Composition for coating medical devices

Abstract

The invention relates to a A coating composition, comprising a. at least one lipid L1, having a Tm <20°C; b. at least one lipid L2, having a Tm >40°C; c. optionally one or more components C other than lipids L1 and L2; wherein the at least one lipid L1 is present in an amount 5 < n(L1) < 95 mol% and the at least one lipid L2 is present 5 < n(L2) < 95 mol% and wherein n(L1) mol% and n(L2) mol% are determined relative to the sum of mol% of lipids L1 and L2; wherein components C can be present in an amount N(C) up to 50 mol% relative to the amount of lipids L1, L2 and components C; wherein lipids L1 and L2 independently have a connecting group X, a headgroup Z and 2 tailgroups R1 and R2, according to Formula (1) wherein the composition is in a liquid disordered phase (Lα) and / or a liquid ordered phase (Lo) when present as an aqueous dispersion at a temperature of 37°C; wherein Tm is the chain melting temperature of a lipid dispersed in PBS buffer (1X, pH 7.4), as known from literature or as determined as described in the experimental section; and wherein lipids L1 and lipids L2 do not contain any polyethyleneglycol (PEG)-moieties.

Description

[0001] COMPOSITION FOR COATING MEDICAL DEVICES

[0002] The present invention relates to a composition comprising lipids that can be used for coating medical devices, coated medical devices and the use of the coated medical devices.

[0003] Background art

[0004] Coatings for medical devices and coated medical devices are known in the art.

[0005] US6521286 describes a coating composition having dipalmitoylphosphatidyl choline (DPPC) as lipid on a catheter.

[0006] US5798117 describes a coating composition having dipalmitoylphosphatidyl choline (DPPC) and a prepolymerized compound of 1,2-dipentacosanoyl-10,12-diyne-sn-glycero-3- phosphorylcholine (DAPC) as lipid on a medical device. This compound is known as 23:2 diyne PC, and has a chain melting temperature (Tm) of 45°C.

[0007] Coating compositions comprising a lipid having a Tmabove about 37°C, have as disadvantage that the lipids can be released from the coating upon use in a subject by generating rigid particles of sizes that can block blood vessels of a subject (embolism). Problem with the medical devices coated with lipids that have a very low melting temperature, is that the coating is rather instable, resulting in disintegration of the coating from the medical device, and thereafter easy fouling with bacteria or proteins can occur resulting in challenges during use of the medical device in patients and unwanted contamination and side effects. Moreover these coatings tend to be very sticky and, therefore, impractical in use.

[0008] It is an object of the present invention to provide a composition that can be easily applied to a medical device, and which has improved stability, less fouling and which can be used in treatment of a human or animal body with less complications, such as embolism.

[0009] Summary of the invention.

[0010] The invention relates to a coating composition, comprising a. at least one lipid Li, having a Tm<20°C; b. at least one lipid L2, having a Tm>40°C; c. optionally one or more components C other than lipids Li and L2; wherein the at least one lipid Li is present in an amount 5 mol% < n(Li) < 95 mol% and the at least one lipid L2 is present 5 mol% < n(L2) < 95 mol% and wherein n(Li) mol% and n(L2) mol% are determined relative to the sum of mol% of lipids Li and L2.; wherein components C can be present in an amount N(C) up to 50 mol% relative to the amount of lipids Li , L2 and components C; wherein lipids Li and L2 independently have a connecting group X, a headgroup Z and 2 tailgroups R1 and R2, according to Formula 1): wherein the composition is in a liquid disordered phase (La) and / or a liquid ordered phase (Lo) when present as an aqueous dispersion at a temperature of 37°C; wherein Tmis the chain melting temperature of a lipid dispersed in PBS buffer (1X, pH 7.4), as known from literature or as determined as described in the experimental section; and wherein lipids Li and lipids L2 do not contain any polyethyleneglycol (PEG)-moieties.

[0011] The coating composition is suitable as a coating on a medical device, for in vivo use of the medical device. The coating composition can be preferably applied to a medical device after dissolution of the coating composition in a (volatile) organic solvent, to obtain a dissolved coating composition, applying the dissolved coating composition onto the medical device and drying the coating by evaporation of the (volatile) organic solvent. After evaporation of the solvent a thin coating is formed on the medical device, which is stable, has a high lubricity and superior antifouling properties towards bacteria and / or proteins. The coating is stable, but can gradually (and slowly) dissolve and / or disperse in an aqueous solution, like a bodily fluid (like for example blood). The coating is a lipid-based coating, which preferably comprises lipid bilayers, wherein the lipid bilayers are preferably in a lamellar phase. The lipids which have been dissolved and / or dispersed from the coating into the aqueous solution do not form large and rigid particles that may block blood vessels in a human or animal body (embolism).

[0012] Detailed description

[0013] The composition of the invention contains at least two different lipids Li and L2. The lipids independently have a connecting group X, a headgroup Z and 2 tailgroups R1 and R2, according to Formula 1):

[0014] In general, any suitable chemical moiety known in the art may be chosen for Z, X, Ri, and R2. The terms moiety and group may be used interchangeably. The skilled person is familiar with lipids according to Formula 1), for example phospholipids, glycerolipids, and sphingolipids fulfilling Formula 1). The skilled person may appreciate that the choice of Z, X, Ri, and R2can influence the behavior of the lipids in the coating composition, and in forming a coating from said coating composition, and in a coating formed from said coating composition. It may be appreciated that the choice of headgroup Z can affect the interaction of the lipid with an aqueous environment, and may contribute to steric hindrance, electrostatic interactions and hydrogen-bonding interactions, and may influence bilayer packing and surface hydration of the lipids, and thereby phase behavior. It may be further appreciated that the choice of connecting group X can influence the orientation and rigidity of the lipid when in a bilayer. Also, the choice of tailgroups Ri and R2, independently, may influence phase behavior and chain melting temperatures (Tm), and can influence fluidity and packing of lipid bilayers comprising lipids comprising tailgroups Ri and R2. The lipids Li and L2do not contain PEG- moieties.

[0015] Lipids with the chemical structure of Formula 1), in which the Z group is a hydrophilic moiety, i.e. a water-loving moiety, and the Ri and R2groups are hydrophobic moieties i.e. waterrepelling moieties, such that lipids according to Formula 1) when arranged into a lipid bilayer formed in an aqueous environment have the Z groups substantially facing outward towards the aqueous environment, and the Ri and R2groups facing inwards away from the aqueous environment.

