A composition comprising a polymer lipid analog for reducing wear of an implantable device or a material forming such a device.

Abstract

A composition is provided comprising a polymer compound or a lipid bilayer (e.g., liposomes) formed by such compound as described and defined in the present specification and claims, said composition is intended to be used in combination with an implantable device to treat a subject requiring an implantable device and / or to be used in a pin-on-disk system for determining the wear resistance of an implantable device.

Description

Technology Field

[0001] Related applications

[0002] This application claims the benefit of priority under 35 USC §119(e) to U.S. Provisional Application No. 63 / 622,121 filed January 18, 2024, the contents of said application are incorporated herein by reference in their entirety.

[0003] Field of Invention and Background Technology

[0004] The present invention relates to treatment in some embodiments, and more specifically, but not limited thereto, to a method of using liposomes or bilayer lipids made of lipid-containing polymeric materials in combination with implantable devices, particularly wear-exposed implantable devices such as prosthetic implants and / or orthopedic implants, when treating a medical condition requiring the implantation of such devices and / or when evaluating the wear resistance of materials used to form implantable devices. Background Technology

[0005] Osteoarthritis (OA) is a group of degenerative joint diseases characterized by the progressive loss of normal cartilage structure and function. Structural changes in the knee joint are accompanied by symptoms such as joint pain, limited range of motion, crepitus during movement, and deformity. Osteoarthritis is associated with the loss of cartilage, which efficiently lubricates and reduces wear. Wear is a process in which surface material is removed and deformed as contacting surfaces mechanically interact while moving; therefore, an effective lubricant is one that inhibits wear by reducing friction [Affatato S., Tribological interactions of modern biomaterials used in total hip arthroplasty (THA), Ed. Saverio Affatato, Perspectives in Total Hip Arthroplasty, Woodhead Publishing, 2014, pages 99-116, ISBN 9781782420316].

[0006] Conventional treatments include analgesics and anti-inflammatory drugs, as well as surgeries such as bone fusion (e.g., in ankle arthritis) and joint replacement.

[0007] In early osteoarthritis, no clear cartilage lesions or associated abnormalities requiring surgical treatment are observed. Several treatments have been proposed and are currently used in clinical practice for patients in the stage defined as early osteoarthritis who do not show clear signs of osteoarthritis [Luyten et al., Knee Surg Sports Traumatol Arthrosc 2012, 20:401-406]. Non-surgical treatments available for the management of early osteoarthritis include non-pharmacological therapies such as lifestyle modifications, exercise, and physical therapy, as well as pharmacological therapies such as dietary supplements, analgesics, anti-inflammatory drugs, or sustained-release medications, and also include the local delivery of various substances via minimally invasive injection approaches [Kon et al., Knee Surg Sports Traumatol Arthrosc 2012, 20:436-449].

[0008] Mucus replacement therapy involves the intra-articular injection of hyaluronic acid (HA), a glycosaminoglycan that provides joint lubrication and shock absorption and acts as a scaffold for proteoglycans in the extracellular matrix. In normal adult knees, HA concentrations range from 2.5 to 4.0 mg / ml, whereas in osteoarthritis, HA concentrations are reduced by 33–50% [Kon et al., Knee Surg Sports Traumatol Arthrosc 2012, 20:436-449]. However, there is no clear evidence that mucus replacement therapy affects the natural course of OA. Some reports showed changes in serum and urine biomarkers, while others did not show changes in the structural composition of cartilage [Conrozier et al., J Orthop Res 2012, 30:679-685].

[0009] Total Joint Replacement (TJR) is a surgical procedure that replaces a damaged or diseased joint with a prosthetic implant. While TJR is generally performed on major weight-bearing joints such as the hip and knee, other joints like the shoulder, elbow, and ankle may also be candidates for replacement.

[0010] The most common cause of TJR is osteoarthritis, but inflammatory joint disorders such as rheumatoid arthritis (RA), severe joint injury, fractures or other injuries caused by trauma, and other degenerative joint diseases such as avascular necrosis may also require total joint replacement.

[0011] Joint replacement surgery is currently a common and highly effective treatment for conditions such as osteoarthritis, rheumatoid arthritis, and other degenerative joint diseases. Modern joint replacement procedures are often minimally invasive, resulting in shorter recovery times and improved outcomes. This field is continuously advancing based on ongoing research, technological innovation, and a focus on optimizing patient outcomes and satisfaction.

[0012] The Pin-on-Disk (POD) wear tester is a widely used knee simulator that simulates the clinical conditions of total joint replacement (TJR) implants. TJR typically uses various combinations of biomaterials, such as ceramics, metals, and / or polymers, to form artificial joint prostheses.

[0013] Ultra-high molecular weight polyethylene (UHMWPE) is the most widely used bearing polymer for artificial joint prostheses due to its good tribological properties, low friction and wear, and good biocompatibility [Zdero et al., Chapter 19 - Pin-on-Disk Wear Testing of Biomaterials Used for Total Joint Replacements, Ed. R. Zdero, Experimental Methods in Orthopedic Biomechanics, Academic Press, 2017, Pages 299-311, ISBN 9780128038024]. Although UHMWPE has been used in orthopedics for the past 45 years, moderately cross-linked UHMWPE (e.g., Marathon and XLK) is also being marketed as a second generation of orthopedic polymers [SM Kurtz, 25 - Compendium of HXLPEs, Eds. Steven M. Kurtz, UHMWPE Biomaterials Handbook (Third Edition), William Andrew Publishing, 2016, Pages 449-466, ISBN 9780323354011].

[0014] Metal components commonly used in TJRs include cobalt-chromium (CoCr), titanium alloys, and / or stainless steel. Therefore, artificial joint models can be assembled from metal circular plates (discs) and polymer cylindrical rods (pins).

[0015] An exemplary pin-on-disk system is illustrated in the background art Fig. 1A (Source: Sui-Lai Wong, The effect of lubricant composition on the wear behavior of polyethylene for orthopedic applications, Thesis, University of Manitoba, 2013). A UHMWPE pin and a CoCr disc are placed together in an acrylic bath filled with a standard lubricant or the lubricant under test, and covered with an acrylic lid to prevent evaporation of the lubricant during the test.

[0016] POD measurements are performed under repetitive movement of the interface and contact stress applied to the POD during a certain number of cycles, which is schematically illustrated in the background art Fig. 1B (Source: Zdero et al., 2017, cit.). Wear parameters are determined by weight measurement as the weight loss of the pin during the experiment. After the test, each pin is washed, dried in a desiccator to remove lubricant absorbed during the experiment, and then weighed [Zdero et al., 2017, cit.].

[0017] Polyethylene-based pins tend to absorb liquids, which can affect wear measurements [Brandt et al. Proc. Inst. Mech. Eng. H. 2011, 225(3), 324-331]. To prevent this effect, PE pins are often pre-immersed in distilled water at 37 °C for several weeks or months prior to POD measurements to reach absorption saturation levels. This has been understood to provide optimal reproducibility by allowing fluid absorption to better simulate in vivo knee conditions, minimizing lubricant absorption, and eliminating artifacts in weight change measurements [Brandt et al., 2011, cit.]. However, other reports describe that hydration of the pins increased mass loss and wear rates compared to non-immersed pins [Yao et al., Wear, Volume 255, Issues 7-12, 2003, Pages 1113-1120, ISSN 0043-1648].

[0018] In POD wear tests, it is ideal to use actual synovial fluid (SF) as a wear test lubricant; however, due to ethical concerns and physiological limitations, it is not possible to obtain large quantities of SF from a single source [Sui-Lai Wong, The effect of lubricant composition on the wear behavior of polyethylene for orthopedic applications, Thesis, University of Manitoba, 2013]. Inter-patient variability can also introduce confounding variables into the test. Therefore, calf serum (BCS)-based solutions are currently the most widely used lubricants in orthopedic material testing to reproduce the composition of human SF and simulate its action [Chang, Effect of select fluids on the friction of metal-on-polyethylene joint replacement surfaces, Thesis, Massachusetts Institute of Technology, 2005].

[0019] Several parameters influence the determination of wear values ​​using a POD system. For accurate comparisons between POD tests, similar parameters and conditions must be used.

[0020] In various biological systems, wear values ​​are known to increase sharply at a protein concentration of 20 mg / ml, reach a peak, and then gradually decrease [Saikko, ASME. J. Tribol. July 2003, 125(3), Pages 638-642]. Additionally, when protein concentration is at physiological levels, wear increases with increasing lipid concentration. Increased interaction between protein molecules and lipid molecules and lipid diffusion onto polyethylene surfaces may be causes of increased wear [Saikko, 2013, ibid.]. Bacterial contamination of protein-containing lubricants can increase wear due to protein degradation [Wimmer et al., Wear, Volume 301, Issues 1-2, 2013, Pages 264-270, ISSN 0043-1648].

[0021] WO 2015 / 193888 describes a method for reducing the coefficient of friction of a surface by attaching a water-soluble polymer to a surface and contacting the water-soluble polymer with a liposome to coat the surface with an amphiphilic lipid. It also discloses a method for treating synovial joint disorders associated with increased joint friction.

[0022] WO 2015 / 193887 discloses a formulation used for cleaning and / or immersing contact lenses or for treating ocular discomfort (e.g., ocular discomfort associated with contact lenses), said formulation comprising at least one water-soluble polymer, liposomes, and an aqueous carrier.

[0023] WO 2017 / 109784 discloses polymeric compounds comprising a lipid portion and an ionic polymeric portion (e.g., pMPC [poly(O-(2-methacryloyloxyethyl)phosphorylcholine)] portion), as well as bilayers and liposomes formed by combining such polymeric compounds with bilayer-forming lipids. Bilayers and / or liposomes formed from and / or containing such polymeric compounds are described as useful for reducing the coefficient of friction of surfaces and / or inhibiting biofilm formation.

[0024] WO 2023 / 031928 discloses a stable sterile composition comprising an aqueous carrier, a liposome comprising a bilayer-forming material and a lipid-polymer conjugate such as that described in WO 2017 / 109784, and a sterile manufactured article formed therefrom. The sterile composition was used as a lubricant in pin-on-disk measurements and was shown to significantly reduce wear.

[0025] WO 2024 / 047647 filed by the present applicant discloses a newly designed polymeric compound comprising a lipid portion (lipid-polymer conjugate) that can be used to form lipid bilayers and liposomes exhibiting improved performance.

[0026] Additional prior art includes international patent applications published WO 2016 / 051413 and WO 2018 / 150429.

[0027] Summary of the Invention

[0028] According to one aspect of some embodiments of the present invention, a composition (e.g., a sterile composition) for use in combination with an implantable device is provided, comprising an aqueous carrier and a polymer compound represented by the following general formula I:

[0029]

[0030] General formula I

[0031] In the above formula:

[0032] m is 0 or a positive integer and;

[0033] n is an integer greater than or equal to 2, greater than or equal to 5, preferably greater than or equal to 10 (e.g., 10 to 200);

[0034] Y is a main chain unit that forms the polymer main chain of a polymer compound;

[0035] L is an absent or connected part;

[0036] Z has the following general formula II:

[0037]

[0038] General Formula II

[0039] In the above formula:

[0040] The dashed line (curve) indicates the attachment point for each Y main chain unit or, if present, the connecting part L;

[0041] A is a substituted or unsubstituted hydrocarbon;

[0042] B is an oxygen atom or is absent;

[0043] R1-R3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0044] X is the lipid portion represented by the following general formula IV:

[0045]

[0046] General Formula IV

[0047] In the above formula:

[0048] The dotted line (curve) indicates the attachment points to the polymer main chain;

[0049] F1, F2, F3, and F4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, acyl, alkoxy, thioalkoxy, carboxy, and thiocarboxyl, at least one of F1, F2, F3, and F4 is not hydrogen and has at least 10 carbon atoms;

[0050] J is -OP(=O)(OH)-O- or is absent;

[0051] K is a substituted or unsubstituted hydrocarbon having 1 to 10 carbon atoms, or is absent;

[0052] M is a linker selected from the group consisting of -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, and sulfonamide, or is absent;

[0053] Q is a substituted or unsubstituted hydrocarbon having 1 to 10 carbon atoms, or is absent, and

[0054] If M is absent, Q is also absent, and if J is absent, M is not absent, and

[0055] However, the following conditions are satisfied:

[0056] If J is -OP(=O)(OH)-O-, M is not an amido and / or Q contains an aryl part.

[0057] According to some embodiments of any embodiment described herein, the composition is a sterile composition as described herein.

[0058] According to some embodiments of any embodiment described herein, at least one of F1, F2, F3 and F4 is an alkoxy, thioalkoxy, acyl, or carboxyl having at least 10 carbon atoms.

[0059] According to some embodiments of any embodiment 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, palmitoleoil, oleoil and linoleoil.

[0060] According to some embodiments of any embodiment described herein, M is carboxyl.

[0061] According to some embodiments of any of the embodiments described herein, K is an alkyl.

[0062] According to some embodiments of any of the embodiments described herein, J is -P(=O)(OH)-O-, M is an amido, and Q is a hydrocarbon substituted with at least one aryl (e.g., phenyl) according to any one of the embodiments described herein and any combination thereof.

[0063] According to some embodiments of any of the embodiments described herein, Q is methylene substituted with at least one aryl group.

[0064] According to some embodiments of any embodiment described herein, J is absent.

[0065] According to some embodiments of any embodiment described herein, J and K are each absent.

[0066] According to some embodiments of any embodiment described herein, J and K are each absent and M is carboxyl.

[0067] According to some embodiments of any embodiment described herein, at least one or at least two of F1, F2, F3, and F4 are each independently the thioalkoxy.

[0068] According to some embodiments of any embodiment described herein, at least one or at least two of F1, F2, F3 and F4 are each independently the carboxy.

[0069] According to some embodiments of any embodiment described herein, at least one or both of F1 and F2 are the carboxyl group and at least one of F3 and F4 is the alkyl group.

[0070] According to some embodiments of any embodiment described herein, Q is -C(CH3)2-.

[0071] According to some embodiments of any of the embodiments described herein, Y is a substituted or unsubstituted alkylene unit.

[0072] According to some embodiments of any embodiment described herein, Y is a substituted or unsubstituted ethylene unit.

[0073] According to some embodiments of any embodiment described herein, B is an oxygen atom.

[0074] According to some embodiments of any embodiment described herein, A is a substituted or unsubstituted hydrocarbon having 1 to 4 carbon atoms.

[0075] According to some embodiments of any embodiment described herein, R1-R3 are each independently hydrogen or C 1-4 - It is an alkyl.

[0076] According to some embodiments of any embodiment described herein, n is in the range of 10 to 200.

[0077] According to some embodiments of any embodiment described herein, n is at least 30.

[0078] According to some embodiments of any embodiment described herein, n is in the range of 30 to 70.

[0079] According to some embodiments of any embodiment described herein, n is at least 50.

[0080] According to some embodiments of any embodiment described herein, n is in the range of 50 to 150 or 50 to 80.

[0081] According to some embodiments of any embodiment described herein, n is at least 80.

[0082] According to some embodiments of any embodiment described herein, n is in the range of 80 to 120.

[0083] According to some embodiments of any embodiment described herein, m is in the range of 0 to 50.

[0084] According to some embodiments of any embodiment described herein, at least a portion of the main chain unit Y, L and / or Z comprises at least one targeting portion.

[0085] According to some embodiments of any embodiment described herein, the composition further comprises at least one bilayer-forming lipid.

[0086] According to some embodiments of any embodiment described herein, the molar ratio of the at least one bilayer-forming lipid to the polymer 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, or 100:1 to 500:1.

[0087] According to some embodiments of any embodiment described herein, the at least one bilayer-forming lipid comprises at least one zwitterionic glycerophosphate lipid (e.g., DSPC).

[0088] According to some embodiments of any embodiment described herein, the at least one bilayer-forming lipid further comprises a negatively charged bilayer-forming lipid (e.g., DPPG).

[0089] According to some embodiments of any embodiment described herein, the polymer compound and the at least one bilayer-forming lipid form a lipid bilayer, for example, a liposome.

[0090] According to some embodiments of any embodiment described herein, the composition further comprises at least one water-soluble polymer.

[0091] According to some embodiments of any embodiment described herein, the composition is used in combination with at least one water-soluble polymer, and the water-soluble polymer is co-administered to a subject before, simultaneously with, or after the administration of the composition.

[0092] According to some embodiments of any embodiment described herein, the at least one water-soluble polymer comprises hyaluronic acid.

[0093] According to some embodiments of any embodiment described herein, the weight ratio of the lipid bilayer to the water-soluble polymer is in the range of 100:1 to 1:100, or 50:1 to 1:50, or 20:1 to 1:20, or 10:1 to 1:10, or 5:1 to 1:5, or 2:1 to 1:2.

[0094] According to some embodiments of any embodiment described herein, the concentration of the lipid bilayer is in the range of 0.1 to 100 mM based on the total weight of the composition.

[0095] According to some embodiments of any embodiment described herein, the composition is intended to reduce wear of the implantable device upon implantation.

[0097] According to some embodiments of any embodiment described herein, the composition is administered to a subject requiring the implantable device before, simultaneously with, or after implantation.

[0098] According to some embodiments of any embodiment described herein, the implantable device is a joint replacement implantable device, and the composition is intended for use in a total joint replacement procedure.

[0099] According to some embodiments of any embodiment described herein, the implantable device is a prosthetic implant.

[0100] According to some embodiments of any embodiment described herein, the implantable device is a solid device or a liquid device (e.g., a curable device that hardens upon implantation).

[0101] According to some embodiments of any embodiment described herein, the implantable device is made of a polymer material, a biological material (e.g., proteinaceous material, ECM component), a metal material, and / or a ceramic material.

[0102] According to some embodiments of any embodiment described herein, the polymer material is selected from polyethylene (e.g., ultra-high molecular weight polyethylene), polyurethane, polyurethaneurea, biodegradable polyester amide, and any other biodegradable polymer, and is a polymer that exhibits, for example, one or more of the mechanical properties described herein.

[0103] According to some embodiments of any embodiment described herein, the biological material comprises an ECM material, e.g., collagen.

[0104] According to some embodiments of any embodiment described herein, the ceramic material is selected from bioabsorbable ceramic materials and non-bioabsorbable ceramic materials.

[0105] According to one aspect of some embodiments of the present invention, a pin-on-disk system is provided comprising a composition described in any one of the respective embodiments and any combination thereof.

[0106] According to some embodiments of any embodiment described herein, the pin is made of the materials described herein, e.g., polymeric materials, biological materials (e.g., proteinaceous materials, ECM components), metallic materials and / or ceramic materials.

[0107] According to one aspect of some embodiments of the present invention, a method for determining the wear resistance of an implantable device is provided, comprising using a system described in any one of the embodiments or any combination thereof, or using a composition described in any one of the embodiments or any combination thereof to perform a wear resistance measurement (e.g., pin-on-disk measurement).

[0108] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as generally understood by a person skilled in the art to which the present invention pertains. Methods and materials similar or equivalent to those described herein may be used to carry out or test embodiments of the present invention, but exemplary methods and / or materials are described below. In the event of a conflict, this specification, including definitions, shall prevail. Furthermore, materials, methods, and embodiments are merely illustrative and are not intended to be limiting.

[0109] Implementation of a method and / or system according to an embodiment of the present invention may include performing or completing selected tasks manually, automatically, or in a combination thereof. Additionally, depending on the actual equipment and device of an embodiment of the method and / or system of the present invention, several selected tasks may be implemented by hardware, software, or firmware using an operating system, or by a combination thereof.

[0110] For example, hardware for performing selected tasks according to embodiments of the present invention may be implemented as a chip or circuit. As software, selected tasks according to embodiments of the present invention may be implemented as a plurality of software instructions executed by a computer using any suitable operating system. In exemplary embodiments of the present invention, one or more tasks according to exemplary embodiments of the method and / or system described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, the data processor includes volatile memory for storing instructions and / or data and a non-volatile storage device, such as a magnetic hard disk and / or removable media, for example, for storing instructions and / or data. Optionally, a network connection is also provided. A display and / or user input device, such as a keyboard or mouse, is also optionally provided. Brief explanation of the drawing

[0111] Some embodiments of the present invention are described herein merely as examples with reference to the accompanying drawings. Now, with specific reference to the drawings, it should be emphasized that the details illustrated are intended to illustrate embodiments of the present invention. In this regard, from the description provided in conjunction with the drawings, those skilled in the art will clearly understand how embodiments of the present invention can be practiced. In the drawing: Figures 1A-B (background art) show a photograph of an exemplary pin-on-disk test apparatus taken from Sui-Lai Wong's 2013 paper (the aforementioned literature) (Figure 1A) and a schematic diagram of POD measurements performed under repetitive motion of the interface and contact stress applied to the POD, taken from Zdero et al., 2017, the aforementioned literature (Figure 1B). FIGS. 2A-B (background art) is a bar graph showing the average wear rate measured using BCS or AJ in the POD system described in Examples 1 and 2, showing the average wear rate after 0.5 Mc cycles (Fig. 2A) and the average wear rate during 2.0 Mc cycles (Fig. 2B; taken from WO 2023 / 031928). Figure 3 is a bar graph showing the average wear rate measured in the POD system described in Examples 1 and 3, showing the results using BCS or various concentrations of AJ* after 0.5 Mc cycles. Figure 4 is a bar graph showing the average wear rate measured in the POD systems described in Examples 1 and 3 during 2.0 Mc cycles, showing the results using BCS, AJ* 50%, HA 50%, or AJ* 25% + HA 25%. Specific details for implementing the invention

[0112] The present invention relates to treatment in some embodiments, and more specifically, but not limited thereto, to a method of using liposomes or bilayer lipids made of lipid-containing polymeric materials in combination with implantable devices, particularly wear-exposed implantable devices such as prosthetic implants and / or orthopedic implants, when treating a medical condition requiring the implantation of such devices and / or when evaluating the wear resistance of materials used to form implantable devices.

[0113] Before describing at least one embodiment of the invention in detail, it should be understood that the invention is not necessarily limited to the application of details presented in the following description or illustrated in the embodiments. Other embodiments of the invention are possible and may be implemented or carried out in various ways.

[0114] Before describing at least one embodiment of the invention in detail, it should be understood that the invention is not necessarily limited to the details of the configuration and the arrangement and / or methods of the components presented in the following description or illustrated in the drawings and / or embodiments. Other embodiments of the invention are possible and may be implemented or carried out in various ways.

[0115] As previously described in the background art section of the present invention, WO 2017 / 109784 describes the design and manufacture of a polymeric compound having a phosphocholine analog as a pendant group and conjugated to a lipid portion, said polymeric compound can stabilize a lipid layer, such as the lipid layer of a liposome, while exhibiting significantly enhanced stability, particularly in a saline environment (e.g., physiological environment) and / or high pressure, and provides effective lubrication between sliding surfaces.

[0116] As additionally described herein, WO 2023 / 031928 describes a stable sterile composition comprising an aqueous carrier, a bilayer-forming material, and a liposome comprising a lipid-polymer conjugate such as that described in WO 2017 / 109784, and a sterile manufactured article comprising or formed therefrom. WO 2023 / 031928 explains that when used as a lubricant in pin-on-disk measurements, this sterile composition was shown to significantly reduce wear.

[0117] The inventors have now designed additional polymeric compounds containing a lipid portion (lipid-polymer conjugate) that can be used to form lipid bilayers and liposomes, and have confirmed that the performance of the formed lipid bilayers and liposomes is improved. Refer to PCT / IL2023 / 050927 (publication WO 2024 / 047647).

[0118] While further exploring the performance of lipid bilayers and liposomes formed from the newly designed lipid-polymer conjugates described in WO 2024 / 047647, the inventors discovered that compositions (e.g., aqueous solutions) containing these lipid bilayers and liposomes significantly reduce the wear of materials used to form implantable devices, such as joint replacement implants, even at very low concentrations when the wear resistance of these materials is tested in pin-on-disk measurements. For example, refer to FIGS. 3 and 4, which show improved wear resistance compared to the composition described in WO 2023 / 031928 in the presence of these compositions (see FIGS. 2A-B). Due to these improved performances, these compositions are not only highly suitable for inclusion when conducting POD tests, but, importantly, are also highly suitable for use in combination with implantable medical devices, particularly joint replacement devices, when treating conditions requiring implantation.

