl halide (-C(=O)-halogen), isocyanate (-NCO) and isothiocyanate (-N=C=S) groups, which can form covalent bonds with nucleophilic groups (e.g., as described herein) on a target; For example, carboxylate (-C(=O)OH) groups may form covalent bonds with hydroxyl groups on the target to form ester bonds, and / or may form covalent bonds with amine groups (e.g., primary amines) on the target to form amide bonds (optionally by reaction with a coupling reagent such as a carbodiimide), and / or carboxylate groups may be present on the target to form amide or ester bonds with amine or hydroxyl groups, respectively, on the targeting moiety; an oxo group (optionally on an aldehyde group (-C(=O)H)) that can form a covalent imine bond with an amine group (e.g., a primary amine) on the target, and / or an oxo group (optionally on an aldehyde group) on the target that can form a covalent imine bond with an amine group on the targeting moiety; and / or A thiohydroxy group that can form a covalent disulfide (-SS-) bond with a thiohydroxy group on the target.

[0272] Optionally, modification of a monomer (e.g., before polymerization) or a monomeric unit of a polymer moiety (e.g., after polymerization) to include any of the functional groups described herein can be carried out using any technique suitable for conjugation known in the art. One of skill in the art will readily be able to select a suitable technique for modifying any given molecule.

[0273] As used herein, the term "dihydroxyphenyl" refers to an aryl group (as defined herein) that is phenyl substituted with two hydroxyl groups at any position thereof. The phenyl may optionally be substituted with additional substituents (which may optionally include additional hydroxyl groups), thereby forming a substituted dihydroxyphenyl group, or alternatively, the phenyl does not include any substituents other than the two hydroxyl groups, such that the dihydroxyphenyl group is an unsubstituted dihydroxyphenyl group.

[0274] In some embodiments of any one of the embodiments described herein, the dihydroxyphenyl group is ortho-dihydroxyphenyl (where the hydroxyl groups are attached to adjacent phenyl rings) or para-dihydroxyphenyl (where the hydroxyl groups are attached to opposite sides of the phenyl ring), each substituted or unsubstituted. In some such embodiments, the ortho-dihydroxyphenyl or para-dihydroxyphenyl is unsubstituted dihydroxyphenyl.

[0275] Dihydroxyphenyl groups according to any corresponding embodiment described herein may optionally be covalently and / or non-covalently bound to a target by any one or more of the binding mechanisms described for dihydroxyphenyl (catechol) groups in Lee et al. [PNAS 2006, 103:12999-13003], Brodie et al. [Biomedical Materials 2011, 6:015014] and / or International Patent Application PCT / IL2015 / 050606 (published as WO 2015 / 193887).

[0276] In some embodiments of any one of the embodiments described herein, the functional group capable of forming a bond with the target is a functional group capable of forming a covalent bond with an amine group, optionally a primary amine group. In some such embodiments, the target comprises one or more amino acid residues, e.g., a peptide or polypeptide of any length (e.g., at least two amino acid residues, e.g., a protein), and the amine group may optionally be a lysine side chain amine group and / or an N-terminal amine group. In some embodiments, the target comprises an extracellular matrix protein, e.g., collagen. In some embodiments, the target comprises cartilage (e.g., articular cartilage).

[0277] In some embodiments of any one of the embodiments described herein, the targeting moiety comprises (and optionally consists of) at least one functional group capable of forming a non-covalent bond with a target (e.g., as described herein in any one of the corresponding embodiments).

[0278] In some embodiments of any one of the embodiments described herein, the functional group capable of forming a non-covalent bond with the target comprises (and optionally consists of) a polysaccharide and / or a polypeptide (e.g., a protein and / or a fragment thereof), wherein the target optionally comprises a polysaccharide and / or polypeptide ligand, and / or wherein the target comprises a polysaccharide and / or a polypeptide (e.g., a protein and / or a fragment thereof) and the functional group capable of forming a non-covalent bond with the target is a polysaccharide and / or polypeptide ligand.

[0279] Examples of suitable polysaccharides and / or polypeptides and their ligands include, without limitation: avidin or streptavidin as the polypeptide described herein and biotin as its ligand; a polysaccharide-binding polypeptide as a polypeptide described herein and a complementary polysaccharide as its ligand (or a polypeptide that binds to a complementary polysaccharide as a ligand of a polysaccharide described herein); a collagen-binding polypeptide as a polypeptide described herein and a complementary collagen as its ligand (or a collagen as a polypeptide described herein and a complementary collagen-binding polypeptide as its ligand); A cell receptor expressed in a cell and a ligand to which the receptor selectively binds, an antibody against any antigen (e.g., where the target described herein optionally includes the antigen) or a fragment of such an antibody as a polypeptide described herein and the respective antigen as its ligand; and Antibody mimetics against any antigen (e.g., where the targets described herein optionally include antigens).

[0280] Examples of cellular receptors expressed on cells include, without limitation, receptors characteristic of particular cell types and / or tissues and receptors overexpressed on cancer cells. The cellular receptor or cell is optionally a target as described herein, and the targeting moiety optionally includes any ligand of the receptor. Examples of such ligands include, without limitation, transferrin, a ligand of the transferrin receptor that can optionally target the transferrin receptor, which is overexpressed in some cancer cells; keratinocyte growth factor (KGF or FGF7), which is specific to cells of epithelial origin and can optionally target the KGF receptor, which is overexpressed in endometrial or pancreatic cancer [Visco et al., Int J Oncol 1999, 15:431-435; Siegfried et al., Cancer 1997, 79:1166-1171]; and epidermal growth factor (EGF), which can optionally target the EGF receptor, such as that overexpressed in glioma and endometrial cancer, optionally erbB [Normanno et al., Curr Drug Targets 2005, 6:243-257].

[0281] As used herein, the term "antibody" encompasses any type of immunoglobulin.

[0282] As used herein, the phrase "antibody mimetics" includes any type of molecule, optionally a polypeptide, said in the art to have the ability to selectively (e.g., non-covalently) bind to an antigen. Non-limiting examples of antibody mimetics include, for example, those described by Nygren [FEBS J 2008, 275:2668-2676], Ebersbach et al. [J Mol Biol 2007, 372:172-185], Johnson et al. [Anal Chem 2012, 84:6553-6560], Krehenbrink et al. [J Mol Biol 2008, 383:1058-1068], Desmet et al. [Nature Comm 2014, 5:5237], Skerra [FEBS J 2008, 275:2677-2683], Silverman et al. [Nature Biotechnol 2005, 23:1556-1561], Stumpp et al. [Drug Discovery Today 2008, 13:695-701], Grabulovski et al. [J Biol Chem 2007, 282:3196-3204], Nixon & Wood [Curr Opin Drug Discov Devel 2006, 9:261-268], Koide & Koide [Methods Mol Biol 2007, 325:95-109] and Gebauer & Skerra [Curr Opin Chem Biol 2009, 13:245-255] (the contents of each of which are incorporated by reference in their entirety, particularly with respect to their content relating to particular types of antibody mimetics).

[0283] As used herein, the phrase "polysaccharide-binding polypeptide" encompasses any polypeptide or oligopeptide (a peptide chain at least 2 and preferably at least 4 amino acid residues in length) capable of selectively (e.g., non-covalently) binding to a polysaccharide. A wide variety of polysaccharide-binding polypeptides and their binding specificities are known to those skilled in the art and include short peptide sequences (e.g., 4-50, optionally 4-20 amino acid residues in length) and longer polypeptides such as proteins or fragments thereof (e.g., carbohydrate-binding modules and / or domains). In addition, the phrase "polysaccharide-binding polypeptide" encompasses antibodies capable of specifically binding to a polysaccharide. Such antibodies will be available to those skilled in the art and / or will know how to prepare such antibodies using immunological techniques known in the art.

[0284] Examples of polysaccharide-binding polypeptides that may be used in some of the embodiments of any one of the present invention include, without limitation, carbohydrate-binding modules (CBMs); and hyaluronic acid-binding peptides, polypeptides, and / or modules (see, e.g., WO 2013 / 110056, WO 2014 / 071132, Barta et al. [Biochem J 1993, 292:947-949], Kohda et al. [Cell 1996, 86:767-775], Brisset & Perkins [FEBS Lett 1996, 388:211-216], Peach et al. [J Cell Biol 1993, 122:257-264], Singh et al. [Nature Materials 2014, 13:988-995], and Zaleski et al. [Antimicrob Agents Chemother 1996, 13:988-995]). 2006, 50:3856-3860] (the contents of each of which are incorporated by reference in their entirety, particularly with respect to the content relating to certain polysaccharide-binding polypeptides, e.g., GAHWQFNALTVR (hyaluronic acid-binding peptide sequence)).

[0285] Examples of CBMs that may be used in some of the embodiments of any one of the present invention include, without limitation, CBMs belonging to the family CBM3, CBM4, CBM9, CBM10, CBM17 and / or CBM28 (which may optionally be used for binding to cellulose, e.g., in cellulose-containing targets); CBM5, CBM12, CBM14, CBM18, CBM19 and / or CBM33 (which may optionally be used for binding to chitin and / or other N-acetylglucosamine-containing polysaccharides, e.g., in chitin-containing targets); CBM15 (which may optionally be used for binding to hemicellulose, e.g., in hemicellulose-containing targets); and / or CBM20, CBM21 and / or CBM48 (which may optionally be used for binding to starch and / or glycogen, e.g., in starch-containing and / or glycogen-containing targets).

[0286] As used herein, the phrase "collagen-binding polypeptide" encompasses any polypeptide or oligopeptide (a peptide chain at least two and preferably at least four amino acid residues long) capable of selectively (e.g., non-covalently) binding to collagen (e.g., one type of collagen, several types of collagen, or all types of collagen), including glycosylated polypeptides and oligopeptides such as peptidoglycans and proteoglycans. A wide variety of collagen-binding polypeptides and their binding specificities are known to those of skill in the art and include short peptide sequences (e.g., 4-50, optionally 4-20 amino acid residues long) and longer polypeptides such as proteins or fragments thereof (e.g., collagen-binding domains). In addition, the phrase "collagen-binding polypeptide" encompasses antibodies capable of specifically binding to collagen. Such antibodies are available to those of skill in the art and / or the skilled artisan would know how to prepare such antibodies using immunological techniques known in the art.

[0287] Examples of collagen-binding polypeptides that may be used in embodiments of the present invention include, without limitation, collagen-binding proteins (e.g., decorin), fragments thereof, and / or other polypeptides as described in U.S. Pat. No. 8,440,618, Abd-Elgaliel & Tung [Biopolymers 2013, 100:167-173], Paderi et al. [Tissue Eng Part A 2009, 15:2991-2999], Rothenfluh et al. [Nat Mater 2008, 7:248-254], and Helms et al. [J Am Chem Soc 2009, 131:11683-11685] (the contents of each of which are incorporated by reference in their entirety, particularly with respect to particular collagen-binding polypeptides, e.g., the sequence WYRGRL).

[0288] It is expected that numerous relevant binding functional groups and moieties will be developed and / or discovered during the life of this application until the expiration of the patent, and it is intended that all such new technologies be included a priori within the scope of the terms "targeting moiety," "functional group," "cellular receptor," "antibody," "antibody mimetics," "collagen-binding polypeptide," and "polysaccharide-binding polypeptide," etc.

[0289] In some embodiments of any embodiment described herein, the functional group of the targeting moiety (according to any corresponding embodiment described herein) is attached to a linking group (as defined herein). The linking group may optionally be any linking group or moiety described herein, including, but not limited to, substituted or unsubstituted hydrocarbons. In some embodiments, the targeting moiety (optionally a substituent of backbone unit Y) consists essentially of a functional group attached to the remainder of the polymer segment via a linking group.

[0290] The functional group may optionally be attached to a linking moiety by a covalent bond achievable by reaction between two functional groups, such as any of the covalent bonds and / or functional groups described herein in connection with forming a covalent bond between a functional group and a target.

[0291] In some embodiments of any of the embodiments described herein with respect to functional groups comprising peptides or polypeptides, amino acid residues of the peptides or polypeptides are optionally linked to the linking group of the targeting moiety, for example, by an amide bond formed between an amine or carboxylate group on the peptide or polypeptide (e.g., on the N-terminus, lysine side chain, C-terminus, glutamic acid side chain, and / or aspartic acid side chain), an ester bond formed between a hydroxyl or carboxylate group on the peptide or polypeptide (e.g., on the serine side chain, threonine side chain, C-terminus, glutamic acid side chain, and / or aspartic acid side chain), and / or a disulfide bond formed between a thiohydroxy group on the peptide or polypeptide (e.g., on a cysteine ​​side chain). In some embodiments, the amino acid residues linked to the linking group are N- and / or C-terminal residues, e.g., any amino acid residue linked via its N-terminal amino group or C-terminal carboxylate group, and / or terminal lysine, glutamic acid, aspartic acid, serine, threonine, and / or cysteine ​​residues linked via their side chains.

[0292] In some embodiments, amino acid residues and / or peptides (e.g., 2-20 amino acid residues in length) are added to the N-terminus and / or C-terminus of a peptide or polypeptide sequence of a functional group (according to any corresponding embodiment described herein) to link said sequence to a linking group. Examples of such terminal amino acid residues and / or peptides include, without limitation, glycine residues and peptides with a terminal glycine residue (according to any corresponding embodiment described herein) which may be used to attach a linking group to the N-terminus or C-terminus; serine and threonine residues and a terminal serine or threonine residue (according to any corresponding embodiment described herein) which may be used to attach a linking group to the hydroxyl group of the serine or threonine side chain, optionally via an ester bond; and cysteine ​​residues and peptides with a terminal cysteine ​​residue (according to any corresponding embodiment described herein) which may be used to attach a linking group to the peptide via a disulfide bond.

[0293] In some embodiments, attaching a peptide or polypeptide to a linking group via a terminal amino acid residue minimizes interference (e.g., steric interference) with the functionality of the peptide or polypeptide after attachment to the linking group.

[0294] In some embodiments, attachment of a peptide or polypeptide to a linking group via a terminal glycine facilitates conjugation by minimizing interference (e.g., steric interference) from the amino acid side chain (which lacks glycine) upon attachment to the linking group.

[0295] In some embodiments of any of the embodiments described herein in which at least a portion of the monomer units comprise a targeting moiety, the monomer units comprising the targeting moiety are, on average, closer to the end of the polymer portion distal to the lipid portion, e.g., the average distance of the monomer units comprising the targeting moiety from the lipid portion (measured in atoms or backbone units along the backbone of the polymer portion) is greater than the average distance of the other monomer units from the lipid portion.

[0296] In some embodiments, at least some (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 contains 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.

[0297] Without being bound to any particular theory, it is postulated that a targeting moiety that is located distal to the 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 exposed to the target in an aqueous environment, and therefore is able to make better contact with the target.

[0298] In an alternative embodiment, the polymeric portion does not include a targeting moiety as described herein in any corresponding embodiment.

[0299] Lipid layers and liposomes: According to certain aspects of some embodiments of the present invention, there is provided a lipid bilayer (interchangeably referred to herein simply as a "bilayer") comprising a polymeric compound according to any corresponding embodiment described herein. In some such embodiments, the bilayer further comprises at least one bilayer-forming lipid in addition to the polymeric compound. In some of the embodiments described herein or any combination thereof, the at least one bilayer-forming lipid comprises at least one zwitterionic bilayer-forming lipid as described herein, and optionally further comprises at least one negatively charged bilayer-forming lipid.

[0300] As used herein, the term "bilayer-forming lipid" includes any compound that can form a bilayer from a pure aqueous solution of the compound, the bilayer comprising two parallel molecular layers of the compound (referred to as "lipids").

[0301] Typically, a bilayer 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 at the interior of the bilayer, at the interface between these two layers of bilayer-forming lipid molecules.

[0302] In some embodiments, the bilayer-forming lipids are amphipathic lipids.

[0303] As used herein, the term "amphipathic lipid" refers to a compound comprising at least one hydrophilic portion and at least one lipophilic portion. Examples of amphipathic lipids include, without limitation, fatty acids (e.g., at least 6 carbon atoms in length) and their derivatives, such as phospholipids and glycolipids, sterols (e.g., cholesterol), and steroid acids.

[0304] As used herein, the term "phospholipid" refers to a compound comprising a substituted or unsubstituted phosphate group and at least one alkyl chain (optionally at least two alkyl chains) optionally at least 5 carbon atoms in length, optionally at least 7 atoms in length, and optionally at least 9 atoms in length. The at least one alkyl chain is optionally part of an acyl group (e.g., a fatty acid moiety) or an alkyl group itself (e.g., a fatty alcohol moiety). In some embodiments, the phosphate group and one or two (optionally two) alkyl chains (e.g., acyl or alkyl) are attached to the glycerol moiety via an oxygen atom of glycerol.

[0305] In the context of this embodiment, the term "phospholipid" encompasses lipids with a (phosphorylated) glycerol backbone, referred to as glycerophospholipids (e.g., monoacylglyceride and / or diacylglyceride phospholipids).

[0306] In some embodiments of any one of the embodiments described herein, the phospholipid is a glycerophospholipid. In some embodiments, the glycerophospholipid is a diacylglyceride comprising two fatty acid acyl groups and one phosphate group attached to a glycerol backbone.

[0307] Examples of bilayer-forming lipids include glycerophospholipids (e.g., glycerophospholipids according to any corresponding embodiment described herein). It should be understood that the polymeric compounds described herein can optionally be bilayer-forming lipids capable of forming bilayers by themselves or in combination with one or more additional bilayer-forming lipids.

[0308] In some embodiments of any one of the embodiments described herein, the bilayer-forming lipid comprises at least one charged group (e.g., one or more negatively charged groups and / or one or more positively charged groups).

[0309] In some embodiments, the bilayer-forming lipids are zwitterionic and contain both (eg, equal numbers of) negatively and positively charged groups (eg, one of each).

[0310] 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, including any intermediate values ​​and subranges therebetween.

[0311] Throughout this specification, the terms "mol ratio" and "molar ratio" are used interchangeably and refer to the ratio between the mole percentages of the indicated components in a lipid bilayer or liposome.

[0312] In some embodiments of any of the embodiments described herein with respect to bilayers, the molar ratio of bilayer-forming lipids (included in addition to the polymeric compound) to polymeric compound in the bilayer is in the range of 10:1 to 1,000:1 (bilayer-forming lipids:polymeric compound), optionally in the range of 10:1 to 500:1, optionally in the range of 10:1 to 100:1, and optionally in the range of 10:1 to 50:1, including any intermediate values ​​and subranges therebetween.

[0313] In some embodiments of any of the embodiments described herein with respect to bilayers, the molar ratio of bilayer-forming lipids (included in addition to the polymeric compound) to polymeric compound in the bilayer is in the range of 10:1 to 100:1 (bilayer-forming lipids:polymeric compound), optionally in the range of 10:1 to 50:1, optionally in the range of 30:1 to 40:1, including any intermediate values ​​and subranges therebetween.