[0016] The Z group is a hydrophilic moiety / group. Typically, the Z group comprises charged moieties and / or hydroxy groups. Z is preferably chosen from OH, phosphatidic acid (PA), phospho choline (PC), inverted phospho choline (CP), phospho ethanolamine (PE), phospho glycerol (PG), phospho inositol (PI), phospho serine (PS), phospho thioethanol, phospho ethylene glycol (PtdEG), glucosyl, lactosyl, (sulfated) galactosyl, succinate (DGS), galloyl glycerol (GG), pyrophosphate (PP), p-amino benzoic acid (BAQ I BAT), trimethyl homoserine (TS), carbo betaine (CB), sulfo betaine (SB), ethyl phospho choline (EPC), dimethyl ammonium (DMA / DAP), trimethyl ammonium (TMA / TAP), and hydroxy ethyl ammonium (RI). More preferably, Z is a hydrophilic moiety with limited steric hindrance, which may facilitate packing of lipids into bilayers. Z is thus more preferably chosen from OH, phosphatidic acid (PA), phospho choline (PC), inverted phospho choline (CP), phospho ethanolamine (PE), phospho glycerol (PG), phospho serine (PS), phospho thioethanol, phospho ethylene glycol (PtdEG), succinate (DGS), galloyl glycerol (GG), p-amino benzoic acid (BAQ), trimethyl homoserine (TS), carbo betaine (CB), sulfo betaine (SB), ethyl phospho choline (EPC), dimethyl ammonium (DMA / DAP), trimethyl ammonium (TMA / TAP), and hydroxy ethyl ammonium (Rl);

[0017] Most preferably, Z is chosen from phospho choline (PC), phospho ethanolamine (PE), and phospho glycerol (PG). It is an advantage of these Z groups that they provide a combination of steric hindrance, electrostatic interactions and hydrogen-bonding interactions balanced for preparing coatings from coating compositions according to the invention.

[0018] The X group is a connecting group that connects the Z, Ri and R2 groups through covalent bonds. The X group is preferably a connecting group derived from a chemical moiety with three spaced functional groups that allow for selective attachment of groups Z, R1, and R2 and allows for head-tail segregation in lipid bilayers. Correspondingly, X is preferably a connecting group derived from glycerol, sphingosine, dihydroxy sphingosine, or dihydro sphingosine. Preferred examples of connecting group X are depicted in Formulas 2) to 5). Formula 2) to 5) depict Formula 1) wherein the preferred chemical structures of connecting group X is depicted, connected to groups Z, R1, and R2. The preferred connecting groups X are derived from glycerol (2)), sphingosine (3)), dihydroxy sphingosine (4)), and dihydro sphingosine (5)): More preferably, X is the connecting group derived from glycerol or sphingosine, shown in Formula 2) and 3), respectively. It is an advantage of these X groups that they impose a defined molecular polarity and flexibility, which can contribute to the stability of lipid bilayers. Most preferably, X is the connecting group derived from glycerol, shown in Formula 2).

[0019] It is an advantage of this X group that it is a connecting group that has inherent flexibility and limited hydrogen bonding potential.

[0020] In an embodiment, X and Z are combinedly present as a derivative of dimethyl ammonium bromide (DAB, 6)) or trimethyl ammonioacetyl diethanolamine chloride (DC, 7)). Formula 6) and 7) depict Formula 1), wherein the derivatives of DAB or DC are depicted, respectively, combinedly representing groups Z and X, connected to groups R1 and R2.

[0021] Ri and R2 are hydrophobic tailgroups. R1 and R2 may be independently chosen and are typically hydrophobic linear hydrocarbon groups. Preferably, R1 and R2 are independently alkyl (8)) or acyl (9)) groups:

[0022] 8) wherein A is a linear hydrocarbon chain with 1 - 28 carbon atoms, with optionally up to 6 unsaturated double carbon-carbon bonds, or optionally up to 2 unsaturated triple carboncarbon bonds, and / or optionally up to 4 branched methyl groups.

[0023] More preferably, R1 and R2 are chosen independently as a group corresponding to an acyl moiety (9)), wherein A is a linear hydrocarbon chain with 4 - 23 carbon atoms, with optionally up to 6 unsaturated double carbon-carbon bonds, and / or optionally up to 2 unsaturated triple carbon-carbon bonds. It is an advantage of said groups that they represent biologically common hydrophobic linear hydrocarbon chains, comprising a carbonyl group which provides sufficient hydrophobic length for stable bilayer incorporation while preventing excessive crystallinity.

[0024] Most preferably, Ri and R2 are chosen independently as a group corresponding to an acyl (9)), wherein A is a linear hydrocarbon chain with 12 - 20 carbon atoms, with optionally up to 3 unsaturated double carbon-carbon bonds and / or optionally up to 2 unsaturated triple carbon-carbon bonds. It is an advantage of said groups that they represent hydrophobic linear hydrocarbon chains with a carbonyl group resembling those most commonly found in biological membranes, facilitating forming lamellar phases at physiological temperatures.

[0025] In a preferred embodiment Z is chosen from OH, phosphatidic acid (PA), phospho choline (PC), inverted phospho choline (CP), phospho ethanolamine (PE), phospho glycerol (PG), phospho serine (PS), phospho thioethanol, phospho ethylene glycol (PtdEG), succinate (DGS), galloyl glycerol (GG), p-amino benzoic acid (BAQ), trimethyl homoserine (TS), carbo betaine (CB), sulfo betaine (SB), ethyl phospho choline (EPC), dimethyl ammonium (DMA / DAP), trimethyl ammonium (TMA / TAP), hydroxy ethyl ammonium (RI);

[0026] X is a connecting group derived from glycerol or sphingosine, shown in Formula 2) and 3), respectively, and Ri and R2 are independently a hydrocarbon chain with a carbonyl group (acyl, 9)): wherein A is a linear hydrocarbon chain with 4 - 23 carbon atoms, with optionally multiple unsaturated double or triple carbon-carbon bonds.

[0027] More preferably, Z is chosen from phospho choline (PC), phospho ethanolamine (PE), or phospho glycerol (PG);

[0028] X is the connecting group derived from glycerol, shown in Formula 2), and Ri and R2 are chosen independently from hydrocarbon chains with a carbonyl group (acyl, 9)) wherein A is a linear hydrocarbon chain with 12 - 20 carbon atoms, with optionally up to 3 unsaturated double carbon-carbon bonds or optionally up to 2 unsaturated triple carboncarbon bonds.

[0029] Specific examples of lipids Li are 1 ,2-dilinolenoyl-sn-glycero-3-phospho choline (18:3 (cis) PC), 1 ,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DOPG), 1 ,2-dioleoyl-sn-glycero-3- phospho choline (DOPC), 1 ,2-dioleoyl-sn-glycero-3-phospho ethanolamine (DOPE), 1 ,2- dilauroyl-sn-glycero-3-phospho choline (DLPC), 1-palmitoyl-2-oleoyl-glycero-3-phospho choline (POPC), 1-stearoyl-2-oleoyl-sn-glycero-3-phospho choline (SOPC).

[0030] Specific examples of lipids L2 are 1 ,2-distearoyl-sn-glycero-3-phospho choline (DSPC), 1 ,2- bis(10,12-tricosadiynoyl)-sn-glycero-3-phospho choline (23:2 diyne PC), 1 ,2-dipalmitoyl-sn- glycero-3-phospho choline (DPPC), N-palmitoyl-D-erythro-sphingosylphosphoryl choline (PSM), 1 ,2-dihexadecanoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG) and 1 ,2- distearoyl-sn-glycero-3-phospho ethanolamine (DSPE).

[0031] Lipid synthesis procedures are known in the art. Lipids can be synthesized using standard glycerol-based lipid, phospholipid, or sphingolipid synthesis protocols. For example, glycerolbased lipids can be synthesized via esterification of glycerol-3-phosphate with fatty acid chlorides or via enzymatic transesterification; and sphingosine-based lipids can be synthesized by amide coupling of fatty acids to sphingosine, followed by phosphorylation of the headgroup.

[0032] In addition to synthesis, many lipids can be extracted from natural sources using well- established lipid extraction procedures. For example, phospholipids can be extracted from egg yolk, soybeans, or animal tissue using organic solvent mixtures such as chloroform / methanol (e.g., using Folch or Bligh & Dyer methods), followed by purification steps like column chromatography or thin-layer chromatography.