[0119] Accordingly, embodiments of the present invention relate to using a composition comprising a newly designed lipid-polymer conjugate and optionally a bilayer-forming lipid as described in WO 2024 / 047647 in combination with an implantable device to reduce wear on the implantable device upon implantation, thereby improving the treatment of conditions requiring implantation, such as osteoarthritis and other synovial joint disorders. Embodiments of the present invention further relate to using such a composition in a pin-on-disk system used to evaluate the wear resistance of materials used to form the implantable device. Polymeric compound:

[0120] The newly designed polymeric compound according to the present embodiment has a phosphocholine analog as a pendant group and is conjugated to a lipid (e.g., phospholipid) portion. An example of such a polymeric compound is represented by General Formula I. Such a polymeric compound is also referred to herein as a 'lipid-containing polymeric compound', or simply 'polymeric compound', 'lipid-polymer conjugate', or the abbreviation 'LPC'.

[0121] According to some embodiments of any of the embodiments of the present invention, the polymer compound is collectively represented by General Formula I:

[0122]

[0123] General formula I

[0124] In the above formula:

[0125] m is 0 or a positive integer and;

[0126] n is an integer greater than or equal to 2, greater than or equal to 5, preferably greater than or equal to 10 (e.g., 10 to 200);

[0127] Y is a main chain unit that forms the polymer main chain of a polymer compound;

[0128] X is a lipid portion according to any one of the embodiments described herein;

[0129] L is an absent or connected part;

[0130] Z has the following general formula II:

[0131]

[0132] General Formula II

[0133] In the above formula:

[0134] The dashed line (curve) indicates the attachment point for each Y main chain unit or, if present, the connecting part L;

[0135] A is a substituted or unsubstituted hydrocarbon;

[0136] B is an oxygen atom or is absent;

[0137] R1-R3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, and

[0138] More specifically, it is as described below.

[0139] General formula I can also simply be written as follows:

[0140] X-[Y(-LZ)]n[Y]m-

[0141] This is considered interchangeable with the previous schematic city, where X is a lipid portion attached to the -[Y(-LZ)]n[Y]m- polymer portion.

[0142] Polymer part:

[0143] In this document, the term “polymer” refers to a compound having at least two repeating units (more preferably at least three repeating units), said repeating units being identical or similar. It will be understood that a compound of General Formula I is a polymer by definition when n is at least 2. This is because it contains at least two main chain units denoted by Y.

[0144] In this document, the phrase “polymer portion” refers to a portion of a polymer compound according to any embodiment described herein with respect to General Formula I, having General Formula Ia:

[0145]

[0146] General formula Ia

[0147] In the above formula, m, n, Y, L, and Z are as defined herein for general formula I, and the dashed line (curve) indicates the attachment point for the X lipid portion.

[0148] General formula Ia may also be simply described herein as follows:

[0149] -[Y(-LZ)]n[Y]m-

[0150] This is considered interchangeable with the aforementioned schematic city.

[0151] The phrase “polymer compound” herein additionally comprises a compound having at least one unit (e.g., a unit according to General Formula Ia where n is at least 1) having a “polymer portion” described herein, provided that the lipid portion described herein (e.g., a lipid portion denoted by X) 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 may be considered as repeating units.

[0152] However, in a preferred embodiment, n is at least 2, so the polymer portion itself has at least 2 units. In some embodiments, n is at least 3.

[0153] As used herein, the term “main chain unit” refers to a repeating unit, and when multiple repeating units are connected (e.g., connected sequentially), they form a polymer main chain. The multiple repeating units connected to each other are also referred to herein as a “polymer main chain.” The polymer portion described herein may form a homopolymer portion by including multiple identical repeating main chain units, or alternatively, may form a copolymer portion by including two or more types of repeating main chain units that can be connected to each other, either randomly or in a specific order (e.g., in two or more blocks or in an alternating order).

[0154] As illustrated in general formulas I and Ia, L and Z together form at least a portion of the pendant group of the main chain unit, and this group is simply referred to herein as the 'pendant group'.

[0155] Each main chain unit Y having a pendant group (i.e., a unit denoted as Y(-LZ), the number of which is denoted by the variable n) and each main chain unit Y not having a pendant group (the number of which is denoted by the variable m) are also referred to herein as 'monomer units'.

[0156] The main chain unit may optionally be a unit of a polymerizable monomer or a polymerizable portion of a monomer. Various polymerizable monomers and portions will be known to those skilled in the art, and the structure of the unit produced by the polymerization of these monomers after polymerization (e.g., monomer unit) will also be known to those skilled in the art.

[0157] 'Unit of polymerizable monomer' refers to a modified form of polymerizable monomer and / or a portion of the polymerizable monomer remaining after polymerization.

[0158] A portion of the polymerizable monomer may be formed, for example, by a condensation reaction, in which case at least one atom or group (e.g., a hydrogen atom or a hydroxyl group) in the monomer, and optionally at least two atoms or groups (e.g., a hydrogen atom and a hydroxyl group) in the monomer are substituted by covalent bonding with another polymerizable monomer.

[0159] Modified forms of polymerizable monomers can be formed, for example, by ring opening (breaking the covalent bond between two atoms in the ring and each of the two atoms is optionally connected to another polymerizable monomer) and / or by addition to unsaturated bonds. In this case, the unsaturated bond between two adjacent atoms is broken (e.g., an unsaturated double bond is converted to a saturated bond or an unsaturated triple bond is converted to an unsaturated double bond) and each of the two atoms is optionally connected to another polymerizable monomer.

[0160] A modified form of a polymerizable monomer may consist of atoms essentially identical to those of the original monomer, differing, for example, only in the rearrangement of covalent bonds. Alternatively, the modified form may have a different atomic composition, for example, if the polymerization involves a condensation reaction (e.g., as described herein).

[0161] Examples of main chain units include, without limitation, substituted or unsubstituted hydrocarbons (which may form a substituted or unsubstituted hydrocarbon main chain), e.g., alkylene units; hydroxycarboxylic acid units (which may form a polyester main chain), e.g., glycolate, lactate, hydroxybutyrate, hydroxyvalerate, hydroxycaproate, and hydroxybenzoate units; dicarboxylic acid units (which may form a polyester main chain in combination with a diol and / or form a polyamide main chain in combination with a diamine), e.g., adipate, succinate, terephthalate, and naphthalene dicarboxylic acid units; Diol units (which can form a polyether main chain or, in combination with a dicarboxylic acid, form a polyester main chain), e.g., ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, and bisphenol A units; diamine units (which can form a polyamide main chain in combination with a dicarboxylic acid), e.g., alkylene diamines such as para-phenylenediamine and hexylenediamine; carbamate units (which can form a polyurethane main chain); amino acid residues (which can form a polypeptide main chain); and sugar portions (which can form a polysaccharide main chain) are included.

[0162] In some embodiments of any of the embodiments described herein, Y is a substituted or unsubstituted alkylene unit.

[0163] In some embodiments, Y is a substituted or unsubstituted ethylene unit, that is, an alkylene unit of length 2 atoms.

[0164] The polymer backbone in which Y is a substituted or unsubstituted ethylene unit may optionally be a polymer backbone formed by polymerizing ethylene (CH2=CH2) and / or its substituted derivatives (these are also referred to herein as 'vinyl monomers'). Such polymerization is a very well-studied procedure, and those skilled in the art will be aware of numerous techniques for carrying out such polymerization.

[0165] Any embodiment described herein relating to a polymer main chain formed by polymerization should be understood to include any polymer main chain having a structure that can be formed by such polymerization, regardless of whether the polymer main chain was actually formed by such polymerization (or any other type of polymerization).

[0166] As is well known in the art, the unsaturated bonds of ethylene and substituted ethylene derivatives become saturated upon polymerization, so the main chain units of the polymer main chain formed by polymerization become saturated. However, they can be referred to as units of unsaturated compounds similar to themselves (e.g., 'vinyl monomers' or 'olefin monomers').

[0167] Polymers that can be formed from unsaturated monomers, such as vinyl monomers and olefin monomers, are also referred to as 'polyvinyl' and 'polyolefin', respectively.

[0168] In this document, an 'unsubstituted' alkylene unit (e.g., an ethylene unit) refers to an alkylene unit that does not have any substituent other than the pendant group (-LZ) discussed herein. That is, an alkylene unit attached to the aforementioned pendant group is considered unsubstituted if there is no substituent at any other position of the alkylene unit.

[0169] In some embodiments of any of the embodiments described herein, Y has the general formula -CR4R5-CR6D-.

[0170] If Y is a main chain unit not attached to L or Z (i.e., the pendant group described herein), D is R7 (the terminal group defined herein), and if Y is a main chain unit attached to L or Z, D is a covalent bond or linker that attaches Y to L or Z. The linker may 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.

[0171] R4-R7 are each independently hydrogen, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azide, 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.

[0172] Throughout this invention, the term ‘linker’ describes a group (e.g., a substituent) attached to two or more parts of a compound.

[0173] In this document, the term 'terminal group' describes a group (e.g., a substituent) that is attached to a single part of a compound through a single atom.

[0174] Where R4-R6 are each hydrogen and D is a covalent bond or linker, Y is an unsubstituted ethylene group attached to the pendant group described herein through D.

[0175] R4-R7 are each hydrogen (D is R7), and Y is an unsubstituted ethylene group not attached to the pendant group described herein.

[0176] In some embodiments of any of the embodiments described herein, R4 and R5 are each hydrogen. These embodiments comprise polymeric main chains formed from many widely used vinyl monomers including ethylene, for example, olefins (e.g., ethylene, propylene, 1-butylene, isobutylene, 4-methyl-1-pentene), vinyl chloride, styrene, vinyl acetate, acrylonitrile, acrylates and derivatives thereof (e.g., acrylate esters, acrylamide), methacrylates and derivatives thereof (e.g., methacrylate esters, methacrylamide).

[0177] In some embodiments of any of the embodiments described herein, R6 is hydrogen. In some of these embodiments, R4 and R5 are each hydrogen.

[0178] In some of the embodiments of any of the embodiments described herein, R6 is methyl. In some of these embodiments, R4 and R5 are hydrogen, respectively. In some of these embodiments, the main chain unit is a unit of methacrylate or a derivative thereof (e.g., methacrylate ester, methacrylamide).

[0179] In some embodiments of any of the embodiments described herein, the linker denoted by variable D is -O-, -C(=O)O-, -C(=O)NH-, or phenylene. In an exemplary embodiment, D is -C(=O)O-.

[0180] For example, if D is -O-, the main chain unit may optionally be a vinyl alcohol derivative (e.g., an ester or ether of a vinyl alcohol unit); if D is -C(=O)O-, it may be an acrylate or methacrylate derivative (e.g., an ester of an acrylate or methacrylate unit); if D is -C(=O)NH-, it may be an acrylamide or methacrylamide unit; and / or if D is phenylene, it may be a styrene derivative (e.g., a substituted styrene unit).

[0181] In some embodiments of any of the embodiments described herein, L is a substituted or unsubstituted hydrocarbon having 1 to 10 carbon atoms. In some embodiments, the hydrocarbon is unsubstituted. In some embodiments, the hydrocarbon is a linear unsubstituted hydrocarbon, i.e., -(CH2) where i is an integer from 1 to 10. i -am.

[0182] 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-).

[0183] In some embodiments of any of the embodiments described herein, B is an oxygen atom. In some of these embodiments, L is a hydrocarbon according to any one of the embodiments described herein (i.e., L is not absent), and Z is a phosphate group attached to L.

[0184] In some embodiments of any of the embodiments described herein, B is absent. In these embodiments, L is a hydrocarbon according to any one of the embodiments described herein (i.e., L is not absent), and Z is a phosphonate group attached to L. Since L is also absent in some embodiments, the phosphorus atom of General Formula II is directly attached to Y.

[0185] In some embodiments of any of the embodiments described herein, A is a substituted or unsubstituted hydrocarbon having 1 to 4 carbon atoms.

[0186] In some embodiments of any of the embodiments described herein, A is an unsubstituted hydrocarbon. In some of these embodiments, the unsubstituted hydrocarbon has 1 to 4 carbon atoms. In some embodiments, the hydrocarbon is a linear unsubstituted hydrocarbon, i.e., -(CH2) where j is an integer from 1 to 4. j -am.

[0187] In some embodiments of any of the embodiments described herein, A is a substituted or unsubstituted ethylene group.

[0188] In some of the embodiments of any of the embodiments described herein, A is an unsubstituted ethylene group (-CH2CH2-). In these embodiments, the portion having General Formula II (indicated by variable Z) is similar to or identical to the phosphoethanolamine portion or the phosphocholine portion. The phosphoethanolamine portion and the phosphocholine portion are present in many naturally occurring compounds (e.g., phosphatidylcholine, phosphatidylethanolamine).

[0189] In some embodiments of any of the embodiments described herein, A is an ethylene group substituted with a C-carboxyl group. In some embodiments, the C-carboxyl is attached to a carbon atom adjacent to the nitrogen atom shown in General Formula II (not the carbon atom attached to the oxygen atom shown). In these embodiments, the portion having General Formula II (indicated by the variable Z) is similar or identical to the phosphoserine portion. Phosphooserine is present in many naturally occurring compounds (e.g., phosphatidylserine).

[0190] Although not bound by a specific theory, parts similar or identical to naturally occurring parts such as phosphocholine, phosphoethanolamine, and / or phosphoserine are believed to be particularly biocompatible.

[0191] In some embodiments of any of the embodiments described herein, R1-R3 (substituents of the nitrogen atom shown 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 of these embodiments, R1-R3 are each hydrogen.

[0192] The variable n can be considered to represent the number of main chain units (represented by variable Y) substituted with pendant groups denoted by (-LZ), and the variable m can be considered to represent the number of main chain units not substituted with such pendant groups. The sum of n+m can be considered to represent the total number of main chain units within the polymer main chain. The ratio of n / (n+m) can be considered to represent the proportion of main chain units substituted with pendant groups denoted by (-LZ).

[0193] In some embodiments of any of the embodiments described herein, the percentage of main chain units substituted with a pendant group represented by (-LZ) (represented by variable Y) (represented as 100%*n / (n+m)) is at least 20%. In some embodiments, the percentage of main chain units substituted with the above-described pendant group is at least 30%. In some embodiments, the percentage is at least 40%. In some embodiments, the percentage is at least 50%. In some embodiments, the percentage is at least 60%. In some embodiments, the percentage is at least 70%. In some embodiments, the percentage is at least 80%. In some embodiments, the percentage is at least 90%. In some embodiments, the percentage is at least 95%. In some embodiments, the percentage is at least 98%.

[0194] In some embodiments of any embodiment described herein, since m is 0, each main chain unit represented by variable Y is replaced with a pendant group represented by (-LZ).

[0195] In some embodiments of any embodiment described herein, n is at least 5. In some embodiments, n is at least 10. In some embodiments, n is at least 15.

[0196] In some embodiments of any embodiment described herein, n is in the range of 2 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 2 to 500 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 2 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 2 to 100 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 2 to 50 and includes any intermediate and sub-ranges therebetween. In these embodiments, m is 0.

[0197] In some embodiments of any embodiment described herein, n is in the range of 3 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 3 to 500 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 3 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 3 to 100 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 3 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 5 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 10 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments of any of the embodiments described herein, n is in the range of 10 to 25 and includes any intermediate values ​​and lower ranges therebetween. In some of these embodiments, m is 0.

[0198] In some embodiments of any embodiment described herein, n is in the range of 10 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 10 to 180 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 10 to 150 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 10 to 120 and includes any intermediate and sub-ranges therebetween. In these embodiments, m is 0.

[0199] In some embodiments of any embodiment described herein, n is at least 30.

[0200] In some embodiments of any embodiment described herein, n is in the range of 30 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 30 to 180 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 30 to 150 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 30 to 120 and includes any intermediate and sub-ranges therebetween. In these embodiments, m is 0.

[0201] In some embodiments of any embodiment described herein, n is in the range of 30 to 70 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 35 to 65 and includes any intermediate and sub-ranges therebetween. In these some embodiments, m is 0.

[0202] In some embodiments of any embodiment described herein, n is at least 50, or at least 60, or at least 80.

[0203] In some embodiments of any embodiment described herein, n is in the range of 50 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 50 to 180 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 50 to 150 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 50 to 120 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 80 to 120 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 50 to 100 and includes any intermediate and sub-ranges therebetween. In some embodiments of any embodiment described herein, n is in the range of 50 to 80 and includes any intermediate and sub-ranges therebetween. In these embodiments, m is 0.

[0204] According to some embodiments of any embodiment described herein, where n is less than 80, less than 70, less than 50, or less than 30, or is in the range of 10 to 50, 30 to 60, 30 to 80, 30 to 70, or 50 to 80 according to any one of the embodiments described herein, the polymer compound is referred to herein as 'short' or 'S'.

[0205] According to some embodiments of any embodiment described herein, where n is greater than 80 or greater than 100, or in the range of 50 to 150, 50 to 120, 80 to 150, or 80 to 120 according to any one of the embodiments described herein, the polymer compound is referred to herein as 'long' or 'L'.

[0206] According to some embodiments of any embodiment described herein, n is in the range of 10 to 50 and includes any intermediate values ​​and lower ranges therebetween. In some of these embodiments, m is 0.

[0207] According to some embodiments of any embodiment described herein, n is in the range of 50 to 80 and includes any intermediate values ​​and lower ranges therebetween. In some of these embodiments, m is 0.

[0208] According to some embodiments of any embodiment described herein, n is in the range of 80 to 120 and includes any intermediate values ​​and lower ranges therebetween. In some of these embodiments, m is 0.

[0209] According to some embodiments of any embodiment described herein, m is in the range of 0 to 1,000 and includes any intermediate and sub-ranges therebetween. In some of these embodiments, n is in the range of 2 to 1,000 and includes any intermediate and sub-ranges therebetween, so the total number of main chain units is in the range of 2 to 2,000 and includes any intermediate and sub-ranges therebetween. In some of these embodiments, n is in the range of 3 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 500 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 100 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 5 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 10 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 50 to 80 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 80 to 120 and includes any intermediate and sub-ranges therebetween.

[0210] According to some embodiments of any embodiment described herein, m is in the range of 0 to 500 and includes any intermediate and sub-ranges therebetween. In some of these embodiments, n is in the range of 2 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 500 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 100 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 5 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 10 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 50 to 80 and includes any intermediate and lower ranges therebetween. In some embodiments, n is in the range of 80 to 120 and includes any intermediate and lower ranges therebetween.

[0211] According to some embodiments of any embodiment described herein, m is in the range of 0 to 200 and includes any intermediate and sub-ranges therebetween. In some of these embodiments, n is in the range of 2 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 500 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 100 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 5 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 10 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 50 to 80 and includes any intermediate and lower ranges therebetween. In some embodiments, n is in the range of 80 to 120 and includes any intermediate and lower ranges therebetween.

[0212] According to some embodiments of any embodiment described herein, m is in the range of 0 to 100 and includes any intermediate and sub-ranges therebetween. In some of these embodiments, n is in the range of 2 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 500 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 100 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 5 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 10 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 50 to 80 and includes any intermediate and lower ranges therebetween. In some embodiments, n is in the range of 80 to 120 and includes any intermediate and lower ranges therebetween.

[0213] According to some embodiments of any embodiment described herein, m is in the range of 0 to 50 and includes any intermediate and sub-ranges therebetween. In some of these embodiments, n is in the range of 2 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 500 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 100 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 5 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 10 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 50 to 80 and includes any intermediate and lower ranges therebetween. In some embodiments, n is in the range of 80 to 120 and includes any intermediate and lower ranges therebetween.

[0214] According to some embodiments of any embodiment described herein, m is in the range of 0 to 20 and includes any intermediate and sub-ranges therebetween. In some of these embodiments, n is in the range of 2 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 500 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 100 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 5 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 10 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 50 to 80 and includes any intermediate and lower ranges therebetween. In some embodiments, n is in the range of 80 to 120 and includes any intermediate and lower ranges therebetween.

[0215] According to some embodiments of any embodiment described herein, m is in the range of 0 to 10 and includes any intermediate and sub-ranges therebetween. In some of these embodiments, n is in the range of 2 to 1,000 and includes any intermediate and sub-ranges therebetween. In some of these embodiments, n is in the range of 3 to 1,000 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 500 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 200 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 100 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 3 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 5 to 50 and includes any intermediate and sub-ranges therebetween. In some embodiments, n is in the range of 10 to 50 and includes any intermediate and sub-ranges therebetween. In some of the embodiments of any of the embodiments described herein regarding such m, n is in the range of 30 to 70 according to any of the embodiments described herein, or represents a short-chain polymer portion as described herein. In some of these embodiments, n is in the range of 50 to 80 and includes any intermediate values ​​and sub-ranges in between.

[0216] In some embodiments of any embodiment of m described herein, n is in the range of 80 to 120 according to any one of the embodiments described herein, or represents a long-chain polymer portion as described herein.

[0217] According to some embodiments of any embodiment described herein, a main chain unit Y substituted with a pendant group denoted by (-LZ) is identical to a main chain unit Y not substituted with a pendant group (e.g., when m is at least 1). In an alternative embodiment, at least a portion of the main chain unit Y substituted with a pendant group is different from a portion of the main chain unit Y not substituted with a pendant group (e.g., when m is at least 1).

[0218] According to some embodiments of any embodiment described herein, a plurality of main chain units Y (represented by variable n) substituted with a pendant group denoted by (-LZ) are identical to one another. In an alternative embodiment, at least a portion of the plurality of main chain units Y substituted with a pendant group denoted by (-LZ) is different from a second portion of the plurality of main chain units Y substituted with a pendant group.

[0219] According to some embodiments of any embodiment described herein, a plurality of pendants (-LZ) attached to a plurality of main chain units Y are identical to one another. In an alternative embodiment, at least some of the pendants attached to a plurality of main chain units Y are different from one another (e.g., the identity of one or more of A, B, R1, R2, R3, and L is different).

[0220] In any embodiment described herein, where one or more main chain units Y are not substituted with the pendant units described herein (i.e., m is greater than 1), the plurality of main chain units Y not substituted with pendant units (indicated by the variable m) are identical to each other. In an alternative embodiment where m is greater than 1, at least a portion of the main chain units Y not substituted with the pendant units described herein is different from at least a second portion of the plurality of main chain units Y not substituted with pendant units.

[0221] The number of types of main chain units substituted with pendant groups, the number of types of main chain units not substituted with pendant groups (if such units exist), and / or the number of types of pendant groups within the polymer portion may each be an independent arbitrary number (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more).

[0222] According to some embodiments of any of the embodiments described herein, the polymer portion is a copolymer portion, that is, a polymer portion comprising at least two different types of monomer units. In these embodiments, the different types of monomer units differ in whether they include a pendant group (-LZ) according to any one of the embodiments described herein (e.g., when m is at least 1), and / or the different types of monomer units differ in the type of main chain unit Y, and / or the different types of monomer units differ in the type of pendant group (-LZ).

[0223] For example, in some embodiments of any embodiment described herein, the main chain unit Y of each Y(-LZ) unit may optionally be the same or different, while the L and Z portions are the same among the Y(-LZ) units. In these embodiments, the main chain unit not substituted with a pendant group (if such a unit exists) may optionally be the same as the main chain unit Y of each Y(-LZ) unit. Alternatively, the main chain unit not substituted with a pendant group (if such a unit exists) may optionally be different from the main chain unit Y of each Y(-LZ) unit, provided that they are the same among all main chain units not substituted with a pendant group.

[0224] According to some embodiments of any embodiment described herein, the L portion of each Y(-LZ) unit may optionally be the same or different, while the main chain unit Y and Z portions between the Y(-LZ) units are the same. In some of these embodiments, the main chain unit not substituted with a pendant (if such a unit exists) may optionally be the same as the main chain unit Y of each Y(-LZ) unit. Alternatively, the main chain unit not substituted with a pendant (if such a unit exists) may optionally be different from the main chain unit Y of each Y(-LZ) unit, provided that it is the same among all main chain units not substituted with a pendant.

[0225] According to some embodiments of any embodiment described herein, the Z portion of each Y(-LZ) unit may optionally be the same or different, while the main chain unit Y and Z portion between Y(-LZ) units are the same. In some of these embodiments, the main chain unit not substituted with a pendant (if such a unit exists) may optionally be the same as the main chain unit Y of each Y(-LZ) unit. Alternatively, the main chain unit not substituted with a pendant (if such a unit exists) may optionally be different from the main chain unit Y of each Y(-LZ) unit, provided that it is the same between all main chain units not substituted with a pendant.

[0226] In any of the embodiments described herein, where the polymer portion is a copolymer portion, two or more different types of monomer units may be distributed randomly or non-randomly throughout the polymer portion. Where different types of monomer units are distributed non-randomly, the copolymer may be characterized by any non-random distribution, such as, for example, an alternating copolymer, a periodic copolymer, and / or a block copolymer.