[0314] In some embodiments of any of the embodiments described herein with respect to bilayers, the molar ratio of bilayer-forming lipids (included in addition to the polymeric compound) to polymeric compound in the bilayer is in the range of 10:1 to 1,000:1 (bilayer-forming lipids:polymeric compound), optionally in the range of 100:1 to 1,000:1, optionally in the range of 101:1 to 500:1, and optionally in the range of 100:1 to 200:1, including any intermediate values ​​and subranges therebetween.

[0315] The bilayer according to some of the present embodiments may optionally be self-closed (e.g., such that the bilayer has no edges), thereby forming an interior volume separated from the surrounding environment by the bilayer, which is referred to herein and in the art as a "liposome." Alternatively or additionally, the bilayer may be open and / or have edges.

[0316] According to an aspect of some embodiments of the present invention there is provided a liposome comprising at least one lipid bilayer according to any corresponding embodiment described herein.

[0317] As used herein and in the art, the term "liposome" refers to an artificially prepared vesicle comprising a bilayer composed of amphiphilic lipid molecules. In an aqueous medium, the bilayer is typically configured such that the hydrophilic portions of the amphiphilic lipids are exposed to the medium on both surfaces of the bilayer, while the lipophilic portions of the lipids are located in the inner portion of the bilayer and are therefore less exposed to the medium. Examples of liposomes that can be used in any one of the embodiments described herein include, without limitation, small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), and large multilamellar vesicles (MLVs).

[0318] Liposomes according to embodiments as described herein comprise, inter alia, at least one bilayer-forming lipid.

[0319] It is understood that the polymeric compound comprised 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.

[0320] Liposomes may optionally comprise a single bilayer (e.g., unilamellar vesicles) or multiple bilayers (e.g., multilamellar vesicles), where each bilayer optionally independently forms a closed vesicle, e.g., comprising concentric bilayer vesicles and / or multiple individual bilayer vesicles contained within the same bilayer vesicle.

[0321] As used herein, the term "unilamellar" refers to a liposome characterized by a single lipid bilayer, while the term "multilamellar" refers to a liposome characterized by multiple lipid bilayers, e.g., concentric bilayers.

[0322] As used herein, the phrase "small unilamellar vesicles" refers to unilamellar liposomes having a diameter of less than 100 nm, while the phrase "large unilamellar vesicles" refers to unilamellar liposomes having a diameter of at least 100 nm.

[0323] As used herein, the term "small multilamellar vesicles" refers to multilamellar liposomes less than 100 nm in diameter, while the term "large multilamellar vesicles", MLVs, refers to multilamellar liposomes at least 100 nm in diameter.

[0324] In some embodiments of any one of the embodiments described herein, the liposomes comprise multilamellar vesicles. In some embodiments, the liposomes are predominantly (greater than 50 weight percent) multilamellar vesicles, preferably large multilamellar vesicles (MLVs).

[0325] In some embodiments of any one of the embodiments described herein, the liposomes comprise small unilamellar vesicles, hi some embodiments, the liposomes are predominantly (greater than 50 weight percent) small unilamellar vesicles.

[0326] In some embodiments of any one of the embodiments described herein, the liposomes comprise large unilamellar vesicles, hi some embodiments, the liposomes are predominantly (greater than 50 weight percent) large unilamellar vesicles.

[0327] Liposomes according to any corresponding embodiment described herein may be approximately spherical in shape, or may assume some other shape, such as elongated tubes and / or flattened (e.g., sheet-like) shapes.

[0328] In some embodiments of any one of the embodiments described herein, the concentration of phospholipid in the liposomes in a composition or formulation as described herein is in the range of 0.5 mM to 500 mM. In some embodiments, the concentration is in the range of 0.5 mM to 150 mM. In some embodiments, the concentration is in the range of 0.5 mM to 50 mM. In some embodiments, the concentration is in the range of 0.5 mM to 10 mM. In some embodiments, the concentration is in the range of 0.5 mM to 5 mM. In some embodiments, the concentration is in the range of 1 mM to 10 mM. In some embodiments, the concentration is in the range of 1 mM to 5 mM (e.g., 3 mM).

[0329] In any of the embodiments or any combination thereof described herein, the total amount of at least one bilayer-forming lipid in the liposome is in the range of 50 to 99 mole %, including any intermediate values ​​and subranges therebetween.

[0330] In some of the embodiments described herein, the amount of polymeric compound (LPC) is within the range of 0.1 to 10, or 0.1 to 5, or 0.1 to 3, or 0.1 to 1, or 0.2 to 0.8 mol % (including any intermediate values ​​and subranges therebetween) relative to the total amount of lipid in the liposome.

[0331] In some of the embodiments described herein, the amount of polymeric compound (LPC) is in the range of 1-50, or 1-40, or 1-30, or 5-50, or 5-40, or 5-30 wt. % (including any intermediate values ​​and subranges therebetween) of the total amount of lipid in the liposome, with the remainder being one or more bilayer-forming lipids.

[0332] In some of the embodiments described herein, the average diameter of the liposomes is within the range of about 100 nm to about 2000 nm, or about 100 nm to about 1000 nm, or about 100 nm to about 500 nm, or about 100 nm to about 200 nm, or about 150 nm to about 200 nm, or about 150 nm to about 180 nm (including any intermediate values ​​and subranges therebetween).

[0333] The mean diameter according to any corresponding embodiment described herein can optionally be the arithmetic mean (ratio of the sum of the values ​​to the number of values) or the Z-average (shortened to the intensity-weighted harmonic mean) as that term is defined in the art of dynamic light scattering. In exemplary embodiments, the mean diameter is the Z-average diameter determined by dynamic light scattering.

[0334] The number average molecular weight (Mn), and / or molecular weight (Mw), and / or number average degree of polymerization (DPn) of the liposomes in the composition can optionally be determined by gel permeation chromatography (GPC) analysis.

[0335] The polydispersity index (PDI) and / or mean diameter of the liposomes in the composition can optionally be determined by dynamic light scattering (e.g., using commercially available equipment) using a two-parameter fit to the data (e.g., according to ISO 13321 and ISO 22412 standards) to determine the PDI and Z-average diameter.

[0336] In some of the embodiments of any of the present disclosure, the liposomes have a PDI of less than 1.

[0337] In some of the embodiments described herein, the zeta potential of the liposome is in the range of 10 mV to 50 mV, or 0 mV to -50 mV, or 0 mV to -30 mV, or -5 mV to -25 mV, or -10 mV to -25 mV (including any intermediate values ​​and subranges therebetween).

[0338] In some of the embodiments described herein, the zeta potential of the liposome is at least −3 mV (ie, −3 mV or more negative), optionally at least −3.5 mV, and optionally at least −4 mV.

[0339] In some of the embodiments described herein that involve polymeric compounds comprising negatively charged bilayer-forming lipids (e.g., DPPG), the zeta potential of the liposomes is in the range of 10 mV to −10 mV (e.g., 5 mV to −5 mV), optionally in the range of 0 to −10 mV (e.g., 0 to −5 mV or −3 mV to −5 mV).

[0340] The zeta potential can be determined using any suitable technique known in the art, such as electrophoretic light scattering (e.g., using a commercially available instrument). The zeta potential of liposomes can be determined by diluting the liposomes in an aqueous salt solution (e.g., NaCl) of a predetermined salt concentration (e.g., 10 μM).

[0341] In some of any of the embodiments described herein, the bilayer-forming lipids or liposomes comprise at least one zwitterionic bilayer-forming lipid, such as a zwitterionic glycerophospholipid.

[0342] In some of any of the embodiments described herein, the bilayer-forming lipid or liposome comprises at least one zwitterionic bilayer-forming lipid, e.g., a zwitterionic glycerophospholipid, and at least one negatively charged bilayer-forming lipid, e.g., a negatively charged phosphatidylglycerol, in any of the embodiments described herein.

[0343] In some of any of the embodiments or any combination thereof described herein, at least one negatively charged bilayer-forming lipid is phosphatidylglycerol (eg, DPPG).

[0344] In some of any of the embodiments or any combination thereof described herein, the at least one bilayer-forming lipid further comprises at least one zwitterionic glycerophospholipid (e.g., a phosphatidylcholine such as DSPC and / or a phosphatidylethanolamine such as DPPE).

[0345] As used herein and in the art, the term "phosphatidylcholine" refers to a glycerophospholipid containing a phosphocholine group and two fatty acyl groups attached to a glycerol backbone (i.e., a diacylglyceride).

[0346] As used herein and in the art, the term "phosphatidylethanolamine" refers to a glycerophospholipid containing a phosphoethanolamine group and two fatty acyl groups attached to a glycerol backbone (i.e., a diacylglyceride).

[0347] According to some embodiments of any embodiment of the present invention, the bilayer-forming lipid comprises a negatively charged bilayer-forming lipid (eg, a phosphatidylglycerol such as DPPG).

[0348] According to some embodiments of any embodiment of the present invention, the bilayer-forming lipids comprise a zwitterionic glycerophospholipid (e.g., a phosphatidylcholine such as DSPC or a phosphatidylethanolamine such as DPPE) and a negatively charged glycerophospholipid (e.g., a phosphatidylglycerol such as DPPG). According to some embodiments of any embodiment of the present invention, the total amount of bilayer-forming lipids in the liposome is in the range of 50 to 99 mole %, including any intermediate value and subranges therebetween.

[0349] According to some embodiments of any embodiment of the present invention, the amount of negatively charged bilayer-forming lipid, if present, is in the range of 0.1 to 40 mol %, or 0.1 to 20 mol %, or 0.1 to 20 mol %, relative to the lipids in the liposome (bilayer-forming lipid, LPC, and cholesterol, if present), including any intermediate values ​​and subranges therebetween.

[0350] According to some embodiments of any of the embodiments of the present invention, the liposome further comprises a sterol, for example cholesterol.

[0351] According to some embodiments of any embodiment of the present invention, the sterol (eg, cholesterol) is associated with (but does not form) the lipid bilayer.

[0352] The term "sterol" as used herein encompasses all sterols derived from any source, including synthetic sterols, animal-derived sterols, and plant-derived sterols (known in the art as "phytosterols"), as well as sterols in their saturated forms (i.e., stanols). Thus, the term "sterol" as used herein encompasses both sterols and stanols. Sterols are steroids with a hydroxyl group at C3 (steroid alcohols), which is the backbone of cholestane (IUPAC Steroid Nomenclature, 1987). The side chain, usually C 17 There may be an additional carbon atom at the C position. In nature, sterols are 26 ~C30 They are found as steroid alcohols. While the cyclopentanoperhydrophenanthrene ring structure is common to all sterols, the side chains can vary in structure. In nature, sterols can be found as conjugates (e.g., glycoconjugates, lipoconjugates, etc.). Thus, the term "sterol" as used herein is further intended to encompass conjugated sterols, including, but not limited to, phytosteryl fatty acid esters and phytostanyl fatty acid esters. An exemplary sterol is cholesterol. According to some embodiments of any of the present invention, the amount of sterol (e.g., cholesterol) is in the range of 0.1 to 50 mole % of the total lipid in the liposome, including any intermediate value and subranges therebetween.

[0353] According to some embodiments of any embodiment of the present invention, the amount of polymeric compound (LPC) is in the range of 0.1 to 10, or 0.1 to 5, or 0.1 to 1, mol % relative to the total amount of lipid in the liposome, including any intermediate value and subranges therebetween.

[0354] In any of the embodiments or any combination thereof described herein, the amount of at least one negatively charged bilayer-forming lipid, if present, is in the range of 0.1 to 40 mol % or 0.1 to 20 mol % relative to the lipid in the liposome, including any intermediate values ​​and subranges therebetween.

[0355] In some embodiments of any of the embodiments described herein with respect to liposomes, the liposome further comprises at least one functional moiety or agent bound to or associated with the surface of the liposome and / or located within the lipid bilayer and / or core of the liposome (e.g., located within and / or enveloped by the liposome bilayer). In exemplary embodiments, the functional moiety is bound to the liposome, e.g., it is covalently attached to the liposome, e.g., by covalent bonding to one or more lipids. In exemplary embodiments, the functional agent is either chemically associated with the liposome, e.g., by covalent or electrostatic bonding, and / or physically by being encapsulated in or entangled within the lipid bilayer or core.

[0356] Examples of functional moieties and agents suitable for inclusion in the embodiments described herein include, without limitation, therapeutically active agents or portions of therapeutically active agents (e.g., where the active agent is releasable upon cleavage of the moiety), labeling moieties or agents, and / or targeting moieties or agents (e.g., targeting moieties or agents on the surface of the liposome). Any other moiety or agent that may contribute to or improve the indicated use of the liposome is contemplated. According to some embodiments, the liposome further comprises a sterol, such as cholesterol. According to some of these embodiments, the cholesterol is incorporated into and / or associated with the lipid bilayer.

[0357] According to some of the embodiments described herein, the functional moiety or agent is a therapeutically active agent or portion thereof, a labeling moiety or agent, and / or a targeting moiety or agent.

[0358] According to some of the embodiments described herein, the functional moiety or agent is a therapeutically active agent or portion thereof, and in some of these embodiments, the therapeutically active agent or portion thereof is in the lipid bilayer and / or core of the liposome. According to some of these embodiments, the liposome further comprises a sterol, e.g., cholesterol, in an amount of 0.1 to 50 mol % relative to the total lipid in the liposome. According to some of these embodiments, the polymeric compound is a long-chain polymeric compound as described and defined herein in any corresponding embodiment.

[0359] According to some embodiments, the liposome comprises a therapeutically active agent bound to or associated with the surface of the liposome and / or in the lipid bilayer and / or core of the liposome (e.g., in and / or enveloped by the liposome bilayer), and cholesterol (e.g., associated in the lipid bilayer).

[0360] In some of any of the embodiments described herein, the liposomes lack a therapeutically active agent.

[0361] In some of the embodiments described herein, the liposomes include a therapeutically active agent optionally incorporated onto the liposome and / or the surface of the liposome. In some such embodiments, the therapeutically active agent is a therapeutically active agent described in WO 2018 / 150429.

[0362] 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), including a portion of a bilayer-forming lipid or polymeric compound, that yields the agent having a therapeutic effect upon release (e.g., upon cleavage of one or more covalent bonds). Thus, while bilayer-forming lipids and polymeric compounds themselves are excluded from the definition of therapeutically active agent, the bilayer-forming lipids and / or polymeric compounds may optionally yield a therapeutically active agent upon release, in which case the portion of the bilayer-forming lipid and / or polymeric compound that yields the therapeutically active agent is also considered a therapeutically active agent as defined herein.

[0363] When associated with liposomes, therapeutically active agents may optionally be bound to the liposomes (e.g., to the outer and / or inner surfaces of the liposome membrane) by covalent or non-covalent (e.g., electrostatic and / or hydrophobic) bonds, may be incorporated into the liposome membrane (e.g., a lipophilic agent stably partitioned into the lipid phase of the liposome), and / or may be entrapped in the liposome core (e.g., a hydrophilic agent in the aqueous component of the liposome). The therapeutically active agent may optionally be a moiety covalently bound to the liposome (e.g., a moiety bound to a lipid to form a lipid derivative containing the moiety). Such binding may, in some embodiments, be achieved using techniques known in the art (e.g., amide bond formation).

[0364] In some embodiments, the therapeutically active agent is bound to the liposome by electrostatic interactions, e.g., the therapeutically active agent is a positively charged agent that binds to or is complexed with a negatively charged bilayer-forming lipid as described herein.

[0365] In some embodiments of any of the embodiments described herein, the therapeutically active agent is, for example, an analgesic, a steroidal anti-inflammatory agent, an antiproliferative agent, an antimicrobial agent (including an antibacterial agent, an antimycobacterial agent, an antiviral agent, an antifungal agent, an antiprotozoal agent, and / or an antiparasitic agent), and / or a vaccine antigen. In some such embodiments, the therapeutically active agent is an analgesic and / or a steroidal anti-inflammatory agent. In some such embodiments, the therapeutically active agent can be used, either alone or in combination with additional therapeutically active agents, in the treatment of osteoarthritis.

[0366] As used herein, the phrase "antimicrobial" refers to the property of a substance (e.g., a compound or composition) that can affect a parameter of a microorganism as defined herein, including killing, eradicating, eliminating, reducing the number, reducing the growth rate, inhibiting growth, and altering the population distribution of one or more species of microbial life forms. The term encompasses antibacterial agents, also referred to herein as antibiotics. Examples of antimicrobial agents include, without limitation, antibacterial agents, antimycobacterial agents, antiviral agents, antifungal agents, antiprotozoal agents, and / or antiparasitic agents as known in the art.

[0367] The phrase "vaccine antigen," as used herein, refers to an agent within the vaccine that can stimulate the immune system to recognize and respond to a specific pathogen or foreign agent. Antigens provoke an immune response upon introduction into a patient's body, thereby leading to the production of antibodies in the patient's body. Examples of vaccine antigens include, without limitation, inactivated or subunit vaccines (e.g., influenza vaccine, hepatitis B vaccine), live attenuated vaccines (e.g., yellow fever vaccine), viral vector vaccines (e.g., COVID-19 vaccine), toxoid vaccines (e.g., tetanus vaccine), and / or conjugate vaccines (e.g., Haemophilus influenzae type b (Hib) vaccine).