[0033] Preferably, lipids Li and lipids L2 do not contain any polyethylene glycol (PEG)-moieties. PEG-moieties tend to increase the solubility in aqueous media, which is an undesired property for a coating on a medical device to be used in vivo (especially in blood vessels).

[0034] Lipid Li has a Tm<20°C, preferably <18°C, or <15°C, or <10°C. Lipid Li may also be a mixture of lipids Li having (independently) a structure according to Formula 1) and a Tmas indicated.

[0035] Lipid L2 has a Tm>40°C. Lipid L2 may also be a mixture of lipids L2 having (independently) a structure according to Formula 1) and a Tm> 40°C.

[0036] The Tm(chain melting temperatures) of lipids Li and L2, are known from literature or can be determined as described in the experimental section in PBS buffer (1X, pH 7.4).

[0037] The coating composition may contain components C, for example lipids other than defined under Li and L2, sterols, fatty acids and other lipid-miscible compounds. These components C influence the interactions between lipids in a lipid bilayer and, thereby affect the molar ratios of Li and L2 at the phase transitions. Such effects have been reported in literature for example for n-alkanes and sterols, like cholesterol. In order to maintain the properties of a coating on a medical device produced from the coating composition, it is desirable that the amount of components C does not exceed 50 mol% with respect to the total moles Li + L2 + C, more preferably does not exceed 30 mol%.

[0038] Examples of components C are lipids other than lipids Li and L2, for example 1-palmitoyl-2- hydroxy-sn-glycero-3-phospho choline, 1-hydroxy-2-oleoyl-sn-glycero-3-phospho choline, 1 ,2-dimyristoyl-sn-glycero-3-phospho choline (DMPC), 1 ,2-dipentadecanoyl-sn-glycero-3- phospho choline, 1 ,2-dimyristoyl-sn-glycero-3-phospho-(T-rac-glycerol) (DMPG), 1 ,2- dilauroyl-sn-glycero-3-phospho ethanolamine (DLPE); sterols and sterol derivatives, for example cholesterol, lanosterol, desmosterol, stigmasterol, ergosterol, cholesteryl ester laurate; fatty acids, for example palmitic acid, oleic acid, lauric acid, sapienic acid; and other lipid miscible compounds, for example sphingosine, ethyl linoleate, ethyl arachidonate, [2- (2,6-di-chloro anilino)phenyl] acetic acid, iso-butyl propanoic phenylic acid, N-(4- hydroxyphenyl) ethanamide, TWEEN20, tannic acid, Poloxamer 188 and Poloxamer 408. Preferred examples of component C are 1-palmitoyl-2-hydroxy-sn-glycero-3-phospho choline, 1-hydroxy-2-oleoyl-sn-glycero-3-phospho choline, cholesterol, tannic acid, Poloxamer 188 and Poloxamer 408, sterols and sterol derivatives. More preferably, components C are sterols, sterol derivates, cholesterol, or combinations thereof. Most preferably, component C is cholesterol.

[0039] Other additives may be added to the coating composition prior to forming a coating from the coating composition comprising Li + L2 + optional components C. Such other additives should not substantially affect the phase transitions of the coating composition. Examples of such additives can be antimicrobial, reactive or hydrating molecules, pharmaceutically active compounds or dyes. Such additives can be present up to 25 wt%, preferably up to 20 wt%, or 10 wt% relative to the total weight of Li + L2 + optional components C + other additives.

[0040] The combination of lipids Li and L2 provides a composition that is stable in an aqueous environment. Although the composition can be (slowly) dissolved and dispersed in an aqueous medium, the components that are dispersed appear as very small particles and / or particles that can be easily deformed such that they can pass blood vessels of a patient, thereby not presenting any risk of embolism in a subject.

[0041] In order to have a stable coating having no release or slow release, in combination with release of small, deformable particles that give no embolism in a subject, the molar ratio between lipids Li and lipids L2 is important.

[0042] The coating composition (which is essentially a mixture of lipids Li and lipids L2 with optionally components C) should have a liquid phase known as La(a disordered liquid phase) and / or Lo(an ordered liquid phase). Such liquid phases are also commonly referred to as fluid phases. The coating composition comprises preferably at least 75 wt% of lipids Li , L2 and component C, more preferably at least 80 wt%, or 90 wt% of Li , L2 and component C.

[0043] For many lipid combinations Li and L2, phase diagrams and miscibility diagrams at temperatures of 20, 22, 23, 28 or 37°C are known in literature, which clearly indicate areas of La, Lo, La+Lo, also known as liquid phases, and Lp-containing phases (Lp, Lp+La, Lp+L0, Lp+La+Lo), depending on the chosen combination of lipids Li , lipids L2, and optionally components C, the molar ratio of lipids Li , lipids L2, and optionally components C, see for example Figures 1-10. Generally, upon increase of the amount of lipids L2, the composition will enter a phase that consists (at least partially) of more tightly packed lipids, characterized as Lp, which exhibit the formation of rigid and large particles when dispersed. An Lp phase is also commonly referred to as a gel phase. The composition should not be in a Lp-containing phase, i.e. gel-containing phase, in order to prevent formation of large and rigid coating particles when dispersed in an aqueous environment. The amount of L2 ranges between 5 and 95 mol%, preferably between 5 and 90 mol% relative to the total of Li, L2 and component C.

[0044] The amounts of lipids Li and lipids L2 are chosen in such a way that the coating composition is in a liquid phase (Laand / or Lo). The boundary between the disordered liquid phase (La, Loor La+Lo) and the phase (Lp-containing) where release of large and rigid particles can take place, occurs at a defined molar ratio of Li and L2 relative to each other (depending on the choice of Li , L2 and component C): this boundary is at n(Li)transition (mol%) for lipid Li and n(l_2)transition (mol%) for lipid L2 for a specific mixture, at a specific temperature.

[0045] The relation between n(Li)transition and n(l_2)transition is given in Formula 10) and is related to the fraction containing Li and L2 of the composition (having of Li and L2 and component C): n(Li)transition (mol%) = 100 - [n(L2)transition (mol%)] Formula 10)

[0046] Preferably the amount of n(Li) (mol%) in the fraction of Li and L2 of the composition (of Li and L2 and component C) ranges between 95 and [n(Li)transition]. More preferably the amount of n(Li) (mol%) ranges between 92.5 and [n(Li)transition + 0.02*n(l_2) transition] . Even more preferably the amount of n(Li) (mol%) ranges between 90 and [n(Li) transition + 0.04 n(l_2)transition] .

[0047] In case no other components are present in the composition except Li and L2, the mol% of Li and l_2 are relative to the composition. When for example 10 mol% of a component C is present, the fraction of Li and L2 is 90% of the composition of Li and L2 and component C.

[0048] These ranges are valid for binary systems (only having lipids Li and L2, and where n(C) = 0 mol%), and for ternary systems (lipids Li , L2 and components C). In case one or more of component C are present, the ratio between Li and L2 follows the above ranges for the fraction of Li and L2 of the composition at a given amount of component C present. The molar ratio between Li and L2 at the phase transitions will likely change upon change of the nature of component C and / or amount of component C. Therefore the ratio of Li to L2 for a specific transition is determined at the given amount of component C.

