Supramolecular polymer composition and preparation method thereof

Abstract

The present invention relates to a composition comprising one or more monomer units having a structure of formula (I). The one or more monomer units in the composition can encapsulate a hydrophobic substance. Further, the present invention provides a method for preparing the composition. The present invention also provides a method for killing the microorganism or controlling the growth of the microorganism by contacting the microorganism with the composition.

Description

Technical Field

[0001] The present invention relates to a composition comprising one or more monomer units encapsulating a hydrophobic substance. In particular, the monomer units form a self-assembling polymer. The present invention also relates to a method for preparing the composition and a method for killing microorganisms or controlling the growth of microorganisms. Background Art

[0002] Compositions capable of directed and reversible intermolecular self-assembly have attracted great attention and may be effective candidates for antimicrobial coatings due to their excellent biocompatibility and antimicrobial properties. These compositions can be endowed with additional properties, such as antimicrobial functionality.

[0003] Currently, the most widely used inorganic antibacterial substances are silver nanoparticles (Ag NPs) and zinc oxide nanoparticles (ZnO NPs). However, these substances lack selectivity and may inhibit and kill pathogenic microorganisms as well as normal cells in the human body, qualities that are not conducive to and limit widespread practical applications. These substances also tend to inevitably become damaged during use, which shortens the service life and significantly increases costs.

[0004] Therefore, there is a need for self-healing compositions having advantageous qualities such as strong mechanical properties, antimicrobial properties, and extended release properties. Summary of the invention

[0005] A first aspect of the present invention relates to a composition comprising one or more monomer units having a structure of formula (I), and wherein the one or more monomer units encapsulate a hydrophobic substance.

[0006]

[0007] Formula (I),

[0008] in:

[0009] - n is an integer selected from 1 to 10;

[0010] -R represents a substituted or unsubstituted cyclic group.

[0011] In one embodiment, the cyclic group is a 4-, 5-, 6-, 7-, or 8-membered aryl or heteroaryl group.

[0012] In one embodiment, the cyclic group is a 6-membered aryl group, and R has the structure of formula (IIa):

[0013]

[0014] Formula (IIa)

[0015] in:

[0016] R1 and R2 are independently selected from the group consisting of: (i) a straight chain or branched chain alkyl group optionally containing a heteroatom; a straight chain or branched chain alkenyl group optionally containing a heteroatom; a straight chain or branched chain alkynyl group optionally containing a heteroatom; (ii) a cycloalkyl group optionally containing a heteroatom; (iii) an aryl group optionally containing a heteroatom; and (iv) a heteroatom;

[0017] R3, R4, R5 and R6 are independently selected from the group consisting of: (i) a straight or branched alkyl group optionally containing a heteroatom; a straight or branched alkenyl group optionally containing a heteroatom; a straight or branched alkynyl group optionally containing a heteroatom; (ii) a cycloalkyl group optionally containing a heteroatom; (iii) an aryl group optionally containing a heteroatom; (iv) a heteroatom; and (v) a hydrogen atom; and

[0018] Dashed lines indicate that there are no double bonds, one double bond, two double bonds, or three double bonds in the cyclic group.

[0019] In another embodiment, R has the structure of Formula (IIb):

[0020]

[0021] Formula (IIb)

[0022] in:

[0023] R1 and R2 are independently selected from the group consisting of: (i) a linear or branched alkyl group optionally containing a heteroatom; and (ii) a cycloalkyl group optionally containing a heteroatom;

[0024] R3, R4, R5 and R6 are independently selected from the group consisting of: (i) a linear or branched alkyl group optionally containing a heteroatom, (ii) a heteroatom, and (iii) a hydrogen atom; and

[0025] The dashed line indicates the absence or one double bond.

[0026] In a specific embodiment, R has a structure of formula (IIb), wherein R1, R2, R3 and R4 are straight or branched chain alkyl groups, and R5 and R6 are hydrogen atoms.

[0027] In a further embodiment, the monomer unit has the structure of formula (III):

[0028]

[0029] Formula (III).

[0030] In one embodiment, the hydrophobic substance is a liquid.

[0031] In one embodiment, the hydrophobic substance comprises a pharmaceutically active ingredient. Preferably, the hydrophobic substance comprises an antimicrobial compound.

[0032] In a preferred embodiment, the hydrophobic substance is an essential oil. For example, the hydrophobic substance comprises a compound selected from the group consisting of carvacrol, thymol, eugenol, p-cymene and limonene.

[0033] In one embodiment, the hydrophobic substance disrupts bonds in the one or more monomer units.

[0034] In another embodiment, the composition is a self-healing sustained release antimicrobial agent.

[0035] Preferably, the composition has an elastic modulus of at least 50 MPa at 25°C and an elastic modulus of less than 5 MPa at 100°C.

[0036] A second aspect of the present invention relates to a method for preparing a composition, the method comprising the steps of: (a) providing one or more monomer units, the monomer units having a structure of formula (I):

[0037]

[0038] Formula (I),

[0039] in:

[0040] - n is an integer selected from 1 to 10;

[0041] -R represents a substituted or unsubstituted cyclic group;

[0042] (b) mixing the one or more monomer units with a hydrophobic substance, and

[0043] (c) obtaining the composition, wherein the one or more monomer units encapsulate the hydrophobic substance.