[0368] Examples of suitable antiproliferative agents include, without limitation, acivicin, aclarubicin, acodazole (e.g., acodazole hydrochloride), acronine, adriamycin, adozelesin, aldesleukin, altretamine, ambomycin, amethantrone (e.g., amethantrone acetate), aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene (e.g., bisantrene hydrochloride), visnafide (e.g., visantrene HCl ... , bisnafide dimesylate), bizelesin, bleomycin (e.g., bleomycin sulfate), brequinar (e.g., brequinar sodium), bropirimine, busulfan, cactinomycin, calsterone, caracemide, carbetimer, carboplatin, carmustine, carubicin (e.g., carubicin hydrochloride), carzelesin, cedefingol, chlorambucil, ciloremycin, cisplatin, cladribine, combrestatin A-4 phosphate, crisnatol (e.g., crisnatol mesylate), cyclophosphamide, cytarabine, dacarbazine dactinomycin, daunorubicin (e.g., daunorubicin hydrochloride), decitabine, dexorumaplatin, deazaguanine (e.g., deazaguanine mesylate), diaziquone, docetaxel, doxorubicin (e.g., doxorubicin hydrochloride), droloxifene (e.g., droloxifene citrate), dromostanolone (e.g., dromostanolone propionate), duazomycin, edatrexate, eflornithine (e.g., eflornithine hydrochloride), elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin (e.g., For example, epirubicin hydrochloride), elbrozole, esorubicin (e.g., esorubicin hydrochloride), estramustine (e.g., estramustine sodium phosphate), etanidazole, etoposide (e.g., etoposide phosphate), etopurine, fadrozole (e.g., fadrozole hydrochloride), fazarabine, fenretinide, floxuridine, fludarabine (e.g., fludarabine phosphate), fluorouracil, flurocitabine, foskidone, fostriecin (e.g., fostriecin sodium), gemcitabine (e.g., gemcitabine hydrochloride),Hydroxyurea, idarubicin (e.g., idarubicin hydrochloride), ifosfamide, ilmofosine, interferon alfa-2a, interferon alfa-2b, interferon alfa-n1, interferon alfa-n3, interferon beta-Ia, interferon gamma-Ib, iproplatin, irinotecan (e.g., irinotecan hydrochloride), lanreotide (e.g., lanreotide acetate), letrozole, leuprolide (e.g., leuprolide acetate), liarozole (e.g., liarozole hydrochloride), lometrexol (e.g., For example, lometrexol sodium), lomustine, losoxantrone (e.g., losoxantrone hydrochloride), masoprocol, maytansine, mechlorethamine (e.g., mechlorethamine hydrochloride), megestrol (e.g., megestrol acetate), melengestrol (e.g., melengestrol acetate), melphalan, menogaril, mercaptopurine, methotrexate (e.g., methotrexate sodium), metoprine, meturedepa, mitindomide, mitocalcin, mitochromine, mitogillin, mitomarcine, mitomycin, mitospel, mitoxantrone ... tan, mitoxantrone (e.g., mitoxantrone hydrochloride), mycophenolate, nocodazole, nogalamycin, ombrabulin, ormaplatin, oxisuran, paclitaxel, pegaspargase, periomycin, pentamustine, peplomycin (e.g., peplomycin sulfate), perfosfamide, pipobroman, piposulfan, piroxantrone (e.g., piroxantrone hydrochloride), plicamycin, promestane, porfimer (e.g., porfimer sodium), porfiromycin, prednimustine, procarbazine ( For example, procarbazine hydrochloride), puromycin (for example, puromycin hydrochloride), pyrazofurin, ribopurine, rogletimide, safingol (for example, safingol hydrochloride), semustine, simtrazene, sparfosate (for example, sparfosate sodium), sparsomycin, spirogermanium (for example, spirogermanium hydrochloride), spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, tallysomycin, tecogalan (for example, tecogalan sodium), tegafur, teloxantrone (for example,teroxantrone hydrochloride), temoporfin, teniposide, teroxylone, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, topotecan (e.g., topotecan hydrochloride), toremifene (e.g., toremifene citrate), trestrone (e.g., trestrone acetate), triciribine (e.g., triciribine phosphate), trimetrexate (e.g., trimetrexate glucuronate), triptorelin, tuborozol vinorelbine (e.g., tubrozole hydrochloride), uracil mustard, uredepa, vapreotide, verteporfin, vinblastine, vincristine (e.g., vincristine sulfate), vindesine (e.g., vindesine sulfate), vinepidine, vinglycinate, vinleurosine, vinorelbine (e.g., vinorelbine tartrate), vinrocidine, vinzolidine, vorozole, zeniplatin, zinostatin, and zorubicin (e.g., zorubicin hydrochloride). Additional anti-cancer agents include those disclosed in Chapter 52, Antineoplastic Agents (Paul Calabresi and Bruce A. Chabner) and its compendium, pp. 1202-1263, of Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Eighth Edition, 1990, McGraw-Hill, Inc. (Health Professions Division), the contents of which are incorporated herein by reference.

[0369] In some of any of the embodiments described herein, the lipid bilayer of a liposome according to any of the embodiments described herein includes a sterol, such as cholesterol.

[0370] In some of the embodiments described herein, the amount of sterol (e.g., cholesterol) is in the range of 0.1 to 50 mole % of the total lipid in the liposome, including any intermediate values ​​and subranges therebetween. Examples of therapeutically active agents suitable for inclusion in liposomes (e.g., as a drug molecule or moiety) include, without limitation, amphotericin B, cisplatin, cytarabine, daunorubicin, doxorubicin, estradiol, influenza virosomes, morphine, surfactant protein B, surfactant protein C, verteporfin, and vincristine.

[0371] Examples of labeling moieties or agents include chromogenic (e.g., that absorb visible light), fluorescent, phosphorescent, and / or radioactive moieties and compounds. Many such compounds and moieties (and techniques for preparing such moieties) will be known to those of skill in the art.

[0372] The targeting moiety in the liposome according to any corresponding embodiment described herein can optionally be a targeting moiety according to any corresponding embodiment described herein. The targeting moiety in the liposome can be included in a polymeric compound (according to any corresponding embodiment described herein) according to some embodiments of the invention, where the liposome comprises the polymeric compound. Alternatively or in addition, the targeting moiety in the liposome can optionally be included in another compound in the liposome, where optionally a bilayer-forming lipid (according to any corresponding embodiment described herein) is conjugated to the targeting moiety according to any corresponding embodiment described herein.

[0373] As used herein, a "targeting agent" refers to a compound ("agent") that includes (and optionally consists essentially of) a targeting moiety according to any corresponding embodiment described herein (e.g., in reference to a targeting moiety included in a polymeric compound described herein). Typically, the phrase "targeting agent" is used to refer to a compound other than a polymeric compound that includes a targeting moiety, as described herein.

[0374] In some embodiments, the functional moiety (e.g., targeting or labeling moiety) is covalently attached to the liposome, which in some embodiments may be achieved using techniques known in the art (e.g., amide bond formation).

[0375] Compositions of matter and articles: According to another aspect of embodiments of the present invention, there is provided a composition comprising a substrate at least a portion of whose surface is coated with a lipid bilayer according to any corresponding embodiment described herein.

[0376] According to another aspect of embodiments of the present invention, there is provided an article of manufacture comprising a composition according to any one of the embodiments described herein.

[0377] As used herein, the term "composition" refers to any composition that includes multiple substances (e.g., a substrate, one or more water-soluble polymers, and amphiphilic lipids) in a form that does not occur in nature and does not include human parts. A non-natural form may optionally include naturally occurring substances in a combination that does not occur in nature and / or may optionally include one or more substances that do not occur in nature. It should be understood that this definition is not necessarily the same as the standard legal definition of the term.

[0378] As used herein, the term "article of manufacture" refers to any article made from materials in such a way as to result in a new form, quality, property, or combination of materials. It is understood that this definition is not necessarily the same as the standard legal definition of the term. An article of manufacture as described herein may optionally consist essentially of its components or may instead include additional materials and / or parts.

[0379] At least a portion of the amphipathic lipid molecules are oriented so that their polar groups (eg, charged groups) point outward at the surface of the construct.

[0380] As used herein, the phrase "surface-facing outward" refers to a group of a molecule (e.g., a lipid) that is closer to the surface of the composition than from the center of mass of the molecule to the surface of the composition, and further away from the substrate than from the substrate to the center of mass of the molecule.

[0381] As discussed herein, and without being bound by any 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 adhesion, biofouling and / or biofilm formation inhibition (e.g., as described herein) at least in part due to the properties of hydrated polar groups (e.g., hydrated lubrication), particularly hydrated charged groups.

[0382] In any of the embodiments described herein, the substrate can comprise any type of material or 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, and combinations thereof.

[0383] In some embodiments, the substrate comprises a physiological surface (e.g., physiological tissue) and / or a surface that is intended to contact and / or come into contact with a physiological surface (e.g., as described herein in any one of the corresponding embodiments).

[0384] In some embodiments of any of the embodiments described herein, the article of manufacture is a medical device, e.g., a medical device having lipids 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 prone to infection, such as the interior 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 interior of the body) and contact lenses (which contact the surface of the eye).

[0385] As used throughout this specification, the phrase "medical device" includes any material or device used on, in, or through the body of a subject during the course of medical treatment (e.g., of disease or injury). Because subjects can be humans or non-human animals, the phrase "medical device" also includes veterinary devices. Medical devices include, but are not limited to, medical implants (including permanent and temporary implants), wound care devices, drug delivery medical devices, 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, and heart valves. Wound care devices include, but are not limited to, general wound dressings, biological implants, tape closures and dressings, and surgical incise drapes. Drug delivery medical devices include, but are not limited to, injection needles, drug delivery skin patches, drug delivery mucosal patches, and medical sponges. Body cavity and personal protective equipment includes, but is 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.

[0386] In the context of medical devices, it is understood that the medical device is coated with a bilayer as described herein, and that the lipid bilayer or liposomes comprising the bilayer are not themselves considered medical devices herein.

[0387] Examples of suitable articles of manufacture include, but are not limited to: 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 valve annulus 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. meat and / or dairy product packaging and / or containers for storing or transporting meat and / or dairy products, such as storage tanks, milk holding equipment, conveyor belts for dairy 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, etc.), medical device packaging, agricultural packaging and containers (for pesticides), packaging and containers for biological samples such as blood samples and any other packaging or container for various items, and Components, equipment, vessels, filters, piping, solutions, gases, etc. of water treatment systems (e.g., for containing and / or transporting and / or treating aqueous media or water).

[0388] With respect to medical devices, it is understood that the medical device is coated with a bilayer as described herein, and that the bilayer or liposomes comprising the bilayer are not themselves considered medical devices herein.

[0389] Exemplary articles include: Medical devices, such as, but not limited to, 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 valve annulus 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 food packaging and containers, beverage packaging and containers, medical device packaging, agricultural (pesticides) packaging and containers, blood sample or other biological sample packaging and containers and any other packaging or container for various items; Food packaging, such as dairy packaging and / or containers for storing or transporting dairy products; Milk storage and processing equipment, including but not limited to containers, storage tanks, milk holding equipment, conveyor belts for milk processing operations, pipe walls, gaskets, rubber seals, stainless steel coupons, piping systems, fillers, silo tanks, heat exchangers, post-pasteurization equipment, pumps, valves, separators and spray equipment; Energy harvesting devices, such as microelectronic devices, microelectromechanical devices, photovoltaic devices, etc. Microfluidic devices, such as micropumps or microvalves, Sealing parts, such as O-rings, Articles with corrosive surfaces, agricultural equipment, such as those described herein; Textiles, such as tough cotton, fuel transport equipment, Architectural elements, such as, but not limited to, paint, walls, windows, door handles, etc. Water treatment system elements (such as those for containing and / or transporting and / or treating aqueous media or water), equipment, vessels, filters, piping, solutions and gases, etc.; and Elements of organic waste treatment systems (such as for containing and / or disposing of and / or transporting and / or treating organic waste), equipment, containers, filters, pipes, solutions and gases.

[0390] In some of any one of the embodiments described herein, the article of manufacture includes a hydrogel surface, for example, at least a portion of which has lipid attached thereto.

[0391] Contact lenses are exemplary articles of manufacture that include a hydrogel surface. In some embodiments, contact lenses include a hydrogel surface and a hard core. In some embodiments, contact lenses consist essentially of hydrogel.

[0392] 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.

[0393] 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 monomer), ethylene glycol dimethacrylate (cross-linking monomer), and / or 3-(ethyldimethyl-ammonium)propyl methacrylamide (cationic monomer).

[0394] 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 lipid bilayer liposome, wherein the lipid bilayer of the liposome comprises at least one bilayer-forming lipid and a polymeric compound according to any corresponding embodiment described herein.

[0395] As used herein, the term "sterile" refers to the absence of observable microbial growth when the composition is exposed to conditions (e.g., culture medium, incubation temperature) for a suitable period of time, e.g., according to any standard protocol for testing for sterility. Optionally, sterility is tested in thioglycollate broth medium, e.g., for up to 3 days at a temperature ranging from 30 to 35°C, and / or in soybean casein digest medium (also known as trypticase soy broth or trypticase soy agar), e.g., for up to 5 days at a temperature ranging from 20 to 25°C, whereby the composition is deemed sterile, e.g., if no microbial growth is observable in either medium. The contents and / or procedures for the thioglycollate broth medium and / or soybean casein digest medium for testing sterility can optionally be as described in U.S. Pharmacopeia Chapter 71, the contents of which are incorporated herein by reference.

[0396] In some of the embodiments described herein, the sterile composition is further characterized by a bacterial endotoxin concentration below an acceptable threshold, e.g., below a threshold of 35 endotoxin units (EU) per ml (e.g., endotoxin units are defined according to the United States Pharmacopoeia standard). Bacterial endotoxin levels can be determined by any suitable test known in the art, for example, using horseshoe crab (Limulus sp.) amoebocyte lysate (e.g., according to U.S. Pharmacopoeia Chapter 85, the contents of which are incorporated herein by reference), for example, by comparison with a commercially available reference sample containing endotoxin.

[0397] In some of any corresponding embodiments, the sterile composition includes an article of manufacture immersed therein, such as a solid or semi-solid article of manufacture (which is also sterile as part of the sterile composition), which is often 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 correspond to a contact lens storage solution.

[0398] A sterile composition according to any corresponding embodiment described herein may optionally be prepared according to a method described herein according to any corresponding embodiment.

[0399] According to an aspect of some embodiments of the present invention, there is provided a method for preparing a sterile composition comprising an aqueous carrier (e.g., according to any corresponding embodiment described herein) and liposomes (e.g., according to any corresponding embodiment described herein), the method comprising providing an aqueous composition comprising an aqueous carrier and liposomes 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 greater than 100°C.

[0400] The sterile composition obtained by this method may optionally be a sterile composition according to any corresponding embodiment described herein.

[0401] In some of any corresponding embodiments described herein, the aqueous composition comprising an aqueous carrier and liposomes further comprises an article of manufacture (e.g., according to any corresponding embodiment described herein) immersed therein, such that exposing the aqueous composition to a temperature greater than 100°C renders the immersed article of manufacture sterile. In some exemplary embodiments, the article of manufacture comprises a contact lens. Such methods may enable efficient and relatively low-cost simultaneous sterilization of a solid or semi-solid article of manufacture and a liposome-containing aqueous composition (e.g., which are often packaged together), such as one or more contact lenses immersed in a liposome-containing contact lens solution (e.g., contact lens storage solution).

[0402] According to another aspect of some embodiments of the present invention, there is provided a method for preparing a sterile article of manufacture having a lipid bound 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 a lipid bound to at least a portion of its surface, and exposing the article of manufacture having a lipid bound to at least a portion of its surface to a temperature 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.

[0403] According to this embodiment, it should be understood that the lipids bound to at least a portion of the surface may be in the form of liposomes and / or in another form, such as an open bilayer (i.e., a bilayer that does not enclose a volume), which may be obtained, for example, by "bursting" the liposomes upon contact with the surface. Optionally, at least a portion of the lipids bound to the surface may be in a different form before application of a temperature above 100°C than 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 bilayers) after sterilization by heat. Alternatively or additionally, the form of the lipids gradually changes (e.g., from liposomes to another form) when the article of manufacture is incubated in the aqueous composition and then subsequently sterilized by heat (e.g., over the course of at least one hour, or at least one day, or even at least one month after sterilization).

[0404] Such methods may allow for efficient and relatively low-cost sterilization of solid or semi-solid manufactured articles having lipids bound to at least a portion of their surface, such as one or more lipid-coated contact lenses.

[0405] In some of any corresponding embodiments described herein, according to any aspect described herein, the temperature to which the aqueous composition is exposed is 150°C or less, e.g., 110°C to 150°C, or 115°C to 150°C, or 121°C to 150°C, or 130°C to 150°C.

[0406] In some of the corresponding embodiments described herein, the temperature to which the aqueous composition is exposed is 140°C or less, e.g., 110°C to 140°C, or 115°C to 140°C, or 121°C to 140°C, or 130°C to 140°C.

[0407] In some of the corresponding embodiments described herein, the temperature to which the aqueous composition is exposed is 134°C or less, for example, 110°C to 134°C, or 115°C to 134°C, or 121°C to 134°C.

[0408] In some of the corresponding embodiments described herein, the temperature to which the aqueous composition is exposed is 130°C or less, for example, 110°C to 130°C, or 115°C to 130°C, or 121°C to 130°C.

[0409] In some of the corresponding embodiments described herein, the temperature to which the aqueous composition is exposed is 125°C or less, for example, 110°C to 125°C, or 115°C to 125°C, or 121°C to 125°C.

[0410] In some of the corresponding embodiments described herein, exposing the aqueous composition to a temperature greater than 100°C is carried out under elevated pressure, i.e., at a pressure greater than ambient atmospheric pressure. Such pressure may be achieved, for example, by heating the aqueous composition in a sealed container, such that water vapor formed by heating contributes to the increased 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 (as per any corresponding embodiment described herein).

[0411] Exposing the composition to elevated temperatures (and optionally elevated pressures) according to any corresponding embodiment described herein may optionally be carried out using commercially available equipment configured for such use, such as an autoclave.

[0412] According to some of any of the embodiments described herein, the sterile composition is obtained or obtainable by a method as described herein for any corresponding embodiment and any combination thereof.

[0413] Lubrication: The liposomes and lipid bilayers described herein can optionally be useful for lubricating surfaces, such as surfaces coated by the bilayers described herein and / or surfaces in contact with the liposomes described herein.

[0414] According to an aspect of some embodiments of the present invention there is provided a lubricant composition comprising a liposome or lipid bilayer according to any corresponding embodiment described herein.

[0415] As used herein, "lubricant composition" refers to a composition intended to reduce the coefficient of friction of a surface (e.g., by the methods described herein).

[0416] In some embodiments, the lubricant composition comprises a carrier. The carrier may optionally be a liquid carrier. In some embodiments, the carrier comprises an aqueous liquid.

[0417] In some embodiments, the lubricant composition (or any other composition or formulation described herein that includes liposomes) further comprises a water-soluble polymer, optionally as part of the carrier.

[0418] As used herein, the phrase "water-soluble polymer" includes polymers that have a solubility of at least 1 gram per liter in an aqueous (eg, water) environment at pH 7 (25° C.).

[0419] In some embodiments of any of the embodiments described herein, the water-soluble polymer has a solubility (under the conditions described above) of at least 2 grams per liter. In some embodiments, the solubility is at least 5 grams per liter. In some embodiments, the solubility is at least 10 grams per liter. In some embodiments, the solubility is at least 20 grams per liter. In some embodiments, the solubility is at least 50 grams per liter. In some embodiments, the solubility is at least 100 grams per liter.

[0420] The one or more water-soluble polymers according to any embodiment described herein may comprise at least one ionic polymer and / or at least one non-ionic polymer that is water-soluble as defined herein.

[0421] As used herein, the phrase "nonionic polymer" refers to a polymer that does not have charged groups. Examples of suitable nonionic water-soluble polymers include, without limitation, polyvinylpyrrolidone (also interchangeably referred to herein as povidone and / or PVP) and polyethylene oxide (also interchangeably referred to herein as PEO, PEG, and / or polyethylene glycol).

[0422] As used herein, the phrase "ionic polymer" refers to a polymer having at least one charged group, and includes polymers that have a net negative charge in an aqueous (e.g., water) environment at pH 7 (also referred to herein as "anionic polymers"), polymers that have a net positive charge (also referred to herein as "cationic polymers"), and polymers that have no net charge (also referred to herein as "zwitterionic polymers").