[0227] In some of the embodiments described herein, the polymer portion attached to the lipid portion X at one end may have various end groups at the other end (i.e., if m is at least 1, the end adjacent to the main chain unit Y without a pendant group, or if m is 0, the other end adjacent to the main chain unit Y having a pendant group).

[0228] The end group may be an intrinsic end group derived from the monomer used to form the polymer compound and / or the process used to polymerize the monomer, or it may be attached to the end of the polymer portion in a different way or generated within it. For example, the end group may be hydrogen, halo, alkyl, hydroxy, carboxyl, etc., or a targeting portion described in more detail below. In some of the embodiments described herein, the end group is hydrogen or halo. In some of the embodiments described herein, the end group is derived from the initiator used to form the polymer compound according to any one of the embodiments described herein, and is exemplified in the following examples, in some of these embodiments the end group is halo (e.g., chloro or bromo).

[0229] In some of the embodiments described herein, the terminal group is a functional group suitable for electron transfer radical polymerization, for example, a variable Ri of the general formula V according to any one of the embodiments described herein.

[0230] Geological part:

[0231] The lipid portion according to any embodiment of this section (represented by variable X in General Formula I of this Appendix) may be attached to the polymer portion according to any embodiment of this Appendix regarding the polymer portion.

[0232] The lipid portion may be selectively derived from any lipid known in the art (including, but not limited to, naturally occurring lipids). Deriving the lipid portion from a lipid may be accomplished by selectively substituting a hydrogen atom at any position in the lipid with a polymeric portion represented by [Y(-LZ)]n[Y]m in general formula I (i.e., a polymeric portion represented by general formula Ia).

[0233] In some of the embodiments of any of the embodiments described herein, the lipid portion (the lipid portion according to any one of the embodiments described herein) is attached to a Y(-LZ) unit according to any embodiment relating to Y, L and / or Z described herein, i.e., a main chain unit substituted with a pendant group described herein (e.g., not a main chain unit not substituted with a pendant group).

[0234] Alternatively or additionally, in some of the embodiments of any embodiment described herein where m is at least 1, the lipid portion (the lipid portion according to any one of the embodiments described herein) may be optionally attached to a main chain unit (Y) that is not substituted with a pendant group as described herein (e.g., not attached to a main chain unit substituted with a pendant group). For example, the polymer portion may be a copolymer in which the type of main chain unit attached to the lipid portion varies randomly among molecules. Thus, it is optional and not intended to be limiting that X in General Formula I is depicted as being attached to a main chain unit (Y-(LZ)) substituted with a pendant group and not as being attached to an unsubstituted main chain unit Y.

[0235] In some of the embodiments described herein, the lipid portion is a lipid portion that is a fatty acid, monoglyceride, diglyceride, triglyceride, glycerophosphate lipid, sphingolipid, or sterol. In some embodiments, the lipid is a glycerophosphate lipid.

[0236] In some of the embodiments described herein, the lipid portion comprises at least one fatty acid portion (e.g., an acyl group derived from a fatty acid). The fatty acid portion may be derived from a saturated or unsaturated fatty acid. For example, the lipid portion may consist of a fatty acid portion, or may be a monoglyceride portion comprising one fatty acid portion, a diglyceride portion comprising two fatty acid portions, or a triglyceride portion comprising three fatty acid portions.

[0237] Examples of fatty acid portions that may be optionally included in the lipid portion include, without limitation, lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0238] Suitable examples of glycerophosphate lipids include, without limitation, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, and phosphatidylinositol.

[0239] In some of the embodiments described herein, the lipid portion represented by variable X in General Formula I is represented by General Formula IV:

[0240]

[0241] General Formula IV

[0242] In the above formula:

[0243] The dotted line (curve) indicates the attachment points through the polymer main chain, i.e., each Y main chain unit;

[0244] F1, F2, F3, and F4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, acyl, alkoxy, thioalkoxy, carboxy, and thiocarboxyl, at least one of F1, F2, F3, and F4 is not hydrogen and has at least 10 carbon atoms;

[0245] J is -OP(=O)(OH)-O- or is absent;

[0246] K is a substituted or unsubstituted hydrocarbon having 1 to 10 carbon atoms, or is absent;

[0247] M is a linker selected from the group consisting of -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, and sulfonamide, or is absent;

[0248] Q is a substituted or unsubstituted hydrocarbon having 1 to 10 carbon atoms, or is absent, and

[0249] If M is absent, Q is also absent, and

[0250] Q is attached to a main chain unit of a polymer main chain according to any one of the embodiments described herein, and alternatively, when Q is absent, M is attached to the main chain unit described above.

[0251] If M is absent, Q is also absent, and K is attached to the main chain unit of the polymer main chain according to any one of the embodiments described herein.

[0252] In some of the embodiments of any of the embodiments described herein regarding General Formula IV, if J is absent, M is not absent.

[0253] In some of the embodiments of any of the embodiments described herein with respect to General Formula IV, where J is -OP(=O)(OH)-O-, M is not an amido and / or Q includes an aryl portion.

[0254] In some of the embodiments of any of the embodiments described herein regarding General Formula IV, at least one of F1, F2, F3 and F4 is an alkoxy, thioalkoxy, acyl, or carboxyl, and preferably the number of carbon atoms is at least 10, for example 8 to 40, or 10 to 40, or 10 to 30.

[0255] In some of these embodiments, the alkoxy, thioalkoxy, acyl and / or carboxyl has an alkyl moiety derived from fatty acid acyl as described herein, e.g., lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoil, oleoil, and linoleoil.

[0256] In some of the embodiments of any of the embodiments described herein regarding General Formula IV, at least one or at least two of F1, F2, F3, and F4 are each independently thioalkoxy. In some of these embodiments, the thioalkoxy has at least 10 carbon atoms, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms. In an exemplary embodiment, the alkyl has 15 carbon atoms and is derived from palmitic acid. In some of these embodiments, the thioalkoxy has an alkyl group derived from lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, F1 and F2 are each thioalkoxy as described herein, and may be the same or different from one another, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0257] In some of the embodiments described herein, at least one or at least two of F1, F2, F3, and F4 are each independently carboxyl. In some of these embodiments, the carboxyl has at least 10 carbon atoms, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms. In an exemplary embodiment, the carboxyl has 16 carbon atoms and is derived from palmitic acid. In some of these embodiments, the carboxyl has an alkyl group derived from 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 carboxyl as described herein for any one of the respective embodiments. In some of these embodiments, both F1 and F2 are carboxyl according to any one of the respective embodiments described herein, and may be the same or different from each other, preferably the same. In some of these embodiments, at least one of F3 and F4 is an alkyl that may be the same or different from each other. In some of these embodiments, the alkyl is a lower alkyl having 1 to 6 or 1 to 4 carbon atoms, e.g., methyl. Alternatively, F3 and F4 are each hydrogen.

[0258] According to some of the embodiments described herein, M is not an Amido.

[0259] According to some of the embodiments described herein, M is carboxyl.

[0260] According to some of the embodiments described herein, M is a carboxyl group and at least one or at least two of F1, F2, F3, and F4 are each independently a thioalkoxy group. In some of these embodiments, the thioalkoxy group has at least 10 carbon atoms, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms. In an exemplary embodiment, the alkyl group has 15 carbon atoms and is derived from palmitic acid. In some of these embodiments, the thioalkoxy group has an alkyl group derived from lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, F1 and F2 are each a thioalkoxy group as described herein, and may be the same or different from one another, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0261] According to some of the embodiments described herein, M is a carboxyl and at least one or at least two of F1, F2, F3, and F4 are each independently carboxyl. In some of these embodiments, the carboxyl has at least 10 carbon atoms, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms. In an exemplary embodiment, the carboxyl has 16 carbon atoms and is derived from palmitic acid. In some of these embodiments, the carboxyl has an alkyl group derived from 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 carboxyl as described herein for any one of the respective embodiments. In some of these embodiments, both F1 and F2 are carboxyl according to any one of the respective embodiments described herein, and may be the same or different from each other, preferably the same. In some of these embodiments, at least one of F3 and F4 is an alkyl that may be the same or different from each other. In some of these embodiments, the alkyl is a lower alkyl having 1 to 6 or 1 to 4 carbon atoms, e.g., methyl. Alternatively, F3 and F4 are each hydrogen.

[0262] According to some of the embodiments described herein, J is absent.

[0263] According to some embodiments of any embodiment described herein, J is absent and M is not Amid.

[0264] According to some embodiments of any embodiment described herein, J is absent and M is carboxyl.

[0265] According to some embodiments of any embodiment described herein, J is absent, and at least one or at least two of F1, F2, F3, and F4 are each independently thioalkoxy. In some of these embodiments, the thioalkoxy has at least 10 carbon atoms, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms. In an exemplary embodiment, the alkyl has 15 carbon atoms and is derived from palmitic acid. In some of these embodiments, the thioalkoxy has an alkyl group derived from lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, F1 and F2 are each thioalkoxy as described herein, and may be the same or different from one another, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0266] According to some embodiments of any embodiment described herein, J is absent, M is a carboxyl group, and at least one or at least two of F1, F2, F3, and F4 are each independently a thioalkoxy group. In some of these embodiments, the thioalkoxy group has at least 10 carbon atoms, e.g., 8 to 40, or 10 to 40, or 10 to 30 carbon atoms. In an exemplary embodiment, the alkyl group has 15 carbon atoms and is derived from palmitic acid. In some of these embodiments, the thioalkoxy group has an alkyl group derived from lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, F1 and F2 are each a thioalkoxy group as described herein, and may be the same or different from one another, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0267] According to some embodiments of any 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 carboxyl. In some of these embodiments, the carboxyl has at least 10 carbon atoms, e.g. 8 to 40, or 10 to 40, or 10 to 30 carbon atoms. In an exemplary embodiment, the carboxyl has 16 carbon atoms and is derived from palmitic acid. In some of these embodiments, the carboxyl has an alkyl group derived from 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 carboxyl as described herein for any one of the respective embodiments. In some of these embodiments, both F1 and F2 are carboxyl according to any one of the respective embodiments described herein, and may be the same or different from each other, preferably the same. In some of these embodiments, at least one of F3 and F4 is an alkyl that may be the same or different from each other. In some of these embodiments, the alkyl is a lower alkyl having 1 to 6 or 1 to 4 carbon atoms, e.g., methyl. Alternatively, F3 and F4 are each hydrogen.

[0268] According to some embodiments of any of the embodiments described herein, J is absent, M is a carboxyl, and at least one or at least two of F1, F2, F3, and F4 are each independently a carboxyl. In some of these embodiments, the carboxyl has at least 10 carbon atoms, e.g. 8 to 40, or 10 to 40, or 10 to 30 carbon atoms. In an exemplary embodiment, the carboxyl has 16 carbon atoms and is derived from palmitic acid. In some of these embodiments, the carboxyl has an alkyl group derived from 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 carboxyl as described herein for any one of the respective embodiments. In some of these embodiments, both F1 and F2 are carboxyl according to any one of the respective embodiments described herein, and may be the same or different from each other, preferably the same. In some of these embodiments, at least one of F3 and F4 is an alkyl that may be the same or different from each other. In some of these embodiments, the alkyl is a lower alkyl having 1 to 6 or 1 to 4 carbon atoms, e.g., methyl. Alternatively, F3 and F4 are each hydrogen.

[0269] According to some of the embodiments described herein, if J is absent in General Formula IV, Q is -C(CH3)2-.

[0270] According to some embodiments of any embodiment described herein, in some embodiments of General Formula IV, J is absent, M is carboxyl, and Q is -C(CH3)2-.

[0271] The hydrocarbon length of K refers to the number of atoms located between J and M in the absence of J in General Formula IV (i.e., the number of atoms along the shortest path between J and M), or, in the absence of J, the number of atoms located between M and the lipid framework formed by F1 to F4.

[0272] If K is a substituted hydrocarbon, M can be attached to the carbon atoms or substituents of the hydrocarbon itself.

[0273] According to some embodiments of any embodiment described herein, K is a hydrocarbon consisting only of a carbon skeleton.

[0274] According to some embodiments of any embodiment described herein, K is an unsubstituted hydrocarbon.

[0275] According to some embodiments of any of the embodiments described herein, K is an unsubstituted hydrocarbon consisting only of a carbon skeleton.

[0276] According to some of the embodiments described herein, K is an alkyl (alkylene chain or linker), preferably unsubstituted, and optionally a lower alkyl or alkylene having 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0277] According to some embodiments of any embodiment described herein, K is absent.

[0278] According to some embodiments of any embodiment described herein, J is absent and K is absent. In some embodiments, M is carboxyl.

[0279] According to some embodiments of any of the embodiments described herein, Q is a hydrocarbon substituted with at least one aryl, for example, phenyl.

[0280] According to some embodiments of any embodiment described herein, Q is a hydrocarbon consisting only of a carbon skeleton. In some of these embodiments, Q is an alkyl (alkylene linker), preferably a lower alkyl / alkylene having 1 to 6 carbon atoms or 1 to 4, preferably 1 or 2, and is substituted with at least one aryl, for example, phenyl.

[0281] According to some embodiments of any of the embodiments described herein, Q is at least one aryl, e.g., methylene substituted with phenyl.

[0282] According to some embodiments of any of the embodiments described herein, J is -P(=O)(OH)-O-, M is an amido, and Q is at least one aryl, e.g., a hydrocarbon substituted with phenyl, according to any one of the embodiments described herein and any combination thereof.

[0283] According to some embodiments of any of the embodiments described herein, J is -P(=O)(OH)-O-, M is an amido, and Q is at least one aryl, e.g., a methylene substituted with phenyl, according to any one of the embodiments described herein and any combination thereof.

[0284] In some of the embodiments of any of the general formula I described herein, the lipid portion X has general formula III.

[0285]

[0286] General Formula III

[0287] In the above formula:

[0288] The dotted line (curve) indicates the attachment point for each Y main chain unit;

[0289] W1 and W2 are each independently hydrogen, alkyl, alkenyl, alkynyl, or acyl, and at least one of W1 and W2 is not hydrogen;

[0290] J is -P(=O)(OH)-O- or is absent (therefore K is directly bonded to the oxygen atom depicted in the glycerol portion);

[0291] K is a substituted or unsubstituted hydrocarbon having 1 to 10 carbon atoms;

[0292] M is a linker selected from the group consisting of -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, or sulfonamide, or is absent (thus K is directly attached to Q);

[0293] Q is a substituted or unsubstituted hydrocarbon having 1 to 10 carbon atoms, or is absent;

[0294] Q is attached to a main chain unit of a polymer main chain according to any one of the embodiments described herein, or alternatively, if Q is absent, M is attached to said main chain unit;

[0295] If M is absent, Q is also absent, and K is attached to the above main chain unit.

[0296] In some of the embodiments of any of the general formula III described herein, one of W1 and W2 is hydrogen and the other is not hydrogen.

[0297] In some of the embodiments of any of the general formula III described herein, neither W1 nor W2 is hydrogen.

[0298] In some embodiments of General Formula III, at least one of W1 and W2 is an alkyl, alkenyl, alkynyl, or acyl having 10 to 30 carbon atoms. In some of these embodiments, both W1 and W2 have 10 to 30 carbon atoms.

[0299] Examples of acyl groups that can be optionally used independently as W1 and / or W2 include, without limitation, lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoil, oleoil, and linoleoil.

[0300] In some of the embodiments of any of the general formula III described herein, J is -P(=O)(OH)-O-, and the lipid portion is, for example, a glycerophosphate lipid.

[0301] In general formula III, the hydrocarbon length of K refers to the number of atoms located between J and M (i.e., the number of atoms along the shortest path between J and M).

[0302] If K is a substituted hydrocarbon, M can be attached to the carbon atoms or substituents of the hydrocarbon itself.

[0303] In some of the embodiments of any of the general formula III described herein, K is an acyl group, e.g., -C(=O)-C(CH3)2-. In some of these embodiments, J is absent, and thus K is directly attached to the illustrated glycerol oxygen. In some of these embodiments, K has a -C(=O)- linker, which is bonded to the oxygen atom of the glycerol group through an ester bond.

[0304] In some of the embodiments of any of the general formula III described herein, K is an ethanolamine moiety, e.g., -CH2-CH2-NH- or -CH2-CH2- which is attached to N; a serine moiety, e.g., -CH2-CH(CO2H)-NH- or -CH2-CH(CO2H)- which is attached to N; a glycerol moiety, e.g., -CH(OH)-CH(OH)-CH-O-; or an inositol moiety, e.g., -cyclohexyl(OH)4-O-. In some embodiments, J is -P(=O)(OH)-O-.

[0305] In some of the embodiments of any of the general formula III described herein, M is amido and optionally -C(=O)NH-.

[0306] In some embodiments, the N atom of amido is attached to K. In these embodiments, K is an ethanolamine or serine moiety.

[0307] In some embodiments, Q is a substituted alkylene, for example, methylene having a length of 1 to 6, or 1 to 4, or 1 to 2 carbon atoms. In some of these embodiments, M is an amido or carboxyl, and the C (=O) of the amido or carboxyl is attached to Q.

[0308] In some embodiments, Q is the alkylene group described herein, and the methylene group is substituted with one or two substituents, at least one of which is an aryl (e.g., phenyl) or includes such a substituent. In some of these embodiments, M is an amido, and the C(=O) of the amido is attached to Q. Alternatively, M is a carboxyl, and the C(=O) of the carboxyl is attached to Q.

[0309] In some embodiments, Q is methylene substituted with two substituents, at least one substituent is an aryl, e.g., phenyl, and the other may be an aryl or an alkyl having a length of 1 to 6 or 1 to 4 carbon atoms. In these some embodiments, the methylene is C 1-4 - It is substituted with alkyl and aryl, e.g., phenyl. In some embodiments, M is amido. In some embodiments, M is carboxyl.

[0310] In some of the embodiments of any of the general formula III described herein, Q is a substituted alkylene (e.g., an alkylene having 1 to 6, 1 to 4, or 1 to 2 carbon atoms, e.g., a methylene group). In some of these embodiments, M is an amido or carboxyl. In some embodiments, the C (=O) of the amido or carboxyl is attached to Q.

[0311] In some embodiments, Q is the alkylene group described herein, and the methylene group is substituted with one or two substituents. In some embodiments, the methylene group is one or two alkyl groups (e.g., C 1-4 It is substituted with -alkyl. In some embodiments, M is not an amido. In some embodiments, M is a carboxyl.

[0312] In some embodiments, Q is methylene substituted with two substituents. In some embodiments, the two substituents are each C 1-4 - It is an alkyl. In some embodiments, methylene is substituted with two methyl groups to form dimethylmethylene -C(CH3)2-. In some embodiments, M is not an amido. In some embodiments, M is a carboxyl.

[0313] According to some of the embodiments of any of the embodiments described herein with respect to General Formula III, where M is amido, Q is an alkylene substituted with at least one aryl as described in any one of the embodiments described herein.

[0314] According to some embodiments of any embodiment described herein, M is not an amido, and Q is as described in any one of the embodiments described herein.

[0315] In some of the embodiments of any of the embodiments described herein with respect to General Formula III, M and Q are each absent, and the terminal of K is a substituted or unsubstituted methylene group according to any of the embodiments described herein with respect to Q, for example, a methylene group substituted with two substituents (e.g., dimethylmethylene(-C(CH3)2-)). In some embodiments, K further comprises a carbonyl group according to any of the embodiments described herein.

[0316] In some of the embodiments described herein, J, M, and Q are each absent. In some of these embodiments, K comprises a carbonyl linker (-C(=O)-) (via ester bond) directly attached to the oxygen atom of the illustrated glycerol portion and a substituted or unsubstituted methylene group (e.g., dimethylmethylene). In some embodiments, K consists of a carbonyl linker (via ester bond) directly attached to the oxygen atom of the illustrated glycerol portion and a substituted or unsubstituted methylene group, for example, K is -C(=O)-C(CH3)2-.

[0317] According to some of the embodiments described herein with respect to General Formula IV, F1 is as described herein with respect to 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 not amido.

[0318] According to some of the embodiments described herein with respect to General Formula IV, F2 is as described herein with respect to 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 not amido.

[0319] According to some of the embodiments described herein with respect to General Formula IV, F1 is as described herein with respect to OW1 and F2 is as described herein with respect to 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 not amido.

[0320] According to some embodiments of any embodiment described herein, the lipid portion does not include the portion of General Formula III described herein.

[0321] According to some embodiments of any embodiment described herein, the lipid portion has a portion of the general formula III described herein, provided that M is not an amido (e.g., M is a carboxyl) and / or Q comprises an aryl substituent described herein.

[0322] In some of the embodiments of any of the embodiments described herein with respect to General Formula IV, polymeric compounds in which the lipid portion X is described in WO 2017 / 109784 or WO 2023 / 031928 are excluded from the scope of the embodiments.

[0323] Targeting part:

[0324] In some of the embodiments described herein, at least a portion of the monomer units of the polymer portion comprises a targeting portion according to any embodiment described herein regarding the targeting portion.

[0325] In this document, the “targeting portion” refers to a portion capable of bringing a compound (e.g., a compound according to some embodiments of the present invention) into proximity to a selected substance and / or material (hereinafter referred to as the “target”). The target is optionally a cell (e.g., a proliferating cell associated with a proliferative disease or disorder), wherein proximity is to the extent that the targeting portion facilitates the attachment and / or internalization of the compound to the target cell and enables the compound to exert a therapeutic effect.

[0326] In some of the embodiments of any of the embodiments described herein, the targeting portion comprises a main chain unit Y according to any one of the embodiments described herein, optionally a linking portion L according to any one of the embodiments described herein and / or a portion Z according to any one of the embodiments described herein, for example, a substituent according to any one of the embodiments described herein comprises the targeting portion (optionally composed thereof);

[0327] For example, in some embodiments where at least a portion of the main chain unit Y has the general formula -CR4R5-CR6D- according to each embodiment described herein, one or more of R4 to R6 and D (optional, where D is R7 described herein) comprises a targeting portion according to any one of each embodiment described herein (e.g., one or more of R4 to R6 and D is a substituted group comprising a substituent that is a targeting portion), and optionally one or more of R4 to R6 and D are the targeting portion. However, many other structures of monomer units comprising (optionally composed of) a substituent comprising a targeting portion are also included in the embodiments of the present invention.

[0328] In some embodiments where the polymer portion according to each embodiment described herein is a copolymer portion, at least one of the monomer units described herein includes a targeting portion according to any one of the embodiments described herein, and at least one other monomer unit does not include such a targeting portion. The distribution of monomer units including the targeting portion may follow any distribution described herein with respect to the distribution of monomer units in the copolymer portion (e.g., random, alternating, periodic copolymers and / or block copolymers). In any embodiment described herein where m is at least 1, at least some of the monomer units include a targeting portion according to any one of the embodiments described herein. In these some embodiments, at least some of the monomer units including the targeting portion are monomer units that do not include a pendant group denoted by (-LZ) according to any one of the embodiments described herein. In these some embodiments, the number of monomer units including the targeting portion is denoted by a variable m according to any one of the embodiments described herein. In these some embodiments, none of the monomer units including a pendant group denoted by (-LZ) include the targeting portion.

[0329] In any embodiment described herein where m is at least 1, each monomer unit not containing a pendant group represented by (-LZ) (the number of which is denoted by the variable m) comprises a targeting portion according to any one of the embodiments described herein. In some of these embodiments, each monomer unit containing a targeting portion is a monomer unit not containing a pendant group represented by (-LZ), that is, none of the monomer units containing a pendant group represented by (-LZ) comprises the targeting portion, and each monomer unit not containing a pendant group represented by (-LZ) comprises the targeting portion.

[0330] In any embodiment described herein where m is at least 1, the monomer unit comprising the targeting portion may essentially consist of a main chain unit Y substituted with the targeting portion according to any one or more of the embodiments described herein.

[0331] In some of the embodiments described herein, at least some of the monomer units containing the targeting portion according to any one of the embodiments described herein are monomer units containing a pendant group represented by (-LZ) according to any one of the embodiments described herein. In these embodiments, the number of monomer units containing the targeting portion is represented by a variable n according to any one of the embodiments described herein (i.e., each monomer unit containing the targeting portion according to any one of the embodiments described herein is a monomer unit containing a pendant group). In these embodiments, none of the monomer units not containing the pendant group represented by (-LZ) contain the targeting portion.

[0332] In some of the embodiments of any of the embodiments described herein, a monomer unit containing a targeting portion may be structurally (optionally significantly) different from a monomer unit containing another targeting portion (i.e., the structure may be different if Y and / or L and / or Z are present as defined in each embodiment described herein). For example, the main chain unit Y of a monomer unit containing a targeting portion may be structurally different from the main chain unit Y of another monomer unit in the polymer portion according to any one of the embodiments described herein.