[0044] In an exemplary embodiment, step (b) is performed by dissolving the one or more monomer units in the hydrophobic substance at a temperature of 50°C to 150°C.

[0045] In one embodiment of the second aspect, R of formula (I) has the structure of formula (IIa):

[0046]

[0047] Formula (IIa)

[0048] in:

[0049] R1 and R2 are independently selected from the group consisting of: (i) a straight chain or branched chain alkyl group optionally containing a heteroatom; a straight chain or branched chain alkenyl group optionally containing a heteroatom; a straight chain or branched chain alkynyl group optionally containing a heteroatom; (ii) a cycloalkyl group optionally containing a heteroatom; (iii) an aryl group optionally containing a heteroatom; and (iv) a heteroatom;

[0050] R3, R4, R5 and R6 are independently selected from the group consisting of: (i) a straight or branched alkyl group optionally containing a heteroatom; a straight or branched alkenyl group optionally containing a heteroatom; a straight or branched alkynyl group optionally containing a heteroatom; (ii) a cycloalkyl group optionally containing a heteroatom; (iii) an aryl group optionally containing a heteroatom; (iv) a heteroatom; and (v) a hydrogen atom; and

[0051] Dashed lines indicate that there are no double bonds, one double bond, two double bonds, or three double bonds in the cyclic group.

[0052] In a further embodiment, R of formula (I) has the structure of formula (IIb):

[0053]

[0054] Formula (IIb)

[0055] in:

[0056] R1 and R2 are independently selected from the group consisting of: (i) a linear or branched alkyl group optionally containing a heteroatom; and (ii) a cycloalkyl group optionally containing a heteroatom;

[0057] R3, R4, R5 and R6 are independently selected from the group consisting of: (i) a linear or branched alkyl group optionally containing a heteroatom; (ii) a heteroatom; and (iii) a hydrogen atom; and

[0058] The dashed line indicates the absence or one double bond.

[0059] Preferably, the monomer unit in step (a) is prepared by reacting a compound having formula (IVa) with a compound having formula (IVb):

[0060]

[0061] Formula (IVa),

[0062]

[0063] Formula (IVb),

[0064] in:

[0065] - m is an integer selected from 1 to 10;

[0066] -R7, R8, R9, R 10 are independently selected from the group consisting of: a linear or branched alkyl group optionally containing a heteroatom; a heteroatom; and a hydrogen atom; and

[0067] - The dashed line indicates that there are no double bonds, one double bond, two double bonds or three double bonds in the cyclic group of formula (IVb).

[0068] In another embodiment, the monomer unit has the structure of formula (III):

[0069]

[0070] Formula (III).

[0071] In one embodiment, the hydrophobic substance is a liquid.

[0072] In yet another embodiment, the hydrophobic substance is an essential oil.

[0073] Preferably, the hydrophobic substance comprises an antimicrobial compound, for example, a compound that kills microorganisms or controls the growth of microorganisms, such as but not limited to an antibacterial compound or an antifungal compound.

[0074] In one embodiment, the hydrophobic substance comprises a compound selected from the group consisting of carvacrol, thymol, eugenol, p-cymene and limonene.

[0075] In a third aspect, the present invention also relates to a method for killing microorganisms or controlling the growth of microorganisms, which comprises contacting the microorganisms with the above composition. In particular, the microorganisms are bacteria.

[0076] It will be understood by those skilled in the art that, in addition to the contents specifically described, variations and modifications are permitted to the invention described herein. The present invention includes all such variations and modifications. The present invention also includes all steps and features mentioned or indicated in the specification, either individually or collectively, and any and all combinations of said steps or features.

[0077] Other features and aspects of the invention will become apparent by consideration of the following detailed description and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 is a schematic diagram of components of a composition according to an exemplary embodiment, including one or more monomer units having a structure of formula (I) and a hydrophobic substance.

[0079] Figure 2 An indentation curve of a nanoindentation test performed on a composition according to an example embodiment is shown.

[0080] Figure 3Dynamic mechanical analysis of a composition according to an example embodiment is shown.

[0081] Figure 4A is an in situ microscope photograph of a composition according to an example embodiment.

[0082] Figure 4B is an in situ microscope photograph of a composition according to an example embodiment.

[0083] Figure 4C is an in situ microscope photograph of a composition according to an example embodiment.

[0084] Figure 5 is a line graph showing tensile testing of compositions having different healing times according to example embodiments.

[0085] Figure 6 is a bar graph showing the repair efficiency of a composition according to an example embodiment at different time points.

[0086] Fig. 7A is a photograph of an agar plate showing the results of antimicrobial testing of the composition in the presence of the Gram-positive bacterium Staphylococcus aureus.

[0087] Figure 7B is a photograph of an agar plate showing the results of antimicrobial testing of the composition in the presence of the Gram-positive bacterium Staphylococcus aureus.

[0088] Figure 7C is a photograph of an agar plate showing the results of an antimicrobial test in the presence of the Gram-positive bacterium Staphylococcus aureus.

[0089] Fig.7D is a photograph of an agar plate showing the results of antimicrobial testing of the composition in the presence of Gram-negative bacteria Escherichia coli.

[0090] Fig. 7E is a photograph of an agar plate showing the results of antimicrobial testing of the composition in the presence of Gram-negative bacteria Escherichia coli.