[0423] Throughout this specification, the phrase "charged group" refers to any functional group (e.g., a functional group described herein) that is ionic (as defined herein), including, for example, amine, carboxylic acid, sulfate, sulfonate, phosphate, and phosphonate. Thus, each charge in a moiety or molecule is associated with one charged group, although a single charged group (e.g., unsubstituted phosphate) may be associated with two or more charges of the same sign (e.g., a dianion, a dication).

[0424] Throughout this specification, the term "ionic" refers to the presence of a charge on at least one atom of a moiety and / or molecule (at least 50% of the moieties and / or molecules in a population) in an aqueous medium (e.g., water) at pH 7. The charge can be negative (anionic) or positive (cationic). When more than one charge is present, the charges can be negative (anionic) and / or positive (cationic), for example, both negative and positive charges can be present (zwitterionic).

[0425] Examples of ionic polymers include, without limitation, ionic polysaccharides such as hyaluronic acid, chondroitin sulfate, alginic acid, xanthan gum, chitosan, and N-alkyl chitosan derivatives.

[0426] According to another aspect of the embodiments described herein, there is provided a method of reducing the coefficient of friction of a surface, the method comprising contacting the surface with a liposome according to any corresponding embodiment described herein. In some embodiments, the method is carried out by contacting the surface with a composition comprising the liposome and a carrier (optionally a lubricant composition according to any corresponding embodiment described herein).

[0427] In some of any one of the embodiments described herein with respect to lubrication, according to any one of the aspects described herein, lubrication is optionally carried out according to any of the embodiments described in International Patent Application No. PCT / IL2015 / 050605 (published as WO 2015 / 193887) and / or PCT / IL2015 / 050606 (published as WO 2015 / 193888).

[0428] In some embodiments, the method optionally further comprises contacting the surface with a water-soluble polymer (e.g., according to any corresponding embodiment described herein) prior to and / or simultaneously with contacting the surface with the liposomes. In some embodiments, the method is carried out by contacting the surface with a composition comprising liposomes and a water-soluble polymer (optionally a lubricant composition comprising a water-soluble polymer according to any corresponding embodiment described herein), optionally in combination with an aqueous liquid.

[0429] In some of the embodiments of any one of the methods and / or lubricating compositions described herein for reducing the coefficient of friction of a surface, the surface is a hydrogel surface. In some embodiments, the hydrogel consists essentially of a polymer and an aqueous liquid (optionally water).

[0430] In some of any one of the embodiments described herein relating to methods and / or lubricating compositions for reducing the coefficient of friction of a surface, the surface is a contact lens surface.

[0431] In some of any one of the embodiments described herein relating to contact lenses, according to any one of the aspects described herein, the contact lens comprises a hydrogel surface. In some embodiments, the contact lens comprises a hydrogel surface and a hard center. In some embodiments, the contact lens consists essentially of hydrogel.

[0432] The hydrogel may comprise any material known in the art for use in contact lens hydrogels. Examples of such hydrogel materials include, without limitation, 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.

[0433] 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 with vinylpyrrolidone, methyl methacrylate, methacrylic acid (anionic monomers), ethylene glycol dimethacrylate (cross-linking monomers), and / or 3-(ethyldimethyl-ammonium)propyl methacrylamide (cationic monomers) in the contact lens hydrogel.

[0434] Physiological surface: In some embodiments of any of the embodiments described herein with respect to methods for reducing the coefficient of friction of a surface and / or lubricating compositions, the surface is a physiological surface, and the carrier used with the liposomes (e.g., in a lubricant (e.g., sterile) composition according to any corresponding embodiment described herein) is a physiologically acceptable carrier.

[0435] In some embodiments, the surface for which the coefficient of friction is reduced by any corresponding embodiment described herein is an articular surface of a synovial joint.

[0436] In some embodiments, the method of reducing the coefficient of friction of a surface is for use in treating a synovial joint disorder associated with an increased coefficient of friction of the articular surfaces in a synovial joint.

[0437] In some embodiments of any of the embodiments described herein with respect to liposomes, the liposome is for use in treating a synovial joint disorder associated with an increased coefficient of friction of the articular surfaces in the synovial joint.

[0438] According to another aspect of the embodiments described herein, there is provided use of a liposome according to any corresponding embodiment described herein in the manufacture of a medicament for the treatment of a synovial joint disorder associated with an increased coefficient of friction of the articular surfaces in a synovial joint.

[0439] Examples of synovial joint disorders that are associated with an increased coefficient of friction of the articular surfaces and that are treatable by embodiments of various aspects of the present invention include, without limitation, arthritis, traumatic joint injuries, joint incarceration (also known in the art as joint locking), and surgery-related joint injuries.

[0440] In some embodiments, the arthritis is osteoarthritis, rheumatoid arthritis and / or psoriatic arthritis.

[0441] In some embodiments, the joint incarceration is associated with osteochondritis dissecans and / or synovial osteochondromatosis.

[0442] The surgery-related joint damage described herein can optionally be associated with surgery that directly damages the joint surface (e.g., by incision) and / or surgery that only indirectly compromises the joint surface. For example, surgery that repairs or otherwise affects tissues around the joint (e.g., ligaments and / or menisci) can be associated with joint damage because it alters joint mechanics.

[0443] The traumatic joint injury described herein can optionally be injury caused directly by the trauma (e.g., injury sustained at the time of the trauma) and / or injury caused by a previous trauma (e.g., post-traumatic injury that develops some time after the trauma).

[0444] In some of any corresponding embodiments, the (e.g., sterile) composition according to any corresponding embodiment described herein, and any combination thereof, is for use in treating a synovial joint disorder, e.g., the treatment comprises intra-articular administration of the (e.g., sterile) composition.

[0445] According to an aspect of some embodiments of the present invention, there is provided a (e.g., sterile) composition according to any corresponding embodiment described herein for use in the manufacture of a medicament for the treatment of a synovial joint disorder, e.g., the treatment comprising intra-articular administration of the (e.g., sterile) composition.

[0446] 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, for example by intra-articular administration, a sterile composition according to any corresponding embodiment described herein.

[0447] Examples of synovial joint disorders treatable according to embodiments of various aspects of the present invention include, but are not limited to, arthritis (e.g., osteoarthritis, rheumatoid arthritis, and / or psoriatic arthritis), bursitis, carpal tunnel syndrome, fibromyositis, gout, locking joints (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 thereafter), and joint injury associated with surgery (optionally, surgery that directly damages the joint surface, e.g., via 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, can involve joint injury due to changes in joint mechanics). Osteoarthritis is an exemplary synovial joint disorder treatable according to some embodiments of the present invention.

[0448] In some of any corresponding embodiments, treatment of synovial joint disorders (eg, osteoarthritis) is characterized by, for example, a reduction in pain during movement, at night, and / or at rest.

[0449] In such embodiments, pain reduction may be determined by any suitable technique known in the art. Examples of suitable techniques for determining pain reduction include, but are not limited to, a brief pain questionnaire (e.g., a shortened version), a physical activity test (e.g., a Timed Up & Go), a VAS (visual analog scale) questionnaire for assessing pain (from no pain to unbearable pain), the WOMAC (Western Ontario-McMaster University) scale, and / or the KOOS (Knee Injury and Osteoarthritis Outcome Score).

[0450] In some of any corresponding embodiments, the treatment of synovial joint disorders (eg, osteoarthritis) is characterized by an improvement in joint physiology.

[0451] In some of any corresponding embodiments, improvement in joint physiology is determined by the Kellgren-Lawrence scale of radiological severity, e.g., improvement is characterized by a reduction in severity. In some such embodiments, treatment is further characterized by a reduction in pain (e.g., according to any corresponding embodiment described herein).

[0452] 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).

[0453] 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 according to the Kellgren-Lawrence scale and / or increased range of motion (e.g., according to any corresponding embodiment described herein). In some such embodiments, treatment is further characterized by reduced pain (e.g., according to any corresponding embodiment described herein).

[0454] In some of any corresponding embodiments, the improvement in joint physiology is 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 addition to being characterized by an increase in quality of life. In some such embodiments, treatment is further characterized by a reduction in pain (e.g., according to any corresponding embodiment described herein).

[0455] In some of any 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, treatment is further characterized by a reduction in pain (e.g., according to any corresponding embodiment described herein).

[0456] Compositions 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.

[0457] Examples of suitable analgesics include, but are not limited to, allylprodine, alphamethylfentanyl, AP-237, bezitramide, butorphanol, buprenorphine, carfentanil, clonidine, codeine, desmethylprodine, dextromoramide, dexocin, difenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, diphenoxylate, dipipanone, eluxadoline, ethylmorphine, etorphine, fentanyl, heterocodeine, hydrocone, hydromorphone, ketone ... Examples of antihistamines include acetaminophen, 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, sulfentanil, tapentadol, tilidine, and tramadol.

[0458] Steroidal as well as nonsteroidal anti-inflammatory drugs (eg, those described herein) can be used as analgesics.

[0459] Examples of suitable anti-inflammatory agents 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, anilora, anitrazafen, apazone, aspirin, balsalazide disodium, bendazac, benoxaprofen, benzydamine (e.g., benzydamine hydrochloride), bromelain, and broperamol. , budesonide, carprofen, cycloprofen, synthasone, criprofen, clobetasol (e.g., clobetasol propionate, clobetasone butyrate), clopirac, cloticasone (cloticasone propionate), cormetasone (cormethasone acetate), cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone (e.g., dexamethasone dipropionate), diclofenac (e.g., diclofenac potassium, diclofenac sodium), diflorasone (e.g., diflorasone diacetate), diflumidone (e.g., Diflu midon sodium), diflunisal, difluprednate, diphthalone, drocinonide, endrison, enlimomab, enolicam (e.g., enolicam sodium), epirizole, etodolac, etofenamate, felbinac, fenamol, fenbufen, fenclofenac, fenclorac, fendosal, fenpiparone, fentiazac, furazarone, fluazacort, flufenamic acid, flumizole, flunisolide (e.g., flunisolide acetate), flunixin (e.g., flunixin meglumine), fluocortin (e.g., flu ocortin butyl), fluorometholone (e.g., fluorometholone acetate), fluquasone, 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), romoxicam, loteprednol (e.g., loteprednol etabonate), meclofenamate (e.g., meclofenamate sodium, meclofenamic acid), meclorizone (e.g., meclorizone dibutyrate), mefenamic acid, mesalamine, meseclazone, methylprednisolone methicone (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 umglycerate), pirfenidone, piroxicam (e.g., piroxicam cinnamate, piroxicam olamine), pirprofen, prednazate, priferon, prodolate, proquazone, proxazole (e.g., proxazole citrate), rimexolone, romazarit, sarcorex, salicylates (e.g., salicylic acid), salnacedin, salsalate, sanguinarium (e.g., sanguinarium chloride), seclazone, selmetacin, Examples include sudoxicam, 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).

[0460] Alternatively or additionally, a liposomal composition as described herein in any corresponding embodiment is co-administered to a subject with a therapeutically active agent as described herein.

[0461] The liposomes (and optionally also the water-soluble polymers described herein) can optionally be administered as part of a (e.g., sterile) composition (e.g., a solution) that includes a physiologically acceptable carrier, e.g., an aqueous carrier that is a physiologically acceptable carrier.

[0462] 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 abolish the activity and properties of the composition (e.g., sterile) (e.g., the ability of the liposomes therein to treat a pathology and / or reduce the coefficient of friction of a surface, as described herein in any one of the corresponding embodiments). Examples of carriers include, without limitation, propylene glycol, saline, emulsions and mixtures of organic solvents and water (or saline), and solid (e.g., powdered) and gaseous carriers.

[0463] Techniques for formulating and administering compounds (e.g., liposomes) may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co. (Easton, PA), latest edition, which is incorporated herein by reference.

[0464] A (eg, sterile) composition (eg, solution) according to any one of the embodiments of the present invention may be prepared by methods well known in the art, eg, by conventional mixing or dissolving methods.

[0465] Thus, (e.g., sterile) compositions (e.g., solutions) for use in accordance with the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers that facilitate processing of the liposomes (and optionally the water-soluble polymers also described herein) into pharmaceutically usable preparations. Appropriate formulations will depend on the selected route of administration.

[0466] For injection, a (e.g., sterile) composition according to any corresponding embodiment described herein or a liposome described herein (optionally comprising a water-soluble polymer described herein) may be formulated in aqueous solution using a suitable aqueous carrier, preferably a physiologically compatible buffer such as Hank's solution, Ringer's solution, histidine buffer, or saline buffer, with or without organic solvents, such as propylene glycol, polyethylene glycol, etc.

[0467] A (e.g., sterile) composition according to any corresponding embodiment described herein or a liposome described herein (optionally comprising a water-soluble polymer described herein) can be formulated for parenteral administration, for example, by bolus injection or continuous infusion. Formulations for injection can be provided in unit dosage form, for example, in ampoules or multi-dose containers, optionally with added preservatives. The (e.g., sterile) composition can be a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0468] A (e.g., sterile) composition according to any corresponding embodiment described herein or a liposome described herein (optionally comprising a water-soluble polymer described herein) may be formulated as an aqueous solution per se. In addition, the (e.g., sterile) composition (e.g., solution) may be in the form of a suspension and / or emulsion (e.g., the aqueous phase of a suspension or a water-in-oil, oil-in-water, or water-in-oil-in-oil emulsion), e.g., 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, the suspension may also contain suitable stabilizers or agents that increase the solubility of the liposomes described herein (and / or any water-soluble polymer described herein), e.g., to allow for the preparation of highly concentrated solutions.

[0469] In some embodiments, the liposomes described herein (optionally comprising a water-soluble polymer described herein) may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0470] A (e.g., sterile) composition or solution according to any corresponding embodiment described herein may be formulated to contain liposomes in an amount effective to achieve its intended purpose, e.g., an amount effective to prevent, reduce, or ameliorate symptoms of the disorder being treated in the subject. Additionally or alternatively, the (e.g., sterile) composition may be in the form of a suspension and / or emulsion (e.g., water-in-oil, oil-in-water, or water-in-oil-in-oil emulsion), e.g., 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, the suspension may also contain suitable stabilizers or agents that increase the solubility and / or stability of the liposomes described herein, e.g., to allow for the preparation of highly concentrated solutions.

[0471] Dosages may vary depending on the dosage form employed, the route of administration utilized, the site of administration (eg, the volume and / or surface of the area contacted with the liposomes), the judgment of the prescribing physician, etc.

[0472] 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.

[0473] Compositions (e.g., sterile) according to embodiments of the invention (e.g., solutions) may, if desired, be presented in a pack or dispenser device, such as an FDA (U.S. Food and Drug Administration)-approved kit, which may contain one or more unit dosage forms containing the active ingredient (e.g., liposomes described herein). The pack may comprise, for example, but 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 have attached to it a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, the notice reflecting approval by the government agency of the form of the composition (e.g., sterile) for human or animal administration. Such notice may, for example, be labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions (e.g., sterile) comprising liposomes as described herein in any one of the corresponding embodiments (optionally together with a water-soluble polymer as described herein) formulated in a physiologically acceptable carrier may also be prepared, placed in a suitable container, and labeled for the treatment or diagnosis of an indicated condition, as detailed herein.

[0474] Inhibition of biofilm formation and biofouling: The liposomes and bilayers described herein may optionally be useful in inhibiting adhesion, biofouling, and / or biofilm formation on surfaces, such as surfaces coated by a bilayer described herein and / or surfaces in contact with a liposome described herein.

[0475] According to an aspect of some embodiments of the present invention, there is provided a method for inhibiting adsorption of a biofouling-promoting agent onto a surface of a substrate, the method being carried out, according to some embodiments of the present invention, by contacting the substrate with a composition comprising a liposome according to any corresponding embodiment described herein.

[0476] As used throughout this specification, the term "biofouling-promoting agent" refers to an agent whose presence facilitates and / or contributes to the formation of a biofilm (as defined herein) on a substrate surface. An agent is considered to facilitate the formation of a biofilm on a substrate surface when the presence of the agent enhances the formation of a biofilm on the substrate surface compared to the formation of a biofilm on the same substrate surface in the absence of the agent. An agent is considered to contribute to the formation of a biofilm on a substrate surface when the biofilm formed on the surface includes the agent as part of the biofilm.

[0477] In some embodiments of any of the embodiments described herein, an agent is identified as a pro-biofouling agent by comparing the growth of biofilm (e.g., P. aeruginosa) on a surface in the presence of an aqueous liquid (e.g., water or broth, optionally at 37°C) and the agent (e.g., over the course of 1, 2, 3, 4, 5, 6, or 7 days) to the growth of biofilm (under the same conditions) on the surface in the presence of the same aqueous liquid (e.g., water or broth) but in the absence of the agent. The agent is optionally mixed in the aqueous liquid, or alternatively, adsorbed onto the surface before exposing the surface to the aqueous liquid. Biofilm growth is considered to be the biofilm load at the end of the growth period (e.g., 1, 2, 3, 4, 5, 6, or 7 days) minus the initial biofilm load. Optionally, measurements are taken such that the initial biofilm is substantially zero (e.g., absent or at least undetectable), e.g., the microorganisms are in planktonic form, and thus the biofilm growth is considered to be the biofilm burden at the end of the growth period. In some embodiments of any of the embodiments described herein, the biofilm burden is defined as the area of ​​the biofilm.

[0478] In some embodiments of any of the embodiments described herein, the biofilm burden is defined as the mass and / or volume of the biofilm.

[0479] In some embodiments of any of the embodiments described herein, the biofilm burden is defined as the number of cells in the biofilm.

[0480] Biofilm burden can optionally be determined using any technique known in the art for detecting and quantifying the amount of cells and / or microorganisms in a biofilm.

[0481] In some of these embodiments, an agent is considered a pro-biofouling agent if biofilm growth in its presence is at least 10% greater than biofilm growth in the absence of the agent.

[0482] In some of these embodiments, an agent is considered a pro-biofouling agent if biofilm growth in its presence is at least 20% greater than biofilm growth in the absence of the agent.

[0483] In some of these embodiments, an agent is considered a pro-biofouling agent if biofilm growth in its presence is at least 50% greater than biofilm growth in the absence of the agent.

[0484] In some of these embodiments, an agent is considered a pro-biofouling agent if biofilm growth in its presence is at least 100% greater (i.e., 2-fold) than biofilm growth in the absence of the agent.

[0485] Examples of biofouling agents include, without limitation, biofouling proteins and biofouling polysaccharides, i.e., any protein or polysaccharide that is a biofouling agent as defined herein.

[0486] In some embodiments of any of the embodiments described herein, the biofouling-promoting agent is a protein.

[0487] In some embodiments of any of the embodiments described herein, the method is considered to be capable of inhibiting adsorption of a selected biofouling-promoting agent (e.g., the selected agent is generally considered to be representative of a biofouling-promoting agent). In some embodiments, the selected biofouling-promoting agent is a protein. In some embodiments, the selected protein is an antibody (e.g., an anti-IgG antibody as exemplified herein) that does not exhibit any specific affinity for the substrate.