[0049] Also the temperature has an influence on the n(Li)transition and n(l_2)transition of a given composition. At higher temperatures (for example 37°C), the phase change tends to shift to higher L2 values and lower Li values compared to lower temperatures, like 20°C.

[0050] For example, for a system DOPC (Li), PSM (L2), with N(C) = 0, at a temperature of T = 37°C, (which corresponds to the base of the phase diagram of Figure 7, upper right diagram), the transition between the Laand La+Lp phases is found at values of n(Li)transition = 50 mol% and n(l_2)transition = 50 mol% (these mol% are relative to the fraction of Li and L2), which is in this example 100% of the total composition). Compositions having a mol% of DOPC between 100 mol% DOPC and 50 mol% DOPC are expected to yield coating compositions that form a liquid (La) phase when in contact with water. Dispersions of this coating do not form rigid and large particles. The 100 mol% DOPC however forms an instable and sticky coating layer, with as result more easy fouling.

[0051] Therefore the amount of DOPC in the coating composition having (only) DOPC and PSM ranges preferably between 95 mol% and 50 mol%. More preferably between 92.5 mol% and 51 mol%. Even more preferably between 90 mol% and 52 mol%.

[0052] For a similar coating composition having DOPC (Li), PSM (L2) and N(C) = 10 mol% cholesterol phase transitions can be found in the same miscibility diagram, see Figure 7, lower left diagram. In this case, at a temperature of T = 37°C a transition between the La+L0and La+Lo+Lp phases is found at values of n(Li)transition = 28 mol% and n ^transition = 72 mol%. Again, the values of n(Li)transition and n ^transition are determined relative to the fraction of Li and L2, in this specific example being 90 mol% of the total composition. Thus, the amount of DOPC relative to the amount of PSM in the Li and L2 fraction of the coating composition should range between 95 mol% and 28 mol%. More preferably between 92.5 mol% and 29.4 mol% . Even more preferably between 90 mol% and 30.9 mol%. The amount of Li relative to Li + L2 + C in this specific example ranges between 85.5 mol% and 25.2 mol% (for the broadest range). For the broadest range the amount of L2 ranges between 4.5 mol% and 64.8 mol%. The mol% of the preferred ranges relative to Li + L2 + C can be calculated in a similar way.

[0053] So, in general, the preferred ranges depend on the individual lipids Li and L2 and can be easily derived when the transition mol% of lipids Li and L2 are known, see also Figures 1-10.

[0054] In a ternary phase diagram, the relative amounts of Li and L2 in the Li and L2 fraction of the composition at a point can be determined by drawing a line through this point and the corner of the diagram where N(C) = 100. The intersection of this line and the axis opposite to the corner of N(C) = 100 provides the relative amounts of Li and L2 in the Li and L2 fraction of the composition, see also Figure 7.

[0055] Examples of suitable combinations of lipids Li and lipids L2 can be found in Table 1 below. In the table the transition points between Laand / or Lophases and Lp-containing phases are indicated. The transition ratios have been determined from phase diagrams or miscibility diagrams found in literature, from Figures 1 - 7 and 10, as indicated in Table 1. Based on the transition ranges, the preferred ranges of lipids n(Li) and n(L2) in a coating composition according to the present invention are also indicated.

[0056] Table 1

[0057] The chemical structure of the lipids influence Tmand phase behavior. Hence, the choice for specific lipids with specific Z, X, R1 and R2 impact Tmand phase behavior.

[0058] For a given lipid, the Tmand / or phase behavior may be adjusted by following general trends. These trends allow the skilled person to manufacture a coating composition complying with the parametric definition of the present invention. Non limitative trends which can be followed to adjust the Tmand / or phase behavior of lipids are in general the following:

[0059] The hydrocarbon chain length of Ri and / or R2 may be increased to raise the Tmand promote the formation of Lp phases, and vice versa.

[0060] Double bonds in R1 and / or R2, particularly in a cis configuration, introduce kinks and reduce packing, thereby lowering Tmand promote the formation of Laphases over R1 and / or R2 without double bonds.

[0061] R1 and R2 chain branching or the inclusion of triple bonds generally disrupt regular packing and may reduce Tm, and vice versa.

[0062] Regarding connecting group X, glycerol-derived connecting group 2) promotes bilayer formation, while sphingosine derivatives 3) - 5) can increase rigidity and may promote the formation of Lophases.

[0063] A skilled person may follow other known trends in the art to adjust the Tmand / or phase behavior of lipids to manufacture coating compositions according to the present invention. In a preferred embodiment lipids Li are chosen from the group of 1,2-dilinolenoyl-sn-glycero- 3-phospho choline (18:3 (cis) PC), 1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phospho choline (DOPC), 1,2-dioleoyl-sn-glycero-3- phospho ethanolamine (DOPE), 1,2-dilauroyl-sn-glycero-3-phospho choline (DLPC), 1- palmitoyl-2-oleoyl-glycero-3-phospho choline (POPC), 1-stearoyl-2-oleoyl-sn-glycero-3- phospho choline(SOPC), and lipids L2 are chosen from the group of 1,2-distearoyl-sn- glycero-3-phospho choline (DSPC), 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phospho choline (23:2 diyne PC), 1,2-dipalmitoyl-sn-glycero-3-phospho choline (DPPC), N-palmitoyl- D-erythro-sphingosylphosphorylcholine (PSM) and 1,2-dihexadecanoyl-sn-glycero-3- phospho-(T-rac-glycerol) (DPPG), 1,2-distearoyl-sn-glycero-3-phospho ethanolamine (DSPE).

[0064] In an embodiment, the composition comprises DOPC, DPPC and optionally cholesterol as main components (at least 75 wt% of the total composition), wherein the amount of cholesterol ranges between 0 and 30 mol% relative to the sum of the amounts of DOPC, DPPC and cholesterol, the amount of DOPC ranges between 25-95 mol% relative to fraction of DOPC and DPPC of the composition, and the amount of DPPC ranges between 5-75 mol% relative to the fraction DOPC and DPPC of the composition.

[0065] In an embodiment, the composition comprises DLPC, DSPC and optionally cholesterol as main components (at least 75 wt% of the total composition), wherein the amount of cholesterol ranges between 0 and 30 mol% relative to the sum of the amounts of DLPC, DSPC and cholesterol, the amount of DLPC ranges between 83-95 mol% relative to the fraction DLPC and DSPC of the composition, and the amount of DSPC ranges between 5-17 mol% relative to the fraction of DLPC and DSPC of the composition.

[0066] In an embodiment, the composition comprises POPC, DPPC and optionally cholesterol as main components (at least 75 wt% of the total composition), wherein the amount of cholesterol ranges between 0 and 30 mol% relative to the sum of the amounts of POPC, DPPC and cholesterol, the amount of POPC ranges between 52-95 mol% relative to the fraction of POPC and DPPC of the composition, and the amount of DPPC ranges between 5- 48 mol% relative to the fraction of POPC and DPPC of the composition.