[0091] Figure 7F is a photograph of an agar plate showing the results of an antimicrobial test in the presence of the Gram-negative bacterium Escherichia coli.

[0092] Fig. 8A is a line graph showing the time-dependent antimicrobial activity of the composition against the Gram-positive bacteria Staphylococcus aureus.

[0093] Figure 8B is a line graph showing the time-dependent antimicrobial activity of the composition against the Gram-negative bacterium Escherichia coli.

[0094] Figure 8C is a scatter plot showing the mass of a composition and carvacrol over time according to an example embodiment.

[0095] Fig.8D is a line graph showing the cumulative release of carvacrol from a composition over time in water according to an exemplary embodiment.

[0096] Fig. 9 is a table showing properties of compositions according to example embodiments.

[0097] Fig.10 is a scatter plot showing a frequency sweep in a rheological measurement of a monomer unit in thymol according to an example embodiment.

[0098] Fig.11 is a line graph showing transmittance (in %) of a monomer unit according to example embodiments.

[0099] Fig. 12A is a scatter plot showing a frequency sweep in a rheological measurement of a monomer unit in eugenol according to an example embodiment.

[0100] Fig. 12B is a scatter plot showing a frequency scan in a rheological measurement of a monomer unit in limonene according to example embodiments.

[0101] Fig.13 is a bar graph showing the killing efficiency of compositions according to example embodiments on microorganisms after being released in water for 60 days.

[0102] Fig.14 is a bar graph showing shear stress of a composition on various materials according to example embodiments. DETAILED DESCRIPTION

[0103] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0104] As used herein, "comprising" means including the following elements, but not excluding other elements. "Essentially consisting of" means that the substance consists of the corresponding elements as well as usual and unavoidable impurities (such as by-products) and components usually resulting from the corresponding preparation or process for obtaining the substance (such as trace amounts of other components or solvents). "Consisting of" means that the substance consists of the corresponding elements only, i.e., is formed of the corresponding elements.

[0105] The present invention provides a composition comprising one or more monomer units. The monomer units have a structure of formula (I):

[0106]

[0107] Formula (I),

[0108] n is an integer selected from 1 to 10, and R represents a substituted or unsubstituted cyclic group. The one or more monomer units encapsulate the hydrophobic substance.

[0109] n is an integer representing the number of methylene bridges, i.e. -CH2- groups, and is preferably selected from 1 to 5, more preferably from 1, 2, 3 or 4, further preferably from 2, 3 or 4, and in a particular embodiment of the invention, n is 3. For example, if n is 1, then there is one methylene bridge at the corresponding position.

[0110] In the context used herein, the one or more monomeric units can be connected to each other to form one or more networks that define the core structure or main chain of the composition. The term "connection" covers any type of interaction that allows the formation of a network as described herein, and includes but is not limited to non-covalent bonding, such as hydrogen bonding, metal-ligand interaction, π interaction, ionic bond, van der Waals interaction, hydrophobic bond, other reversible interactions, etc., and covalent bonding. In an example, the one or more monomeric units are connected to each other via a host-guest interaction by maintaining the non-covalent bonding of the 3D structure of the one or more monomeric units. In one embodiment of this article, a monomeric unit forms at least one hydrogen bond with an adjacent monomeric unit, thereby forming a cross-linked network. In another exemplary embodiment, the one or more monomeric units are continuously repeated in a linear manner to form a network. In another embodiment, the one or more monomeric units are repeated in a branched manner to form a network.

[0111] As used herein, the term "monomer unit" is a repeating unit, which is repeated to produce a polymer chain.

[0112] As used herein, the term "supramolecular polymer" refers to a polymer composed of monomeric units held together via non-covalent interactions such as, but not limited to, hydrogen bonding.

[0113] As used herein, the term "cyclic group" refers to a structure having one or more rings (i.e., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, etc.). The rings may vary in size and may include all carbon atoms (carbocycle), no carbon atoms (inorganic cyclic groups), or carbon atoms and non-carbon atoms (heterocycle). Cyclic groups may be aromatic or non-aromatic.

[0114] As used herein, the term "substituted" includes all substituents of compounds permitted in the context of chemical valence rules known to those of ordinary skill in the art. In some cases, substituted may generally refer to replacement of hydrogen atoms with substituents as described herein. In a broad sense, permitted substituents may include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents, and / or may include heteroatoms.

[0115] As used herein, the term "hydrophobic material" relates to a material that repels water. Hydrophobic materials are generally non-polar. The hydrophobicity of a material can be determined by measuring water immiscibility and water solubility. Hydrophobic materials are generally immiscible with water and are insoluble in water. The hydrophobicity of a material, particularly a solid material, can also be determined by measuring the water contact angle, i.e. where the liquid-vapor interface meets the solid surface. If the water contact angle on the solid surface is greater than 90 degrees, the solid surface is considered to be hydrophobic.

[0116] The hydrophobic substance may be a liquid, and may include, for example, oil or fat. The hydrophobic substance in the present invention may contain ingredients such as, but not limited to, pharmaceutically active ingredients.

[0117] In exemplary embodiments, the cyclic group is a 4-, 5-, 6-, 7-, or 8-membered aryl or heteroaryl group.

[0118] In one embodiment, the cyclic group is a 6-membered aryl group, and R has the structure of formula (IIa):

[0119]

[0120] Formula (IIa).