[0333] In any embodiment described herein where m is at least 1, the polymer portion comprises a monomer unit comprising a targeting portion, said monomer unit is located at the end of the polymer portion distal from the lipid portion. In such an embodiment, the compound represented by general formula I has general formula Ib:

[0334]

[0335] General formula Ib

[0336] In the above formula:

[0337] T is a monomer unit comprising a targeting portion according to any one of the embodiments described herein;

[0338] X and T are coupled to the distal terms of the portion denoted by [Y(-LZ)]n[Y]m-1;

[0339] X, Y, L, Z, n, and m are defined according to any embodiment described herein with respect to general formula I, provided that m is at least 1.

[0340] In general formula Ib, T is a type of monomer unit denoted by Y in general formulas I and Ia (i.e., monomer units without a pendant group denoted by (-LZ)), and the number of monomer units denoted by Y other than T (i.e., monomer units without a pendant group denoted by (-LZ)) is denoted by a value of m-1, and thus the total number of monomer units without a pendant group denoted by (-LZ), including T, is denoted by the variable m as in general formulas I and Ia.

[0341] In some embodiments, m is 1, and thus m-1 is 0, and as a result, the compound represented by general formula Ib has the following general formula: X-[Y(-LZ)]nT, where L, T, X, Y, Z and n are defined according to any of the embodiments described herein.

[0342] A monomer unit comprising a targeting portion according to any one of the embodiments described herein may be optionally produced using any suitable technique known in the art, including but not limited to bonding techniques, by preparing a monomer comprising a targeting portion and using said monomer to prepare a polymer portion described herein (e.g., by polymerization of a monomer according to any one of the embodiments described herein) and / or by modifying a monomer unit of a polymer portion prepared by polymerization of a monomer according to any one of the embodiments described herein after preparing the polymer portion.

[0343] In some of the embodiments of any of the embodiments described herein regarding the targeting portion, the targeting portion does not include a portion having General Formula II according to any of the embodiments described herein. For example, even where a portion represented by General Formula II can form a bond with a target as described herein, in some embodiments, the expression “targeting portion” should be understood to refer to a portion distinct from a portion represented by variable Z having General Formula II.

[0344] In some of the embodiments described herein, the pendant group denoted by (-LZ) is selected not to form a bond with the target and / or not to include the structure and / or characteristics of the targeting portion according to any of the embodiments described herein. For example, in an embodiment in which the targeting portion comprising a nucleophilic group (e.g., an amine group) according to any of the embodiments described herein can form a bond (e.g., a covalent bond) with the target, the variable Z having General Formula II is optionally selected such that the illustrated amine / ammonium group is tertiary amine / ammonium (i.e., one or fewer of R1 to R3 are hydrogen) or quaternary ammonium (i.e., none of R1 to R3 are hydrogen), preferably quaternary ammonium (e.g., containing a trimethylamino group as in phosphocholine). The tertiary amine group, particularly the quaternary ammonium group, may be a nucleophilic group that is much less reactive than the primary and secondary amine groups.

[0345] In some of the embodiments of any of the embodiments described herein regarding the targeting portion, the targeting portion comprises at least one functional group capable of forming a covalent or non-covalent bond (preferably an optional non-covalent bond) with a substance and / or material (referred to herein as “target”), for example, a surface of the target (e.g., a surface of a cell and / or tissue); and

[0346] In this document, the term “functional group” includes chemical groups and parts having any size and any functional function as described herein (e.g., any functional function capable of forming a covalent or non-covalent bond with a target).

[0347] Non-covalent bonds according to any one of the embodiments described herein may be selectively formed by non-covalent interactions such as electrostatic attraction, hydrophobic bonds, hydrogen bonds, and aromatic interactions without limitation.

[0348] In some embodiments of any of the embodiments described herein, the targeting portion comprises a functional group capable of forming a selective non-covalent bond to the target. For example, the affinity of the targeting portion and / or the functional group to the target (e.g., determined based on the dissociation constant) is greater than the affinity of the targeting portion and / or the functional group to most (or all) other compounds capable of forming a non-covalent bond with the targeting portion.

[0349] In some of the embodiments described herein, the functional group(s) may form a covalent bond with one or more specific functional groups (e.g., hydroxy, amine, thiohydroxy and / or oxo groups) present in the target (e.g., the target according to any one of the embodiments described herein).

[0350] Examples of functional groups (within the targeting portion) capable of forming a covalent bond with a target according to any one of the embodiments described herein, and types of covalent bonds they can form, include, without limitation, the following:

[0351] As nucleophilic groups such as thiohydroxy, amines (e.g., primary or secondary amines), and hydroxy, these can form covalent bonds with, for example, a nucleophilic leaving group in the target (e.g., any nucleophilic group described herein), a Michael receptor (e.g., any Michael receptor described herein), an acyl halide, an isocyanate, and / or isothiocyanate (e.g., as described herein);

[0352] As nucleophilic leaving groups such as halos, azides (-N3), sulfates, phosphates, sulfonyls (e.g., mesyl, tosyl), N-hydroxysuccinimide (NHS) (e.g., NHS esters), sulfo-N-hydroxysuccinimide, and anhydrides, these can form covalent bonds with, for example, a nucleophilic group in the target (e.g., as described herein);

[0353] As Michael receptors such as enones (e.g., maleimide, acrylate, methacrylate, acrylamide, methacrylamide), nitro groups, and vinyl sulfones, these can form covalent bonds with, for example, nucleophilic groups within the target (e.g., as described herein) and selectively with thiohydroxys;

[0354] A dihydroxyphenyl group according to any one of the embodiments described herein, which can form a covalent bond with, for example, a nucleophilic group in the target (e.g., as described herein) and / or a substituted or unsubstituted phenyl group (e.g., another dihydroxyphenyl group) as described herein;

[0355] As acyl halide (-C(=O)-halogen), isocyanate (-NCO), and isothiocyanate (-N=C=S) groups, these can form covalent bonds with, for example, nucleophilic groups within the target (e.g., as described herein);

[0356] As a carboxyl (-C(=O)OH) group, it may form an ester bond by forming, for example, a covalent bond with a hydroxyl group in the target and / or form an amide bond by forming a covalent bond with an amine group (e.g., a primary amine) in the target (optional by reaction with a coupling reagent such as carbodiimide); and / or the carboxyl group may be in the target and form an amide bond or an ester bond, respectively, with an amine group or a hydroxyl group in the targeting portion;

[0357] As an oxo group (optionally located within an aldehyde group (-C(=O)H)), which can form a covalent imino bond with an amine group (e.g., a primary amine) within the target; and / or an oxo group (optionally located within an aldehyde group) is located within the target and can form a covalent imino bond with an amine group within the targeting portion;

[0358] As a thiohydroxyl group, it can form a covalent disulfide (-SS-) bond with a thiohydroxyl group within the target.

[0359] Modifying a monomer (e.g., before polymerization) or a monomer unit of a polymeric portion (e.g., after polymerization) to include any functional group described herein may be optionally performed using any suitable bonding technique known in the art. Those skilled in the art can readily select a suitable technique for modifying a given molecule.

[0360] In this application, the term “dihydroxyphenyl” refers to an aryl group that is phenyl substituted with two hydroxyl groups at any position (as defined herein). The phenyl may optionally be substituted with an additional substituent (which may optionally include an additional hydroxyl group) to form a substituted dihydroxyphenyl group, or alternatively, the phenyl does not include a substituent other than two hydroxyl groups, and thus the dihydroxyphenyl group is an unsubstituted dihydroxyphenyl group.

[0361] In some of the embodiments described herein, the dihydroxyphenyl group is ortho-dihydroxyphenyl (a hydroxyl group attached to an adjacent position of the phenyl) or para-dihydroxyphenyl (a hydroxyl group attached to opposite sides of the phenyl ring), each of which is a substituted or unsubstituted dihydroxyphenyl. In some of these embodiments, the ortho-dihydroxyphenyl or para-dihydroxyphenyl is an unsubstituted dihydroxyphenyl.

[0362] The dihydroxyphenyl group according to any one of the embodiments described herein may selectively covalently and / or non-covalently bond to a target according to one or more attachment mechanisms described for the dihydroxyphenyl (catechol) group 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 (publication WO 2015 / 193887).

[0363] In some of the embodiments described herein, the functional group capable of forming a bond to the target is an amine group, optionally a functional group capable of forming a covalent bond with a primary amine group. In some of these embodiments, the target comprises one or more amino acids or amino acid residues, for example, 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).

[0364] In some of the embodiments of any of the embodiments described herein, the targeting portion comprises at least one functional group capable of forming a non-covalent bond with the target (optionally composed thereof) (e.g., as described herein for any one of the embodiments);

[0365] In some of the embodiments of any of the embodiments described herein, the functional group capable of forming a non-covalent bond with the target comprises a polysaccharide and / or polypeptide (e.g., a protein and / or a fragment thereof) (optionally composed thereof), wherein the target optionally comprises a ligand of the polysaccharide and / or polypeptide; and / or the target comprises a polysaccharide and / or 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 ligand of the polysaccharide and / or polypeptide.

[0366] Examples of suitable polysaccharides and / or polypeptides and their ligands include, without limitation, the following:

[0367] Avidin or streptavidin, which are polypeptides described herein, and biotin, which is a ligand thereof;

[0368] Polysaccharide-linked polypeptides that are polypeptides described herein and complementary polysaccharides that are ligands thereof (or complementary polysaccharide-linked polypeptides that are ligands of polysaccharides described herein);

[0369] Collagen-binding polypeptide, which is the polypeptide described herein, and complementary collagen, which is the ligand thereof (or collagen, which is the polypeptide described herein, and complementary collagen-binding polypeptide, which is the ligand thereof);

[0370] A cell receptor expressed by a cell and a ligand that selectively binds to said receptor;

[0371] An antibody against any antigen (e.g., the target described herein optionally comprises said antigen) or a fragment of said antibody which is a polypeptide described herein and the corresponding antigen which is a ligand thereof; and

[0372] An antibody mimic for any antigen (e.g., the target described herein optionally comprises said antigen).

[0373] Examples of cell receptors expressed by cells include, without limitation, receptors characteristic of specific types of cells and / or tissues and receptors overexpressed by cancer cells. The cell receptor or cell is optionally the target described herein, and the targeting portion optionally comprises any ligand of the receptor. Examples of such ligands include, without limitation, transferrin; ligands of transferrin receptors capable of selectively targeting transferrin receptors overexpressed by some cancer cells; keratinocyte growth factor (KGF or FGF7) capable of selectively targeting KGF receptors, such as KGF receptors specific to cells of epithelial origin and overexpressed in endometrial or pancreatic cancer [Visco et al., Int J Oncol 1999, 15:431-435; Siegfried et al., Cancer 1997, 79:1166-1171]; It includes epidermal growth factor (EGF) [Normanno et al., Curr Drug Targets 2005, 6:243-257] which can selectively target EGF receptors such as erbB that are overexpressed in gliomas and endometrial cancers.

[0374] The term "antibody" as used herein includes any type of immunoglobulin.

[0375] As used herein, the term "antibody mimic" includes any type of molecule as so referred to in the art, which is capable of selectively binding to an antigen (e.g., by non-covalent bonding), optionally polypeptides. Non-limiting examples of antibody mimics include affibodies, affilins, affimers, affitins, alphabodies, anticalins, avimers, darphines, ffinomers, Kunitz domain peptides, and monobodies, e.g., 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 Includes the contents described in Stumpp et al. [2005, 23:1556-1561], Stumpp et al. [Drug Discov Today 2008, 13:695-701], Grabulovski et al. [J Biol Chem 2007, 282:3196-3204], Nixon and Wood [Curr Opin Drug Discov Devel 2006, 9:261-268], Koide and Koide [Methods Mol Biol 2007, 325:95-109] and Gebauer and Skerra [Curr Opin Chem Biol 2009, 13:245-255], each of which is incorporated herein by reference in its entirety, in particular with respect to specific types of antibody mimics.

[0376] As used herein, the term “polysaccharide-binding polypeptide” comprises any polypeptide or oligopeptide (peptide chain having a length of at least two, preferably at least four, amino acid residues) capable of selectively binding to a polysaccharide (e.g., by non-covalent bonding). Various polysaccharide-binding polypeptides and their binding specificities will be known to those skilled in the art and include shorter peptide sequences (e.g., lengths of 4 to 50, optionally 4 to 20 amino acid residues) and longer polypeptides such as their proteins or fragments (e.g., carbohydrate-binding modules and / or domains). Additionally, the term “polysaccharide-binding polypeptide” comprises antibodies capable of specifically binding to a polysaccharide. Such antibodies are available to those skilled in the art and / or will be known to those skilled in the art of methods to manufacture such antibodies using immunological techniques known in the art.

[0377] Examples of polysaccharide-binding polypeptides that may be used in some of the embodiments of any of the present invention include, without limitation, carbohydrate-binding modules (CBMs) and hyaluronic acid-binding peptides, polypeptides and / or modules (e.g., International Patent Applications Published WO 2013 / 110056 and WO 2014 / 071132; Barta et al. [Biochem J 1993, 292:947-949], Kohda et al. [Cell 1996, 86:767-775], Brisset and 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 2006, It includes sequences described in [50:3856-3860], each of which is incorporated herein by reference in its entirety, in particular with respect to specific polysaccharide-binding polypeptides. For example, there is GAHWQFNALTVR (hyaluronic acid-binding peptide sequence).

[0378] Examples of CBMs that may be used in some of the embodiments of any embodiment of the present invention include, without limitation, CBMs belonging to the CBM3, CBM4, CBM9, CBM10, CBM17, and / or CBM28 families (which may optionally be used to bind cellulose, e.g., in cellulose-containing targets); CBM5, CBM12, CBM14, CBM18, CBM19, and / or CBM33 (which may optionally be used to bind other polysaccharides including chitin and / or N-acetylglucosamine, e.g., in chitin-containing targets); and CBM15 (which may optionally be used to bind hemicellulose, e.g., in hemicellulose-containing targets). and / or CBM20, CBM21 and / or CBM48 (which can optionally be used to bind starch and / or glycogen, for example, in starch-containing and / or glycogen-containing targets) are included.

[0379] As used herein, the expression “collagen-binding polypeptide” comprises any polypeptide or oligopeptide (peptide chain having a length of at least 2, preferably at least 4, amino acid residues) capable of selectively binding to collagen (e.g., one type of collagen, some types of collagen, or all types of collagen) (e.g., by non-covalent bonding), and includes glycosylated polypeptides and oligopeptides such as peptidoglycans and proteoglycans. Various collagen-binding polypeptides and their binding specificities will be known to those skilled in the art and include longer polypeptides such as short peptide sequences (e.g., lengths of 4 to 50, optionally 4 to 20 amino acid residues) and their proteins or fragments (e.g., collagen-binding domains). Additionally, the expression “collagen-binding polypeptide” includes antibodies capable of specifically binding to collagen. These antibodies are available to and / or are known to those skilled in the art, or those skilled in the art will know how to manufacture these antibodies using immunological techniques known in the art.

[0380] 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 described in U.S. Patent No. 8,440,618, Abd-Elgaliel and 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 these are incorporated herein by reference in their entirety, in particular with respect to specific collagen-binding polypeptides). For example, there is the WYRGRL sequence.

[0381] It is expected that many functional groups and parts related to binding will be developed and / or discovered during the term of the patent registered from this application, and the scope of terms such as "targeting part," "functional group," "cell receptor," "antibody," "antibody mimic," "collagen-binding polypeptide," and "polysaccharide-binding polypeptide" is intended to include all such new technologies in advance.

[0382] In some of the embodiments described herein, the functional group of the targeting portion (the targeting portion according to any one of the embodiments described herein) is attached to a linker (as defined herein). The linker may be any linker or linking portion described herein without limitation, including substituted or unsubstituted hydrocarbons. In some embodiments, the targeting portion (optional substituent of the main chain unit Y) is essentially composed of a functional group attached to the remainder of the polymer portion via a linker.

[0383] The functional group may be selectively attached to the linkage portion by a covalent bond obtained by a reaction between two functional groups, and may be any covalent bond and / or functional group described herein in the context of forming a covalent bond between the functional group and the target, for example.

[0384] In some of the embodiments of any of the embodiments described herein regarding a functional group comprising a peptide or polypeptide, an amino acid residue of the peptide or polypeptide is optionally attached to a linker of the targeting portion, for example, through an amide bond formed from an amine group or carboxyl group (e.g., N-terminal, lysine side chain, C-terminal, glutamate side chain and / or aspartate side chain) in the peptide or polypeptide, an ester bond formed from a hydroxyl group or carboxyl group (e.g., serine side chain, threonine side chain, C-terminal, glutamate side chain and / or aspartate side chain) in the peptide or polypeptide, and / or a disulfide bond formed from a thiohydroxyl group (e.g., cysteine ​​side chain) in the peptide or polypeptide. In some embodiments, the amino acid residue attached to the linker is an N-terminal and / or C-terminal residue, for example, any amino acid residue attached via an N-terminal amino group or a C-terminal carboxyl group and / or a terminal lysine, glutamate, aspartate, serine, threonine and / or cysteine ​​residue attached via a side chain.

[0385] In some embodiments, amino acid residues and / or peptides (e.g., amino acid residues of length 2 to 20) are added to the N-terminus and / or C-terminus of a peptide or polypeptide sequence of a functional group (according to any one of the embodiments described herein) and link said sequence to a linker. Examples of such terminal amino acid residues and / or peptides include, without limitation, peptides having glycine residues and terminal glycine residues, which may be used to attach a linker to the N-terminus or C-terminus (according to any one of the embodiments described herein); peptides having serine and threonine residues and terminal serine or threonine residues, which may be used to attach a linker to a hydroxyl group of a serine or threonine side chain optionally via an ester bond (according to any one of the embodiments described herein); Peptides having cysteine ​​residues and terminal cysteine ​​residues are included, and these can be used to attach linkers to the peptide through disulfide bonds.

[0386] In some embodiments, when a peptide or polypeptide is attached to a linker through terminal amino acid residues, interference (e.g., steric interference) to the function of the peptide or polypeptide is minimized after attachment to the linker.

[0387] In some embodiments, attaching a peptide or polypeptide to a linker through terminal glycine facilitates attachment by minimizing interference (e.g., steric interference) that prevents amino acid side chains not present in glycine from attaching to the linker.

[0388] In some of the embodiments described herein, which include at least some of the monomer units containing the targeting portion, the monomer unit containing the targeting portion is, on average, closer to the end of the polymer portion that is distal from the lipid portion. For example, the average distance between the monomer unit containing the targeting portion and the lipid portion (measured in atomic or main chain units along the main chain of the polymer portion) is greater than the average distance between other monomer units and the lipid portion.

[0389] In some embodiments, at least some (optional all) of the monomer units containing the targeting portion form a block composed of one or more monomer units near (optional at the end) of the polymer portion distal from the lipid portion. In some of these embodiments, the copolymer portion comprises a single monomer unit containing the targeting portion, said monomer unit is at the end of the polymer portion distal from the lipid portion.

[0390] Although I do not wish to be bound by any specific theory, it is presumed that a targeting part located distal from the lipid part may be more effective as a targeting part because, for example, the targeting part is less shielded three-dimensionally (e.g., by the surface to which the lipid part is bound) and thus is more exposed to the target in an aqueous environment and consequently has a better ability to contact the target (e.g., is more effective at binding to the target).

[0391] In an alternative embodiment, the polymer portion does not include a targeting portion according to any one of the embodiments described herein.

[0392] Lipid layer and liposome:

[0393] According to one aspect of some embodiments of the present invention, a lipid bilayer (also simply referred to herein as “bilayer”) comprising a polymeric compound according to any one of the embodiments described herein is provided. In some of these embodiments, the lipid 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.

[0394] In this document, the term “double-layer forming lipid” includes any compound from which a double layer can be formed from a pure aqueous solution of the compound, and the double layer comprises two parallel layers of molecules of said compound (referred to as “lipid”).

[0395] Typically, the bilayer contains relatively polar portions of lipids on two surfaces of the bilayer, which may optionally include an interface with an aqueous solution and / or an interface with a solid surface; and the interior of the bilayer, which is the interface between two layers of lipid molecules forming the bilayer, contains relatively hydrophobic portions of lipids.

[0396] In some embodiments, the bilayer-forming lipid is an amphiphilic lipid.

[0397] As used herein, the term “amphiphilic lipid” refers to a compound comprising at least one hydrophilic portion and at least one lipophilic portion. Examples of amphiphilic lipids include, without limitation, fatty acids (e.g., having at least 6 carbon atoms) and derivatives thereof such as phospholipids and glycolipids; sterols (e.g., cholesterol) and steroid acids.

[0398] As used herein, the term “phospholipid” refers to a compound comprising a substituted or unsubstituted phosphate group and at least one alkyl chain (optional at least two alkyl chains), wherein the alkyl chain optionally has at least five carbon atoms, optionally has at least seven atoms of length, and optionally has at least nine atoms of length. At least one alkyl chain is optionally part of an acyl group (e.g., fatty acid portion) or the alkyl group itself (e.g., fatty alcohol portion). In some embodiments, the phosphate group and one or two (optional two) alkyl chains (e.g., acyl or alkyl) are attached to the glycerol portion through the oxygen atoms of glycerol.

[0399] In the context of the present example, the term “phospholipid” includes lipids having a (phosphorylated) glycerol main chain (e.g., monoacylglyceride and / or diacylglyceride phospholipids), which are referred to as glycerophosphate lipids.

[0400] In some of the embodiments described herein, the phospholipid is a glycerophosphate lipid. In some embodiments, the glycerophosphate lipid is a diacylglyceride comprising two fatty acyl groups and one phosphate group attached to a glycerol main chain.

[0401] Examples of bilayer-forming lipids include glycerophosphate lipids (e.g., glycerophosphate lipids according to any one of the embodiments described herein). It should be understood that the polymeric compounds described herein may be bilayer-forming lipids capable of forming a bilayer either by themselves or in combination with one or more additional bilayer-forming lipids.

[0402] In some 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).

[0403] In some embodiments, the bilayer-forming lipid is zwitterionic and contains both negatively charged groups and positively charged groups (e.g., equal number of groups) (e.g., one of each).

[0404] A bilayer according to some of the embodiments of the present invention may optionally be closed by itself (e.g., so that the bilayer does not have edges) to form an internal volume separated from the surrounding environment by the bilayer, which is referred to as a "liposome" in the present invention and in the art. Alternatively or additionally, the bilayer may have an open surface and / or edges.

[0405] According to some embodiments of the present invention, the composition comprises a liposome comprising at least one lipid bilayer according to any one of the embodiments described herein.

[0406] According to some embodiments of the present invention, the composition comprises a liposome comprising at least one polymer compound according to any one of the embodiments described herein and optionally, preferably, at least one bilayer-forming lipid.

[0407] The term “liposome” as used in this invention and in the art refers to an artificially manufactured vesicle comprising a bilayer composed of molecules of amphiphilic lipids. In an aqueous medium, the bilayer is typically configured such that the hydrophilic portion of the amphiphilic lipid is exposed to the medium at both surfaces of the bilayer, while the lipophilic portion of the lipid is located in the inner portion of the bilayer and is less exposed to the medium. Examples of liposomes that may be used in any of the embodiments described herein include, without limitation, small monolayer vesicles (SUVs), large monolayer vesicles (LUVs), and large multilayer vesicles (MLVs).

[0408] As described herein, the liposome according to the present embodiment comprises, in particular, at least one bilayer-forming lipid.

[0409] It should be understood that the polymeric compound included in the liposome (according to any one of the embodiments described herein) may be a bilayer-forming lipid capable of forming a bilayer either by itself or in combination with one or more additional bilayer-forming lipids.

[0410] Liposomes may optionally comprise a single bilayer (e.g., a single-layer vesicle) or multiple bilayers (e.g., multiple-layer vesicles), each bilayer optionally independently forms a closed vesicle, e.g., concentric bilayer vesicles and / or multiple distinct bilayer vesicles contained within the same bilayer vesicle.

[0411] As used herein, the term "single-layer" refers to a liposome characterized by a single lipid bilayer, whereas the term "multilayer" refers to a liposome characterized by multiple lipid bilayers, for example, a concentric bilayer.

[0412] The expression "small monolayer vesicle" used herein refers to a monolayer liposome with a diameter of less than 100 nm, whereas the expression "large monolayer vesicle" refers to a monolayer liposome with a diameter of at least 100 nm.