[0067] In an embodiment, the composition comprises SOPC, DSPC and optionally cholesterol as main components (at least 75 wt% of the total composition), wherein the amount of cholesterol ranges between 0 and 30 mol% relative to the sum of the amounts of SOPC, DSPC and cholesterol, the amount of SOPC ranges between 72-95 mol% relative to the fraction of SOPC and DSPC of the composition, and the amount of DSPC ranges between 5- 28 mol% relative to the fraction of SOPC and DSPC of the composition. In an embodiment, the composition comprises DOPC, DPPG and optionally cholesterol as main components (at least 75 wt% of the total composition), wherein the amount of cholesterol ranges between 0 and 30 mol% relative to the sum of the amounts of DOPC, DPPG and cholesterol, the amount of SOPC ranges between 65-95 mol% relative to the fraction of DOPC and DPPG of the composition, and the amount of DSPC ranges between 5-35 mol% relative to the fraction of SOPC and DSPC of the composition.

[0068] A skilled person can identify suitable Li and L2 lipids combinations to achieve Laand / or Lophases without Lp, for which no phase diagram is available, by following these principles:

[0069] The method described in the experimental section under “Particle Release” can be used as a fast method for gaining preliminary insight into the phase behavior of a coating composition comprising lipids Li and L2 and optionally optional components C. In general, the desired Laand / or Lophases will form small (< 50 pm) and regularly shaped (spherical) particles, see for an example Figure 11 , whereas the undesired Lp-containing phases will form large (> 50 pm) irregularly shaped (non-spherical) particles, see for an example Figure 12. If a lipid mixture is found to be Lp-containing, desired Laand / or Lophases may be achieved by increasing the relative amount of Li lipids and / or the amount of additive C. Any of the general trends to adjust the Tmand / or phase behavior disclosed in the present invention and / or known from the art may be applied to achieve coating compositions complying with the parametric definition of the present invention. If the method described in the experimental section under “Particle Release” indicates the presence of desired Laand / or Lophases, without undesired Lp-containing phases, the phase behavior may be confirmed I checked by way of the method as described in the experimental section under “Determination Miscibility Diagram”.

[0070] For a coating composition, the phase diagram can be easily derived by way of the method as described in the experimental section under “Determination Miscibility Diagram”. This experimental procedure should be used to confirm the exact location of phase transition.

[0071] The coating composition can be dissolved using a suitable organic solvent. Preferably the organic solvent is a polar organic solvent, which can easily evaporate. Examples of suitable organic solvents are methanol, ethanol, isopropanol, n-butanol, tert-butanol, dichloromethane, chloroform, acetonitrile, diethyl ether, tetrahydrofuran, ethyl acetate, n- heptane, toluene and cyclohexane.

[0072] The amount of organic solvent to dissolve the coating composition and to prepare a dissolved coating composition preferably ranges between 80 and 99.99 wt% relative to the dissolved coating composition, more preferably between 90 and 99.9 wt%. Application of the dissolved coating composition on a medical device results in a medical device having a wet coating. Drying of the medical device with wet coating results in a coated medical device having a thin coating layer, preferably comprising lipid bilayers, wherein the lipid bilayers are preferably in a lamellar phase. Drying can be applied for example by air flow, heat or other known techniques.

[0073] The invention also relates to a medical device containing a coating produced from the coating composition of the invention. The coating can be applied to a part of the medical device.

[0074] Hip and knee implants are prosthetic devices surgically implanted to replace damaged or diseased joints, typically due to arthritis or traumatic injury. These implants restore mobility and alleviate pain by mimicking the natural function of the joint. Tissue engineering implants are designed to support the regeneration of damaged tissues and organs. These implants often utilize scaffolds made from biocompatible materials that provide a structure for cell attachment and growth. Endotracheal tubes are used to maintain an open airway in patients undergoing surgery or in critical care. They facilitate mechanical ventilation by ensuring unobstructed air flow to and from the lungs. Central venous catheters are inserted into large veins, typically in the neck, chest, or groin, to administer medications, fluids, or nutrition over an extended period. CVCs are crucial in intensive care settings and for patients requiring long-term intravenous therapy. Peripheral intravenous catheters are inserted into peripheral veins, usually in the arms or hands, for the short-term administration of fluids, medications, or blood products. Peripherally inserted central catheters are long, thin tubes inserted through a vein in the arm and advanced to the central veins near the heart. PICCs are used for extended intravenous access, allowing for the prolonged administration of medications, chemotherapy, or parenteral nutrition. Hemodialysis catheters are specialized central venous catheters used for hemodialysis, a process that filters waste products from the blood in patients with renal failure. These catheters provide a conduit for blood to be removed, cleaned, and returned to the body. Coated hemodialysis catheters can prevent infection and thrombosis, ensuring efficient and safe dialysis treatment. Foley catheters are indwelling urinary catheters that are inserted into the bladder to drain urine. They are commonly used in patients with urinary retention, during surgery, or for those who are immobile. Intermittent catheters are used to periodically drain the bladder in patients with urinary retention or neurogenic bladder conditions. These catheters are inserted, used to drain urine, and then removed. The application of advanced coatings on these devices can significantly enhance their performance, safety, and patient outcomes by reducing the risks of infection, thrombosis, and other complications. Examples of medical devices are surgical instruments, for example, scalpels, forceps, retractors, sutures; implant devices, for example, hip and knee implants, tissue engineering implants, dental implants; respiratory devices, for example, endotracheal tubes; vascular access devices, for example central venous catheters (CVC), peripheral intravenous catheters, peripherally inserted central catheters (PICC), hemodialysis catheters; urinary catheters, for example, foley catheters, intermittent catheters; gastrointestinal tubes, for example, nasogastric tubes, percutaneous endoscopic gastrostomy (PEG) tubes, jejunostomy tubes; personal care devices, for example, contact lenses. Preferred medical devices are hip and knee implants, tissue engineering implants, endotracheal tubes, central venous catheters (CVC), peripheral intravenous catheters, peripherally inserted central catheters (PICC), hemodialysis catheter, foley catheters and intermittent catheters. Even more preferred medical devices are central venous catheters, peripheral intravenous catheters (CVC), peripherally inserted central catheters (PICC) and hemodialysis catheters.

[0075] The invention also relates to the use of the medical device, especially a catheter for safe treatment of a subject.

[0076] Figures.

[0077] Figure 1 relates to the miscibility diagram of DOPC [(18:1cA9)2PC]: DPPC [(16:0)2PC]. In this figure, F is a liquid disordered phase (La), G is a gel phase (Lp) and F+G is a liquid / gel phase (La+ Lp). Literature Source: D. Marsh, Handbook of Lipid Bilayers, 2013, 2, p. 645.

[0078] Figure 2 relates to the miscibility diagram of DLPC [(12:0)2PC]: DSPC [(18:0)2PC]. In this figure, F is a liquid disordered phase (La), G2 is a gel phase (Lp), G1+G2 is a gel / gel phase (Lp) and F+G is a liquid / gel phase (La+ Lp). Literature Source: D. Marsh, Handbook of Lipid Bilayers, 2013, 2, p. 624.

[0079] Figure 3 relates to the miscibility diagram of POPC [1-(16:0)-2-(18:1cA9)PC]: DPPC [(16:0)2PC]. In this figure, F is a liquid disordered phase (La), G2 is a gel phase (Lp), F+G2 is liquid / gel phase (La+ Lp) and G1+G2 is a gel / gel phase (Lp). Literature Source: D. Marsh, Handbook of Lipid Bilayers, 2013, 2, p. 655.