[0121] R1 and R2 are independently selected from the group consisting of: (i) a straight chain or branched alkyl group optionally containing a heteroatom; a straight chain or branched alkenyl group optionally containing a heteroatom; a straight chain or branched alkynyl group optionally containing a heteroatom; (ii) a cycloalkyl group optionally containing a heteroatom; (iii) an aryl group optionally containing a heteroatom; and (iv) a heteroatom.

[0122] R3, R4, R5 and R6 are independently selected from the group consisting of: (i) a straight chain or branched alkyl group optionally containing a heteroatom; a straight chain or branched alkenyl group optionally containing a heteroatom; a straight chain or branched alkynyl group optionally containing a heteroatom; (ii) a cycloalkyl group optionally containing a heteroatom; (iii) an aryl group optionally containing a heteroatom; (iv) a heteroatom; and (v) a hydrogen atom.

[0123] For example, the heteroatom may be selected from N, O or S. Dashed lines indicate that there are no double bonds, one double bond, two double bonds or three double bonds in the cyclic group, and wavy lines indicate bonds between the R group and adjacent atoms.

[0124] In a preferred embodiment, R has the structure of formula (IIb):

[0125]

[0126] Formula (IIb).

[0127] R1 and R2 are independently selected from the group consisting of: (i) a linear or branched alkyl group optionally containing heteroatoms; and (ii) a cycloalkyl group optionally containing heteroatoms. Preferably, R1 and R2 are linear or branched alkyl groups, more preferably C5-C 10 Alkyl. In a particular embodiment of the present invention, R1 and R2 are the same linear C8 alkyl.

[0128] In an exemplary embodiment, R3, R4, R5 and R6 can be independently selected from the group consisting of: (i) a linear or branched alkyl group optionally containing a heteroatom, (ii) a heteroatom, and (iii) a hydrogen atom. In a preferred embodiment, R3 and R4 are linear or branched alkyl groups, preferably C1-C 10 Alkyl, more preferably C5-C 10 Preferably, R5 and R6 are heteroatoms or hydrogen atoms.

[0129] In an exemplary embodiment, Formula (IIb) has no double bonds. In an alternative embodiment, Formula (IIb) has a double bond.

[0130] In a specific embodiment of the present invention, formula (IIb) has a double bond, and R1 and R2 are the same unsubstituted C8 alkyl group, R3 is an unsubstituted C8 alkyl group, R4 is an unsubstituted C6 alkyl group, and R5 and R6 are hydrogen atoms.

[0131] In certain embodiments, the monomer unit has the structure of formula (III):

[0132]

[0133] Formula (III).

[0134] In a preferred embodiment, the composition comprises one or more repeating monomer units with a structure of formula (III), which form a network or core structure of the composition. In one embodiment, the monomer unit is repeated in a straight chain to form a network. In another embodiment, the monomer unit is repeated in a branched manner to form a network. In a specific embodiment, the monomer unit is composed of a dimer diamine terminated with ureidopyrimidone (UPy). The monomer unit may include one or more UPy motifs. In an exemplary embodiment, the one or more monomer units are continuously repeated in a straight chain, and the UPy motifs in the monomer unit cross-link the straight chain to form a network. Preferably, the monomer unit has two UPy motifs. In an alternative embodiment, the monomer unit includes at least three UPy motifs, and wherein one or more monomer units are repeated to form a branched network.

[0135] The one or more monomeric units are connected by polymerization and intermolecular crosslinking to form the core structure of the composition, and the hydrogen bonding between the crosslinked network of the one or more monomeric units is advantageously provided for the core structure with high mechanical strength. The inventors have found that the ureido-pyrimidone end caps form strong quadruple hydrogen bonds, which promote chain extension, particularly straight chain extension, and are conducive to monomer properties, and the weaker hydrogen bonds between urea, i.e., NH2CONH2, also provide intermolecular crosslinking between the main chains of the one or more monomeric units. The inventors have also found that the ureido-pyrimidone end caps of the monomeric units can associate and dissociate under certain stimuli, which advantageously provides self-assembly and self-repair properties when damaged for the composition.

[0136] The intermolecular crosslinking or connection between the monomer units gives the composition high mechanical strength and rapid repair properties. The hydrophobic substance is encapsulated in the one or more monomer units. The term "encapsulation" means that a substance or compound is surrounded or partially surrounded by another substance, i.e., the monomer unit herein. The encapsulated hydrophobic substance can react with the one or more monomer units and form non-covalent bonds, i.e., is stably carried by the monomer unit.

[0137] In one embodiment, the hydrophobic substance is a liquid. For example, the hydrophobic substance is a hydrophobic liquid containing volatile aromatic compounds. After applying the composition, the volatile aromatic compounds can be released into the surrounding environment.

[0138] In an exemplary embodiment, the hydrophobic substance comprises an antimicrobial compound. The antimicrobial compound may include, but is not limited to, an antibacterial, an antifungal, an antiviral, or an antiparasitic agent. For example, the composition of the present invention may be applied as an antimicrobial coating for the prevention or treatment of clinical skin and wound infections, such as infections caused by gram-positive and / or gram-negative bacteria.

[0139] In further embodiments, the hydrophobic substance comprises a pharmaceutically active ingredient, and the composition can be used to prepare sustained-release dosage forms for various medical purposes.