[0413] The expression "small multilayer vesicle" used herein refers to a multilayer liposome with a diameter of less than 100 nm, whereas the expressions "large multilayer vesicle" and MLV refer to a multilayer liposome with a diameter of at least 100 nm.

[0414] In some of the embodiments described herein, the liposome comprises a multilayer vesicle. In some embodiments, the liposome is primarily (more than 50% by weight) a multilayer vesicle, preferably a large multilayer vesicle (MLV).

[0415] In some of the embodiments described herein, the liposome comprises small monolayer vesicles. In some embodiments, the liposome is mainly (more than 50% by weight) small monolayer vesicles.

[0416] In some of the embodiments described herein, the liposome comprises large monolayer vesicles. In some embodiments, the liposome is primarily (more than 50% by weight) large monolayer vesicles.

[0417] Liposomes according to any one of the embodiments described herein may be approximately spherical or may have any alternative shape, such as an elongated tube and / or flat (e.g., sheet-like) shape.

[0418] In some of the embodiments of any of the embodiments described herein, the molar ratio of the bilayer-forming lipid (in addition to the polymer compound) in the liposome and the polymer compound (according to any one of the embodiments described herein), or the molar ratio in the composition containing the same, is in the range of 5:1 to 5,000:1 (bilayer-forming lipid:polymer 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, and includes intermediate values ​​and lower ranges in between.

[0419] Throughout this invention, the terms “mol ratio” and “molar ratio” are used interchangeably and describe the ratio between the mol% of the indicated components in a lipid bilayer or liposome, or a composition containing the same.

[0420] In some of the embodiments of any of the embodiments described herein regarding the bilayer, the molar ratio of the bilayer-forming lipid (in addition to the polymer compound) in the bilayer and the polymer compound, or the molar ratio in the composition containing the same, is in the range of 10:1 to 1,000:1 (bilayer-forming lipid:polymer 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, and includes any intermediate values ​​and lower ranges in between.

[0421] In some of the embodiments described herein regarding the bilayer, the molar ratio of the bilayer-forming lipid (in addition to the polymer compound) in the bilayer and the polymer compound, or the molar ratio in the composition containing the same, is in the range of 10:1 to 100:1 (bilayer-forming lipid:polymer compound), optionally in the range of 10:1 to 50:1, optionally in the range of 30:1 to 40:1, and includes any intermediate values ​​and lower ranges in between.

[0422] In some of the embodiments of any of the embodiments described herein regarding the bilayer, the molar ratio of the bilayer-forming lipid (in addition to the polymer compound) in the bilayer and the polymer compound, or the molar ratio in a composition containing the same, is in the range of 10:1 to 1,000:1 (bilayer-forming lipid:polymer compound), optionally in the range of 100:1 to 1,000:1, optionally in the range of 100:1 to 500:1, and optionally in the range of 100:1 to 300:1 or 100:1 to 200:1, and includes any intermediate values ​​and lower ranges in between.

[0423] In some of the embodiments described herein, the molar ratio of the bilayer-forming lipid (in addition to the polymer compound) and the polymer compound (according to any one of the embodiments described herein) in the composition is in the range of 5:1 to 5,000:1 (bilayer-forming lipid:polymer 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, and includes any intermediate values ​​and lower ranges in between.

[0424] In some of the embodiments described herein, the concentration of the phospholipid in the liposome or the composition or formulation described herein is in the range of 0.1 mM to 500 mM. In some embodiments, the concentration is in the range of 0.1 mM to 150 mM. In some embodiments, the concentration is in the range of 0.1 mM to 50 mM. In some embodiments, the concentration is in the range of 0.1 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).

[0425] In some of the embodiments described herein or any combination thereof, the total amount of at least one bilayer-forming lipid in the liposome is 50 to 99 mol%, weight per volume, and includes any intermediate and sub-ranges in between.

[0426] In some of the embodiments described herein, the amount of (one or more) polymeric compounds (LPCs) is in the range of 0.1 to 10 mol%, or 0.1 to 5 mol%, or 0.1 to 3 mol%, or 0.1 to 1 mol%, or 0.2 to 0.8 mol%, or 0.1 to 0.5 mol% of the total lipid amount in the liposome, and includes any intermediate values ​​and sub-ranges in between.

[0427] In some of the embodiments described herein, the amount of the polymer compound (LPC) is in the range of 1 to 50 weight%, or 1 to 40 weight%, or 1 to 30 weight%, or 5 to 50 weight%, or 5 to 40 weight%, or 5 to 30 weight% of the total lipid amount in the liposome, and the remainder is the bilayer-forming lipid(s), and includes any intermediate and sub-ranges in between.

[0428] In some of the embodiments described herein, the total amount of polymeric compound (LPC) and bilayer-forming lipid in the composition (which represents the total amount of lipid in the composition) is in the range of 0.01 to 10 wt%, or 0.05 to 10 wt%, or 0.05 to 5 wt%, or 0.1 to 10 wt%, or 0.1 to 5 wt%, or 0.05 to 5 wt%, or 1 to 10 wt%, or 1 to 5 wt%, or 0.01 to 3 wt%, or 0.5 to 3 wt%, or 0.1 to 3 wt%, or 1 to 3 wt% with respect to the total volume or total weight of the composition, and includes any intermediate values ​​and sub-ranges in between.

[0429] In some of the embodiments described herein, the concentration of the lipid bilayer or liposome in the composition (which represents the total lipid concentration or total lipid concentration in the composition) is in the range of 0.1 to 100 mM, or 0.1 to 50 mM, or 0.1 to 30 mM, or 0.1 to 10 mM, or 0.1 to 5 mM, or 0.1 to 2 mM, or 1 to 100 mM, or 1 to 50 mM, or 1 to 30 mM, or 1 to 10 mM, or 1 to 5 mM, and includes any intermediate values ​​and sub-ranges in between.

[0430] In some of the embodiments described herein, the concentration of the lipid bilayer or liposome in the composition (which represents the total lipid concentration or total lipid concentration in the composition) is in the range of 10 to 100 mM, or 10 to 50 mM, or 10 to 30 mM, or 10 to 20 mM, or 20 to 100 mM, or 20 to 80 mM, or 20 to 60 mM, or 20 to 50 mM, or 20 to 40 mM, or 20 to 30 mM, and includes any intermediate values ​​and sub-ranges in between.

[0431] In some of the embodiments described herein, the average diameter of the liposome is in the range of about 100 nm to about 2,000 nm, or about 100 nm to about 1,000 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, and includes any intermediate values ​​and sub-ranges in between.

[0432] The average diameter according to any one of the embodiments described herein may optionally be an arithmetic mean (the ratio of the sum of values ​​to the number of values) or a Z-mean as defined in the field of dynamic light scattering (simply put, an intensity-weighted harmonic mean). In an exemplary embodiment, the average diameter is the Z-mean diameter determined by dynamic light scattering.

[0433] The number average molecular weight (Mn) and / or molecular weight (Mw) and / or number average degree of polymerization (DPn) of liposomes in the composition can be selectively determined by gel permeation chromatography (GPC) analysis.

[0434] The polydispersity index (PDI) and / or mean diameter of liposomes in the composition may optionally be determined by dynamic light scattering using 2-parameter fitting to the data (e.g., according to ISO 13321 and ISO 22412 standards) to determine the PDI and Z-mean diameter (e.g., using commercially available instruments).

[0435] In some of the embodiments described herein, the PDI of the liposome is less than 1.

[0436] 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, and includes any intermediate values ​​and lower ranges in between.

[0437] In some of the embodiments described herein, the zeta potential of the liposome is at least -3 mV (i.e., -3 mV or a more negative value), optionally at least -3.5 mV, and optionally at least -4 mV.

[0438] In some of the embodiments of any of the polymeric compounds described herein, including negatively charged bilayer-forming lipids (e.g., DPPG), the zeta potential of the liposome 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).

[0439] The zeta potential can be selectively measured using any suitable technique known in the art (e.g., using commercially available instruments), for example, electrophoretic light scattering. The zeta potential of liposomes can be measured by diluting the liposomes in an aqueous salt solution (e.g., NaCl) at a predetermined salt concentration (e.g., 10 μM).

[0440] In some of the embodiments described herein, the bilayer-forming lipid or liposome comprises at least one zwitterionic bilayer-forming lipid, for example, a zwitterionic glycerophosphate lipid.

[0441] In some of the embodiments described herein, the bilayer-forming lipid or liposome comprises at least one zwitterionic bilayer-forming lipid, e.g., zwitterionic glycerophosphate lipid, and at least one negatively charged bilayer-forming lipid according to any embodiment described herein, e.g., negatively charged phosphatidyl glycerol.

[0442] In some of the embodiments described herein or any combination thereof, at least one negatively charged bilayer-forming lipid is phosphatidyl glycerol (e.g., DPPG).

[0443] In some of the embodiments described herein or any combination thereof, at least one bilayer-forming lipid further comprises at least one zwitterionic glycerophosphate lipid (e.g., phosphatidylcholine such as DSPC and / or phosphatidyl ethanolamine such as DPPE).

[0444] In the present invention and in the art, the term "phosphatidylcholine" refers to a glycerophosphate lipid comprising a phosphocholine group and two fatty acyl groups (i.e., diacylglycerides) attached to a glycerol main chain. The fatty acyl groups may have a length of 8 to 30 carbon atoms, or 8 to 20, or 10 to 30, or 10 to 20, or 12 to 30, or 12 to 30, including any intermediate and sub-ranges in between, preferably having a length of at least 12, or at least 14, more preferably at least 16 carbon atoms (e.g., having a length of 16 to 30 or 16 to 22 carbon atoms).

[0445] In the present invention and in the art, the term "phosphatidylethanolamine" refers to a glycerophosphate lipid comprising a phosphoethanolamine group and two fatty acyl groups (i.e., diacylglycerides) attached to a glycerol main chain.

[0446] According to some embodiments of the present invention, the bilayer-forming lipid comprises a negatively charged bilayer-forming lipid (e.g., phosphatidyl glycerol such as DPPG).

[0447] According to some embodiments of the present invention, the bilayer-forming lipids comprise zwitterionic glycerophosphate lipids (e.g., phosphatidyl choline such as DSPC or phosphatidyl ethanolamine such as DPPE) and negatively charged glycerophosphate lipids (e.g., phosphatidyl glycerol such as DPPG). According to some embodiments of the present invention, the total amount of bilayer-forming lipids in the liposome is 50 to 99 mol%, including any intermediate and sub-ranges therebetween.

[0448] According to some embodiments of the present invention, when negatively charged bilayer-forming lipids are present, the amount is in the range of 0.1 to 40 mol% or 0.1 to 20 mol% of lipids in the liposomes (bilayer-forming lipids, LPC, and cholesterol in the presence of cholesterol), and includes any intermediate and lower ranges in between.

[0449] According to some embodiments of the present invention, the liposome further comprises sterols, for example, cholesterol.

[0450] According to some embodiments of the present invention, sterols (e.g., cholesterol) are associated with a lipid bilayer but do not form a lipid bilayer.

[0451] As used herein, the term “sterol” includes all sterols derived from any source, including synthetic sterols, animal-derived sterols, and plant-derived sterols (referred to as “phytosterols” as known in the art), as well as their saturated forms (i.e., stanols). Accordingly, as used herein, the term “sterol” includes both sterols and stanols. Sterols are steroids (steroid alcohols) having a hydroxyl group at C3 and possess most of the skeleton of cholestan (IUPAC Steroid Nomenclature, 1987). An additional carbon atom is a side chain, typically C 17 It can exist in the location. In nature, sterols are C 26 -C 30It is found as a steroid alcohol. While the cyclopentanoperhydrophenanthrene ring structure is common to all sterols, the side chains may vary in structure. In nature, sterols can be found as conjugates (e.g., sugar conjugates, lipid conjugates, etc.). Therefore, as used herein, the term "sterol" is intended to further include 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 the present invention, the amount of sterol (e.g., cholesterol) is in the range of 0.1 to 50 mol% of the total lipids in the liposome, including any intermediate and sub-ranges therebetween.

[0452] In some of the embodiments described herein or any combination thereof, where negatively charged bilayer-forming lipids are present, the amount is in the range of 0.1 to 40 mol% or 0.1 to 20 mol% of the lipids in the liposomes, and includes any intermediate and lower ranges in between.

[0453] In some of the embodiments of any of the embodiments described herein regarding liposomes, the liposomes further comprise at least one functional portion or agent (e.g., within the liposomal bilayer and / or surrounded by the liposomal bilayer) that is bound to or associated with the surface of the liposomes and / or within the lipid bilayer and / or the core of the liposomes. In exemplary embodiments, the functional portion is bound to the liposomes, for example, by covalent bonding with one or more lipids. In exemplary embodiments, the functional agent is chemically bound to or associated with the liposomes, for example by covalent bonding or electrostatic bonding, and / or is physically associated with the liposomes by being captured or entangled within the lipid bilayer or core.

[0454] Examples of functional parts and agents suitable for inclusion in the embodiments described herein include, without limitation, therapeutic active agents or parts of therapeutic active agents (e.g., the active agent is released upon cleavage of said part), labeled parts or agents and / or targeting parts or targeting agents (e.g., targeting parts or agents on the surface of the liposome). Other parts or agents that may contribute to or improve the indicated use of the liposome are also considered. According to some embodiments, the liposome further comprises sterols, e.g., cholesterol. According to some of these embodiments, cholesterol is incorporated into and / or associated with the lipid bilayer.

[0455] According to some embodiments of any embodiment described herein, the functional part or agent is a therapeutically active agent or part thereof, a labeled part or agent and / or a targeting part or agent.

[0456] According to some embodiments of any of the embodiments described herein, the functional part or agent is a therapeutically active agent or a part thereof, and in some of these embodiments, the therapeutically active agent or a part thereof is located within 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% of the total lipids within the liposome.

[0457] According to some of these embodiments, the polymer compound is a long-chain polymer compound as described and defined in any one of the embodiments described herein.

[0458] According to some of these embodiments, the liposome comprises a therapeutic active agent (e.g., within the liposome bilayer or surrounded by the liposome bilayer) and cholesterol (e.g., associated within the lipid bilayer) that are bound to or associated with the surface of the liposome and / or within the lipid bilayer and / or core of the liposome.

[0459] According to some embodiments of any embodiment described herein, the liposome does not contain a therapeutic active agent.

[0460] According to some embodiments of any of the embodiments described herein, the liposome comprises a therapeutically active agent, said agent optionally incorporated into the liposome and / or on the surface of the liposome. In some of these embodiments, the therapeutically active agent is the therapeutically active agent described in International Patent Application Publication WO 2018 / 150429.

[0461] In this application, the term “therapeutic active agent” refers to any agent (e.g., a compound) having a therapeutic effect, provided that said compound is not a bilayer-forming lipid or polymeric compound contained in a liposome (according to any one of the embodiments described herein), but comprises any portion of an agent (e.g., a portion of a compound) that generates a therapeutic agent upon release (e.g., upon cleavage of one or more covalent bonds), and comprises a portion of a bilayer-forming lipid or polymeric compound. Accordingly, the bilayer-forming lipid and / or polymeric compound themselves are excluded from the definition of a therapeutic active agent, but the bilayer-forming lipid and / or polymeric compound may selectively generate a therapeutic active agent upon release, in which case the portion of the bilayer-forming lipid and / or polymeric compound that generates the therapeutic active agent is also considered to be a therapeutic active agent as defined herein.

[0462] When associated with a liposome, the therapeutic active agent may be optionally attached to the liposome (e.g., the outer surface and / or inner surface of the liposome membrane) by covalent or non-covalent bonds (e.g., electrostatic and / or hydrophobic bonds), incorporated into the liposome membrane (e.g., a lipophilic agent stably distributed on the lipid of the liposome), and / or surrounded within the core of the liposome (e.g., a hydrophilic agent within the aqueous compartment of the liposome). The therapeutic active agent may optionally be a portion attached to the liposome by covalent bonds (e.g., a portion attached to the lipid to form a lipid derivative comprising said portion). Such attachment may be achieved in some embodiments using techniques known in the art (e.g., amide bond formation).

[0463] In some embodiments, the therapeutic active agent is attached to the liposome via electrostatic interaction, for example, the therapeutic active agent is a positively charged agent attached to or complexed with a negatively charged bilayer-forming lipid as described herein.

[0464] In some of the embodiments described herein, the therapeutic active agent is, for example, an analgesic (e.g., as described in any one of the embodiments described herein), an anti-inflammatory agent (e.g., as described in any one of the embodiments described herein), an antiproliferative agent (e.g., as described in any one of the embodiments described herein), an antimicrobial agent (including antibacterial agents, antimycobacterial agents, antiviral agents, antifungal agents, antiprotozoal agents and / or antiparasitic agents) and / or a vaccine antigen. In some of these embodiments, the therapeutic active agent is an analgesic and / or anti-inflammatory agent. In some of these embodiments, the therapeutic active agent may be used alone or in combination with additional therapeutic active agents for the treatment of osteoarthritis.

[0465] As used herein, the term “antimicrobial” refers to the properties of a substance (e.g., a compound or composition) that may affect the parameters of microorganisms as defined herein, including the killing, eradication, elimination, reduction in number, reduction in growth rate, inhibition of growth, and alteration of population distribution of one or more species of microbial life forms. This term includes antimicrobial agents, also referred to herein as antibiotics. Examples of antimicrobial agents include, without limitation, antimicrobial agents, antimycobacterial agents, antiviral agents, antifungal agents, antiprotozoal agents, and / or antiparasitic agents as known in the art.

[0466] As used herein, the term “vaccine antigen” refers to an agent within a vaccine that can stimulate the immune system to recognize and respond to a specific pathogen or foreign agent. When introduced into a patient’s body, the antigen triggers an immune response that causes antibodies to be produced within the patient’s body. Examples of vaccine antigens include, without limitation, inactivated vaccines 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 (Haemophilus influenzae type b (Hib) vaccine).

[0467] Examples of suitable antiproliferative agents include, without limitation, the following: ashibisin; aclarubicin; acodazole (e.g., acodazole hydrochloride); acrronin; adriamycin; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone (e.g., ametantrone acetate); aminoglutethimide; amsacrine; anastrozole; antramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; vatimastat; benzodepa; bicalutamide; vasantren (e.g., vasantren hydrochloride); bisnafide (e.g., bisnafide dimesylate); bizelesin; bleomycin (e.g., bleomycin sulfate); brequinar (e.g., brequinar sodium); bropyrimin; busulfan; cactinomycin; Calosterone; Carasemide; Carvetimer; Carboplatin; Camustine; Carubicin (e.g., Carubicin Hydrochloride); Carzelesin; Sedepingol; Chlorambucil; Sirolemycin; Cisplatin; Cladribine; Combrestatin A-4 Phosphate; Crisnatol (e.g., Crisnatol Mesylate); Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin (e.g., Daunorubicin Hydrochloride); Decitabine; Dexormaplatin; Desaguanine (e.g., Desaguanine Mesylate); Diaziquone; Docetaxel; Doxorubicin (e.g., Doxorubicin Hydrochloride); Droloxifene (e.g., Droloxifene Citrate); Dromostanolone (e.g., Dromostanolone Propionate); Duazomycin; Edatrexate; Eflornitine (e.g., Eflornitine hydrochloride); Elsamitursine; Enroplatin; Enpromate; Epipropidine; Epirubicin (e.g., Epirubicin hydrochloride); Erbulozol; Esolubicin (e.g., Esolubicin hydrochloride); Estramustine (e.g., Estramustine sodium phosphate); Ethanidazole; Etoposide (e.g., Etoposide phosphate); Etoprine; Padrozol (e.g., Padrozol hydrochloride); Pazarabine; Fenretinide; Fluoxuridine; Fludarabine (e.g., Fludarabine phosphate); Fluorouracil; Flurositabine; Fosquidone; Postriesin (e.g., Postriesin sodium);Gemcitabine (e.g., gemcitabine hydrochloride); hydroxyurea; idarubicin (e.g., idarubicin hydrochloride); ifosfamide; ilmorphosin; interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-Ia; interferon gamma-Ib; iproplatin; irinotecan (e.g., irinotecan hydrochloride); lanreotide (e.g., lanreotide acetate); letrozole; leuprolide (e.g., leuprolide acetate); riaozole (e.g., riaozole hydrochloride); rometrexole (e.g., rometrexole sodium); lomustine; rhoxantrone (e.g., rhoxantrone hydrochloride); masoprocol; mytansine; 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; mitocarcin; mitocromin; mitogyline; mitomalcin; mitomycin; mitosper; mitotan; mitoxantrone (e.g., mitoxantrone hydrochloride); mycophenolic acid; nocodazole; nogalamycin; ombrabulin; ormaplatin; oxysuran; paclitaxel; pegaspargase; peliomycin; pentamustine; pepromycin (e.g., pepromycin sulfate); perphosphamide; pipobroman; piposulfan; Piroxantrone (e.g., piroxantrone hydrochloride); plicamycin; plomestane; porfimer (e.g., porfimer sodium); porpyromycin; prednimustine; procarbazine (e.g., procarbazine hydrochloride); furomycin (e.g., furomycin hydrochloride); pyrazopurine; riboprine; logletimide; safingol (e.g., safingol hydrochloride); semustine; simtrazen; sparphosate (e.g., sparphosate sodium); sparsomycin; spirogermanium (e.g., spirogermanium hydrochloride); spiromustine; spiroplatin; streptonigreen; streptozosin; sulopenur; thalisomycin; tecogalan (e.g., tecogalan sodium); tegafur;Teloxantrone (e.g., teloxantrone hydrochloride); temoporfin; tenifoside; teroxylon; testolactone; thiamiphrine; thioguanine; thiotepa; thiazopurine; tirapazamine; topotecan (e.g., topotecan hydrochloride); toremifene (e.g., toremifene citrate); trestolone (e.g., trestolone acetate); trisyribin (e.g., trisyribin phosphate); trimetrexate (e.g., trimetrexate glucoronate); triptorelin; tubulozol (e.g., tubulozol hydrochloride); uracil mustard; uredepa; bapreotide; verteporfin; vinblastine; vincristine (e.g., vincristine sulfate); vindesin (e.g., vindesin sulfate); vinepidine; binglicinate; Vinrulosin; vinorelvin (e.g., vinorelvin tartrate); vinrosidine; vinzolidine; borozol; geniplatin; genostatin; and zorubicin (e.g., zorubicin hydrochloride) are included. Additional anticancer agents include those disclosed in Chapter 52, Antitumor Agents (Paul Calabresi and Bruce A. Chabner), and the introduction, 1202–1263, of Goodman and Gilman's "The Pharmacological Basis of Therapeutics," 8th edition, 1990, McGraw-Hill, Inc. (Health Professions Division), the contents of which are incorporated herein by reference. In some of the embodiments described herein, sterols, e.g., cholesterol, are included in the lipid bilayer of liposomes according to any of the embodiments described herein.;

[0468] In some of the embodiments described herein, the amount of sterol (e.g., cholesterol) is in the range of 0.1 to 50 mol% of the total lipids in the liposome, including any intermediate and sub-ranges therebetween. Examples of therapeutic active agents suitable for inclusion in the liposome (e.g., molecules or parts of said agents) include, without limitation, amphotericin B, cisplatin, cytarabine, daunorubicin, doxorubicin, estradiol, influenza virosome, morphine, surfactant protein B, surfactant protein C, verteporfin, and vincristine.

[0469] Examples of labeled parts or agents include chromogenic (e.g., absorbs visible light), fluorescent, phosphorescent, and / or radioactive parts and compounds. Many of these compounds and parts (and techniques for manufacturing such parts) will be known to those skilled in the art.

[0470] The targeting portion within the liposome according to any one of the embodiments described herein may optionally be the targeting portion according to any one of the embodiments described herein. The targeting portion within the liposome may be contained by a polymeric compound according to some embodiments of the present invention (according to any one of the embodiments described herein), and the liposome comprises said polymeric compound. Alternatively or additionally, the targeting portion within the liposome may be contained by another compound within the liposome, optionally a bilayer-forming lipid conjugated to the targeting portion according to any one of the embodiments described herein.

[0471] In this document, “targeting agent” refers to a compound (“agent”) comprising (optionally consisting essentially of) a targeting portion according to any one of the embodiments described herein (e.g., in the context of a targeting portion included by a polymeric compound described herein). Typically, the expression “targeting agent” is used to refer to compounds other than polymeric compounds comprising a targeting portion as described herein.

[0472] In some embodiments, the functional portion (e.g., the targeting portion or the labeling portion) is attached to the liposome by a covalent bond. In some embodiments, this attachment can be achieved using techniques known in the art (e.g., amide bond formation).