[0080] Figure 4 relates to the miscibility diagram for SOPC [1-(18:0)-2-(18:1cA9)PC]: DSPC [(18:0)2PC]. In this figure, F is a liquid disordered phase (La), G2 is a gel phase (Lp), F+G2 is liquid / gel phase (La+ Lp) and G1+G2 is a gel / gel phase (Lp). Literature Source: D. Marsh, Handbook of Lipid Bilayers, 2013, 2, p. 657. Figure 5 relates to the miscibility diagram for DOPC I DOPG : DPPC I DPPG. In this figure, “One-phase” is a liquid disordered phase (La) and “Two-phase” is liquid / gel phase (La+ Lp). Literature Source: H. Himeno, Soft Matter, 2012.

[0081] Figure 6 relates to the miscibility diagram for DOTAP : DPPC. Literature Source: S. Cinelli et al, J. Phys. Chem., 2007, 111.

[0082] Figure 7 relates to the miscibility diagram for DOPC [(18:1cA9)2]: PSM [ / V-(16:0)PSM] and cholesterol at 37°C. Literature Source: D. Marsh, Handbook of Lipid Bilayers, 2013, 2, p. 755.

[0083] Figure 8 relates to the miscibility diagram for DOPC [(18:1cA9)2PC]: (deuterated) DPPC [(cfei- 16:0)2PC: cholesterol at 28°C. Literature Source: D. Marsh, Handbook of Lipid Bilayers, 2013, 2, p. 743.

[0084] Figure 9 relates to miscibility diagrams for DOPC [(18:1cA9)2PC]: (deuterated) DPPC [(cfei- 16:0)2PC: cholesterol at defined molar ratios of DOPC : DPPC. Literature Source: J. H. Davis et al, Biophysics Journal, 2009, 96, 2, p. 521-539.

[0085] Figure 10 relates to the phase diagram of DOPC : DPPC : Cholesterol (CHOL). Literature Source: J. H. Davis et al, Biophysics Journal, 2009, 96, 2, p. 521-539.

[0086] Figure 11 relates to a representative epifluorescence microscopy image of an aqueous dispersion of DOPC: DPPC at a molar ratio of 80:20 at 37 °C having an Laphase, showing small, regularly shaped particles.

[0087] Figure 12 relates to a representative epifluorescence microscopy image of an aqueous dispersion of DOPC: DPPC at a molar ratio of 20:80 at 37 °C, having an La+ Lp phase, showing large, irregularly shaped particles.

[0088] Experimental Section

[0089] List of Lipids, Components and Additives and Their Properties

[0090] Abbreviation Name Tails Tm

[0091] Experimental Procedures

[0092] Particle Release The release of particles by a coating composition is assessed by a particle release assay. For this assay, 1.9 mg of a lipid cake of the desired composition, including 0.01 mol% of fluorescent Texas Red dipalmitoyl-phosphatidylethanolamine (TR-DHPE), is formed in a 1.5 mL glass vial by mixing chloroform solutions of the individual lipids and evaporating the organic solvent in a stream of N2 followed by at least 1 hour under vacuum in a desiccator. The prepared lipid cake together with a 96 well plate and PBS buffer (1x, pH 7.4) are preheated at the relevant temperature (for example 22 or 37°C) for which the particle release behaviour is to be determined. While maintaining this temperature of the sample, 1 mL of the PBS buffer is added to the vial followed by immediate vortexing for 1 min. The produced suspension is divided over 6 wells in the 96 well plate, which are all quickly analysed by fluorescence microscopy.

[0093] Extrudability

[0094] As a measure for the deformability of a coating, the extrudability of liposomes / particles formed from coating compositions according to the present invention is determined. To this end, 1.9 mg of a lipid cake of the desired composition, including 0.01 mol% of fluorescent TR-DHPE, is formed in a 1.5 mL glass vial by mixing chloroform solutions of the individual lipids and evaporating the organic solvent in a stream of N2 followed by at least 1 hour under vacuum in a desiccator. The prepared lipid cake together with a block extruder setup and PBS buffer (1x, pH 7.4) are preheated at the relevant temperature (for example 22 or 37°C) for which the particle rigidity behaviour is to be determined. While maintaining this temperature of the sample, 1 mL of PBS buffer is added to the vial followed by immediate vortexing for 1 min. This suspension is extruded 10 times through a 0.05 pm diameter pore membrane supported by two filter supports at the relevant temperature, in a back-and-forth motion, while qualitatively noting the required force.

[0095] Dip-Coating

[0096] Dip-coating solutions are prepared by dissolving desired ratios of lipids in ethanol at relevant concentrations. Substrates (cylindrical thermoplastic polyurethane (TPU) catheters or flat TPU strips) are fully immersed at an insertion speed of 3000 mm / min in a bath of this solution and after 2 seconds removed from the organic solvent at relevant constant withdrawal speed, followed by overnight drying in ambient conditions. Coating thickness can be tuned by altering the lipid concentration and the withdrawal speed. Thick coatings can be achieved with high lipid concentrations and withdrawal speeds, while thin coatings can be achieved with low lipid concentrations and withdrawal speeds. In general, withdrawal speeds of 300 - 2400 mm / min are applied. Fluorescent TR-DHPE can be added to the dip-coating solutions at a concentration of 0.2 pg / mL for later imaging purposes.

[0097] Initial Coating Assessment

[0098] TR-DHPE-containing coatings on dip-coated, flat TPU strips with a total coating composition concentration of 10 mg / mL and an extraction speed of 300 mm / min are assessed for their initial appearance. To this end, coated flat TPU strips are carefully cut in to 1 cm pieces (N=3) using a scalpel and placed into a 24 well plate filled with 1 mL of PBS buffer (1X, pH 7.4, 22°C) per well. The samples are than analysed using fluorescence microscopy.

[0099] Stickiness Coating compositions are assessed for stickiness using cylindrical TPU catheters as substrates, dip-coated at a Li + L2 + C lipid concentration of 10 mg / mL and a withdrawal speed of 2400 mm / min. The substrates are cut in to 1 cm long pieces (N=3) and placed on the same sides of separate wells in a 12 well plate, with the coating being brought into contact with the side of the well so that the coating may stick to the side of the well. A humidity chamber with a relative humidity of approximately 80% RH and a temperature of 22°C is prepared using a sealable box and beakers of hot water, monitored using a hygrometer. The well plate with samples (without lid) is incubated in the humidity chamber for 2.5 min. With the lid, the well plate is sealed quickly and taken out of the humidity chamber. While filming with a camera the well plate is brought into a vertical position and tapped with increasing amount of force to initiate movement of the samples within the wells, i.e. either with a soft or a hard tap.

[0100] Protein Fouling Assay

[0101] Protein fouling (PF) is tested using fluorescently-labelled protein variants. To this end, coated and uncoated substrates are incubated in PBS buffer (1X, pH 7.4) containing 0.02 mg / mL BSA-AlexaFluor647 for 2 h at 37°C without agitation. After washing by gentle waving for 10 s in de-ionized water, samples are transferred to fresh PBS buffer (1X, pH 7.4) for fluorescence microscopy imaging.

[0102] Performance in Time

[0103] As measure for the stability of a coating, its performance on the coating assessment and protein fouling assays after in-flow incubation were evaluated. For this, 3.5 mm wide flat TPU strips are used as substrates, which are dip-coated with TR-DHPE-containing compositions at a lipid concentration of 10 mg / mL and a withdrawal speed of 300 mm / min. These strips are carefully cut into 5 cm pieces and placed inside a TPU sample chamber with an inner diameter of 4 mm, connected to a peristaltic pump and a 35 mL reservoir of sterile PBS buffer (1X, pH 7.4). The peristaltic pump is set to a flowrate of 25 mL / min and the full system is incubated at 37°C for 24 h. Thereafter, the samples are carefully taken out of the sample chambers and cut into five 1 cm pieces. The middle three pieces are used for coating assessment using fluorescence microscopy and subsequent protein fouling as described in the previous section.