[0140] The hydrophobic substance may comprise non-pharmaceutical ingredients, such as essential oils or antimicrobial pesticides. In yet another embodiment, the hydrophobic substance may comprise compounds derived from nature such as plants. The compound may be a biologically active compound extracted or synthesized from different plants. In a preferred embodiment, the hydrophobic substance is an essential oil. Preferably, the hydrophobic substance comprises a compound selected from the group consisting of carvacrol, thymol, eugenol, p-cymene and limonene, or a mixture of two or more of these compounds. In a specific embodiment, the hydrophobic substance comprises carvacrol and thymol. In a further preferred embodiment, the hydrophobic substance comprises carvacrol. For example, carvacrol has properties such as being immiscible with water, wherein the saturation concentration of carvacrol oil in water is about 3 mM. In another embodiment, the hydrophobic substance comprises eugenol and / or limonene.

[0141] In a specific embodiment, the hydrophobic substance encapsulated in the one or more monomeric units comprises an essential oil. Essential oils are concentrated hydrophobic substances containing volatile chemical compounds. Essential oils have an aromatic structure and different functional groups that exhibit different chemical effects with the one or more monomeric units. In particular, the inventors have found that changing the amount of essential oil in the composition can change the mechanical strength of the composition, and the hydrophobic substance, particularly the essential oil, affects the mechanical strength by destroying weak hydrogen bond crosslinks. Therefore, the hydrophobic substance destroys the bonding in the monomeric unit while forming non-covalent bonds with the monomeric unit. Therefore, the essential oil content in the composition can be used to control or adjust the mechanical properties of the composition and promote the formation of a gel-like consistency.

[0142] The inventors tested the effect of varying the amount of essential oil in the composition by preparing samples with different monomer unit: essential oil weight ratios, i.e., an initial weight ratio of monomer unit to essential oil of 1:0 (UP1-C0), an initial weight ratio of monomer unit to essential oil of 1:1 (UP1-C1), an initial weight ratio of monomer unit to essential oil of 1:2 (UP1-C2), and an initial weight ratio of monomer unit to essential oil of 1:5 (UP1-C5). The mechanical properties of the compositions with different amounts of essential oil were analyzed using a mechanical tensile-stress test. The inventors performed a dynamic mechanical analysis (DMA) and determined that the elastic modulus of the composition at 25°C was in the range of 50MPa to 500MPa. In a specific embodiment, the composition has an elastic modulus of at least 50MPa at 25°C and an elastic modulus of less than 5MPa at 100°C. In a preferred embodiment, the composition has an elastic modulus of 50-150MPa at 25°C and an elastic modulus of less than 3MPa at 100°C. In the most preferred embodiment, the composition has an elastic modulus of 110 MPa at 25° C. and an elastic modulus of 0.6 MPa at 100° C. In addition, the inventors have also tested the shear stress of the composition on different materials, and determined that the composition exhibits high adhesion strength on glass, metal, wood, paper and plastic, for example, the adhesion strength of composition UP1-C2 (i.e., the initial weight ratio of the monomer unit to the essential oil is 1:2) is in the range of 0.1 MPa to 12 MPa, more specifically, the strength on the surfaces of glass, metal and paper can be in the range of 4 MPa to 12 MPa.

[0143] The inventors have also unexpectedly discovered that the hydrophobic material provides a sustained release property for the composition. The sustained release property of the composition is analyzed by calculating the mass change (%) over time and comparing the amount of release of the hydrophobic material, especially the essential oil, in the composition compared with the pure essential oil. Compared with the pure essential oil, which has a reduction of about 40% of the original mass at 100 days, it is found that the amount released from the composition of the present invention is much less, with 85-90% of the mass remaining at 100 days, indicating that the composition has long-term stability in the air. The release of essential oils in water was also studied, and the cumulative release of essential oils from the composition can last up to 60 days (cumulative release of about 30% to 45%), which advantageously shows that the essential oils have controlled release properties when encapsulated in the composition of the present invention.

[0144] The inventors also found that the composition showed self-repairing properties by performing a repairability test. The composition showed that the self-repairing efficiency increased with the extension of the repair time, that is, about 20% repair efficiency at 10 minutes, and 95% repair efficiency at 40 minutes, and heating to 70°C significantly accelerated the repair process. Relative to the original sample, the repair efficiency of the composition at 40 minutes was 95.6%, indicating that the composition has a beneficial self-repairing ability.

[0145] Disc diffusion assays were performed to test the antimicrobial activity of the composition against Gram-positive and Gram-negative bacteria. The composition comprising the monomer unit and the essential oil advantageously exhibited antibacterial activity in the presence of Gram-negative and Gram-positive bacteria compared to the control sample. The bactericidal ability of the composition was also positively correlated with the essential oil content in the composition, i.e., a higher essential oil weight ratio in the composition achieved a stronger bactericidal ability. Therefore, the composition of the present invention can be made into a structurally stable self-healing sustained-release antimicrobial agent.

[0146] On the other hand, the present invention also relates to a method for preparing a composition, in particular a composition as described above. The method comprises the following steps: (a) providing one or more monomer units having a structure of formula (I):

[0147]

[0148] Formula (I),

[0149] in:

[0150] - n is an integer selected from 1 to 10;

[0151] -R represents a substituted or unsubstituted cyclic group;

[0152] (b) mixing the one or more monomer units with a hydrophobic substance; and

[0153] (c) obtaining the composition, wherein the one or more monomer units encapsulate the hydrophobic substance.