[0473] Composition:

[0474] The compositions described herein comprise one or more polymer compounds described herein according to any one of the respective examples and optionally, preferably, one or more bilayer-forming lipids described herein according to any one of the respective examples.

[0475] According to some embodiments in accordance with any one of the respective embodiments, the amounts of polymer compound(s) and bilayer-forming lipid(s) in the composition and the total amount thereof (total amount of lipid compounds or lipids) are as described in any one of the respective embodiments described herein and any combination thereof.

[0476] According to some embodiments of any one of the respective embodiments, the composition further comprises a carrier, preferably an aqueous carrier, e.g., water, saline solution, or a buffer solution having a physiological pH. According to these embodiments, the composition is an aqueous composition.

[0477] According to some of the embodiments described herein, the composition is a sterile composition.

[0478] In this document, the term “sterile” refers to the absence of observable microbial growth when the composition is exposed to conditions (e.g., medium, culture temperature) for a suitable period, for example, according to any standard protocol for sterile testing. Optionally, sterile is tested in a fluid thioglycolate medium, for example, at a temperature in the range of 30 to 35°C for up to 3 days, and / or in a soy-casein digestion medium (also known as trypticase soy broth or trypticase soy agar), for example, at a temperature in the range of 20 to 25°C for up to 5 days; for example, if no microbial growth is observed in either medium, the composition is sterile. The contents of the fluid thioglycolate medium and / or the soy-casein digestion medium and / or the sterile testing procedure may follow the description in Chapter 71 of the United States Pharmacopoeia General Test Methods, the contents of which are incorporated herein by reference.

[0479] In some of the embodiments described herein, the sterile composition is characterized by a bacterial endotoxin concentration below an acceptable threshold, e.g., a concentration below the threshold of 35 endotoxin units (EU) per mL (e.g., endotoxin units are defined according to U.S. Pharmacopoeia standards). Bacterial endotoxin levels may be determined using any suitable test known in the art, e.g., horseshoe crab (Limulus) amoebosite lysate (e.g., according to Chapter 85 of the U.S. Pharmacopoeia), the details of which are incorporated herein by reference. For example, they may be determined by comparison with a commercially available reference sample containing endotoxin.

[0480] A sterilization composition according to any one of the embodiments described herein may optionally be prepared according to the process described herein according to each embodiment.

[0481] In some embodiments, the process for preparing a sterile composition comprises the steps of: providing an aqueous composition comprising an aqueous carrier and a liposome comprising at least one bilayer-forming lipid (e.g., according to any one of the embodiments described herein) and a polymer compound (e.g., according to any one of the embodiments described herein); and exposing the aqueous composition to a temperature greater than 100°C.

[0482] The sterilization composition obtained according to the above process is optionally a sterilization composition according to any one of the embodiments described herein.

[0483] In some of the embodiments described herein, according to any one of the embodiments described herein, the temperature to which the aqueous composition is exposed is 150°C or lower, for example, 110°C to 150°C, or 115°C to 150°C, or 121°C to 150°C, or 130°C to 150°C.

[0484] In some of the embodiments described herein, the temperature to which the aqueous composition is exposed is 140°C or lower, for example, 110°C to 140°C, or 115°C to 140°C, or 121°C to 140°C, or 130°C to 140°C.

[0485] In some of the embodiments described herein, the temperature to which the aqueous composition is exposed is 134°C or lower, for example, 110°C to 134°C, or 115°C to 134°C, or 121°C to 134°C.

[0486] In some of the embodiments described herein, the temperature to which the aqueous composition is exposed is 130°C or lower, for example, 110°C to 130°C, or 115°C to 130°C, or 121°C to 130°C.

[0487] In some of the embodiments described herein, the temperature to which the aqueous composition is exposed is 125°C or lower, for example, 110°C to 125°C, or 115°C to 125°C, or 121°C to 125°C.

[0488] In some of the embodiments described herein, the exposure of the aqueous composition to a temperature greater than 100°C is performed at an elevated pressure, that is, a pressure greater than ambient atmospheric pressure. This pressure can be obtained, for example, by heating the aqueous composition in a sealed container, whereby the water vapor formed by the heating contributes to raising the pressure. In some of these embodiments, the pressure is such that the boiling point of the aqueous composition at that pressure is equal to the temperature or close to the temperature to which the composition is exposed (e.g., ±10°C or ±5°C).

[0489] Exposing the composition to an elevated temperature (and optionally an elevated pressure) according to any one of the embodiments described herein may optionally be performed using a commercial device configured for such use, e.g., an autoclave.

[0490] According to some of the embodiments described herein, a sterile composition may be obtained or can be obtained by the process described in each of the embodiments described herein and any combination thereof.

[0491] The liposomes of the present embodiment (and optionally including the water-soluble polymers described herein) may be optionally administered as part of a (e.g., sterile) composition (e.g., solution) comprising a physiologically acceptable carrier, for example, an aqueous carrier that is a physiologically acceptable carrier.

[0492] Throughout this invention, the term “physiologically acceptable carrier” refers to a carrier or diluent that, when administered in the intended manner, does not cause significant irritation to the subject and does not compromise the activity and properties of the composition (e.g., the ability of the liposome, as described in any of the embodiments described herein, to treat a pathological condition and / or reduce the coefficient of friction of the surface). Examples of carriers include, without limitation, propylene glycol, saline solution, emulsions, and mixtures of organic solvents and water (or saline solution), as well as solid (e.g., powder) and gaseous carriers.

[0493] Formulation and administration techniques for compounds (e.g., liposomes) can be found in the latest edition of “Remington’s Pharmaceutical Sciences” by Mack Publishing Co., Easton, PA, incorporated herein by reference.

[0494] A composition (e.g., solution) according to any one embodiment of the present invention (e.g., sterile) may be prepared by a process well known in the art, for example, a conventional mixing or dissolving process.

[0495] Accordingly, a composition (e.g., solution) for use (e.g., sterile) according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers, which facilitates processing liposomes (and optionally water-soluble polymers described herein) into pharmaceutically usable formulations. The appropriate formulation depends on the selected route of administration.

[0496] For injection, a composition (e.g., sterile) according to any one of the embodiments described herein or a liposome described herein (optional together with a water-soluble polymer described herein) may be formulated into an aqueous solution using a suitable aqueous carrier, preferably a physiologically compatible buffer such as Hanks' solution, Ringer's solution, histidine buffer, or a physiologically compatible buffer with or without an organic solvent such as propylene glycol or polyethylene glycol.

[0497] A composition (e.g., sterile) according to any one of the embodiments described herein or a liposome described herein (optional together with a water-soluble polymer described herein) may be formulated for parenteral administration, for example by bolus injection or continuous infusion. Injectable formulations may be provided in unit dose form, for example, in ampoules or multi-dose containers optionally containing preservatives. The composition (e.g., sterile) may be a suspension, solution, or emulsion in an oily or aqueous vehicle and may include formulation agents such as suspending agents, stabilizers, and / or dispersing agents.

[0498] A composition (e.g., sterile) according to any one of the embodiments described herein or a liposome described herein (optional together with a water-soluble polymer described herein) may be formulated as an aqueous solution itself. Additionally, the composition (e.g., sterile) (e.g., solution) may be in the form of a suspension and / or emulsion (e.g., oil in water, water in oil, or oil in water in oil emulsion) to increase the viscosity of the formulation (e.g., the aqueous phase of the suspension). An aqueous injection suspension may contain a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain a suitable stabilizer or agent that increases the solubility of the liposome described herein (and / or optionally a water-soluble polymer described herein), for example, an agent that enables the preparation of a high-concentration solution.

[0499] In some embodiments, the liposomes described herein (optional together with the water-soluble polymers described herein) may be in powder form for reconstitution with a suitable vehicle, e.g., sterile non-pyrogenous water, before use.

[0500] A composition or solution (e.g., sterile) according to any one of the embodiments described herein may be formulated to contain liposomes in an amount effective for achieving the intended purpose, for example, an amount effective for preventing, alleviating, or improving symptoms of a disorder in a subject being treated, or an amount effective for preventing, alleviating, or improving symptoms of a disorder in a subject being treated by reducing or preventing wear of an implantable device. Additionally or alternatively, the composition (e.g., sterile) may be in the form of a suspension and / or emulsion (e.g., oil in water, water in oil, or oil in water in oil emulsion) to increase the viscosity of the formulation. An aqueous injectable suspension may contain a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also include a suitable stabilizer or agent that increases the solubility and / or stability of the liposomes described herein, for example, an agent that enables the preparation of a high-concentration solution.

[0501] The dosage may vary depending on the formulation used, the route of administration utilized, the site of administration (e.g., the volume and / or surface of the area in contact with the liposome), and the judgment of the attending physician or surgeon.

[0502] The amount of the composition to be administered varies depending on the target being treated, the severity of the disease, the method of administration, and the judgment of the prescribing physician.

[0503] A composition (e.g., solution) (e.g., sterile) according to an embodiment of the present invention may, if desired, be provided in a package or dispenser device such as a U.S. Food and Drug Administration (FDA) approved kit, which may comprise one or more unit dose forms containing active ingredient(s) (e.g., liposomes described herein or compositions containing them as described herein). The package may include, for example, metal or plastic foil, or, for example, but not limited to, blister packs. The package or dispenser device may be accompanied by administration instructions. The package or dispenser may be accompanied by a notice attached to the container in a form prescribed by a government agency regulating the manufacture, use or sale of the medicine, and such notice reflects the agency's approval of the composition form (e.g., sterile) for human or veterinary administration. Such notice may be, for example, a label or approved product information approved by the U.S. FDA for a prescription drug. A (e.g., sterile) composition comprising liposomes (optional together with the water-soluble polymer or active agent described herein) in a physiologically acceptable carrier, formulated according to any one of the embodiments described herein, may be prepared for the treatment or analysis of an indication as described in detail herein, placed in a suitable container, and labeled.

[0504] In some of the embodiments described herein, the (e.g., sterile) composition (or any other composition or formulation described herein comprising liposomes) optionally further comprises a water-soluble polymer as part of the carrier.

[0505] The expression “water-soluble polymer” as used herein includes a polymer having a solubility of at least 1 g per liter in an aqueous (e.g., water) environment at pH 7 (25°C).

[0506] In some of the embodiments described herein, the water-soluble polymer has a solubility of at least 2 g per liter under the above conditions. In some embodiments, the solubility is at least 5 g per liter. In some embodiments, the solubility is at least 10 g per liter. In some embodiments, the solubility is at least 20 g per liter. In some embodiments, the solubility is at least 50 g per liter. In some embodiments, the solubility is at least 100 g per liter.

[0507] Water-soluble polymer(s) according to any embodiment described herein may comprise at least one ionic polymer and / or at least one nonionic polymer that is water-soluble as defined herein.

[0508] As used herein, the term “nonionic polymer” refers to a polymer that does not have charged groups. Examples of suitable nonionic water-soluble polymers include, without limitation, polyvinylpyrrolidone (also referred to herein as povidone and / or PVP) and polyethylene oxide (also referred to herein as PEO, PEG and / or polyethylene glycol).

[0509] The expression “ionic polymer” as used herein refers to a polymer having at least one charged group, and includes a polymer having a net negative charge in an aqueous (e.g., water) environment of pH 7 (also referred to herein as “anionic polymer”), a polymer having a net positive charge (also referred to herein as “cationic polymer”), and a polymer having no net charge (also referred to herein as “zwitterionic polymer”).

[0510] Throughout this invention, the expression “charged group” refers to any ionic functional group (as defined herein) (e.g., functional groups described herein), including, for example, amines, carboxylic acids, sulfates, sulfonates, phosphates, and phosphonates. Thus, each charge in a part or molecule is associated with a single charged group, but a single charged group (e.g., unsubstituted phosphate) may be associated with more than one charge of the same sign (e.g., divalent anion, divalent cation).

[0511] Throughout the present invention, the term “ionic” refers to the presence of a charge on at least one atom of a portion and / or molecule in an aqueous medium (e.g., water) at pH 7 (in at least 50% of the portion and / or molecule within the population). The charge may be negative (anionic) or positive (cationic). If more than one charge is present, the charge may be negative (anionic) and / or positive (cationic), and, for example, both negative and positive charges may be present (zwitterionic).

[0512] 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.

[0513] According to an exemplary embodiment, the water-soluble polymer is hyaluronic acid or includes it.

[0514] According to some of the embodiments described herein, the amount of a water-soluble polymer (e.g., hyaluronic acid) in the composition is in the range of 0.01 to 10, or 0.05 to 10, or 0.1 to 10, or 0.01 to 5, or 0.1 to 5, or 0.1 to 1, or 0.05 to 1, or 0.05 to 0.5, or 0.1 to 0.5, or in the range of weight% relative to the total weight or total volume of the composition, and includes any intermediate values ​​and sub-ranges in between.

[0515] According to some of the embodiments described herein, the weight ratio of the water-soluble polymer to the liposome or bilayer lipid in the composition is in the range of 20:1 to 1:20, or 10:1 to 1:10, or 5:1 to 1:5, or 3:1 to 1:3, or 2:1 to 1:2, and may include any intermediate and lower ranges in between or be about 1:1.

[0516] According to some of the embodiments described herein, a water-soluble polymer (e.g., hyaluronic acid) does not form part of the composition, but rather is used in combination with the (e.g., sterile) composition in any one of the methods and uses described herein. For example, the water-soluble polymer is co-administered to the subject along with the composition and the implantation of the implantable device. The water-soluble polymer may be administered before, simultaneously with, or after the administration of the composition of the present embodiment.

[0517] When the composition described herein is used to treat the medical condition described herein, the composition may further comprise one or more therapeutic active agents (e.g., according to any one of the respective embodiments described herein). Alternatively, the therapeutic active agent does not form part of the composition but is rather used in combination with the (e.g. sterile) composition in any one of the methods and uses described herein. For example, the therapeutic active agent is co-administered to the subject with the composition and optionally with the water-soluble polymer described herein, and with the implantation of an implantable device. The therapeutic active agent may be administered before, simultaneously with, or after the administration of the composition of the embodiment.

[0518] Examples of suitable therapeutic active agents in the context of the present embodiment include, without limitation, analgesics and anti-inflammatory agents.

[0519] Examples of suitable analgesics include, without limitation, allylprodine, alpha-methylfentanyl, AP-237, vegitramide, butorphanol, buprenorphine, carfentanil, clonidine, codeine, desmethylprodine, dextromoramide, dexosin, diphenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, diphenoxylate, dipipanone, eluxadoline, ethylmorphine, etorphine, fentanyl, heterocodeine, hydrocone, hydromorphone, ketamine, ketovemidone, repetamine, levomethadyl (e.g., levomethadyl acetate), levomethorphan, levorphanol, loperamide, meptaginol, methadone, mexiletine, mitraginine, morphine, nalbuphine, omefentanil, oxycodone. Oxymorphone, paracetamol, pentazocine, pethidine, phenethylphenylacetoxypiperidine, pyritramide, prodine, promedol, propoxyphen, remifentanil, sulfentanil, tapentadol, tylidine, and tramadol are included.

[0520] Not only non-steroidal anti-inflammatory drugs (e.g., non-steroidal anti-inflammatory drugs described herein) but also steroidal anti-inflammatory drugs can be used as analgesics.

[0521] Examples of suitable anti-inflammatory agents include, without limitation, the following: alclofenac; alclomethasone (e.g., alclomethasone dipropionate); aceton (e.g., acetonide); alpha-amylase; amhimnapal; amhimnafide; amfenac (e.g., amfenac sodium); amiprylos (e.g., amiprylos hydrochloride); anakinla; anirolac; anitrazafen; apazone; aspirin; valsalazide disodium; bendazac; benoxaprofen; benzidamine (e.g., benzidamine hydrochloride); bromelain; broperamol; budesonide; caprofen; cycloprofen; syntazone; cliprofen; clobetasol (e.g., clobetasol propionate, clobetasone butyrate); clopyrac; cloticasone (cloticassome propionate); cormethasone (cormethasone acetate); cortoxone; Deflazacort; Desonide; Desoximethasone; Dexamethasone (e.g., Dexamethasone Dipropionate); Diclofenac (e.g., Diclofenac Potassium, Diclofenac Sodium); Diflorasone (e.g., Diflorasone Diacetate); Diflumidone (e.g., Diflumidon Sodium); Diflunisal; Diflupredate; Diphthalone; Drosinonide; Endrisone; Enrimomab; Enolicam (e.g., Enolicam Sodium); Epirizole; Etodolac; Etopenamate; Felbinac; Fenamol; Fenbufen; Penclofenac; Penclolac; Pendosal; Fenpipalon; Pentiazac; Plazaron; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide (e.g., Flunisolide Acetate); Flunixine (e.g., Flunixine Meglumine); Fluocortin (e.g., fluorocortin butyl); fluorometholone (e.g., fluorometholone acetate); fluquazone; flurbiprofen; fluoretofen; fluticasone (e.g., fluticasone propionate); furaprofen; furoffen; halcinodide; halobetasol (e.g., halobetasol propionate); halopredone (e.g., halopredone acetate); ibufenac; ibuprofen (e.g., ibuprofen aluminum, ibuprofen piconol); ilonidab; indomethacin (e.g., indomethacin sodium); indoprofen; indoxol; intrazol; isoflupredone (e.g., isoflupredone acetate); isoxepak; isoxicam; ketoprofen;Lofemizole (e.g., Lofemizole hydrochloride); Romoxicam; Loteprednol (e.g., Loteprednol etabonate); Meclofenamate (e.g., Meclofenamate sodium, Meclofenamic acid); Meclorisone (e.g., Meclorisone dibutyrate); Mefenamic acid; Mesalamine; Meseclazone; Methylprednisolone (e.g., Methylprednisolone suleptanate); Momiflumate; Nabumetone; Naproxen (e.g., Naproxen sodium); Naproxol; Nimazone; Olsalazine (e.g., Olsalazine sodium); Orgotein; Orpanoxin; Oxaprozine; Oxyfenbutazone; Paraniline (e.g., Paraniline hydrochloride); Pentosan polysulfate (e.g., Pentosan polysulfate sodium); Phenylbutazone (e.g., Phenylbutazone sodium glycerate); Pirfenidone; piroxicam (e.g., piroxicam cinnamate, piroxicam olamin); pirprofen; prednazate; prepelon; prodolsan; proquazone; proxazole (e.g., proxazole citrate); rimexolone; romasalite; salcolex; salicylates (e.g., salicylic acid); salnacedine; salsalate; Sanguinarium (e.g., Sanguinarium chloride); seclazone; cermethacin; sudoxicam; sulindac; suprofen; talmethacin; talniflumate; talosalate; tebupelon; tenidaf (e.g., tenidaf sodium); tenoxicam; tesicam; tesimide; tetridamine; thiopinaq; thixocortol (e.g., thixocortol pivalate); tolmetine (e.g., tolmetine sodium); triclonide; triflumidate; zidomethacin; and zomepirac (e.g., zomepirac sodium) are included.;

[0522] Alternatively or additionally, according to any one of the embodiments, the liposomal composition described herein is co-administered to a subject together with the therapeutic active agent described herein.

[0523] According to one aspect of some embodiments of the present invention, a kit is provided comprising a composition according to each of the embodiments described herein and any combination thereof, or a component for preparing a composition. The kit may comprise, for example, dehydrated liposomes and a suitable aqueous solution, optionally a water-soluble polymer and / or a therapeutic active agent and / or an additional agent (e.g., sterol), each of which is individually packaged within the kit and includes, for example, instructions for mixing all components to prepare a composition. Alternatively, the kit may comprise a polymer compound and a bilayer-forming lipid, a suitable aqueous solution, optionally a water-soluble polymer and / or a therapeutic active agent and / or an additional agent (e.g., sterol), each of which is individually packaged within the kit and includes, for example, instructions for mixing all components to prepare a composition. Alternatively, the kit may comprise a ready-to-use composition according to any one of the embodiments described herein. If the composition further comprises a water-soluble polymer, the water-soluble polymer may be included in the composition or individually packaged within the kit, and instructions are provided for mixing it with the composition or co-administering it with the composition as described herein. Alternatively, the kit may include instructions for co-administering the composition and the water-soluble polymer as described herein. The kit may alternatively include a polymer compound and a bilayer-forming lipid, optionally a water-soluble polymer and / or a therapeutic active agent and / or additional agents (e.g., sterols), each of which is individually packaged within the kit, and includes instructions for preparing the composition by mixing all components simultaneously or sequentially in the presence of a suitable aqueous solution. For example, the kit may include instructions for mixing the polymer compound and the bilayer-forming lipid with an aqueous solution to first form a liposome or lipid bilayer, and, if desired, adding additional components to the formed composition.The kit may further include instructions for sterilizing the manufactured or packaged composition before use as described herein (except where the sterilized composition is already packaged in the kit).

[0524] According to any one of the embodiments, the kit described herein may further include instructions for using the composition in combination with the implantable device according to any one of the embodiments described herein and / or instructions for use in any one of the methods or uses described herein according to any one of the embodiments described herein, for example, instructions for reducing wear on the implantable device and / or treating a condition that can be treated by implanting the device. According to any one of the embodiments, the kit described herein may further include the implantable device described herein individually packaged within the kit.

[0525] According to one aspect of some embodiments of the present invention, a kit is provided comprising a composition according to each of the embodiments and any combination thereof described herein and an implantable device according to each of the embodiments and any combination thereof described herein. In some embodiments, the composition comes into contact with the implantable device and is, for example, a solution in which the device is immersed.

[0526] Method and Use:

[0527] According to any one of the embodiments, the composition described herein is intended to be used in combination with an implantable device (also referred to herein as an "implant") during the process of implanting the device into a subject who requires it. According to some of the embodiments, the composition is intended to reduce wear on the implantable device during implantation.

[0528] The subject may be a human or a non-human animal, and therefore the expression "medical device" includes veterinary devices.

[0529] According to one aspect of some embodiments of the present invention, compositions according to each of the embodiments described herein and any combination thereof are provided for use in combination with an implantable device (implant). According to some embodiments, the composition is used in combination with the device while implanting the implantable device to a subject who requires it. According to some embodiments, the composition is administered to a subject while implanting the implantable device to a subject who requires it. According to some embodiments, the composition forms a part of the implantable device (e.g., at least a part of the implantable device, for example, deposited on at least a part of the surface of the implantable device).

[0530] According to one aspect of some embodiments of the present invention, a composition according to any one of the embodiments described herein may be used in combination with an implantable device (implant) or is provided for use in the manufacture of a medicine or medical device for use. According to some embodiments, the composition is used in combination with an implantable device while implanting the implantable device to a subject who requires it. According to some embodiments, the composition is administered to a subject while implanting the implantable device to a subject who requires it. According to some embodiments, the composition forms a part of the implantable device (e.g., is deposited on at least a part of the implantable device).

[0531] According to one aspect of some embodiments of the present invention, a method for implanting an implantable device (implant) to a subject in need thereof is provided, said method comprising the step of co-administering a composition and an implantable device according to each of the embodiments described herein and any combination thereof to the subject. According to some embodiments, the composition is used in combination with the implantable device while implanting the implantable device to the subject in need thereof. According to some embodiments, the composition is administered to the subject while implanting the implantable device to the subject in need thereof. According to some embodiments, the composition forms a part of the implantable device (e.g., deposited on at least a part of the implantable device).

[0532] As used herein, the expression “during implantation of the implantable device” means that the composition is administered to the subject before, simultaneously with, and / or after implantation of the implantable device. The composition may be administered during a period from 1 minute before to 1 day before implantation, or during a period from 1 minute after to 1 day after implantation, or may be administered while the device is implanted during the implantation process. The composition may be administered both before and after implantation, or before and simultaneously with implantation, or simultaneously with implantation and after implantation, or before, simultaneously with, and after implantation.

[0533] According to some of the embodiments described herein, the composition is administered topically to the body part or surrounding area where the implantable device is implanted.

[0534] According to some of the embodiments described herein, the composition is re-administered after implantation as needed while the implant is in the subject's body. In exemplary embodiments, the composition is repeatedly re-administered to the subject at time intervals of 1 week to 1 year, or 1 month to 1 year, or 1 month to 6 months as needed after implantation, including any intermediate and sub-ranges in between, including the time from implantation and the time between administration. The time intervals may be the same or different.