[0488] The term "biofilm" as used throughout this specification refers to an aggregate of living cells that are attached to each other and / or solidified as colonies on a surface and cannot be separated. The cells are often embedded in a matrix of autocrine extracellular polymeric substances (EPS), also known as "slime," which is a sticky polymeric mixture of nucleic acids, proteins, and polysaccharides.

[0489] In the context of this embodiment, the living cells that form the biofilm may be cells of unicellular microorganisms or cells of multicellular organisms, including prokaryotes (e.g., bacteria, archaeal microorganisms) and eukaryotes such as fungi and protists (e.g., algae, euglenoids, protozoa, dinoflagellates, apicomplexa, trypanosomes, amoeba), in which case the biofilm may be considered a colony of cells (as in the case of unicellular organisms) or may also be considered a lower form of tissue.

[0490] According to some embodiments of any embodiment of the present invention, the cells are of microbial origin and the biofilm is a biofilm of microorganisms, such as bacteria, archaeal microorganisms, protists, and fungi. Microbial cells growing in a biofilm are typically physiologically distinct from "planktonic" forms of the same organism, which are single cells that can float or swim in a liquid medium.

[0491] A substrate can be any substrate described herein and includes any surface, structure, product, or material capable of supporting, containing, or promoting microbial growth. A substrate is optionally a portion of an object (e.g., an article of manufacture) capable of supporting, containing, or promoting microbial growth. Such a portion of an object may extend over only a portion of the object's area, and thus the surface of the substrate may represent only a portion of the object's surface (e.g., the portion most likely to support, contain, or promote microbial growth) and / or may extend over only a portion of the object's thickness (e.g., along an axis perpendicular to the substrate and the object's surface), and thus the substrate does not include all of the object's volume underlying the surface of the substrate (which may represent the entire object's surface or only a portion of the object's surface). Non-limiting examples include organic products susceptible to biofouling-related spoilage, such as the interior walls of storage containers (e.g., boxes, cans) and / or pipelines (e.g., tubes, pipes) for food and / or beverages (e.g., food containers, water lines), surfaces intended to come into contact with such organic products (e.g., agricultural and / or food processing machinery, kitchen surfaces, water purification equipment), and surfaces exposed to moisture (e.g., bathroom walls, water supply system components, exterior surfaces of residences exposed to rain, surfaces near water leaks).

[0492] In some embodiments, the substrate is a medical device, as defined herein, or any other device intended to come into contact with living tissue.

[0493] In some embodiments of any of the embodiments described herein, the reduced adsorption described herein is for reducing adhesion of pathogenic microorganisms (e.g., any of the potentially pathogenic biofilm-forming microorganisms described herein) to a medical device (e.g., any of the medical devices described herein).

[0494] In some embodiments of any embodiment described herein, adsorption of a biofouling-promoting agent (any biofouling-promoting agent described herein) onto a surface of a substrate subjected to a method described herein (according to any corresponding embodiment) is reduced by at least 10% compared to adsorption onto the surface of the substrate in the absence of a composition comprising liposomes in some embodiments, and adsorption is reduced by at least 20%. In some embodiments, adsorption is reduced by at least 30%. In some embodiments, adsorption is reduced by at least 40%. In some embodiments, adsorption is reduced by at least 50%. In some embodiments, adsorption is reduced by at least 60%. In some embodiments, adsorption is reduced by at least 70%. In some embodiments, adsorption is reduced by at least 80%. In some embodiments, adsorption is reduced by at least 90%.

[0495] The reduction in the amount of adsorbed biofouling-promoting agent may optionally be determined using any technique known in the art for detecting and quantifying the amount of agent, including, without limitation, using a labeled biofouling-promoting agent (e.g., as exemplified in the Examples section herein). The reduction is optionally measured by contacting each of the aforementioned surfaces (e.g., for 2 hours) with an aqueous solution of the biofouling-promoting agent (optionally containing phosphate buffer, e.g., 0.1 M phosphate) (e.g., at 37°C and / or pH 7), followed by repeated rinsing to remove unadsorbed agent (e.g., as exemplified in the Examples section herein). The concentration of the biofouling-promoting agent in the aqueous solution is optionally 1 μg / mL or the concentration of a saturated solution of the agent, whichever is lower.

[0496] Throughout this specification, the term "biofilm-promoting conditions" refers to conditions suitable for the formation and growth of a biofilm of cells (e.g., P. aeruginosa), e.g., a surface in contact with an aqueous liquid (e.g., water or broth, optionally at 37°C) containing such cells (e.g., over the course of 1, 2, 3, 4, 5, 6, or 7 days).

[0497] In some embodiments of any of the embodiments described herein, the biofilm burden is defined as the area of ​​the biofilm.

[0498] In some embodiments of any of the embodiments described herein, the biofilm burden is defined as the mass and / or volume of the biofilm.

[0499] In some embodiments of any of the embodiments described herein, the biofilm burden is defined as the number of cells in the biofilm.

[0500] Biofilm burden can optionally be determined using any technique known in the art for detecting and quantifying the amount of cells and / or microorganisms in a biofilm.

[0501] In some embodiments of any of the embodiments described herein, the period of biofilm formation after which the biofilm burden is determined is determined according to the biofilm burden, e.g., the period after which the biofilm would cover 100%, 50%, or any other predetermined percentage of the area of ​​the substrate in the absence of inhibition of biofilm formation by contact with a composition comprising liposomes. For example, if a biofilm grows to cover 50% of the surface in the absence of biofilm formation inhibition, and during that intervening period the biofilm grows to cover 30% of the surface in the presence of biofilm formation inhibition, then inhibition of biofilm formation can be considered to result in a 40% reduction in biofilm formation (i.e., (50%-30%) / 50%).

[0502] As used herein, the phrase "upon contact with an agent" means that in addition to biofilm-promoting conditions, the agent is also present (eg, in the aqueous fluid containing the cells).

[0503] @@@ According to an aspect of some embodiments of the present invention, there is provided a method of inhibiting biofilm formation on a surface of a substrate (as defined herein in any embodiment and any combination of embodiments), the method comprising contacting the substrate with a composition comprising liposomes (as described in any corresponding embodiment described herein).

[0504] In some embodiments, "inhibiting biofilm formation" refers to preventing the formation of a biofilm and / or reducing the rate of biofilm accumulation and / or reducing the biofilm mass, biofilm area or volume, or the number of cells forming a biofilm.

[0505] In some embodiments of any of the embodiments described herein, the reduced adsorption described herein is to reduce adhesion of pathogenic microorganisms (e.g., any of the potentially pathogenic biofilm-forming microorganisms described herein) to the medical device. Such a reduction can result in reduced biofilm formation as defined in some embodiments herein.

[0506] In some embodiments of any embodiment described herein, biofilm formation on a surface of a substrate subjected to a method described herein (according to any corresponding embodiment) is reduced by at least 10% compared to biofilm formation on the surface of the substrate in the absence of a composition comprising liposomes. In some embodiments, biofilm formation is reduced by at least 20%. In some embodiments, biofilm formation is reduced by at least 30%. In some embodiments, biofilm formation is reduced by at least 40%. In some embodiments, biofilm formation is reduced by at least 50%. In some embodiments, biofilm formation is reduced by at least 60%. In some embodiments, biofilm formation is reduced by at least 70%. In some embodiments, biofilm formation is reduced by at least 80%. In some embodiments, biofilm formation is reduced by at least 90%.

[0507] The reduction in biofilm formation is optionally determined by measuring the biofilm load (according to any corresponding embodiment described herein) for a biofilm of cells (e.g., P. aeruginosa) on each surface after being subjected to biofouling-promoting conditions as defined herein (e.g., over the course of 1, 2, 3, 4, 5, 6, or 7 days, or any other period as described herein).

[0508] Any embodiment described herein with respect to inhibiting biofilm formation and / or biofouling may optionally be practiced with a composition that is essentially the same as a lubricant composition according to any corresponding embodiment described herein (but optionally identified as being for inhibiting biofilm formation and / or biofouling rather than for lubrication).

[0509] In some of any one of the embodiments described herein with respect to inhibiting adhesion, biofilm formation and / or biofouling, according to any one of the aspects described herein, the inhibition is optionally carried out by any of the embodiments described in Israel Patent Application No. 234929 and / or International Patent Application No. PCT / IL2015 / 050987 (published as WO 2016 / 051413).

[0510] Additional Compositions and Uses: In view of their optional sterile nature, compositions according to corresponding embodiments described herein may be useful for use in physiological environments, such as the internal physiological environment or the ocular environment. Accordingly, aqueous carriers according to any corresponding embodiments described herein may optionally be selected according to the intended use, e.g., physiologically acceptable carriers and / or ophthalmically acceptable carriers as described herein.

[0511] Use in a physiological environment can optionally be for reducing the coefficient of friction (also referred to herein as "lubrication," "lubricating," and variations thereof) of physiological surfaces (e.g., articular surfaces or ocular surfaces) and / or non-physiological surfaces (e.g., contact lens surfaces), for example, in the treatment of diseases or disorders associated with an increased coefficient of friction of the surface. The reduction in the coefficient of friction of the surface can 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.

[0512] In some of any of the embodiments described herein, a (e.g., sterile) composition comprising liposomes as described herein is for rinsing, cleaning, and / or soaking contact lenses in. In some such embodiments, the composition comprises an ophthalmically acceptable carrier as described herein in any corresponding embodiment, and optionally may be allowed to remain on the contact lens after rinsing, cleaning, and / or soaking in the solution, since residual solution will not be 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 a preservative and / or includes a preservative at an ophthalmically unacceptable concentration), and the (e.g., sterile) composition (e.g., a composition having a contact lens immersed therein according to any corresponding embodiment described herein) may optionally be intended for long-term soaking of the contact lens (e.g., when the contact lens is not in use, e.g., overnight) and / or for long-term storage (e.g., between manufacture and first use of the contact lens), during which the risk of bacterial growth in the solution may be limited, e.g., such a composition is rinsed with an ophthalmically acceptable liquid (e.g., water, saline) solution before placing the contact lens on the eye.

[0513] In some of the embodiments of any of the contact lenses described herein, the (e.g., sterile) composition is intended for soaking the contact lens therein (e.g., to maintain the moisture of the contact lens and, optionally, to reduce the coefficient of friction of the contact lens in the process). In some such embodiments, the carrier of the (e.g., sterile) composition includes additional ingredients suitable for cleaning purposes, such as preservatives. Such compositions may optionally be provided as a single product together 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 an additional ophthalmically acceptable composition before placement in the eye.

[0514] In some of any of the embodiments described herein with respect to contact lenses, the (e.g., sterile) composition is for rinsing the contact lens (e.g., thereby removing another composition, such as an ophthalmically unacceptable liquid, from the contact lens and / or reducing the coefficient of friction of the contact lens). Such a composition may optionally be provided as a separate product from the contact lens. In some such embodiments, the carrier of the sterile composition is an ophthalmically acceptable carrier as described herein in any corresponding embodiment.

[0515] In some of the embodiments described herein with respect to contact lenses, the (e.g., sterile) composition is for cleaning used and / or new contact lenses (e.g., thereby removing bacteria and / or other impurities, optionally reducing the coefficient of friction of the contact lens while doing so). In some such embodiments, the carrier of the (e.g., sterile) composition includes additional ingredients suitable for performing the cleaning, e.g., antimicrobial agents (e.g., peroxides and / or other oxidizing agents) and / or surfactants for removing impurities, and is an ophthalmically acceptable carrier as described herein for any corresponding embodiment. Such compositions may optionally be provided as a separate product from the contact lens, which may optionally be intended to be rinsed with an additional ophthalmically acceptable composition before being placed in the eye.

[0516] In some of any corresponding embodiments, the (e.g., sterile) compositions according to any corresponding embodiment described herein are for use in treating ocular diseases, such as dry eye syndrome and any other ocular diseases.

[0517] Compositions (e.g., solutions) according to embodiments of the invention may, if desired, be presented in a pack or dispenser device, such as a kit approved by the FDA (U.S. Food and Drug Administration), which may contain one or more unit dosage forms containing one or more active ingredients (e.g., liposomes described herein). The pack may, for example, comprise metal or plastic foil, such as, but not limited to, a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with its container in a form established by the regulatory agency regulating its manufacture, use, or sale, reflecting that the form of the composition has been approved by that agency for administration to humans or animals. Such notice may, for example, be that approved by the U.S. Food and Drug Administration for prescription drugs or an approved drug package 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 a suitable container, and labeled for treatment of an indicated condition, as detailed herein.

[0518] According to an aspect of some embodiments of the present invention, there is provided a composition or formulation comprising at least one water-soluble polymer (as described herein in any one of the corresponding embodiments), a liposome (as described herein in any one of the corresponding embodiments), an ophthalmically acceptable carrier (e.g., an aqueous carrier) as described herein in any corresponding embodiment, and optionally a saccharide (e.g., a polysaccharide).

[0519] As used herein, the phrase "ophthalmically acceptable carrier" refers to a carrier or diluent that, upon contact with the subject's eye (e.g., cornea and / or sclera), does not cause significant irritation to the subject and does not neutralize the activity and properties of the composition (e.g., the ability of the liposomes therein to reduce the coefficient of friction of the surface of a contact lens and / or the surface of the eye).

[0520] In some of the embodiments described in this aspect, the composition or formulation as described herein is a liquid formulation, which is also referred to interchangeably herein as a "solution." It should be noted that throughout this specification, the term "solution" encompasses any liquid formulation that contains components, i.e., at least a water-soluble polymer and liposomes / lipids, in a liquid carrier, and each of these components can be dissolved or dispersed in the carrier. Thus, the term "solution" as used herein also encompasses a "dispersion." The term "liquid formulation" as used herein encompasses both a solution and a dispersion.

[0521] According to some embodiments of this aspect, the bilayer-forming lipids comprise first and second glycerophospholipids, as described in further detail below. In some such embodiments, the bilayer-forming lipids comprise at least two lipid materials: a first glycerophospholipid characterized by a Tm of less than 25°C and a second glycerophospholipid characterized by a Tm of greater than 40°C.

[0522] According to some of the present embodiments of this aspect, the weight ratio of the first and second glycerophospholipids is such that the bilayer-forming lipids are characterized by a Tm in the range of 25-40, or 26-39, or 26-33, or 28-33°C.

[0523] According to some of the embodiments described herein, the weight ratio of the first and second glycerophospholipids in a composition or formulation as described in this aspect is at least 2:1, such as 2:1, or 3:2, or 3:1, or 4:1, or 5:2, or 5:1, or 5:3 (first glycerophospholipid:second glycerophospholipid).

[0524] According to some of the embodiments described herein, the weight ratio of the first and second glycerophospholipids in the composition or formulation as described in this aspect is 3:1 (first glycerophospholipid:second glycerophospholipid).

[0525] According to some of the embodiments described herein, the weight ratio of the first and second glycerophospholipids in a composition or formulation as described in this aspect is in the range of 4:1 to 1:4, or 3:1 to 1:3, or 3:1 to 1:1 (first glycerophospholipid:second glycerophospholipid), including any intermediate values ​​and subranges therebetween.

[0526] According to some of any of the embodiments of the compositions or formulations as described in this aspect, at least 50%, or at least 60%, or at least 70% by weight of the total weight of the bilayer-forming lipids is a first glycerophospholipid as described herein.

[0527] According to some of any of the embodiments of the compositions or formulations as described in this aspect, less than 50%, or less than 40%, or less than 30% by weight of the total weight of the bilayer-forming lipids is a second glycerophospholipid as described herein.

[0528] According to some of the embodiments of any of the compositions or formulations as described in this aspect, the amount of the first glycerophospholipid as described herein is in the range of 30% to 90%, or 30% to 80%, or 40% to 90%, or 40% to 80%, or 50% to 90%, or 50% to 80%, or 60% to 90%, or 60% to 80%, by weight, based on the total weight of the bilayer-forming lipids, including any intermediate values ​​and subranges therebetween.

[0529] According to some of the embodiments of any of the compositions or formulations as described in this aspect, the amount of the second glycerophospholipid as described herein is in the range of 5% to 50%, or 10% to 50%, or 5% to 40%, or 10% to 40%, or 5% to 30%, or 10% to 30%, or 20% to 50%, or 20% to 40%, or 20% to 30%, by weight, based on the total weight of the bilayer-forming lipids, including any intermediate values ​​and subranges therebetween.

[0530] According to some of the embodiments of any of the compositions or formulations as described in this aspect, the amount of the first glycerophospholipid as described herein is in the range of 30% to 90%, or 30% to 80%, or 40% to 90%, or 40% to 80%, or 50% to 90%, or 50% to 80%, or 60% to 90%, or 60% to 80% by weight, based on the total weight of the bilayer-forming lipids, including any intermediate values ​​and subranges therebetween, and the amount of the second glycerophospholipid as described herein is in the range of 5% to 50%, or 10% to 50%, or 5% to 40%, or 10% to 40%, or 5% to 30%, or 10% to 30%, or 20% to 50%, or 20% to 40%, or 20% to 30%, including any intermediate values ​​and subranges therebetween, based on the total weight of the bilayer-forming lipids.

[0531] In some of any of the embodiments of the compositions or formulations as described in this aspect, the bilayer-forming lipids comprise a first glycerophospholipid characterized by a Tm of less than 25°C and a second glycerophospholipid characterized by a Tm of greater than 40°C, while the weight ratio of the first and second glycerophospholipids is such that the bilayer-forming lipids are characterized by a Tm in the range of 25-40°C, or 26-39°C, or 26-33°C, or 28-33°C, including any intermediate values ​​and subranges therebetween.

[0532] According to some embodiments of any of the compositions or formulations as described in this aspect, the bilayer-forming lipids consist of a first and a second glycerophospholipid as described herein.

[0533] According to some of the embodiments of any of the compositions or formulations as described in this aspect, the first glycerophospholipid is DMPC as described herein, although other glycerophospholipids characterized by a Tm as indicated are also contemplated.

[0534] According to some of the embodiments of any of the compositions as described in this aspect, the second glycerophospholipid is DPPC as described herein, although other glycerophospholipids characterized by a Tm as indicated are also contemplated.

[0535] According to some embodiments of any of the compositions or formulations as described in this aspect, the bilayer-forming lipid material comprises or consists of DMPC and DPPC.

[0536] According to some of any of the embodiments of the compositions or formulations as described in this aspect, the bilayer-forming lipid material comprises DMPC in an amount ranging from 30% to 90%, or 30% to 80%, or 40% to 90%, or 40% to 80%, or 50% to 90%, or 50% to 80%, or 60% to 90%, or 60% to 80%, by weight, based on the total weight of the bilayer-forming lipids, including any intermediate values ​​and subranges therebetween.