[0154] Preferably, step (b) is carried out by dissolving said one or more monomer units in said hydrophobic substance at a temperature of 50°C to 150°C.

[0155] In an exemplary embodiment, the one or more monomer units in step (a) are prepared by reacting a compound having formula (IVa) and a compound having formula (IVb):

[0156]

[0157] Formula (IVa),

[0158]

[0159] Formula (IVb),

[0160] in:

[0161] - m is an integer selected from 1 to 10;

[0162] -R7, R8, R9, R 10 are independently selected from the group consisting of: a linear or branched alkyl group optionally containing a heteroatom; a heteroatom; and a hydrogen atom; and

[0163] - The dashed line indicates that there are no double bonds, one double bond, two double bonds or three double bonds in the cyclic group of formula (IVb).

[0164] In a preferred embodiment, m is selected from 1 to 5, and R7 and R8 are straight or branched chain alkyl groups, preferably C1-C 10 Alkyl, more preferably C5-C 10 Preferably, R9 and R 10 is a heteroatom or a hydrogen atom.

[0165] In a further preferred embodiment of the present invention, formula (IVb) has one double bond, and R7 is an unsubstituted C8 alkyl group, R8 is an unsubstituted C6 alkyl group, and R9 and R 10 It's a hydrogen atom.

[0166] In certain embodiments, the monomer unit has the structure of formula (III):

[0167]

[0168] Formula (III).

[0169] In yet another aspect, the present invention also relates to a method of killing or controlling the growth of microorganisms, which comprises contacting the microorganisms with a composition, in particular a composition as previously discussed.

[0170] It will be appreciated that the invention also relates to a kit comprising a composition as described above and to the use of said composition for medical purposes, such as topical administration.

[0171] Example

[0172] Example 1A

[0173] Molecular design of compositions

[0174] The claimed invention relates in one aspect to a composition comprising one or more monomer units encapsulating a hydrophobic substance. In one embodiment, the monomer unit consists of a dimer diamine terminated with ureidopyrimidone (UPy). The inventors unexpectedly discovered that the composition of the present invention can be constructed by polymerization and intermolecular crosslinking, wherein the hierarchical hydrogen bond crosslinked network can promote the composition to have high mechanical strength and rapid repair properties.

[0175] It was found that the ureidopyrimidone motif forms strong quadruple hydrogen bonds, which promotes linear chain extension and can advantageously achieve monomer properties. It was found that weak hydrogen bonding interactions between urea units provide intermolecular cross-links between the monomer backbones. Introducing a hydrophobic substance such as carvacrol into the one or more monomer unit networks disrupts the weak hydrogen bonding cross-links and promotes the formation of a gel-like composition. The inventors have beneficially found that the content of the hydrophobic substance, particularly carvacrol in this embodiment, can be controlled to adjust the mechanical strength of the composition.

[0176] Figure 1 Monomer units according to example embodiments are shown. The monomer units are terminated by ureidopyrimidone dimers (shown as L-shaped blocks), which associate and dissociate under certain stimuli, allowing the composition to self-repair when damaged and to perform directional and reversible intermolecular self-assembly. The strong quadruple hydrogen bonding between ureidopyrimidones is represented by L-shaped blocks, the weak hydrogen bonding interactions between the urea motifs in the one or more monomer units are shown as cylindrical blocks, and the hydrophobic substance molecules, particularly the carvacrol oil molecules in one embodiment, are shown as spherical blocks. Arrows show that the one or more monomer units and the hydrophobic substance advantageously self-assemble to form the composition.

[0177] Example 1B

[0178] Materials and methods

[0179] Material

[0180] Dimer diamine TM 1074) was purchased from CRODA Coatings & Polymers. 2-Amino-4-hydroxy-6-methylpyrimidine 99% was purchased from Acros Organics. Other chemicals and solvents were obtained from Sigma-Aldrich and used as received.

[0181] Synthesis of monomer units of formula (I)

[0182] In a specific embodiment, the monomer unit has a structure of formula (III), i.e., (UPy-NCO)2Priamine. (UPy-NCO)2Priamine is obtained by reacting 2 equivalents of UPy-NCO and 1 equivalent of priamine 1074. Priamine 1074 is added to a 500 mL round bottom flask equipped with a reflux cooler. TM 1074 (1.593 g, 3 mmol) and DMSO (150 mL), then UPy-NCO (1.758 g, 6 mmol) was added dropwise. After 6 hours of reaction at 90 ° C under nitrogen protection, the solvent DMSO was removed, and the solid product was washed 3 times with 60 mL portions of acetone. (UPy-NCO) 2Priamine was then collected by centrifugation and dried overnight at 60 ° C and high vacuum.

[0183] Preparation of the composition of the present invention

[0184] 1 equivalent of (UPy-NCO)2Priamine powder was stirred and dissolved in 2 equivalents of carvacrol at 80°C and evaporated at room temperature for 12 hours to promote complete network formation. Compositions with different weight ratios of monomer units and hydrophobic substances were prepared according to the above method and are summarized in the following Table 1. UP represents the monomer unit (UPy-NCO)2Priamine, and C represents a hydrophobic substance, especially an essential oil.