[0535] Implantable devices or implants may be permanent or temporary implants and include, but are not limited to, joint prostheses, pacemakers, heart valves, catheters (e.g., urinary catheters, intravascular catheters), catheter access ports, dialysis tubes, gastric bands, shunts, screw plates, artificial spinal disc replacements, internally implantable defibrillators, cardiac resynchronization therapy devices, implantable heart monitors, mitral valve ring repair devices, left ventricular assist devices (LVADs), artificial hearts, implantable infusion pumps, implantable insulin pumps, stents, implantable nerve stimulators, maxillofacial implants, dental implants, injection ports, intubation devices, dialysis shunts, wound drainage tubes, skin sutures, vascular grafts, implantable meshes, intraocular devices, heart valves, medical devices for drug delivery, such as needles, drug delivery skin patches, drug delivery mucosal patches and medical sponges, intrauterine devices (IUDs), diaphragms and condoms.

[0536] In the context of a medical device, it should be understood that where a medical device is coated with a lipid bilayer as described herein, the lipid bilayer or the liposome itself comprising the bilayer is not considered a medical device herein.

[0537] Implantable devices particularly suitable for use in the context of the present embodiment include, but are not limited to, implants and / or wear-exposed implants intended to be maintained in a body part of the subject for at least one week, namely implants that are susceptible to wear and / or are susceptible to wear as a result of physical forces during movement or load-bearing, and / or implants that are susceptible to chemical degradation due to diffusion of proteins and / or lipids and / or cutting or microbial contamination.

[0538] According to some of the embodiments described herein, the implantable device is a wear-exposed implantable device, that is, a device that is exposed to wear as a result of physical forces during movement or load-bearing upon implantation. Depending on the body part where the device is implanted, the device is considered wear-exposed if implanted in a body part that is typically exposed to compressive forces ranging from 1 to 5 times the target body weight and / or shear forces, tensile forces, and / or rotational forces as a result of movement or other activities. Exposure to these forces may occur during movement, standing, lifting, and / or any other activities and / or at rest.

[0539] According to some of the embodiments described herein, the implantable device or the material used to form the implantable device is characterized by high rigidity.

[0540] In some embodiments, the implantable device or the material used to form the implantable device is characterized by an elastic modulus of at least 0.5 GPa, or at least 1 GPa, preferably at least 10 GPa, or at least 20 GPa, or at least 50 GPa, or at least 100 GPa, for example, 1 to 500, or 10 to 500, or 50 to 500, or 100 to 500, or 1 to 400, or 10 to 400, or 50 to 400, or 100 to 400, or 1 to 300, or 10 to 300, or 50 to 300, or 100 to 300 GPa, and includes any intermediate values ​​and sub-ranges therebetween.

[0541] In some embodiments, the implantable device or the material used to form the implantable device is characterized by a tensile strength of at least 20 MPa, or at least 50 MPa, or at least 100 MPa, or at least 200 MPa, or at least 300 MPa, or at least 400 MPa, or at least 500 GPa, or at least 800 MPa, for example, 100 to 2,000, or 100 to 1,500, or 500 to 200, or 500 to 1,500, or 800 to 2,000, or 800 to 1,500 MPa, and includes any intermediate values ​​and sub-ranges therebetween.

[0542] In some embodiments, the implantable device or the material used to form the implantable device is characterized by an elastic modulus of at least 0.5 GPa, or at least 1 GPa, or at least 10 GPa, or at least 20 GPa, or at least 50 GPa, or at least 100 GPa, e.g., 1 to 500, or 10 to 500, or 50 to 500, or 100 to 500, or 1 to 400, or 10 to 400, or 50 to 400, or 100 to 400, or 1 to 300, or 10 to 300, or 50 to 300, or 100 to 300 GPa, including any intermediate values ​​and sub-ranges therebetween, and also at least 20 MPa, or at least 50 MPa, or at least 100 MPa, or at least 200 MPa, or at least 300 It is characterized by a tensile strength of MPa, or at least 400 MPa, or at least 500 GPa, or at least 800 MPa, for example, 100 to 2,000, or 100 to 1,500, or 500 to 200, or 500 to 1,500, or 800 to 2,000, or 800 to 1,500 MPa.

[0543] In the present invention and the art, the term "elastic modulus" refers to the Young's modulus determined by the material's response to the application of tensile stress.

[0544] The elastic modulus is determined by the slope as a function of stress to strain in a stress and strain range where stress is a linear function of strain (e.g., from the point where stress and strain are zero to the elastic proportional limit, and optionally from zero strain to a strain less than or equal to 50% of the elongation at fracture). Depending on the material and test conditions, the elastic modulus can be determined using standard mechanical test methods such as tensile, compression, or bending tests. Exemplary standard methods include ASTM D638, typically used for plastics and hydrogels; ASTM D624, typically used for rubbery elastic materials; ASTM D3039, typically used for fiber-reinforced polymer matrix composites; and ASTM E111, typically used for metals and alloys.

[0545] In this application and in the art, the term "tensile strength" describes the resistance of a material to tension, that is, the material's ability to withstand loads that induce elongation, and is defined as the maximum stress in MPa applied during elongation before the elastic composite ruptures. Tensile strength is typically measured by a tensile test and is determined by the peak of the stress-strain curve as described in this application and in the art. Tensile strength represents the maximum stress that a material can withstand when elongated or stretched before fracture. Depending on the material being tested, tensile strength may also be determined according to, for example, ASTM D-638, ASTM D624, ASTM E8, or ASTM D2370.

[0546] According to some of the embodiments described herein, the implantable device or the material used to form the implantable device is characterized by a fatigue resistance of at least 10 MPa, preferably at least 20 MPa, or at least 40 MPa, or at least 50 MPa, or at least 100 MPa, e.g., 10 to 1,000, or 10 to 500, or 20 to 1,000, or 20 to 800, or 20 to 500 MPa, and includes any intermediate values ​​and sub-ranges therebetween.

[0547] "Fatigue resistance" refers to the repetitive mechanical stress that a device or material can withstand before failure (e.g., crack initiation and propagation due to cyclic stress). This can be measured using pin-on-disk measurements or according to standard analysis methods such as ISO 7206-4.

[0548] According to some of the embodiments described herein, the implantable device is intended for use in replacement therapy and is a prosthetic implant such as a joint replacement device or a spinal disc replacement device, or a prosthetic implant comprising such a device.

[0549] According to some of the embodiments described herein, the implantable device is or includes a total joint replacement device used for, for example, a hip, knee, shoulder, elbow, or ankle replacement. In exemplary embodiments, the total joint replacement is the replacement of the knee or hip, which is a major load-bearing joint. According to these embodiments, the composition is used for total joint replacement treatment during a total joint replacement procedure.

[0550] According to some of the embodiments described herein, the implantable device is an orthopedic implantable device, e.g., an implantable screw, plate and pin, and any other device used in orthopedic procedures.

[0551] According to some of the embodiments described herein, the implantable device is a solid implantable device.

[0552] According to some of the embodiments described herein, the implantable device is in a liquid state before and during insertion into the subject's body and hardens as a result of exposure to conditions affecting hardening upon implantation and / or as a result of a chemical reaction with a biological component. For example, the implantable device may be a liquid that forms a gel upon contact with a biological component. For example, the implantable device may be a liquid that polymerizes upon contact with a biological component or upon contact with a component administered together with it through a chemical reaction optionally combined with, for example, external energy (e.g., heat or irradiation). For example, the implantable device may be a photocurable or thermocurable liquid or gel that hardens upon implantation and application to the implantation site or upon application of irradiation and / or heat. For example, the implantable device may be manufactured from a thermocurable material or a reverse thermal gelling material that hardens at physiological temperatures. Any other device that may be implanted in liquid form (e.g. by injection) and subsequently hardened to form a solid or semi-solid implant in vivo is also considered.

[0553] According to some of the embodiments described herein, the implantable device is a biodegradable or bioabsorbable device, and in some of these embodiments, the device degrades or is absorbed from the subject's body within a period of one week to several years, or one month to several years, or one year to several years, and includes any intermediate and sub-ranges in between.

[0554] Any commercially available implantable device is included within the scope of this embodiment.

[0555] Any commercially available joint replacement device is included within the scope of this embodiment.

[0556] Any commercially available knee or hip replacement device is included within the scope of this embodiment.

[0557] According to some of the embodiments described herein, the implantable device is manufactured from or comprises one or more of polymeric materials, biological materials (e.g., proteinaceous materials, ECM components), metallic materials, and ceramic materials.

[0558] According to some of the embodiments of any of the embodiments described herein, the implantable device is manufactured of or comprises a material capable of withstanding compressive force as described herein and / or characterized by a high modulus of elasticity and / or tensile strength as described herein.

[0559] Exemplary polymeric materials include, but are not limited to, polyethylene (e.g., the ultra-high molecular weight polyethylene described herein), biomedical polyurethanes and / or polyurethaneureas (which may be in solid or solution form), polyester amides such as degradable polyester amides, and any other biodegradable polymers and / or polymers used for coating medical devices (e.g., hydrophilic polymers). Any of these materials may be in the form of fibers, films, meshes and / or membranes, or may be in a polymerizable or curable form that hardens upon implantation as described herein. Preferably, the polymeric material exhibits the mechanical properties described herein for the implantable device.

[0560] Exemplary biological materials include, but are not limited to, materials used for bone filling or regeneration, tissue repair, tissue augmentation, or tissue regeneration, and include, for example, extracellular matrix (ECM) components such as proteinaceous materials, preferably collagen, and the collagen may be derived from human, porcine, or bovine sources, or manufactured by synthetic or recombinant methods. Preferably, the biological material exhibits the mechanical properties described herein for the implantable device.

[0561] Exemplary ceramic materials include reabsorbable and non-reabsorbable materials, hardenable or non-hardenable materials, and inorganic bone materials. Preferably, the ceramic material exhibits the mechanical properties described herein for the implantable device.

[0562] Exemplary metallic materials include, but are not limited to, metals such as cobalt, chromium, cobalt-chromium (CoCr), titanium, platinum, stainless steel, and any alloy comprising any one of the foregoing. Preferably, the metallic material exhibits the mechanical properties described herein for the implantable device.

[0563] According to some of the embodiments described herein, the implantable device comprises polyethylene, preferably ultra-high molecular weight polyethylene as described herein, which may be cross-linked, partially cross-linked, or non-cross-linked, and may be in the form of a fiber, film, mesh and / or membrane, or may be a polymerizable or curable material.

[0564] According to some of the embodiments described herein, any one of the methods and uses described herein is intended to treat a condition treatable by the implantation of the implant described herein. According to such embodiments, the composition described herein is intended to improve treatment by reducing wear on the implant, improving performance, stability and / or durability, and / or preventing contamination of the implant. According to such embodiments, the composition described herein is intended to be used in combination with an implantable device when treating a condition.

[0565] According to some of the embodiments described herein, the composition is used in combination with a joint replacement device in a total joint replacement procedure and is intended to treat medical conditions associated with joint defects or damage. According to some of these embodiments, the composition is administered via intra-articular administration. Alternatively or additionally, the composition is administered locally to the implantation site during surgery.

[0566] According to some embodiments, the method or use described herein is for treating synovial joint disorders.

[0567] Examples of treatable synovial joint disorders according to embodiments of various aspects of the present invention include, without limitation, arthritis (e.g., osteoarthritis, rheumatoid arthritis and / or psoriatic arthritis), bursitis, carpal tunnel syndrome, fibromyositis, gout, joint locking (optionally associated with osteochondritis dissecans and / or synovial osteochondromatosis), tendinitis, traumatic joint injury (optionally associated with direct injury caused by trauma, e.g., during trauma, and / or caused by prior trauma, e.g., post-traumatic injury occurring some time after trauma), and joint injury associated with surgery (optionally associated with surgery that directly damages the joint surface by incision and / or surgery that damages the joint surface only indirectly; for example, surgery that repairs or otherwise affects tissues surrounding the joint, such as ligaments and / or menisci, may be associated with joint injury due to altered joint mechanics). Osteoarthritis is an exemplary treatable synovial joint disorder according to some embodiments of the present invention.

[0568] According to one aspect of some embodiments of the present invention, a method for treating synovial joint disorders in a subject requiring such treatment is provided, the method comprising the step of administering a sterile composition according to each embodiment and any combination thereof described herein to a subject in combination with implanting a joint replacement device in the subject according to each embodiment and any combination thereof described herein.

[0569] In some of the embodiments of each example, the treatment of synovial joint disorders (e.g., osteoarthritis) is characterized by the improvement of joint physiology.

[0570] In some of the embodiments, improvement in joint physiology is determined by the range of motion of the affected joint (e.g., improvement is characterized by an increase in the range of motion of the joint), optionally further characterized by a reduction in severity according to the Kehlgren-Laurence scale. In some of these embodiments, treatment is further characterized by a reduction in pain.

[0571] In some of the embodiments, improvement in joint physiology is characterized by an increase in physical activity (e.g., activity involving the affected joint) and optionally further characterized by a reduction in severity and / or an increase in range of motion according to the Kehlgren-Laurence scale (e.g., according to any one of the embodiments described herein). In some of these embodiments, treatment is further characterized by a reduction in pain.

[0572] In some of the embodiments of each example, improvement in joint physiology is characterized by an increase in quality of life and optionally further characterized by a reduction in severity according to the Kehlgren-Laurence scale, an increase in range of motion and / or an increase in physical activity (e.g., according to any one of the embodiments described herein). In some of these embodiments, treatment is further characterized by a reduction in pain.

[0573] In some of the embodiments, improvement in joint physiology is determined by at least one, or at least two, or at least three or four of the radiographic severity Kehlgren-Laurence scale, range of motion of the joint, physical activity, and quality of life (according to any one of the embodiments described herein). In some of these embodiments, treatment is further characterized by pain reduction.

[0574] In any one of the methods and uses described herein, the implantation procedure may involve the administration of a water-soluble polymer and / or a therapeutic active agent according to any one of the embodiments described herein. These may be administered before implantation, simultaneously with implantation and / or after implantation and / or before, simultaneously with, and / or after the administration of the composition of the present embodiment.

[0575] According to one aspect of some embodiments of the present invention, a method for reducing wear of an implantable device according to any one of the embodiments described herein is provided, said method being constructed or performed by the combined use of the composition and the device described herein, for example by co-administering the composition during implantation of the device according to each of the embodiments described herein and any combination thereof.

[0576] According to some embodiments of the present invention, a kit is provided comprising a composition described herein and optionally combined with a water-soluble polymer and / or a therapeutic active agent described herein. The kit may be identified for use in combination with an implantable device or may comprise a device and / or a material used to form the device. Such a kit may also be identified for use in the pin-on-disk measurements described herein.

[0578] Pin-on-Disk:

[0579] According to any one of the embodiments, the compositions described herein may be used as test fluids in other acceptable and standardly recognized methods for evaluating the wear resistance of wear measurement systems, such as pin-on-disk devices, or implantable devices.

[0580] According to some embodiments of the present invention, a composition according to any one of the embodiments described herein or a kit described herein containing the same is provided for use in measuring wear of an implantable device described herein. In some embodiments, the wear measurement is a pin-on-disk measurement.

[0581] According to some embodiments of the present invention, a pin-on-disk system is provided comprising a composition according to each of the embodiments described herein and any combination thereof.

[0582] Any pin-on-disk system or configuration is considered.

[0583] In some embodiments, the pins of the pin-on-disk system comprise one or more of the materials used to form an implantable device or implant according to each of the embodiments described herein and any combination thereof.

[0584] In some embodiments, these pins are assembled with a disk suitable for providing a pin-on-disk system as well known in the art and illustrated in FIG. 1A-B.

[0585] Generally, a pin-on-disk tribology test system comprises a disk mounted on a rotary drive mechanism; a pin held in a fixture and pressed against the surface of the disk with a controlled vertical force; and a load mechanism for applying a controlled vertical force to the pin.

[0586] A pin-on-disk tribology test system typically includes means for measuring the frictional force between the pin and the disc, and optionally further includes a data acquisition system for recording the frictional force, wear measurements, and other parameters measured during the test. The system may further include an environment control chamber configured to control temperature and humidity during the test.

[0587] When the pin-on-disk system is activated, the disk rotates at a speed controlled by the motor. The direction of rotation can be adjusted as desired.

[0588] The disc is typically a flat rotating surface made of the material described herein. The disc is mounted on a rotating assembly driven by a motor or a similar rotating mechanism. The surface of the disc is typically smooth and polished, but variations in surface texture or coating may be used depending on test requirements. The disc is typically positioned horizontally, but alternative orientations may be used depending on specific test conditions.

[0589] The pin is a test specimen of cylindrical or other geometric shape and is manufactured from a material similar to or representative of the material typically tested (potential material for forming the implantable device or implant described herein). The pin is held in a fixture on a rotating disk and pressed to contact the disk surface under a controlled vertical load. The pin may be oriented perpendicular to the disk surface, but variations in alignment may be made to test different wear scenarios. The pin typically has a smaller diameter than the disk and forms a localized contact area.

[0590] A loading mechanism is typically a device configured to apply a controlled and adjustable vertical force to a pin to press the pin against the surface of a disc. The loading mechanism may include a spring-loaded assembly, a pneumatic actuator, or other force-generating system capable of providing precise force control. The load is typically maintained constant throughout the entire test period or may be changed to simulate different operating conditions.

[0591] The disc is rotated by a motor or other drive assembly to enable controlled rotation of the disc surface in contact with the pin. The rotational speed of the disc can be adjusted to simulate different wear and friction rates.

[0592] Wear can be quantified by measuring the volume or mass loss of the pins and / or discs after a predetermined number of test cycles. High-precision devices, such as laser scanning or optical profilometers, can be used to measure wear mark depth, surface roughness, or other related wear indicators.

[0593] A computer-based control system can be used to coordinate the movement of the disk, the application of loads, environmental conditions, and data collection. The system may also include software for analyzing wear patterns, calculating wear rates, and determining the relationship between friction and wear under different test conditions. The control system can store test data and generate reports on the performance of the tested material.

[0594] As used herein, the term “subject” includes mammals of any age suffering from a pathology, preferably humans. Preferably, this term includes individuals at risk of developing the pathology.

[0595] It is expected that many technologies related to implantable devices, materials included in implantable devices, and systems and methods for measuring wear of implantable devices will be developed during the term of the patent to be registered from this application, and the scope of such terms and expressions is intended to include all such new technologies in advance.

[0596] The term "about" as used here means ±10% or ±5%.

[0597] "Includes," "includes," "includes," "has," and their conjugated forms mean "includes but is not limited thereto."

[0598] The term "composed" means "including and limited thereto."

[0599] The term “essentially made” means that the composition, method, or structure may include additional components, steps, and / or parts, but only if such additional components, steps, and / or parts do not substantially alter the fundamental and novel nature of the claimed composition, method, or structure.

[0600] As used herein, the singular forms "a," "an," and "the" include plural objects unless the context clearly indicates otherwise. For example, the term "compound" or "at least one compound" may include plural compounds, including mixtures thereof.

[0601] Throughout this application, various embodiments of the invention may be presented in the form of ranges. It should be understood that descriptions in the form of ranges are merely for convenience and brevity and should not be interpreted as inflexible limitations on the scope of the invention. Accordingly, descriptions of ranges should be deemed to specifically disclose individual numbers within the range as well as all possible sub-ranges. For example, descriptions of ranges such as 1 to 6 should be deemed to specifically disclose individual numbers within the range, such as 1, 2, 3, 4, 5, and 6, as well as sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc. This applies regardless of the width of the range.

[0602] Whenever a numerical range is indicated herein, it means that any cited numerical value (fraction or integer) within the indicated range. The expressions “range / ranges” between the first indicated numerical value and the second indicated numerical value and “range / ranges” from the first indicated numerical value to the second indicated numerical value are used interchangeably herein and mean that the first and second indicated numerical values ​​and all fractional and integer values ​​in between are included.

[0603] As used herein, the term “method” refers to a method, means, technique, and procedure for achieving a given task, which includes, but is not limited to, methods, means, techniques, and procedures known or readily developed from methods, means, techniques, and procedures known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry, and medicine.

[0604] The term "treating" refers to inhibiting, preventing, or halting the progression of a pathological condition (disease, disorder, or state) and / or causing a reduction, alleviation, or regression of the pathology. Those skilled in the art will understand that various methodologies and analytical methods may be used to evaluate the occurrence of a pathology, and similarly, various methodologies and analytical methods may be used to evaluate the reduction, alleviation, or regression of the pathology.

[0605] As used in this institution, the term "preventive" refers to preventing the occurrence of a disease, disability, or condition in subjects who may be at risk of disease but have not yet been diagnosed with the disease.

[0606] In this document, the term “hydrocarbon” describes an organic portion comprising a basic framework of chains of carbon atoms mainly substituted with hydrogen atoms. The hydrocarbon may be saturated or unsaturated, may consist of an aliphatic, alicyclic, or aromatic portion, and may optionally be substituted with one or more substituents (other than hydrogen). The substituted hydrocarbon may have one or more substituents, and each group of substituents may 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, carboxyl, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The hydrocarbon may be a terminal or linker as defined herein. The hydrocarbon portion may be optionally interrupted by one or more heteroatoms comprising one or more oxygen, nitrogen, and / or sulfur atoms without limitation. In some of the embodiments described herein regarding the hydrocarbon, the hydrocarbon is not interrupted by any heteroatoms.

[0607] Preferably, the hydrocarbon portion has 1 to 20 carbon atoms. Whenever a numerical range, for example, “1 to 20” is mentioned herein, it means that a group such as an alkyl group in this case may have up to 20 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc.

[0608] In this document, the term “alkyl” describes 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 an intermediate alkyl having 1 to 10 carbon atoms. Unless otherwise indicated, most preferably, the alkyl is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. The substituted alkyl may have one or more substituents, and each group of substituents may independently be, for example, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterodicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0609] The term "alkylene" describes a saturated aliphatic hydrocarbon linker as defined herein, and differs from the alkyl group defined herein only in that the alkylene is a linker rather than a terminal group.

[0610] In this document, the term “alkenyl” describes an unsaturated aliphatic hydrocarbon terminal group comprising at least one carbon-carbon double bond, including straight chains and branched chains. Preferably, the alkenyl group has 2 to 20 carbon atoms. More preferably, the alkenyl is an intermediate alkenyl having 2 to 10 carbon atoms. Unless otherwise indicated, most preferably, the alkenyl is a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group may be substituted or unsubstituted. The substituted alkenyl may have one or more substituents, and each group of substituents may independently be, for example, cycloalkyl, alkynyl, aryl, heteroaryl, heterodicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0611] In this document, the term “alkynyl” describes an unsaturated aliphatic hydrocarbon terminal group comprising one or more carbon-carbon triple bonds, including straight chains and branched chains. Preferably, the alkynyl group has 2 to 20 carbon atoms. More preferably, the alkynyl is an intermediate alkynyl having 2 to 10 carbon atoms. Unless otherwise indicated, most preferably, the alkynyl is a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group may be substituted or unsubstituted. The substituted alkynyl may have one or more substituents, and each group of substituents may independently be, for example, cycloalkyl, alkenyl, aryl, heteroaryl, heterodicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0612] The term “cycloalkyl” describes a whole-carbon single ring or fused ring (i.e., a ring sharing an adjacent pair of carbon atoms) group in which one or more rings do not have a fully conjugated pi-electron system. Cycloalkyl groups may be substituted or unsubstituted. Substituted cycloalkyls may have one or more substituents, and each group of substituents may independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterodicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The cycloalkyl group may be a terminal group as defined herein, in which case it may be attached to one adjacent atom or a linker as defined herein, and may connect two or more parts.

[0613] The term “aryl” describes an all-carbon single-ring or fused-ring polycyclic (i.e., a ring sharing an adjacent pair of carbon atoms) terminal group having a fully conjugated pi-electron system (as defined herein). The aryl group may be substituted or unsubstituted. A substituted aryl may have one or more substituents, and each group of substituents may independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterodicyclic, 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 terminal groups.

[0614] The term “heteroaryl” describes a monocyclic or fused ring (i.e., a ring sharing an adjacent pair of atoms) group having one or more atoms, such as nitrogen, oxygen, and sulfur, in the ring(s), and additionally having a fully conjugated pi-electron system. Examples of heteroaryl groups include, without limitation, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, and purine. Heteroaryl groups may be substituted or unsubstituted. The substituted heteroaryl may have one or more substituents, and each group of substituents may independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterodicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The heteroaryl group may be a terminal group as defined herein, in which case it is attached to one adjacent atom, or may be a linker as defined herein, and connects two or more parts. Representative examples include pyridine, pyrrole, oxazole, indole, purine, etc.

[0615] The term "arylene" describes a monocyclic or fused ring polycyclic linker as defined herein, and includes linkers other than aryl or heteroaryl groups defined herein only in that the arylene is a linker rather than a terminal group.