[0537] According to some of any of the embodiments of the compositions or formulations as described in this aspect, the bilayer-forming lipid material comprises DMPC in an amount ranging from 50% to 90%, or 50% to 80%, or 60% to 90%, or 60% to 80%, by weight, based on the total weight of the bilayer-forming lipids, including any intermediate values ​​and subranges therebetween.

[0538] According to some of any of the embodiments of the compositions or formulations as described in this aspect, the bilayer-forming lipid comprises DPPC in an amount in the range of 5% to 50%, or 10% to 50%, or 5% to 40%, or 10% to 40%, or 5% to 30%, or 10% to 30%, or 20% to 50%, or 20% to 40%, or 20% to 30%, by weight, based on the total weight of the bilayer-forming lipid, including any intermediate values ​​and subranges therebetween.

[0539] According to some of the embodiments of any of the compositions or formulations described herein, the bilayer-forming lipid material comprises DMPC in an amount ranging from 50% to 90%, or 50% to 80%, or 60% to 90%, or 60% to 80% by weight, based on the total weight of bilayer-forming lipids, including any intermediate values ​​and subranges therebetween, and DPPC in an amount ranging from 5% to 50%, or 10% to 50%, or 5% to 40%, or 10% to 40%, or 5% to 30%, or 10% to 30%, or 20% to 50%, or 20% to 40%, or 20% to 30% by weight, based on the total weight of bilayer-forming lipids, including any intermediate values ​​and subranges therebetween. According to some of these embodiments, the bilayer-forming lipids consist of DPPC and DMPC.

[0540] According to some of any of the embodiments of the compositions or formulations as described in this aspect, the bilayer-forming lipids comprise or consist of DMPC and DPPC, and the weight ratio of DMPC:DPPC is in the range of 1:1 to 5:1, or 1:1 to 4:1, or 1:1 to 3:1, preferably 2:1 to 4:1 or 2:1 to 3:1, including any intermediate values ​​and subranges therebetween.

[0541] According to some of any of the embodiments of the compositions or formulations as described in this aspect, the bilayer-forming lipids comprise or consist of DMPC and DPPC, and the amount of DMPC is in the range of 20% to 80% or 50% to 80% by weight, based on the total weight of the bilayer-forming lipids, and the amount of DMPC is in the range of 20% to 80% or 20% to 50% by weight, based on the total weight of the bilayer-forming lipids, including any intermediate values ​​and subranges therebetween.

[0542] According to some of the embodiments of any of the compositions or formulations as described in this aspect, the bilayer-forming lipids comprise or consist of DMPC and DPPC, and the amount of DMPC is about 75% by weight, based on the total weight of the bilayer-forming lipids, and the amount of DMPC is about 25% by weight, based on the total weight of the bilayer-forming lipids.

[0543] According to some of any of the embodiments of the compositions or formulations as described in this aspect, the bilayer-forming lipids comprise or consist of DMPC and DPPC, and the amount of DMPC is about 80% by weight, based on the total weight of the bilayer-forming lipids, and the amount of DMPC is about 20% by weight, based on the total weight of the bilayer-forming lipids.

[0544] According to some of the embodiments of any of the compositions or formulations as described in this aspect, the bilayer-forming lipids comprise or consist of DMPC and DPPC, and the amount of DMPC is about 70% by weight, based on the total weight of the bilayer-forming lipids, and the amount of DMPC is about 30% by weight, based on the total weight of the bilayer-forming lipids.

[0545] According to some of the embodiments of any of the compositions or formulations as described in this aspect, the bilayer-forming lipids comprise or consist of DMPC and DPPC, and the amount of DMPC is about 65% by weight, based on the total weight of the bilayer-forming lipids, and the amount of DMPC is about 35% by weight, based on the total weight of the bilayer-forming lipids.

[0546] According to some of any of the embodiments of the compositions or formulations as described in this aspect, the bilayer-forming lipids comprise or consist of DMPC and DPPC, and the amount of DMPC is about 60% by weight, based on the total weight of the bilayer-forming lipids, and the amount of DMPC is about 40% by weight, based on the total weight of the bilayer-forming lipids.

[0547] It will be appreciated that the phase transition, e.g., melting temperature (Tm), of lipid bilayers and liposomes comprising compositions or formulations as described in this embodiment can be determined by one of skill in the art by selecting appropriate fatty acyl groups for inclusion in the lipids, e.g., by selecting relatively short-chain and / or unsaturated fatty acyl groups (e.g., myristoyl) to achieve a relatively low melting point, and / or by selecting relatively long-chain and / or saturated fatty acyl groups (e.g., palmitoyl and / or stearoyl) to achieve a relatively high melting point.

[0548] In some embodiments of any one of the embodiments described herein, the liposomes described in this aspect are characterized by a phase transition in which the melting point is within the ranges as indicated herein.

[0549] In some embodiments of the ophthalmic compositions or formulations as described herein, the average diameter of the liposomes is within the range of about 100 nm to about 200 nm, or about 100 nm to about 180 nm, or about 100 nm to about 160 nm, including any intermediate values ​​and subranges therebetween.

[0550] In some embodiments of any one of the embodiments described herein, the liposomes described herein are characterized by a surface charge, which can be a positive surface charge or a negative surface charge.

[0551] The phrase "surface charge" as used herein refers to a charge at or near a surface, such as the interface between a liposome and a solution. The phrase "surface charge" includes charges related to the potential at the surface (e.g., a positive potential at the surface indicates a positive surface charge, while a negative potential at the surface indicates a negative surface charge, etc.), as well as charges that are closer to the surface than charges of the opposite sign (e.g., as in the case of zwitterions, where positive charges are closer to the surface than negative charges, or vice versa). Thus, ions near the surface will primarily interact with charges near the surface (due to their proximity) as opposed to charges of the opposite sign. For example, phosphatidylcholine liposomes typically exhibit a positive surface charge because the positive charges of the choline groups are closer to the liposome surface than the negative charges of the phosphate groups.

[0552] Optionally, the surface charge of a liposome as described herein is related to the net charge of the lipid molecules in the liposome, e.g., liposomes comprising anionic lipids have a negative surface charge and / or liposomes comprising cationic lipids have a positive surface charge.

[0553] Alternatively or additionally, the surface charge of a liposome as described herein is related to the dipoles of the lipid molecules (e.g., zwitterionic lipid molecules) in the liposome; for example, a liposome comprising a zwitterionic lipid that comprises a phosphocholine group may have a positive surface charge because the positively charged ammonium group in the phosphocholine group is closer (on average) to the surface of the liposome than the negatively charged phosphate group in the phosphocholine group.

[0554] Those skilled in the art will readily be able to determine surface charge. For example, the sign of the surface charge can be determined by comparing the tendency of a surface (e.g., the surface of a liposome) to bind anionic compounds with its tendency to bind cationic compounds (e.g., by labeling the compound). Alternatively or additionally, surface charge can be determined by measuring the zeta potential using techniques well known in the art.

[0555] In some embodiments of any one of the embodiments described herein, a liposome as described herein ruptures upon contact with at least one water-soluble polymer as described herein in any corresponding embodiment (e.g., upon contact with at least one water-soluble polymer on the surface of the liposome). Such liposome rupture can optionally result in the lipid bilayer in the liposome converting from a curved geometry (e.g., as in a relatively spherical liposome) to a flatter geometry that complements the geometry of the surface and / or one or more water-soluble polymers bound to the surface (e.g., thereby increasing the affinity of the lipid for the surface) and / or resulting in a flatter, smoother lipid-coated surface (e.g., thereby further reducing friction).

[0556] In some embodiments of any one of the embodiments described herein, the liposomes and one or more water-soluble polymers as described herein are selected such that upon rupture of the selected liposome, the selected one or more water-soluble polymers become effective.

[0557] In some embodiments of any one of the embodiments described herein in this aspect relating to water-soluble polymers, including ionic polymers, at least 75% of the ionic groups in the polymer have the same charge, i.e., at least 75% of the ionic groups are cationic or anionic, such that the polymer is substantially cationic or anionic, respectively. In some embodiments, at least 90% of the ionic groups in the polymer have the same charge. In some embodiments, at least 95% of the ionic groups in the polymer have the same charge. In some embodiments, at least 98% of the ionic groups in the polymer have the same charge. In some embodiments, at least 99% of the ionic groups in the polymer have the same charge.

[0558] In some embodiments of any one of the embodiments described herein in this aspect, about 50% of the ionic groups in the polymer have a positive charge and about 50% of the ionic groups in the polymer have a negative charge, such that the polymer is substantially zwitterionic.

[0559] In some embodiments of any one of the embodiments described herein, the ionic polymer is characterized by a charge density of 1 to 6 charged groups (ionic groups) per kDa of molecular weight of the polymer. In some embodiments, the ionic polymer has 1.5 to 4 charged groups per kDa. In some embodiments, the ionic polymer has 2 to 3 charged groups per kDa.

[0560] In some embodiments of any one of the embodiments described herein in this aspect, the ionic polymer is characterized by a net charge (i.e., the difference between the number of anionic groups and the number of cationic groups) of 1 to 6 charges per kDa of molecular weight of the polymer. In some embodiments, the ionic polymer has a net charge of 1.5 to 4 charges per kDa. In some embodiments, the ionic polymer has a net charge of 2 to 3 charges per kDa.

[0561] In some embodiments of any one of the embodiments described herein in this aspect, the ionic polymer is an anionic polymer, e.g., a polymer characterized by a net negative charge of 1 to 6 charges per kDa of molecular weight of the polymer.

[0562] In some embodiments of any one of the embodiments described herein in this aspect, the ionic polymer is a polysaccharide (it is an ionic polysaccharide).

[0563] As used throughout this specification, the term "polysaccharide" refers to a polymer composed primarily (at least 50 percent by weight) of monosaccharide units linked by glycosidic bonds.

[0564] As used herein, the term "monosaccharide" encompasses carbohydrates per se (having the formula C(HO)n, where n is at least 3, typically 3-10) as well as derivatives thereof, such as amino sugars, in which at least one hydroxyl group is replaced with an amine or amide group; sugar acids, in which one or two carbon atoms are oxidized to form a carboxylate group; acylated monosaccharides, in which at least one hydroxyl and / or amine group is replaced with an acyl group (e.g., acetyl); and sulfated monosaccharides, in which at least one hydroxyl group is replaced with a sulfate group.

[0565] Examples of monosaccharides include, without limitation, hexoses (e.g., D-hexoses and / or L-hexoses) such as allose, altrose, glucose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, and tagatose; pentoses (e.g., D-pentoses and / or L-pentoses) such as arabinose, lyxose, xylose, ribose, ribulose, and xylulose; and hexose derivatives such as glucuronic acid, iduronic acid, mannuronic acid, guluronic acid, glucosamine and its N-alkyl derivatives, galactosamine and its N-alkyl derivatives, N-acetylglucosamine, N-acetylgalactosamine and monosulfated and disulfated N-acetylgalactosamine, glucuronic acid, and iduronic acid.

[0566] As used herein, the phrase "glycosidic bond" refers to the bond between a hemiacetal group of one compound (e.g., a monosaccharide monomer) and a hydroxyl group of another compound (e.g., another monosaccharide monomer).

[0567] Examples of ionic polysaccharides include, without limitation, hyaluronic acid, chondroitin sulfate, alginic acid, xanthan gum, chitosan, and N-alkyl chitosan derivatives.

[0568] Hyaluronic acid is an anionic polysaccharide that contains anionic glucuronic acid monomer units together with nonionic N-acetylglucosamine monomer units. Hyaluronic acid is an exemplary ionic (e.g., anionic) polymer.

[0569] Chondroitin sulfate is an anionic polysaccharide that contains anionic sulfated (e.g., monosulfated and / or disulfated) N-acetylgalactosamine, glucuronic acid, and / or iduronic acid monomer units and anionic glucuronic acid and / or iduronic acid monomer units along with nonionic N-acetylgalactosamine monomer units.

[0570] Alginate is an anionic polysaccharide containing anionic mannuronic acid and guluronic acid monomer units.

[0571] Xanthan gum is an anionic polysaccharide containing anionic glucuronic acid monomer units along with nonionic glucose and mannose monomer units (including their acetyl and / or pyruvyl derivatives).

[0572] Chitosan is a cationic polysaccharide containing cationic glucosamine monomer units, optionally together with non-ionic N-acetylglucosamine monomer units. In N-alkylchitosan derivatives, at least a portion of the glucosamine units preferably contain one, two or three alkyl groups attached to the nitrogen atom, C 1~4 In some embodiments of any one of the embodiments described herein, each alkyl group attached to the nitrogen atom is independently methyl or ethyl. In some embodiments, the alkyl is methyl. In some embodiments, the N-alkylated monomer unit is N-trimethylglucosamine.

[0573] As used herein, the terms "hyaluronic acid," "chondroitin sulfate," "alginic acid," "xanthan gum," "chitosan," "N-alkyl chitosan derivatives," and any other ionic compounds named herein encompass all salts of the named compounds as well as non-ionic forms (e.g., anionic polysaccharides in acid form and cationic polysaccharides in free base form).

[0574] In some embodiments of any one of the embodiments described in this aspect, the polysaccharide is in the form of a salt. In some embodiments, the salt is a pharmaceutically acceptable salt (e.g., an ophthalmologically acceptable salt for ophthalmic applications as described herein, a salt suitable for parenteral administration for parenteral applications as described herein).

[0575] In some embodiments of any one of the embodiments described in this aspect, the polysaccharide has 0.2 to 1 charged group per monosaccharide moiety. In some embodiments, the polysaccharide has 0.2 to 0.9 charged groups per monosaccharide moiety. In some embodiments, the polysaccharide has 0.3 to 0.7 charged groups per monosaccharide moiety. In some embodiments, the polysaccharide has 0.4 to 0.6 charged groups per monosaccharide moiety. In some embodiments, the polysaccharide has about 0.5 charged groups per monosaccharide moiety.

[0576] It is understood that a monosaccharide moiety as described herein can contain more than one charged group (eg, a sulfate group and a carboxylate group).

[0577] In some embodiments of any one of the embodiments described in this aspect, the monosaccharide moiety comprises no more than two charged groups, ie, 0 or 1 charged group.

[0578] In some embodiments of any one of the embodiments described in this aspect, the polysaccharide is characterized by a net charge (i.e., the difference between the number of anionic groups and the number of cationic groups) of 0.2 to 1 charge per monosaccharide moiety. In some embodiments, the net charge is 0.2 to 0.9 charges per monosaccharide moiety. In some embodiments, the net charge is 0.3 to 0.7 charges per monosaccharide moiety. In some embodiments, the net charge is 0.4 to 0.6 charges per monosaccharide moiety. In some embodiments, the net charge is about 0.5 charges per monosaccharide moiety.

[0579] In some embodiments of any one of the embodiments described herein, the water-soluble polymer comprises one or more biopolymers.

[0580] As used herein, the term "biopolymer" refers to a polymer that occurs naturally in living organisms. Examples of biopolymers include, without limitation, polynucleotides (e.g., RNA and DNA), polypeptides, polysaccharides, and conjugates thereof (e.g., glycoproteins and proteoglycans comprising polypeptide and polysaccharide moieties). It is understood that a biopolymer may optionally contain many different types of related monomer units (e.g., about 20 different types of amino acid residues and / or various types of monosaccharide moieties) with little or no repetition of a particular type of monomer unit, yet still be considered a polymer because at least some of the monomer units are related in structure (e.g., being amino acid residues or monosaccharide moieties).

[0581] In some embodiments of any one of the embodiments described herein, the one or more biopolymers comprise a polypeptide (optionally attached to one or more saccharide moieties) and / or a polysaccharide.

[0582] Examples of suitable biopolymers containing polypeptides include, without limitation, mucins and lubricin.

[0583] As used herein, the term "lubricin" refers to an approximately 345 kDa proteoglycan (also known in the art as "proteoglycan 4"). Human lubricin is encoded by the PRG4 gene. Lubricin optionally includes the polypeptide sequence of lubricin isoform A and / or isoform B, for example, according to NCBI Reference Sequence NP_001121180.

[0584] As used herein, the term "mucin" refers to a family of high molecular weight glycosylated proteins produced by many animals, including, for example, mucin 1 (e.g., according to NCBI Reference Sequence NP_001018016), mucin 2 (e.g., according to NCBI Reference Sequence NP_002448), mucin 3A (e.g., according to NCBI Reference Sequence NP_005951), mucin 3B, mucin 4 (e.g., according to NCBI Reference Sequence NP_004523), mucin 5AC, mucin 5B (e.g., according to NCBI Reference Sequence NP_004523), mucin 5C, mucin 5D (e.g., according to NCBI Reference Sequence NP_004523), mucin 5E, mucin 5F, mucin 5G, mucin 5H, mucin 5I, mucin 5IH ... 02449), mucin 6 (e.g., according to NCBI Reference Sequence NP_005952), mucin 7 (e.g., according to NCBI Reference Sequence NP_001138478), mucin 8, mucin 12, mucin 13, mucin 15, mucin 16 (e.g., according to NCBI Reference Sequence NP_078966), mucin 17 (e.g., according to NCBI Reference Sequence NP_001035194), mucin 19, and mucin 20 (e.g., according to NCBI Reference Sequence NP_001269435).

[0585] A polysaccharide as described herein in this aspect may be a non-ionic polymer (as defined herein) or may be an ionic polymer (as defined herein), e.g., according to any of the embodiments described herein for ionic polysaccharides.

[0586] Hyaluronic acid (eg, according to any corresponding embodiment described herein) is a non-limiting example of a suitable polysaccharide, as well as a non-limiting example of a suitable ionic (eg, anionic) polymer.

[0587] In some embodiments of this aspect, the ionic polymer is hyaluronic acid or a salt thereof.

[0588] Throughout this specification, the term "at least one water-soluble polymer" means that the formulation or solution comprises one water-soluble polymer or a mixture of two or more water-soluble polymers. In some embodiments of any of the embodiments described herein, the formulation or solution as described herein in this aspect comprises one water-soluble polymer.

[0589] In some embodiments of any embodiment described in this aspect, the water-soluble polymer described herein comprises at least two water-soluble polymers according to any corresponding embodiment described herein, hi some embodiments, the water-soluble polymer comprises at least three water-soluble polymers according to any corresponding embodiment described herein.

[0590] In some embodiments of any one of the embodiments described in this aspect, the molecular weight (i.e., average molecular weight or Mw, as known in the art) of the one or more water-soluble polymers is in the range of 3 kDa to 10 MDa, including any intermediate value and subrange therebetween. In some embodiments, the molecular weight is 10 kDa to 10 MDa (including any intermediate value and subrange therebetween). In some embodiments, the molecular weight is 20 kDa to 5 MDa (including any intermediate value and subrange therebetween). In some embodiments, the molecular weight Mw is 30 kDa to 2.5 MDa (including any intermediate value and subrange therebetween).