[0104] Determination Miscibility Diagram

[0105] Miscibility diagrams can be determined by observing giant unilamellar vesicles (GUV) prepared from specific coating compositions with fluorescence microscopy. First, GUV solutions are produced by either gentle hydration (for compositions containing charged lipids) or electroformation.1 For gentle hydration2, coating compositions according to the present invention with a certain composition, including 0.5 mol% TR-DHPE, are dissolved at a concentration of 1 mM in a volatile organic solvent (e.g. chloroform, methanol). 75 pL of lipid solutions is transferred to a glass vial and under flow of N2 formed to a (nearly) dried lipid film. The film is dried further in a desiccator in vacuo for at least 1 hour. While maintaining a temperature at least 5°C higher than the highest Tmout of Li , L2 and optionally component C (if said C is a compound with a Tm) comprised in the coating composition, the dried film is hydrated gently by adding 500 pL of PBS buffer (1X, pH 7.4) of choice and letting it stand for 4 h, thereby forming a GUV solution.

[0106] For electroformation3, lipids according to the desired composition, including 0.5 mol% TR- DHPE, are dissolved at a concentration of 0.5 mg / mL in a volatile organic solvent (e.g. chloroform, methanol). 2.5 pL of lipid solutions is dispensed on a flat Indium Tin Oxide (ITO) electrode inside a volume defined by a 0.3 mm spacer and under flow of N2 formed to a (nearly) dried lipid film. The film is dried further in a desiccator in vacuo for at least 1 hour. On top of the spacer, another electrode is attached with its conductive side facing inwards. The resulting chamber with dried lipid film is then filled with PBS buffer (1X, pH 7.4). While maintaining a temperature at least 5°C higher than the phase transition temperature of the deposited lipids, an alternating current (10 Hz, 1 ) is applied to the electrodes for 2 h, thereby forming a GUV solution.

[0107] To view samples, the prepared GUV solutions are placed between two coverslips, sealed against evaporation and mounted on a temperature-controlled fluorescence microscopy stage at a relevant temperature for phase determination (for example 22 or 37°C).5Phases are determined by the presence and shape of recognizable domains using the fluorescence of TR-DHPE for contrast between phases. The one-liquid phase shows homogeneous distribution of fluorescence intensity; the two-liquid phase shows circular domains; and the liquid-solid phase shows irregularly shaped domains.

[0108] In order to construct a miscibility diagram this procedure needs to be repeated with an appropriate number of mixtures of different molar ratios of lipids and optionally components C.

[0109] Determination Lipid Chain Melting Temperature

[0110] Lipid chain melting temperatures (Tm) can be determined using a differential scanning calorimeter.5To this end, 5 mg of a lipid is dried to a lipid cake from an organic solution in an ampule using a flow of N2 followed by at least 1 h under vacuum in a desiccator. 0.5 mL of PBS buffer (1X, pH 7.4) is added and the ampule is sealed tightly. The reference ampule is filled with an equal volume of PBS buffer. The lipids in the ampule are hydrated by heating the sample to 95°C for 20 min and cooling it to 20°C and incubating it for an additional 20 min. The sample is then subjected to two heating and cooling cycles (-20 - 95°C) in the calorimeter at a scan rate of 10°C / h. In the case of a phase transition within the lipids in these cycles, a thermal transition peak can be observed on the calorimeter thermogram. The Tmcan then be read out by identifying the midpoint of this peak.

[0111] References Experimental Methods

[0112] 1P. Walde et al, ChemBioChem, 2010, 11 , 848.2K. Tsumoto et al., Colloids and Surfaces B: Biointerfaces, 2009, 68, 98.

[0113] 3M.l. Angelova, Prog. Colloid Polym Sci J., 1992, 77, 2090.

[0114] 4S. L. Veatch et al., Biophysics Journal, 2003, 85, 3074.

[0115] 5M. J. Swamy et al., Biophysics Journal, 1997, 73, 2556

[0116] Assay Evaluations Scales The table below shows the scales that were set for the qualitive analysis of the performed assays. In this table, minus signs indicate undesirable behaviour of the coating and, a 0 indicates acceptable behaviour, and plus signs indicate desirable behaviour of the coating. LIPQ24003EPWQ

[0117] Qualitative Results

[0118] Particle Analysis and Extrudability

[0119] Performance Experiments

[0120] Conclusion From the table for particle release and extrudability in combination with the relevant phase- and miscibility diagrams found in literature, it can be deduced that the release of undesirable, large particles that are poorly extrudable, and thus rigid, occurs for compositions showing Lp- containing phases. This observation was subsequently expanded to ternary systems, which revealed identical behaviour for the transition from Laand / or Loto Lp-containing phases. Also for several systems with unknown miscibility diagrams, this transition to the release of large and rigid particles upon an increasing ratio of L2 to Li was demonstrated, likely indicating the Laand / or Loto Lp-containing transition for these systems. Thus, it can be concluded that a coating composition showing an Laand / or Lophase in an aqueous solution at 37 °C is desired over coating compositions showing an Lp-containing phase in an aqueous solution at 37 °C, due to the undesirable release of large and rigid particles from coatings prepared therefrom by compositions showing the latter.

[0121] The table for the qualitative results of the performance experiments predominantly shows that coatings produced from 100% Li are sticky and instable, which is undesirable. Furthermore, it can be deduced that both the stickiness and instability of a coating can be reduced by the addition of L2 lipids to the system.

[0122] Taking both the release of large and rigid particles by the Lp-containing phases and the increase in stickiness and instability at increasing ratio of Li to L2 into account, it can be concluded that optimal coating compositions are the ones that consist of a mixture of Li and L2 that is still in the Laand / or Lophase.

[0123] Furthermore, any components C other than lipids Li and L2 can affect the packing of lipids, and with that change their phase behaviour. For example, these effects have been reported in miscibility diagrams in literature and clearly demonstrated in our experiments for cholesterol, palmitic acid, oleic acid, tannic acid, and 2-(2,6-dichloranilino) phenylacetic acid.

Claims

CLAIMS1 . A coating composition, comprising a. at least one lipid Li, having a Tm<20°C; b. at least one lipid L2, having a Tm>40°C; c. optionally one or more components C other than lipids Li and L2; wherein the at least one lipid Li is present in an amount 5 < n(Li) < 95 mol% and the at least one lipid L2 is present 5 < n(l_2) < 95 mol% and wherein n(Li) mol% and n(l_2) mol% are determined relative to the sum of mol% of lipids Li and L2; wherein components C can be present in an amount N(C) up to 50 mol% relative to the amount of lipids Li, L2 and components C; wherein lipids Li and L2 independently have a connecting group X, a headgroup Z and 2 tailgroups R1 and R2, according to Formula 1):wherein the composition is in a liquid disordered phase (La) and / or a liquid ordered phase (Lo) when present as an aqueous dispersion at a temperature of 37°C; wherein Tmis the chain melting temperature of a lipid dispersed in PBS buffer (1X, pH 7.4), as known from literature or as determined as described in the experimental section; and wherein lipids Li and lipids L2 do not contain any polyethyleneglycol (PEG)-moieties.