[0616] The term "heterocyclic" describes a monocyclic or fused ring group having one or more atoms, such as nitrogen, oxygen, and sulfur, in the ring(s). The ring may also have one or more double bonds. However, the ring does not have a fully conjugated pi-electron system. Heterocyclic groups may be substituted or unsubstituted. Substituted heterocyclic groups may have one or more substituents, and each group of substituents may independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, 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 heterocyclic group may be a terminal group as defined herein, in which case it may be attached to one adjacent atom or a linker as defined herein, and connects two or more parts. Representative examples include piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine, etc.

[0617] As used herein, the terms “amine” and “amino” describe both the -NRxRy terminal group and the -NRx- linker, wherein Rx and Ry are each independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic as defined herein. If Rx or Ry is heteroaryl or heterocyclic, the amine nitrogen atom is bonded to a carbon atom of the heteroaryl or heterocyclic ring. The carbon atom attached to the nitrogen atom of the amine is not substituted with =O or =S, and in some embodiments, is not substituted with any heteroatom.

[0618] Therefore, the amine group may be a primary amine, in which case both Rx and Ry are hydrogen, or a secondary amine, in which case Rx is hydrogen and Ry is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic, or a tertiary amine, in which case Rx and Ry are each independently alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic.

[0619] The terms "hydroxy" and "hydroxyl" describe the -OH group.

[0620] The term "alkoxy" describes all -O-alkyl and -O-cycloalkyl terminal groups, or -O-alkylene or -O-cycloalkyl linkers, as defined herein.

[0621] The term "aryloxy" describes all -O-aryl and -O-heteroaryl terminal groups, or -O-arylene-linkers, as defined herein.

[0622] The term "thiohydroxy" describes the -SH group.

[0623] The term "thioalkoxy" describes all -S-alkyl and -S-cycloalkyl terminal groups, or -S-alkylene or -S-cycloalkyl linkers, as defined herein.

[0624] The term "thioaryloxy" describes both -S-aryl and -S-heteroaryl terminal groups, or -S-arylene- linkers, as defined herein.

[0625] The terms "cyano" and "nitrile" describe the -C≡N group.

[0626] The term "nitro" describes the -NO2 group.

[0627] The term "Oxo" describes the =O group.

[0628] The term "azide" is -N=N + =N - Explains Qi.

[0629] The term "Azo" describes a -N=N-Rx terminal or -N=N= connector having Rx as defined herein.

[0630] The terms "halide" and "halo" refer to fluorine, chlorine, bromine, or iodine.

[0631] "Phosphate" is -OP(=O)(ORx)-OR Y It refers to a terminal or -OP(=O)(ORx)-O- connector, where Rx and R Y is as defined herein.

[0632] The terms "phosphonyl" and "phosphonate" refer to -P(=O)(ORx)-OR Y It refers to a terminal or -P(=O)(ORx)-O- connector, where Rx and R Y It is as defined herein. The term "phosphinyl" refers to -PRxR Y Refers to Qi, where Rx and R Y is defined as described above.

[0633] The terms "sulfoxide" or "sulfinyl" describe -S(=O)-Rx terminal groups or -S(=O)- linkers, wherein Rx is defined herein.

[0634] The terms "sulfonate" and "sulfonyl" describe -S(=O)2-Rx terminal groups or -S(=O)2- linkers, wherein Rx is defined herein.

[0635] As used herein, the terms "sulfonamide" and "sulfonamido" include both S-sulfonamide and N-sulfonamide terminal groups and -S(=O)2-NRx- linkers.

[0636] The term "S-sulfonamide" refers to Rx and R as defined herein. Y -S(=O)2-NRxR having Y Explains the terminal organ.

[0637] The term "N-sulfonamide" refers to Rx and R as defined herein. Y RxS(=O)2-NR having Y - Explains the terminal stage.

[0638] The term "carbonyl" as used herein describes a -C(=O)-Rx terminal or -C(=O)- linker having an Rx as defined herein.

[0639] The term "acyl" as used herein describes a -C(=O)-Rx terminal group having an Rx as defined herein.

[0640] The term "thiocarbonyl" as used herein describes a -C(=S)-Rx terminal or -C(=S)- linker having an Rx as defined herein.

[0641] The terms "carboxy" and "carboxyl" as used herein include both C-carboxy and O-carboxy terminals and -C(=O)-O- linkers.

[0642] The term "C-carboxy" describes a -C(=O)-ORx terminal group having an Rx as defined herein.

[0643] The term "O-carboxy" describes an -OC(=O)-Rx terminal group having an Rx as defined herein.

[0644] The term "urea" describes a -NRxC(=O)-NRyRw terminal or -NRxC(=O)-NRy- linker having Rx and Ry as defined herein and Rw as defined herein for Rx and Ry.

[0645] The term "thiourea" describes the -NRx-C(=S)-NRyRw terminal or -NRx-C(=S)-NRy- linker, where Rx, Ry, and Rw are as defined herein.

[0646] As used herein, the terms "amide" and "amido" include both C-amide and N-amide terminal groups and -C(=O)-NRx- linkers.

[0647] The term "C-amide" describes a -C(=O)-NRxRy terminal group having Rx and Ry as defined herein.

[0648] The term "N-amide" describes an RxC(=O)-NRy- terminal group having Rx and Ry as defined herein.

[0649] The terms "carbamyl" or "carbamate" as used herein include N-carbamate and O-carbamate terminals and -OC(=O)-NRx- linkers.

[0650] The term "N-carbamate" describes a RyOC(=O)-NRx- terminal group having Rx and Ry as defined herein.

[0651] The term "O-carbamate" describes an -OC(=O)-NRxRy terminal group having Rx and Ry as defined herein.

[0652] The terms "thiocarbamyl" or "thiocarbamate" as used herein include O-thiocarbamate, S-thiocarbamate, and N-thiocarbamate terminals and -OC(=S)-NRx- or -SC(=O)-NRx- linkers.

[0653] The terms "O-thiocarbamate" and "O-thiocarbamyl" describe -OC(=S)-NRxRy terminal groups having Rx and Ry as defined herein.

[0654] The terms "S-thiocarbamate" and "S-thiocarbamyl" describe -SC(=O)-NRxRy terminal groups having Rx and Ry as defined herein.

[0655] The terms "N-thiocarbamate" and "N-thiocarbamyl" describe RyOC(=S)NRx- or RySC(=O)NRx- terminal groups having Rx and Ry as defined herein.

[0656] The term "guanidine" describes a -RxNC(=N)-NRyRw terminal or -RxNC(=N)-NRy- linker having Rx, Ry, and Rw as defined herein.

[0657] The term "hydrazine" as used herein describes an -NRx-NRyRw terminal or -NRx-NRy- linker having Rx, Ry, and Rw as defined herein.

[0658] It should be understood that while specific features of the invention have been described in the context of separate embodiments for clarity, they may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may be provided individually, in any suitable sub-combination, or as suitable in any other described embodiment of the invention. Specific features described in the context of various embodiments should not be considered essential features of such embodiments unless the embodiment would not function without such elements.

[0659] The various embodiments and aspects of the present invention described above and the embodiments and aspects claimed in the claims section below find experimental support in the following embodiments.

[0660] Examples

[0661] Now, refer to the following examples, which, together with the description above, illustrate some embodiments of the present invention in a non-limiting manner.

[0662] Example 1

[0663] Design, Materials, and Experimental Methods

[0664] A study was conducted to evaluate the effect of an aqueous composition containing a lipid-polymer conjugate on wear in a pin-on-disk (POD) system.

[0665] POD measurements were performed on an OrthoPOD, model PD-05-06, developed and manufactured by Advanced Mechanical Technology Inc. (AMTI). As shown in Fig. 1A, the POD station used was assembled with cross-linked ultra-high molecular weight polyethylene (UHMWPE) pins (GUR 1020 medical-grade UHMWPE, MW = 2-4 Mg / mol in Examples 2 and 3, and GUR 1050 UHMWPE, MW = 4-6 Mg / mol in Example 4) and CoCr discs immersed inside an acrylic tank with an acrylic cover to prevent lubricant evaporation. All discs were polished to an average roughness Ra ≤ 0.05 ± 0.006 μm. The disc surfaces were visually inspected before and after the test.

[0666] The wear station was programmed to operate at a constant load of 250 N and a frequency of 1.0 Hz in a rectangular pin path. The temperature was maintained at 37±2°C during measurement.

[0667] Parameters such as loading method, sliding distance, contact area, frequency, and temperature were kept constant for all measurements. A constant load of 250 N was applied at a frequency of 1.0 Hz on a rectangular pin path of 10 mm x 15 mm. The temperature was maintained at 37 ± 2°C in all experiments. The volume of the liquid-containing well at each station was 20 mL.

[0668] The measurement period was 0.5 or 2.0 Mc (million cycles), which corresponds to the patient's activity for 3 months or 1 year, respectively.

[0669] In the 2.0 Mc experiment, after every 0.5 Mc interval, all pins were removed, cleaned, and weighed to record the wear of the PE pins, and new lubricant was added. Replacing the lubricant every 0.5 Mc can limit the effect of protein degradation on wear.

[0670] The known wear rate of cross-linked UHMWPE pins used with calf serum (BCS) under similar conditions is 4.987 mg / Mc to 6.008 mg / Mc depending on the exact material constituting the pin [Sui-Lai Wong, Thesis, 2013, cit.].

[0671] Calf serum (BCS) was used as the reference medium. Thawed BCS obtained from Cytiva Hyclone was used.

[0672] The standard BCS solution was diluted with deionized water to a final protein concentration of 20.0 g / L. A 0.2 wt% solution of sodium azide was added as an antimicrobial agent to remove the effects of microbial contamination on abrasion.

[0673] The solution was prepared as follows: Deionized water (DIW) was placed in a beaker and heated to 37.4°C while stirring. After adding EDTA to a final concentration of 20 mM, sodium azide was added to a final concentration of 0.2 wt%. Sodium hydroxide was used to adjust the pH to 6-8 to match the pH of BCS. Subsequently, BCS was added to bring the final protein concentration in the beaker to 20.0 g / L, and the solution was stirred until a homogeneous mixture was obtained.

[0674] Example 2

[0675] A pin-on-disk (POD) test was performed to evaluate the wear performance of a polyethylene (PE) test pin (cross-linked UHMWPE) using an exemplary liposome-containing sterile composition prepared as described in WO 2023 / 031928, also referred to herein as "Aquas Joint" or "AJ". DPPE-dm-pMPC (average 55 MPC units per LPC) was used as the lipid-polymer conjugate, DSPC (distearylphosphocholine) was used as the glycerophosphate lipid bilayer-forming lipid, and the molar ratio of LPC to bilayer-forming lipid in physiological (e.g., PBS) buffer was 0.5:99.5.

[0676] In this setup, a joint simulator simulating cartilage wear in the knee joint was used.

[0677] The test was performed according to ASTM F732-00 / ASTM F2025-06 / ISO 14243-2 (2009).

[0678] Before the start of the test, all discs were ground to an average roughness (Ra) ≤ 0.05±0.006 μm. The pins were weighed before and after the test.

[0679] AJ formulated with a total lipid concentration of 30 mM was designated as a 100% (v / v) solution. AJ formulations diluted to a total lipid concentration of 10 mM were designated as 33% (v / v) AJ. AJ formulations diluted to a total lipid concentration of 5 mM were designated as 17% (v / v) AJ.

[0680] For the preliminary feasibility test, 500,000 cycles (0.5 Mc) were selected as the test period.

[0681] Two POD stations were prepared using BCS as a substitute for synovial fluid, and two stations were prepared using a 1:1 BCS:AJ solution (17% (v / v), equivalent to a 10 mM solution that provides a 5 mM AJ solution by diluting BCS at a 1:1 volume ratio).

[0682] The results obtained are presented in Figure 2A, and the station using 17% (v / v) AJ (total lipid 5 mM) showed a wear reduction of nearly 5 times compared to the case using only BCS.

[0683] Additional experiments were conducted using a 1:1 BCS:AJ solution to evaluate the effect on wear during 2.0 Mc. Six POD stations were prepared, three using BCS and three using 17% AJ.

[0684] At every 0.5 Mc interval, the pin was removed, cleaned, and weighed, and the lubricant solution in the water bath was replaced with a new solution. Then, the station was reassembled and the experiment was continued up to 2.0 Mc.

[0685] The results are presented in Figure 2B, and it was confirmed that the station using 17% (v / v) AJ throughout the test showed a wear reduction of nearly five times compared to the case using only BCS.

[0686] Example 3

[0687] A formulation comprising a newly designed lipid-polymer conjugate as described in WO 2024 / 047647 (the contents of which are incorporated herein by reference as in their entirety) was tested using the POD system described in the preceding example.

[0688] The aqueous formulation tested is also referred to herein as “Aquasjoint*” or “AJ*” and comprises liposomes prepared from DPPE-Ph-pMPC and DSPC in a molar ratio of 0.7:99.3 LPC:DSPC in physiological buffer (e.g., PBS).

[0689] The test was performed at 0.5 Mc intervals for a period of 2.0 Mc, as described in Example 2 above. Two stations of each of the six types (a total of 12 stations) were prepared as follows:

[0690] Two stations used Aquasjoint* (total lipid concentration 30 mM, indicated as 100%) as the lubricating medium; two stations used 1:1 AJ*:BCS (total lipid concentration 15 mM, indicated as 50%); two stations used 1:3 AJ*:BCS (total lipid concentration 7.5 mM, indicated as 25%); two stations used 1:7 AJ*:BCS (total lipid concentration 3.75 mM, indicated as 13%); two stations used 1:15 AJ*:BCS (total lipid concentration 1.875 mM, indicated as 6%); and two stations used 1:31 AJ*:BCS (total lipid concentration approximately 0.94 mM, indicated as 3%).

[0691] The obtained data is presented in Figure 3 and shows a concentration-dependent reduction in wear compared to the case using only BCS. At a volume fraction of 100%-50% of AJ*, the wear is in the range of 0.12-0.29 mg, which is about 27 times reduced compared to the standard BCS solution, and at a volume fraction of 25%-3% of AJ*, the wear is in the range of 1.07-1.74 mg, which is about 4 times reduced compared to the standard BCS solution.

[0692] The obtained data also indicate that a significant reduction in wear compared to the use of BCS alone is already observed even at the lowest AJ*:BCS ratio (indicated as 3%), which suggests that AJ* provides effective wear protection to the pins and consequently the cartilage even at low lipid concentrations.

[0693] The data shown in Figure 3 for the case using only BCS and for the 17% volume fraction AJ* were taken from different sets of measurements performed under the same conditions for comparison.

[0694] Example 4

[0695] In an additional set of experiments, to evaluate the effect on wear characteristics over 2.0 Mc and to further evaluate the effect of HA as a natural synovial joint component on the lubrication characteristics of AJ*, the AJ* formulation described in Example 3 above was combined with hyaluronic acid (HA) and its performance was tested.

[0696] In these experiments, the same POD system as in Examples 2 and 3 was used, but the pin was GUR 1050 UHMWPE.

[0697] GUR 1050 and GUR 1020 are two types of commercial polymers used in orthopedics. The main difference between these polymer materials is their molecular weight. Additionally, GUR 1020 is formed by compression molding, whereas GUR 1050 is manufactured by RAM extrusion. GUR 1050 polymer pins have been reported to exhibit higher wear resistance compared to GUR 1020 polymer pins [Brandt et al., Journal of the Mechanical Behavior of Biomedical Materials, Volume 34, 2014, Pages 208-216, ISSN 1751-6161]. For example, in a knee wear test, the wear of GUR 1020 was 23±6 mm³ / Mc, while the wear of GUR 1050 was 13±4 mm 3 It has been reported that / Mc is [Fisher et al., Clin Orthop Relat Res. 2004, (428), Pages 114-119].

[0698] The general POD test parameters in this experimental set were the same as in Examples 1-3. A 1% (w / v) solution of hyaluronic acid in saline was used. Four solutions were tested in three repetitions as follows: three stations were prepared with BCS alone and labeled as BCS 100%; three stations were prepared with a 1:1 (v / v) mixture of BCS and AJ* to obtain a liposomal solution with a final concentration of 15 mM total lipids and labeled as 50% AJ*; three stations were prepared with a 2:1:1 (v / v / v) mixture of BCS:AJ*:HA to obtain a liposomal solution with a final concentration of 7.5 mM total lipids and 0.25% (w / v) HA and labeled as 25% AJ* + 25% HA; Three stations were prepared with a 1:1 (v / v) mixture of BCS:HA to obtain 0.5% (w / v) HA, which was indicated as 50% HA.

[0699] The wear value was calculated as the average of three measurements taken after each dilution and every 0.5 Mc. The results are presented in Figure 4 and clearly show that when tested at the same dilution concentration (50%), AJ* reduces wear three times more significantly compared to hyaluronic acid, a commonly used treatment for osteoarthritis. Additionally, as the number of cycles increases, the cumulative wear of the pin immersed in HA increases more rapidly than in the AJ* solution, further indicating that AJ* provides a more effective and longer-lasting protective effect.

[0700] Even though the tested lubricant was more diluted, the lowest cumulative wear value was observed in the 25% AJ* + 25% HA mixture, suggesting a synergistic effect that allows for the use of lower concentrations.

[0701] Due to variations resulting from the use of pins made of different types of polymer materials, the wear values ​​do not match those presented in Examples 2 and 3. However, the lower BCS value (4.3 mg / Mc) obtained in these experiments using GUR1050 is consistent with literature data [e.g., Fisher et al., 2004, see the aforementioned literature].

[0702] Although the present invention has been described with specific embodiments thereof, it is obvious to those skilled in the art that many alternatives, modifications, and variations will be apparent. Accordingly, it is intended to encompass all such alternatives, modifications, and variations that fall within the spirit and technical scope of the appended claims.

[0703] The applicant(s) intend that all published documents, patents, and patent applications mentioned herein are incorporated herein by reference in their entirety, as specifically and individually indicated where each individual published document, patent, or patent application is referred to as incorporated herein by reference. Furthermore, any citation or identification of any reference in this application shall not be construed as an acknowledgment that such reference is available as prior art for the present invention. To the extent that section headings are used, this shall not be construed as limiting. Additionally, any priority document(s) of this application are incorporated herein by reference in their entirety.

Claims

Claim 1 A composition for use in combination with an implantable device, comprising an aqueous carrier and a polymer compound represented by general formula I: General Formula I In the above formula: m is 0 or a positive integer; n is an integer at least 2, at least 5, preferably at least 10 (e.g., 10 to 200); Y is a main chain unit forming the polymer main chain of the polymer compound; L is absent or a connecting part; and Z has General Formula II: General Formula II In the above formula: the dashed line (curve) indicates the attachment point to each Y main chain unit or, if present, the linking portion L; A is a substituted or unsubstituted hydrocarbon; B is an oxygen atom or is absent; R1-R3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterodicyclic, aryl, and heteroaryl; X is a lipid portion represented by General Formula IV: General Formula IV In the above formula: the dashed line (curve) indicates the attachment point to the polymer main chain; 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 has at least 10 carbon atoms; J is -OP(=O)(OH)-O- or is absent; K is a substituted or unsubstituted hydrocarbon having 1 to 10 carbon atoms or is absent; M is a linker selected from the group consisting of -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, and sulfonamide or is absent; and Q are substituted or unsubstituted hydrocarbons having 1 to 10 carbon atoms or are absent, and if M is absent, Q is also absent, and if J is absent, M is not absent, provided that the following conditions are satisfied: if J is -OP(=O)(OH)-O-, M is not an amido and / or Q contains an aryl portion. Claim 2 A composition according to claim 1, wherein at least one of F1, F2, F3 and F4 is an alkoxy, thioalkoxy, acyl, or carboxyl having at least 10 carbon atoms. Claim 3 A composition according to claim 1 or 2, wherein 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, palmitoleoil, oleoil, and linoleoil. Claim 4 In any one of claims 1 to 3, M is a carboxyl composition. Claim 5 A composition according to any one of claims 1 to 4, wherein K is an alkyl. Claim 6 A composition according to claim 1 or 2, wherein J is -P(=O)(OH)-O-; M is an amido; and Q is a hydrocarbon substituted with at least one aryl group. Claim 7 A composition according to any one of claims 1 to 6, wherein Q is methylene substituted with at least one aryl group. Claim 8 A composition in which J is absent in any one of claims 1 to 7. Claim 9 In any one of claims 1 to 7, J and K are each absent from the composition. Claim 10 A composition according to any one of claims 1 to 7, wherein J and K are each absent and M is a carboxylate. Claim 11 In any one of claims 1 to 10, at least one or at least two of F1, F2, F3 and F4 are each independently the thioalkoxyne composition. Claim 12 In any one of claims 1 to 10, at least one or at least two of F1, F2, F3 and F4 are each independently the carboxyl composition. Claim 13 A composition according to claim 12, wherein at least one or both of F1 and F2 are carboxyl and at least one of F3 and F4 is alkyl. Claim 14 A composition according to any one of claims 8 to 13, wherein Q is -C(CH3)2-. Claim 15 A composition according to any one of claims 1 to 14, wherein Y is a substituted or unsubstituted alkylene unit. Claim 16 A composition according to claim 15, wherein Y is a substituted or unsubstituted ethylene unit. Claim 17 A composition according to any one of claims 1 to 16, wherein B is an oxygen atom. Claim 18 A composition according to any one of claims 1 to 17, wherein A is a substituted or unsubstituted hydrocarbon having 1 to 4 carbon atoms. Claim 19 In any one of claims 1 to 18, R1-R3 are each independently hydrogen or C 1-4 Alkyl composition. Claim 20 A composition according to any one of claims 1 to 19, wherein n is in the range of 10 to 200. Claim 21 A composition according to any one of claims 1 to 20, wherein n is at least 30. Claim 22 A composition according to any one of claims 1 to 20, wherein n is in the range of 30 to 70. Claim 23 A composition according to any one of claims 1 to 20, wherein n is at least 50. Claim 24 A composition according to any one of claims 1 to 20, wherein n is in the range of 50 to 150 or in the range of 50 to 80. Claim 25 A composition according to any one of claims 1 to 20, wherein n is at least 80. Claim 26 A composition according to any one of claims 1 to 20, wherein n is in the range of 80 to 120. Claim 27 A composition according to any one of claims 1 to 26, wherein m is in the range of 0 to 50. Claim 28 A composition according to any one of claims 1 to 27, wherein at least a portion of the main chain unit Y, the L and / or the Z comprises at least one targeting portion. Claim 29 A composition according to any one of claims 1 to 28, further comprising at least one bilayer-forming lipid. Claim 30 A composition according to any one of claims 1 to 29, wherein the molar ratio of the at least one double-layer forming lipid to the polymer 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, or 100:1 to 500:

1. Claim 31 A composition according to claim 29 or 30, wherein the at least one double-layer forming lipid comprises at least one zwitterionic glycerophosphate lipid. Claim 32 The composition of claim 31, wherein the at least one double-layer forming lipid further comprises a negatively charged double-layer forming lipid. Claim 33 In any one of claims 29 to 32, the polymer compound and the at least one double-layer forming lipid are a composition that forms a lipid double layer. Claim 34 A composition according to any one of claims 1 to 33, further comprising at least one water-soluble polymer. Claim 35 In claim 34, the composition wherein at least one water-soluble polymer comprises hyaluronic acid. Claim 36 A composition according to any one of claims 33 to 35, wherein the weight ratio of the lipid bilayer to the water-soluble polymer is in the range of 100:1 to 1:100, or 50:1 to 1:50, or 20:1 to 1:20, or 10:1 to 1:10, or 5:1 to 1:5, or 2:1 to 1:

2. Claim 37 A composition according to any one of claims 33 to 36, wherein the concentration of the lipid bilayer is in the range of 0.1 to 100 mM by weight relative to the total weight of the composition. Claim 38 In any one of claims 1 to 37, the implantable device is to be reduced during implantation. Composition. Claim 39 A composition according to any one of claims 1 to 38, wherein the composition is administered to a subject requiring the implantable device before, simultaneously with, or after the implantation thereof. Claim 40 A composition according to any one of claims 1 to 39, wherein the implantable device is an articular replacement implantable device and the composition is intended for use in a total articular replacement procedure. Claim 41 A composition according to any one of claims 1 to 39, wherein the implantable device is a prosthetic implant. Claim 42 A pin-on-disk system comprising a composition defined in any one of claims 1 to 37. Claim 43 A method for determining the wear resistance of an implantable device, comprising the step of performing a pin-on-disk measurement using the system of claim 42.

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