[0591] In some embodiments of any one of the embodiments described in this aspect, the molecular weight (i.e., average molecular weight or Mw) of the one or more water-soluble polymers is in the range of 10 kDa to 1 MDa, including any intermediate value and subrange therebetween. In some embodiments, the molecular weight Mw is from 20 kDa to 500 kDa (including any intermediate value and subrange therebetween). In some embodiments, the molecular weight Mw is from 30 kDa to 250 kDa (including any intermediate value and subrange therebetween).

[0592] In some embodiments of any one of the embodiments described in this aspect, the molecular weight (i.e., average molecular weight or Mw) of the one or more water-soluble polymers is in the range of 0.05 to 10 MDa, including any intermediate values ​​and subranges therebetween. In some embodiments, the molecular weight Mw is 0.05 to 5 MDa (including any intermediate values ​​and subranges therebetween). In some embodiments, the molecular weight Mw is 0.5 to 10 MDa (including any intermediate values ​​and subranges therebetween). In some embodiments, the molecular weight Mw is 0.5 to 5 MDa (including any intermediate values ​​and subranges therebetween). In some embodiments, the one or more water-soluble polymers comprise an ionic polymer (according to any corresponding embodiment described herein) having the aforementioned molecular weights, optionally an ionic polysaccharide. In some embodiments, the ionic polymer is hyaluronic acid having the aforementioned molecular weights. In some embodiments of this aspect, the water-soluble polymer comprises a mixture of one or more water-soluble polymers (e.g., anionic ones), each having a different Mw within the ranges as indicated herein.

[0593] In some embodiments, the concentration of the water-soluble polymer (according to any corresponding embodiment described in this aspect) in the solution is in the range of 0.01 to 10 mg / ml, including any intermediate value and subranges therebetween. In some embodiments, the concentration is in the range of 0.03 to 10 mg / ml, including any intermediate value and subranges therebetween. In some embodiments of this aspect, the concentration is in the range of 0.1 to 10 mg / ml, including any intermediate value and subranges therebetween. In some embodiments, the concentration is in the range of 0.3 to 10 mg / ml, including any intermediate value and subranges therebetween.

[0594] In some embodiments, the total concentration of one or more water-soluble polymers (according to any corresponding embodiment described herein) in the solution is in the range of 0.01-20 mg / ml. In some embodiments, the total concentration is in the range of 0.03-20 mg / ml. In some embodiments, the total concentration is in the range of 0.1-10 mg / ml. In some embodiments, the total concentration is in the range of 0.3-10 mg / ml.

[0595] In some embodiments of this aspect of the present embodiment, the concentration of the water-soluble polymer (according to any corresponding embodiment described herein) in the solution is in the range of 0.01-1 mg / ml. In some embodiments, the concentration is in the range of 0.03-1 mg / ml. In some embodiments, the concentration is in the range of 0.1-1 mg / ml. In some embodiments, the concentration is in the range of 0.3-1 mg / ml. In some embodiments, the water-soluble polymer is an ionic polymer and / or a polysaccharide (e.g., as described herein in any one of the corresponding embodiments of this aspect), optionally hyaluronic acid.

[0596] In some embodiments of this aspect of the present embodiment, the concentration of each water-soluble polymer (according to any corresponding embodiment described herein) in the solution is in the range of 0.01-1 mg / ml. In some embodiments of this aspect, the concentration is in the range of 0.03-1 mg / ml. In some embodiments of this aspect, the concentration is in the range of 0.1-1 mg / ml. In some embodiments of this aspect, the concentration is in the range of 0.3-1 mg / ml. In some embodiments, the water-soluble polymer is hyaluronic acid.

[0597] In some embodiments of this aspect of the present embodiment, the total concentration of one or more water-soluble polymers (according to any corresponding embodiment described herein) in the solution is in the range of 0.01-2 mg / ml. In some embodiments of this aspect, the total concentration is in the range of 0.03-2 mg / ml. In some embodiments of this aspect, the total concentration is in the range of 0.1-1 mg / ml. In some embodiments of this aspect, the total concentration is in the range of 0.3-1 mg / ml.

[0598] In some embodiments of any one of the embodiments described in this aspect, the one or more water-soluble polymers comprise hyaluronic acid at a concentration of less than 3 mg / ml. In some embodiments, the hyaluronic acid concentration is at least 0.01 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.03 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.1 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.3 mg / ml.

[0599] In some embodiments of any one of the embodiments described in this aspect, the one or more water-soluble polymers comprise hyaluronic acid at a concentration of less than 0.75 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.01 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.03 mg / ml. In some embodiments, the hyaluronic acid concentration is at least 0.1 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.3 mg / ml.

[0600] In some embodiments of any one of the embodiments described in this aspect, the one or more water-soluble polymers comprise hyaluronic acid at a concentration of less than 0.5 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.01 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.03 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.1 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.3 mg / ml.

[0601] In some embodiments of any one of the embodiments described in this aspect, the one or more water-soluble polymers comprise hyaluronic acid at a concentration of less than 0.25 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.01 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.03 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.1 mg / ml.

[0602] In some embodiments of any one of the embodiments described in this aspect, the one or more water-soluble polymers comprise hyaluronic acid at a concentration of less than 0.1 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.01 mg / ml. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.03 mg / ml.

[0603] In some embodiments of any one of the embodiments described in this aspect, the viscosity of the solution (which may reflect, at least in part, the concentration of the one or more water-soluble polymers therein) does not exceed 1000 cP (centipoise). In some embodiments of this aspect, the viscosity does not exceed 500 cP. In some embodiments of this aspect, the viscosity does not exceed 200 cP. In some embodiments of this aspect, the viscosity does not exceed 100 cP. In some embodiments of this aspect, the viscosity does not exceed 50 cP. In some embodiments of this aspect, the viscosity does not exceed 20 cP. In some embodiments of this aspect, the viscosity does not exceed 10 cP. In some embodiments of this aspect, the viscosity does not exceed 5 cP. In some embodiments of this aspect, the viscosity does not exceed 3 cP. In some embodiments of this aspect, the viscosity does not exceed 2 cP. In some embodiments of this aspect, the solution is an aqueous solution having a viscosity as described herein.

[0604] In this embodiment, the viscosity of the solution is measured at a temperature of 20° C. and 1 s -1 The shear rate is determined by the

[0605] According to some of the embodiments of any of the aspects described herein, the composition, or formulation, or solution as described herein is not a polysaccharide as described herein and comprises one or more saccharides which may be, for example, a monosaccharide as described herein, a disaccharide (composed of two monosaccharides linked together as described herein) or an oligosaccharide composed of 3 to 10, or 3 to 8, or 3 to 6 monosaccharide units linked together as described herein.

[0606] An exemplary sugar in a composition or formulation as described in this aspect is trehalose.

[0607] In some of the embodiments described in this aspect, the amount of sugar is in the range of 0.1-10 wt. % or 0.1-5, or 1-10, or 1-5 wt. % of the total weight of the composition / formulation / solution, including any intermediate values ​​and subranges therebetween.

[0608] In some embodiments of this aspect, the ratio of a water-soluble polymer described herein to a saccharide described herein is within the range of 100:1 to 1:100, or 20:1 to 1:20, including any intermediate values ​​and subranges therebetween.

[0609] Therefore, compositions (e.g., solutions) or formulations for use in the present invention can be formulated in a conventional manner using one or more ophthalmologically acceptable carriers that facilitate the processing of one or more water-soluble polymers and / or liposomes into formulations that can be used as described herein. One or more water-soluble polymers and / or liposomes described herein can be formulated as an aqueous solution itself. In addition, the solution can be in the form of a suspension and / or emulsion (e.g., a suspension or the aqueous phase of a water-in-oil, oil-in-water, or water-in-oil-in-oil emulsion), for example, to increase the viscosity of the formulation.

[0610] According to some of the optional embodiments described herein, the composition or formulation as described in this aspect of the present embodiments is for use in the treatment of ocular discomfort.

[0611] According to some of the optional embodiments described herein, there is provided a method of treating ocular discomfort, which is carried out by ocular or intraocular administration of a composition or formulation as described in this aspect of the present embodiment.

[0612] In some embodiments of any one of the embodiments described herein with respect to ocular discomfort, the ocular discomfort is associated with contact lenses. The association of the ocular discomfort with contact lenses can be based on a contact lens wearer's observation, e.g., that discomfort occurs while wearing the contact lenses, and / or can be based on a medical (e.g., ophthalmologist) diagnosis, e.g., that the ocular discomfort (e.g., chronic discomfort) is caused by contact lenses.

[0613] According to another aspect of embodiments of the present invention, there is provided a method of treating ocular discomfort in a subject in need thereof, the method comprising ocularly administering to the subject an effective amount of a composition or formulation (e.g., a solution) comprising liposomes and one or more water-soluble polymers as described herein in any one of the corresponding embodiments. According to another aspect of embodiments of the present invention, there is provided use of a composition or formulation (e.g., a solution) comprising liposomes and one or more water-soluble polymers as described herein in any one of the corresponding embodiments in the manufacture of a medicament for treating ocular discomfort.

[0614] Drug Delivery: According to some embodiments of the present invention, there is provided a liposome, as described herein, comprising at least one bilayer-forming lipid, a polymeric compound according to any corresponding embodiment described herein, and a therapeutically active agent incorporated within and / or on the liposome, which in some embodiments is for use in delivering the therapeutically active agent to a subject (e.g., to a body site of a subject) in need thereof.

[0615] According to an aspect of some embodiments of the present invention, there is provided the use of a liposome comprising at least one bilayer-forming lipid, a polymeric compound according to any corresponding embodiment described herein, and a therapeutically active agent incorporated within and / or on the liposome, in the manufacture of a medicament for use in delivering a therapeutically active agent to a subject (e.g., to a body site of the subject) in need thereof.

[0616] According to an aspect of some embodiments of the present invention, there is provided a method of delivering a therapeutically active agent to a subject in need thereof (e.g., to a body site of the subject), the method comprising administering to the subject a liposome comprising at least one bilayer-forming lipid, a polymeric compound according to any corresponding embodiment described herein, and a therapeutically active agent incorporated within and / or on the liposome, thereby delivering the therapeutically active agent to the subject in need thereof.

[0617] In some embodiments of any embodiment according to any aspect described herein, the use of the liposomes and / or methods described herein is for treating a medical condition treatable by a therapeutically active agent (according to any corresponding embodiment described herein) in subject matter.

[0618] In some embodiments of any embodiment according to any aspect described herein, delivering the therapeutically active agent comprises sustained release of the therapeutically active agent according to any corresponding embodiment described herein.

[0619] In some embodiments of any embodiment according to any aspect described herein, the liposome is selected as being capable of sustained release of a therapeutically active agent according to any corresponding embodiment described herein.

[0620] As used herein, "delivery" or "delivering" (these terms are used interchangeably herein) of a therapeutically active agent or drug refers to the administration of a therapeutically active agent to a subject while controlling the duration and / or proportion of the agent at the desired body site (e.g., the body site where the agent desirably exerts a therapeutic effect) depending on the condition of the subject. Thus, the terms "delivery" and "delivering" (and grammatical variations thereof) encompass targeting a therapeutically active agent to a particular body site, thereby ensuring that a greater proportion of the agent reaches the body site (e.g., using a suitable targeting moiety), and / or controlling the duration of presence of such agent in the body (e.g., in the blood), e.g., by sustained release, which may relate to the duration of time that such agent is at the desired body site (even in the absence of specific targeting to the body site).

[0621] As used herein, "sustained release" refers to formulation of an agent to provide for a gradual and / or delayed ("sustained") release of the agent (e.g., from such liposomal reservoirs according to any corresponding embodiment described herein) such that the agent is present at a body site (e.g., in the blood when administered systemically or at a body site where the agent is administered topically) for a longer period of time and / or at a later time point (relative to administration) than if the agent itself were administered (by the same route of administration).

[0622] For example, in the context of embodiments of the present invention, a drug administered per se (as opposed to a sustained release formulation) optionally refers to a formulation of the drug that lacks liposomes according to embodiments of the present invention and includes the same carriers (if any) as the sustained release formulation.

[0623] In some embodiments, sustained release is characterized by a concentration of the therapeutically active agent (e.g., in the blood when administered systemically or at a body site to which the agent is administered locally) that is at least half of its maximum concentration (Cmax) in a period that is at least 50% longer than the corresponding time (i.e., the time it takes for the concentration of the agent to be at least half of its maximum concentration) when the therapeutically active agent itself (e.g., as defined herein) is administered in an amount that results in the same maximum concentration. In some such embodiments, the time (for the sustained release) is at least 100% longer (i.e., twice as long) than the corresponding time (for the agent itself). In some embodiments, the time (for the sustained release) is at least 200% longer (i.e., three times as long) than the corresponding time (for the agent itself). In some embodiments, the time (for the sustained release) is at least 400% longer (i.e., five times as long) than the corresponding time (for the agent itself).

[0624] In some embodiments, sustained release is characterized by a concentration of therapeutically active agent (e.g., in the blood upon systemic administration or at the body site where the agent is administered locally) that is at least half of the maximum concentration (Cmax) over a period of at least 6 hours. In some such embodiments, this period is at least 12 hours. In some embodiments, this period is at least 24 hours. In some embodiments, this period is at least 2 days. In some embodiments, this period is at least 4 days. In some embodiments, this period is at least 1 week. In some embodiments, this period is at least 2 weeks. In some embodiments, this period is at least 4 weeks.

[0625] Sustained release (according to any corresponding embodiment described herein) may, for example, allow for regimens characterized by less frequent dosing and / or greater therapeutic efficacy for any given dose. One of skill in the art will be readily able to determine an appropriate dosing frequency for a given therapeutically active agent based on the duration of the sustained release (e.g., the time for the concentration of the agent to be at least half of its maximum concentration and / or at least its minimum effective concentration, according to any corresponding embodiment described herein) and the ratio of maximum to minimum effective concentration desired for the given agent (e.g., the agent's "therapeutic window").

[0626] In some such embodiments, the therapeutically active agent is an analgesic and / or a steroidal anti-inflammatory agent, hi some such embodiments, the therapeutically active agent can be used in the treatment of osteoarthritis, either alone or in combination with additional therapeutically active agents.

[0627] In some of the embodiments described herein, the liposomes of the present embodiments are administered to a subject in need thereof in combination with, or a pharmaceutical composition comprising, an additional therapeutically active agent that can be used to treat the indicated medical condition. The additional therapeutically active agent can be incorporated into the liposomes of the present embodiments, into other liposomes that may have the same or different drug residence times, or simply mixed with a suitable non-liposome carrier.

[0628] According to some embodiments of the invention, the therapeutically effective agent is selected from the group consisting of an analgesic, a steroidal anti-inflammatory agent, an antiproliferative agent, an antimicrobial agent, and a vaccine antigen.

[0629] In some such embodiments, the therapeutically active agent is an analgesic and / or a steroidal anti-inflammatory agent, hi some such embodiments, the therapeutically active agent can be used in the treatment of osteoarthritis, either alone or in combination with additional therapeutically active agents.

[0630] According to some embodiments of the invention, delivery is performed by parenteral systemic administration.

[0631] According to some embodiments of the invention, the delivery is performed by intra-articular administration.

[0632] According to some embodiments of the invention, the liposomes are for use in the treatment of synovial joint disorders.

[0633] According to some embodiments of the invention, the synovial joint disorder is selected from the group consisting of arthritis, bursitis, carpal tunnel syndrome, fibromyositis, gout, impinged joints, tendonitis, traumatic joint injuries, and surgery-related joint injuries.

[0634] According to some embodiments of the present invention, the therapeutically active agent is an analgesic and / or a steroidal anti-inflammatory agent.

[0635] According to some embodiments of the invention, the liposomes are formulated as part of a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier.

[0636] According to some embodiments of the present invention, the carrier comprises an aqueous liquid.

[0637] According to some embodiments of the invention, the pharmaceutical composition further comprises a water soluble biopolymer.

[0638] According to some embodiments of the invention, the biopolymer comprises hyaluronic acid.

[0639] Those skilled in the art will be readily able to determine which one or more medical conditions may be treatable by a given therapeutically active agent, as well as which one or more therapeutically active agents may be suitable for treating a given medical condition.

[0640] In some embodiments of any of the embodiments described herein, the liposome is for use in the treatment of a proliferative disease or disorder (e.g., cancer), and the therapeutically active agent is an antiproliferative agent according to any corresponding embodiment described herein.

[0641] In some embodiments of any of the embodiments described herein, the liposome is for use in the treatment of an inflammatory disease or disorder (e.g., cancer), and the therapeutically active agent is an analgesic and / or a steroidal anti-inflammatory agent according to any corresponding embodiment described herein.

[0642] In some embodiments of any of the embodiments described herein, the liposomes are for use in the treatment (e.g., by systemic and / or intra-articular administration) of synovial joint disorders, optionally inflammatory synovial joint disorders. Examples of synovial joint disorders treatable by embodiments of the invention include, without limitation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, and / or psoriatic arthritis), bursitis, carpal tunnel syndrome, fibromyositis, gout, joint incarceration (e.g., joint incarceration associated with osteochondritis dissecans and / or synovial osteochondromatosis), tendonitis, traumatic joint injury, and surgery-related joint injury.

[0643] Surgery-related joint damage can optionally be associated with surgery that directly damages the joint surface (e.g., by incision) and / or surgery that only indirectly damages the joint surface. For example, surgery that repairs or otherwise affects tissues around the joint (e.g., ligaments and / or menisci) can be associated with joint damage because it alters joint mechanics.

[0644] Traumatic joint damage can optionally be damage caused directly by the trauma (e.g., damage sustained at the time of the trauma) and / or damage caused by a previous trauma (e.g., post-traumatic damage that develops some time after the trauma).

[0645] Methods and Intermediates: According to an aspect of some embodiments of the present invention, there is provided a method for preparing a polymeric compound as described herein in any corresponding embodiment, wherein the method is selected to allow for control of the composition of the polymer portion of the polymeric compound, as discussed herein.

[0646] According to some of the optional embodiments described herein, the method includes reacting an initiator compound having formula V: -[YLZ] n -[Y] m - contacting a plurality of monomers that form a polymer backbone, wherein Y, L, Z, n, and m are as described herein for Formula I, under conditions that promote atom transfer radical polymerization (ATRP). [ka] (In the formula, F1, F2, F3, F4, J, K, M, and Q are as defined for formula IV; Ri is an electron transfer functional group.

[0647] According to some of the embodiments described herein, R can be any functional group suitable for electron transfer radical polymerization, typically a group capable of forming a stable radical on itself. Exemplary such groups include halogen (halo), preferably chloro or bromo, more preferably bromo, although any other suitable group is also contemplated.

[0648] As used herein, the term "stable radical" includes any chemical species that contains an unpaired electron in its molecular or atomic structure, but that is relatively long-lived and less reactive than a typical radical. Typically, a stable radical is one that has the ability to energetically stabilize the unpaired electron.

[0649] Conditions that promote ATRP include any conditions known in the art, typically in the presence of a radical-forming reagent such as CuX' or CuX'2 (where X' is typically a halogen) and a suitable ligand.