2. The coating composition according to claim 1 , wherein Z is chosen from OH, phosphatidic acid (PA), phospho choline (PC), inverted phospho choline (CP), phospho ethanolamine (PE), phospho glycerol (PG), phospho inositol (PI), phospho serine (PS), phospho thioethanol, phospho ethylene glycol (PtdEG), glucosyl, lactosyl, (sulfated) galactosyl, succinate (DGS), galloyl glycerol (GG), pyrophosphate (PP), p-amino benzoic acid (BAQ I BAT), trimethyl homoserine (TS), carbo betaine (CB), sulfo betaine (SB), ethyl phospho choline (EPC), dimethyl ammonium (DMA / DAP), trimethyl ammonium (TMA / TAP), and hydroxy ethyl ammonium (Rl). More preferably Z is chosen from OH, phosphatidic acid (PA), phospho choline (PC), inverted phospho choline (CP), phospho ethanolamine (PE), phospho glycerol (PG), phospho serine (PS), phospho thioethanol, phospho ethylene glycol (PtdEG),LIPG24003EPWG succinate (DGS), galloyl glycerol (GG), p-amino benzoic acid (BAQ), trimethyl homoserine (TS), carbo betaine (CB), sulfo betaine (SB), ethyl phospho choline (EPC), dimethyl ammonium (DMA / DAP), trimethyl ammonium (TMA / TAP), and hydroxy ethyl ammonium (Rl); Most preferably Z is chosen from phospho choline (PC), phospho ethanolamine (PE), and phospho glycerol (PG).

3. The coating composition according to claim 1 or 2, wherein X is a connecting group derived from glycerol (2)), sphingosine (3)), dihydroxy sphingosine (4)), dihydro sphingosine (5))4. The coating composition according to claim 1, wherein X and Z are combinedly present as a derivative of dimethyl ammonium bromide (DAB, 6)), or trimethyl ammonioacetyl diethanolamine chloride (DC, 7))5. The coating composition according to any one of claims 1-4, wherein Ri and R2 are independently alkyl (8)) or acyl (9))with A = a linear hydrocarbon chain with 1 - 28 carbon atoms, with optionally up to 6 unsaturated double carbon-carbon bonds, or optionally up to 2 unsaturated triple carbon-carbon bonds, and / or optionally up to 4 branched methyl groups.

6. The coating composition according to claim 1, wherein Z is chosen from OH, phosphatidic acid (PA), phospho choline (PC), inverted phospho choline (CP), phospho ethanolamine (PE), phospho glycerol (PG), phospho serine (PS), phospho thioethanol, phospho ethylene glycol (PtdEG), succinate (DGS), galloyl glycerol (GG), p-amino benzoic acid (BAQ), trimethyl homoserine (TS), carbo betaine (CB), sulfo betaine (SB), ethyl phospho choline (EPC), dimethyl ammonium (DMA / DAP), trimethyl ammonium (TMA / TAP), hydroxy ethyl ammonium (Rl);X is a connecting group derived from glycerol (2)) or sphingosine (3))with A = a linear hydrocarbon chain with 4 - 23 carbon atoms, with optionally multiple unsaturated double or triple carbon-carbon bonds.

7. The coating composition according to claim 1, wherein Z is chosen from phospho choline (PC), phospho ethanolamine (PE), phospho glycerol (PG);X is derived from glycerol (2))and Ri and R2 are chosen independently from hydrocarbon chains with a carbonyl group (9)):with A = a linear hydrocarbon chain with 12 - 20 carbon atoms, with optionally up to 3 unsaturated double carbon-carbon bonds or optionally up to 2 unsaturated triple carbon-carbon bonds.

8. The coating composition according to anyone of claims 1-7, wherein lipids Li are selected from the group 1,2-dilinolenoyl-sn-glycero-3-phospho choline (18:3 (cis) PC), 1 ,2-dioleoyl-sn-glycero-3-phospho-(1 '-rac-glycerol) (DOPG), 1 ,2-dioleoyl-sn-glycero- 3-phospho choline (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho ethanolamine (DOPE), 1,2-dilauroyl-sn-glycero-3-phospho choline (DLPC), 1-palmitoyl-2-oleoyl- glycero-3-phospho choline (POPC), 1-stearoyl-2-oleoyl-sn-glycero-3-phospho choline (SOPC).

9. The coating composition according to any one of claims 1-8, wherein lipids L2 are selected from the group 1,2-distearoyl-sn-glycero-3-phospho choline (DSPC), 1,2- bis(10,12-tricosadiynoyl)-sn-glycero-3-phospho choline (23:2 diyne PC), 1,2- dipalmitoyl-sn-glycero-3-phospho choline (DPPC), N-palmitoyl-D-erythro- sphingosylphosphoryl choline (PSM), 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1'- rac-glycerol) (DPPG) and 1,2-distearoyl-sn-glycero-3-phospho ethanolamine (DSPE).

10. The composition according to anyone of claims 1-8, wherein other components (C) are lipids different from Li and L2, sterols, fatty acids and other lipid miscible compounds, preferably 1-palmitoyl-2-hydroxy-sn-glycero-3-phospho choline, 1- hydroxy-2-oleoyl-sn-glycero-3-phospho choline, 1 ,2-dimyristoyl-sn-glycero-3-phospho choline (DMPC), 1,2-dipentadecanoyl-sn-glycero-3-phospho choline, 1,2-dimyristoyl- sn-glycero-3-phospho-(1'-rac-glycerol) (DM PG), 1,2-dilauroyl-sn-glycero-3-phospho ethanolamine (DLPE), cholesterol, lanosterol, desmosterol, stigmasterol, ergosterol, cholesteryl ester laurate, palmitic acid, oleic acid, lauric acid, sapienic acid,sphingosine, ethyl linoleate, ethyl arachidonate, [2-(2,6-di-chloro anilino)phenyl] acetic acid, iso-butyl propanoic phenylic acid, N-(4-hydroxyphenyl) ethanamide, TWEEN20, tannic acid, Poloxamer 188 and Poloxamer 408; more preferably, 1- palmitoyl-2-hydroxy-sn-glycero-3-phospho choline, 1-hydroxy-2-oleoyl-sn-glycero-3- phospho choline, cholesterol, tannic acid, Poloxamer 188 and Poloxamer 408; more preferably cholesterol.11 . The coating composition according to any one of claims 1-10, wherein further additives are present that do not substantially affect the phase transition of the lipid system up to 25 wt%, preferably up to 20 wt%, or 10 wt%.

12. The coating composition according to any one of claims 1-11 , wherein the relation between n(Li)transition and n(l_2)transition is given in Formula 10): n(Ll)transition (mol%) — 100 - n(l_2)transition (mol%) 10), and wherein the amount of n(Li) (mol%) in the composition of the invention ranges between 95 and [n(Li)transition], preferably the amount of n(Li) (mol%) ranges between 92.5 and [n(Li)transition + 0.02*n(l_2) transition] , more preferably the amount of n(Li) (mol%) ranges between 90 and [n(Li) transition + 0.04*n(L2)transition].

13. The coating composition according to anyone of claims 1-12, wherein Li is DOPC and L2 is DPPC, optionally in the presence of 0-30 mol% of cholesterol.

14. A medical device containing a coating of the coating composition according to any one of claims 1-13.

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