[0185] Composition Weight ratio (UP:C) <![CDATA[UP1-C0]]> 1:0 <![CDATA[UP1-C1]]> 1:1 <![CDATA[UP1-C2]]> 1:2 <![CDATA[UP1-C5]]> 1:5

[0186] Table 1: Weight ratios of different samples of the composition of the invention Example 1C

[0187] Mechanical and self-healing analysis

[0188] For mechanical tensile-stress and self-healing tests, the sample dimensions used were 30 mm long × 6 mm wide × 3 mm high, the gauge length was 10 mm, and the strain rate was 10 mm / min. The tests were repeated at least three times and the average value was recorded. Dynamic mechanical analysis (DMA) was performed on TA instruments (Q800 DMA). For self-healing tests, the polymer film was cut into two pieces and then put together. Healing tests were performed on various samples under different conditions. The tensile stress-strain curves were obtained following the same procedure for the repaired samples. The results were obtained by using a Malvern Kinexus Lab using 20 mm diameter parallel plates. + Rheological testing of the gel was performed. The gap in the apparatus used for rheological testing of the gel was 1.0 mm. A frequency sweep was performed from 0.01 rad / sec to 100 rad / sec. A temperature sweep was performed from 20°C to 100°C.

[0189] Figure 2The results of the nanoindentation tests used to test the mechanical tensile-stress of the composition samples are shown. For UP1-C0, i.e. the composition comprising a 1:0 weight ratio of monomer units: hydrophobic substance (especially carvacrol), a Young's modulus of 1.44 GPa reflects a very high stiffness. The Young's modulus decreases as the content of carvacrol in the composition increases. This is illustrated by the results of the nanoindentation tests, where the elastic modulus of the composition UP1-C1 is 420 MPa, the elastic modulus of the composition UP1-C2 is 210 MPa, and the elastic modulus of the composition UP1-C5 is 85 MPa.

[0190] Further, refer to Figure 3 For composition UP1-C2, the analysis of temperature-dependent dynamic mechanical analysis (DMA) showed that the elastic modulus dropped rapidly from 110 MPa at room temperature to 0.9 MPa at 100°C, indicating that the composition exhibited high strength at room temperature and showed repairable properties at temperatures above 60°C.

[0191] Figure 4A , Figure 4B , Figure 4C , Figure 5 and Figure 6 The results of the repairability test performed on the composition samples UP1-C2 are shown. The sample was cut into two separate pieces with a razor blade and then placed in contact with the hand. Figures 4A-4C In situ microscopic images of UP1-C2 samples at different time points are shown. Figure 4B and Figure 4C Samples at 20 minutes and 40 minutes at 80°C are shown, respectively. The results show that the self-healing efficiency of the composition increases over time. Heating the composition to 70°C also significantly accelerates the healing process, which correlates with rheological and DMA analysis, indicating that the modulus of the composition decreases above this temperature.

[0192] Tensile tests were also performed on the compositions tested at different repair times and are shown in Figure 5 and Figure 6 Relative to the original sample, the repair efficiency of the sample at 40 min was 96.5%, which may be attributed to the chain motion and dynamic hydrogen bonding association.

[0193] Fig. 9 TABLE 1 is a table showing the properties of composition samples, namely UP1-C0, UP1-C1, UP1-C2, UP1-C5, having different amounts of hydrophobic substances. The mechanical properties of the composition samples studied include maximum stress, maximum strain, Young's modulus - tensile test, storage modulus G'-0.1 rad / s, Young's modulus - indentation and glass transition temperature (T g ).

[0194] Fig.10is a scatter plot showing the frequency sweep in the rheological measurement of the monomer units assembled in thymol oil. Over the entire frequency range, the storage modulus (G') is higher than the loss modulus (G"), showing solid-like behavior. Fig.10 Thymol oil has also been shown advantageously to be an effective hydrophobic substance for encapsulation in one or more monomer units.

[0195] Fig.11 is a line graph showing that the composition samples having two different amounts of hydrophobic substances, ie, UP1-C0 and UP1-C2, exhibit good transmittance up to 90% in the visible light region.

[0196] The results advantageously demonstrate that varying the amount of hydrophobic material in the composition can be used to vary or control the mechanical strength of the composition, and that the composition exhibits self-healing properties.

[0197] Fig. 12A Scatter plot showing the frequency scan in the rheological measurement of monomer units assembled in eugenol oil, Fig. 12B The scatter plots of the frequency scans in the rheological measurements of the monomer units assembled in limonene are shown. These results all show that the essential oils can be effectively encapsulated in one or more monomer units, and the essential oils can be selected from (but not limited to) carvacrol, thymol, eugenol, p-cymene and limonene.

[0198] Fig.14 The bar graphs of shear stress of the composition samples UP1-C2 on different materials are further shown, and the composition samples all exhibit excellent adhesion strength on glass, metal, plastic, paper, and wood, which is better than most commercial adhesives. Therefore, the composition of the present invention is particularly suitable for use as an antimicrobial coating, or for use in wound dressings, etc.

[0199] Example 1D

[0200] Antimicrobial analysis

[0201] Disc diffusion assay

[0202] The disc diffusion assay is used to test the antimicrobial capabilities of a composition. If bacterial growth is controlled or the bacteria are killed, a visible area known as the zone of inhibition is seen around the disc.