[0650] As discussed herein, the present inventors have demonstrated that better control of the polymerization process is achieved when the ATRP is ARGET-ATRP.

[0651] According to some of the optional embodiments described herein, the method is carried out under conditions that promote ARGET-ATRP. Exemplary such conditions include any known in the art, typically in the presence of CuX'2 (where X' is typically a halogen), a suitable ligand, and a reducing agent. Exemplary reducing agents and ligands suitable for use in connection with these embodiments are described in the Examples section below. Suitable solvents for carrying out the ATRP or ARGET-ATRP method include, without limitation, polar solvents such as alcohols (e.g., methanol and / or ethanol).

[0652] According to some of the embodiments of any of the methods described herein, the method is carried out by ATRP and M is other than an amide.

[0653] According to some of the optional embodiments described herein, the method is carried out by ATRP, and when M is an amide, Q comprises an aryl group as described herein.

[0654] According to some of the optional embodiments described herein, when M is an amide, the method is carried out by ARGET-ATRP.

[0655] According to some of the embodiments described herein, the method is carried out at a temperature ranging from 10° C. to 50° C., or from 15° C. to 50° C., or from 15° C. to 30° C., including any intermediate values ​​and subranges therebetween. In some of the embodiments described herein, the method is carried out at room temperature (i.e., ambient temperature, about 20° C. to about 25° C.).

[0656] According to some of the optional embodiments described herein, contacting the initiator compound with the plurality of monomers is carried out for a time period of from about 1 to about 48 hours, or from about 3 to about 48 hours, or from about 3 to about 36 hours, or from about 3 to about 24 hours, from about 4 to about 48 hours, or from about 4 to about 36 hours, or from about 4 to about 24 hours, from about 6 to about 48 hours, or from about 6 to about 36 hours, or from about 6 to about 24 hours, including any intermediate values ​​and subranges therebetween.

[0657] Exemplary procedures for carrying out the ATRP and ARGET-ATRP methods are described in the Examples section below. These procedures can be manipulated as needed by selecting the initiator compound, the molar ratio of monomers to initiator, manipulating the catalyst solution, ligand and / or reduction, and selecting the synthesis protocol as exemplified for Procedures 1, 2, and 3.

[0658] According to some of the optional embodiments described herein, the method is carried out by contacting a catalyst solution comprising a catalyst and a ligand with a solution comprising an initiator compound, preferably under an inert atmosphere (e.g., argon), and with a solution of a plurality of monomers, the molar ratio of the plurality of monomers to the initiator compound being selected to provide the desired length (number of repeating backbone units) for the resulting LPC.

[0659] According to some of the optional embodiments described herein, the molar ratio of catalyst to initiator is about 1:1.

[0660] According to some of the embodiments described herein, the method is carried out by ATRP using procedures known in the art. In an exemplary procedure (e.g., Procedure 1), an initiator compound as described herein is dissolved in a solvent (preferably a polar solvent, e.g., dichloromethane, DCM, etc.), and a solution containing a catalyst and a ligand in a polar solvent, such as a protic solvent, e.g., an alcohol, e.g., ethanol or methanol, or even water, is added, followed by a solution of multiple monomers in a polar solvent, also as described. Optionally, the reaction is carried out at a temperature of 20-50°C, or 20-40°C, or 30-50°C, or 30-40°C.

[0661] According to some of the optional embodiments described herein, the method is carried out by ARGET-ATRP using procedures known in the art. In some of these embodiments, a catalyst solution is prepared by dissolving a catalyst and a ligand in a polar solvent (e.g., an alcoholic solvent such as MeOH or EtOH, preferably EtOH). In an exemplary procedure (e.g., Procedure 2), the catalyst solution is added to a mixture of an initiator compound, a reducing agent, and multiple monomers in a polar solvent (e.g., an alcoholic solvent) as described herein. In another exemplary procedure (e.g., Procedure 3), the catalyst solution is added to a mixture of an initiator compound and multiple monomers in a polar solvent (e.g., an alcoholic solvent) as described herein, followed by the addition of a reducing agent.

[0662] In some of the embodiments described herein, the molar ratio of the monomer(s) as described in any corresponding embodiment and any combination thereof to the initiator compound as described herein is in the range of 5:1 to 200:1, or 10:1 to 150:1, or 20:1 to 100:1, or 30:1 to 75:1, including any intermediate values ​​and subranges therebetween, which determines the number of repeat units in the resulting polymeric compound (LPC).

[0663] In some embodiments, a molar ratio of 50:1 or less (e.g., about 30:1 or about 25:1) provides a short-chain LPC as described herein in corresponding embodiments, comprising fewer than 100 or fewer than 80 repeat units (as indicated by variable n in Formula I as described herein) in the polymer portion.

[0664] In some embodiments, a molar ratio of 60:1 or greater (e.g., from about 60:1 to about 80:1) provides a long-chain LPC, as described herein in corresponding embodiments, comprising at least 80 repeat units (e.g., 80 to 120) in the polymer portion (as indicated by variable n in Formula I, as described herein).

[0665] According to some of the optional embodiments described herein, the method further comprises isolating the polymeric compound.

[0666] Isolation of the resulting polymeric compound (e.g., a polymeric compound having Formula I as described herein for any corresponding embodiment and any combination thereof) can be carried out by any work-up method known in the art, preferably in connection with ATRP methods, including, for example, TFF, column chromatography, and / or precipitation. Exemplary such procedures are described in the Examples section below.

[0667] According to some of the optional embodiments described herein, isolation of the polymeric compound does not involve acidification, i.e., does not expose the polymeric compound to an acidic environment.

[0668] According to some of the optional embodiments described herein, isolation of the polymeric compound is carried out by precipitation, i.e., by precipitating the polymeric compound from the polymerization reaction mixture, for example, by contacting the mixture with an antisolvent in which the polymeric compound is insoluble, in a ratio of antisolvent:reaction mixture ranging from 2:1 to 50:1, including any intermediate values ​​and subranges therebetween.

[0669] Exemplary anti-solvents include, but are not limited to, ketones such as acetone, dimethoxyethane (DME), chloroform (CHCl), dichloromethane (DCM), tetrachloroethylene (CCl), dimethyl carbonate (DMC), diethyl carbonate (DEC), and methyl tert-butyl ether (MTBE). In an exemplary embodiment, the anti-solvent is a ketone, e.g., acetone.

[0670] According to some of the optional embodiments described herein, isolating the macromolecular compound further comprises column chromatography before and / or after precipitation.

[0671] According to some of the embodiments described herein, there is provided a compound represented by Formula V, as described herein for any corresponding embodiment and any combination thereof.

[0672] According to some of the optional embodiments described herein, there is provided a compound represented by Formula V, as described herein for any corresponding embodiment, and any combination thereof, for use as an intermediate in the preparation of a polymeric compound, as described herein for any corresponding embodiment, and any combination thereof.

[0673] Exemplary compounds of Formula V and their preparation are described in the Examples section below and are partially illustrated in Figures 4A, 5A, and 6A.

[0674] Other definitions: As used herein, the term "hydrocarbon" refers to an organic moiety that contains, as its basic 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 optionally be 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 hydrocarbons, the hydrocarbon is not interrupted by any heteroatoms.

[0675] Preferably, the hydrocarbon moiety has 1 to 20 carbon atoms. Whenever a numerical range is given herein, e.g., "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.

[0676] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon terminal group, as defined herein, including straight-chain and branched-chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms. More preferably, the alkyl is a medium-sized alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise specified, the alkyl is a lower alkyl having 1 to 4 carbon atoms. The alkyl group can be substituted or unsubstituted. The substituted alkyl can have one or more substituents, each of which can independently be, for example, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0677] The term "alkylene" refers to a saturated aliphatic hydrocarbon linking group, as that term is defined herein, which differs from an alkyl group, as defined herein, only in that the alkylene is a linking group rather than a terminal group.

[0678] As used herein, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon terminal group containing at least one carbon-carbon double bond, including straight-chain and branched-chain groups. Preferably, an alkenyl group has 2 to 20 carbon atoms. More preferably, the alkenyl is a medium-sized alkenyl having 2 to 10 carbon atoms. Most preferably, unless otherwise specified, the alkenyl is a lower alkenyl having 2 to 4 carbon atoms. Alkenyl groups can be substituted or unsubstituted. Substituted alkenyls can have one or more substituents, each of which can independently be, for example, cycloalkyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0679] As used herein, the term "alkynyl" refers to an unsaturated aliphatic hydrocarbon terminal group containing at least one carbon-carbon triple bond, including straight-chain and branched-chain groups. Preferably, the alkynyl group has 2 to 20 carbon atoms. More preferably, the alkynyl is a medium-sized alkynyl having 2 to 10 carbon atoms. Most preferably, unless otherwise specified, the alkynyl is a lower alkynyl having 2 to 4 carbon atoms. Alkynyl groups can be substituted or unsubstituted. Substituted alkynyls can have one or more substituents, each of which can independently be, for example, cycloalkyl, alkenyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0680] The term "cycloalkyl" refers to an all-carbon monocyclic or fused-ring (i.e., rings sharing adjacent pairs of carbon atoms) group in which one or more of the rings does not have a completely conjugated π-electron system. Cycloalkyl groups can be substituted or unsubstituted. Substituted cycloalkyls can have one or more substituents, each of which can independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amido, and hydrazine. A cycloalkyl group can be a terminal group, as this term is defined herein, where it is attached to a single adjacent atom, or a linking group, as this term is defined herein, connecting two or more moieties.

[0681] The term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) end group (as that term is defined herein) having a completely conjugated π-electron system. Aryl groups can be substituted or unsubstituted. Substituted aryls can have one or more substituents, each of which can independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. Phenyl and naphthyl are representative aryl end groups.

[0682] The term "heteroaryl" refers to a monocyclic or fused ring (i.e., rings sharing adjacent pairs of atoms) group having one or more atoms in one or more rings, such as nitrogen, oxygen, and sulfur, and having a completely conjugated π-electron system. Examples of heteroaryl groups include, without limitation, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, and purine. Heteroaryl groups can be substituted or unsubstituted. Substituted heteroaryls can have one or more substituents, each of which can independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. A heteroaryl group, as this term is defined herein, may be a terminal group where it is attached to a single adjacent atom, or it may be a linking group, as this term is defined herein, joining two or more moieties. Representative examples are pyridine, pyrrole, oxazole, indole, purine, and the like.

[0683] The term "arylene" refers to a monocyclic or fused polycyclic linking group, as that term is defined herein, and includes linking groups which differ from aryl or heteroaryl groups, as defined herein, only in that the arylene is the linking group rather than the terminal group.

[0684] The term "heteroalicyclic" refers to a monocyclic or fused ring group containing one or more atoms, such as nitrogen, oxygen, and sulfur, in one or more rings. These rings may also contain one or more double bonds. However, the rings do not have a completely conjugated π-electron system. Heteroalicyclics may be substituted or unsubstituted. Substituted heteroalicyclics may contain one or more substituents, each of which may independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. A heteroalicyclic group, as this term is defined he...

Claims

1. A polymeric compound represented by Formula I: 【Chemical 1】 (In the formula, m is zero or a positive integer; n is an integer that is at least 2, at least 5, and preferably at least 10 (e.g., from 10 to 200); Y is a skeleton unit that forms the polymer skeleton of the polymer compound, L is absent or a linking moiety, and Z has the general formula II: 【Chemistry 2】 (In the formula, dashed (wavy) lines represent points of attachment to the respective Y backbone unit or to the linking moiety L, if present; A is a substituted or unsubstituted hydrocarbon; B is an oxygen atom or is absent; R １ ~R ３ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl, and heteroaryl. X is a lipid moiety represented by formula IV. 【Chemistry 3】 (In the formula, The dashed (wavy) lines represent points of attachment to the polymer backbone; F １ , F ２ , F ３ and F ４ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, acyl, alkoxy, thioalkoxy, carboxy, and thiocarboxy; F １ , F ２ , F ３ and F ４ is not hydrogen and is at least 10 carbon atoms in length; J is —O—P(═O)(OH)—O— or is 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 or is absent; When M is not present, Q is not present, and J is not present, M is not present; provided that when J is —O—P(═O)(OH)—O—, then M is other than an amide and / or Q includes an aryl moiety.

2. F １ , F ２ , F ３ and F ４ 2. The polymeric compound of claim 1, wherein at least one of is an alkoxy, thioalkoxy, acyl, or carboxy having a length of at least 10 carbon atoms.

3. F １ , F ２ , F ３ and F ４ 3. The polymer compound according to claim 1, wherein at least one of the above is derived from a fatty acid selected from the group consisting of lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

4. The polymer compound according to any one of claims 1 to 3, wherein M is carboxy.

5. The polymer compound according to any one of claims 1 to 4, wherein K is alkyl.

6. 3. The polymer compound according to claim 1, wherein J is -P(=O)(OH)-O-, M is an amide, and Q is a hydrocarbon substituted with at least one aryl (e.g., phenyl).

7. 7. The polymer compound according to claim 1, wherein Q is methylene substituted with at least one aryl.

8. The polymer compound according to any one of claims 1 to 7, wherein J is absent.

9. The polymer compound according to any one of claims 1 to 7, wherein J and K are absent.

10. The polymer compound according to any one of claims 1 to 7, wherein J and K are absent, and M is carboxy.

11. F １ , F ２ , F ３ and F ４ The polymer compound according to any one of claims 1 to 10, wherein at least one or at least two of the following are each independently a thioalkoxy.

12. F １ , F ２ , F ３ and F ４ The polymer compound according to any one of claims 1 to 10, wherein at least one or at least two of the following are each independently carboxy.

13. F １ and F ２ At least one or both of the following is carboxy; and F ３ and F ４ The polymer compound according to claim 12, wherein at least one of the groups is alkyl.

14. Q is -C(CH ３ ) ２ The polymer compound according to any one of claims 8 to 13, wherein

15. The polymer compound according to any one of claims 1 to 14, wherein Y is a substituted or unsubstituted alkylene unit.

16. 16. The polymeric compound of claim 15, wherein Y is a substituted or unsubstituted ethylene unit.

17. The polymer compound according to any one of claims 1 to 16, wherein B is an oxygen atom.

18. 18. The polymeric compound of any one of claims 1 to 17, wherein A is a substituted or unsubstituted hydrocarbon of 1 to 4 carbon atoms in length.

19. R １ ~R ３ are each independently hydrogen or C １～４ The polymer compound according to any one of claims 1 to 18, wherein the aryl group is -alkyl.

20. The polymer compound according to any one of claims 1 to 19, wherein n is in the range of 10 to 200.

21. The polymer compound according to any one of claims 1 to 20, wherein n is at least 30.

22. The polymer compound according to any one of claims 1 to 20, wherein n is in the range of 30 to 70.

23. The polymer compound according to any one of claims 1 to 20, wherein n is at least 50.

24. The polymer compound according to any one of claims 1 to 20, wherein n is in the range of 50 to 150 or 50 to 80.

25. 21. The polymer compound according to claim 1, wherein n is at least 80.

26. The polymer compound according to any one of claims 1 to 20, wherein n is in the range of 80 to 120.

27. The polymer compound according to any one of claims 1 to 26, wherein m is in the range of 0 to 50.

28. 28. The polymeric compound according to any one of claims 1 to 27, wherein at least some of the backbone units Y, L and / or Z comprise at least one targeting moiety.

29. A lipid bilayer comprising at least one bilayer-forming lipid and the polymer compound according to any one of claims 1 to 28.

30. 30. The lipid bilayer of claim 29, wherein the molar ratio of the at least one bilayer-forming lipid to the polymeric compound is in the range of 5:1 to 5,000:1, or 10:1 to 1,000:1, or 10:1 to 100:1, or 10:1 to 50:1 (e.g., 30:1 to 40:1), or 100:1 to 200:

1.

31. 31. The lipid bilayer of claim 29 or 30, wherein the at least one bilayer-forming lipid comprises at least one zwitterionic glycerophospholipid.

32. 32. The lipid bilayer of claim 31 , wherein the at least one bilayer-forming lipid further comprises a negatively charged bilayer-forming lipid (e.g., DPPG).

33. A liposome comprising at least one lipid bilayer according to any one of claims 29 to 32.

34. 34. A composition comprising the liposome of claim 33 and a carrier, preferably an aqueous carrier.

35. 35. The composition of claim 34, which is a sterile composition.

36. 36. The composition of claim 34 or 35, which is a lubricant composition.

37. 37. The lubricant composition of claim 36, further comprising a water-soluble polymer.

38. 38. The lubricant composition of claim 36 or 37, for lubricating a physiological surface, wherein the carrier is a physiologically acceptable carrier.

39. 34. A method of reducing the coefficient of friction of a surface, comprising contacting the surface with the liposome of claim 33.

40. 40. The method of claim 39, wherein the method is carried out by contacting the surface with a composition comprising the liposome and a carrier, preferably an aqueous carrier.

41. 41. The method of claim 39 or 40, further comprising contacting the surface with a water-soluble polymer.

42. 42. The method of claim 40 or 41, wherein the surface is a physiological surface and the carrier is a physiologically acceptable carrier.

43. 43. The method of claim 42, wherein the surface is an articular surface of a synovial joint.

44. 34. The liposome of claim 33 for use in the treatment of a synovial joint disorder associated with an increased coefficient of friction of the articular surfaces in the synovial joint.

45. 34. A method of inhibiting biofilm formation on the surface of a substrate, comprising contacting the substrate with a composition comprising the liposome of claim 33.

46. 34. An article of manufacture comprising a composition, said composition comprising a substrate having at least a portion of its surface coated with a lipid bilayer according to any one of claims 29 to 32 or a liposome according to claim 33.

47. A lipid bilayer according to any one of claims 29 to 32, a liposome according to claim 33 or a composition according to any one of claims 34 to 36 for use in the treatment of synovial joint disorders.

48. 48. The lipid bilayer, liposome or composition of claim 47, wherein the treatment comprises intra-articular administration of the lipid bilayer, liposome or composition.

49. 34. The liposome of claim 33 or the composition of claim 34 or 19, wherein the liposome has a therapeutically active agent associated therewith, and the liposome or composition is for use in delivery of the therapeutically active agent to a body site of a subject.

50. 50. The liposome or composition of claim 49 for use in treating a medical condition treatable by said therapeutically active agent in said subject.

51. A method for preparing the polymeric compound of any one of claims 1 to 28, comprising: reacting an initiator compound having formula V with the -[Y-L-Z] ｎ -[Y] ｍ - A method comprising contacting a plurality of monomers that form the polymer backbone under conditions that promote atom transfer radical polymerization (ATRP). 【Chemistry 4】 (In the formula, F １ , F ２ , F ３ , F ４ , J, K, M and Q are as defined for formula IV; Ri is an electron transfer functional group.

52. 52. The method of claim 51, wherein the ATRP is ARGET-ATRP.

53. 53. The method of claim 51 or 52, further comprising isolating the polymeric compound.

54. 54. The method of claim 53, wherein said isolating is by precipitation.

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