[0203] Gram-positive Staphylococcus aureus (S.aureus) and Gram-negative Escherichia coli (E.coli) solutions were tested and diluted to 0.5McFarland turbidity standards. Sterile swabs were immersed in the diluted bacterial solution and rubbed on the entire surface of the LB agar plate. After bacterial inoculation, a disc with coating (10 mg of samples UP1-C0, UP1-C2, UP1-C5 of different weight ratios) was placed in the center of the LB agar plate. These plates were incubated at 37°C for 24 hours, and photos of the inhibition zone were recorded by a Leica camera.

[0204] Figures 7A-7C These are the results of antimicrobial testing of UP1-C5, UP1-C2, and UP1-C0 against Gram-positive bacteria. Figure 7D-7F These are the results of antimicrobial testing of UP1-C5, UP1-C2, and UP1-C0 against Gram-negative bacteria.

[0205] Compared with the control sample UP1-C0 ( Figure 7C and Figure 7F ), the composition comprising one or more monomer units and a hydrophobic substance (i.e., the essential oil in this embodiment) exhibits antibacterial ability against Gram-positive bacteria and Gram-negative bacteria. The bactericidal ability of the composition is also positively correlated with the essential oil content in the composition. Figures 7A-7C and Figure 7D-7F When compared, the composition samples at the same concentration appeared to be more effective in killing Gram-positive bacteria than Gram-negative bacteria.

[0206] Time-dependent disinfection efficiency

[0207] 1 cm x 1 cm glass slides coated with different amounts of essential oil (specifically carvacrol) UP1-C0, UP1-C2 or UP1-C5 (10 mg of each coating) were immersed in 1 mL of Staphylococcus aureus or Escherichia coli solution in a 24-well plate. Every thirty minutes, the bacterial solution was mixed by vortexing, and 100 μL aliquots of the bacterial sample were removed and used for serial dilution on agar plates. The appropriate number of colonies formed was counted, and the total amount of bacteria in the solution was calculated. The experiment was performed three times independently.

[0208] Fig. 8A The time-dependent antimicrobial activity of samples UP1-C2 and UP1-C5 against S. aureus was shown by analyzing the reduction of colony forming units (CFU). Figure 8BThe time-dependent antimicrobial activity of samples UP1-C2 and UP1-C5 against E. coli was shown by analyzing the reduction of CFU. The results showed that UP1-C2 and UP1-C5 were able to reduce the colony forming units of S. aureus and E. coli by more than 5 orders of magnitude after 90 minutes, equivalent to a reduction efficiency of more than 99.999%.

[0209] These results show that the composition of the present invention has excellent antimicrobial ability.

[0210] Example 1E

[0211] Release of carvacrol encapsulated in the composition in air or underwater

[0212] The amount of carvacrol, i.e., the hydrophobic substance in the composition, released into the air was calculated by weight loss and is shown in Figure 8C The release of carvacrol in water was monitored by UV-vis scanning spectrophotometer (Shimadzu 1700), where the UV main peak absorption of carvacrol can be measured at 275 nm and is shown in Fig.8D middle.

[0213] refer to Figure 8C , compared with pure carvacrol, it was found that the amount of carvacrol released from the composition samples UP1-C2 and UP1-C5 over 100 days was much less, indicating that the compositions had long-term stability in air.

[0214] The release of carvacrol encapsulated into the composition was also studied in water, e.g. Fig.8D As shown in . The cumulative release of carvacrol from the composition samples can last up to 60 days, indicating that carvacrol has controlled or sustained release properties when encapsulated into the composition samples. This may be attributed to the strong non-covalent interaction between carvacrol oil and one or more monomer units. Therefore, the composition of the present invention shows a strong extended release behavior, which provides a very advantageous composition with wide applicability, such as in the preparation of sustained release dosage forms for various medical purposes. In addition, as Fig.13 As shown, even if carvacrol has been released from the composition sample for 60 days, the composition sample still has an efficiency of up to 99.9% in killing microorganisms. The above results show that the composition of the present invention has controlled-release antimicrobial activity. The composition of the present invention can achieve a long-term antimicrobial effect.

[0215] The present invention provides a multifunctional composition comprising one or more monomer units, wherein the monomer units are encapsulated with a hydrophobic substance, such as an essential oil. The composition has been shown to exhibit mechanical robustness, rapid repair, strong adhesion, and sustained release of antibiotic properties. Based on a network of supramolecular polymerization and crosslinking of polymer chains, hierarchical hydrogen bonding interactions can achieve high mechanical strength and rapid repair at high temperatures. Specifically, strong quadruple hydrogen bonds can achieve polymerization of monomer units, and weak intermolecular hydrogen bonds contribute to crosslinking and aggregation of monomer units. It has been shown that carvacrol oil easily affects the mechanical strength of the composition by destroying weak intermolecular hydrogen bonding. Therefore, the mechanical properties and repairability of the composition can be controlled, thereby beneficially providing a high-strength, self-healing, extended-release composition with antimicrobial properties.

Claims

1. A composition comprising: a) a supramolecular polymer comprising a plurality of monomer units, wherein each monomer unit of the plurality of monomer units has a structure of formula (I): in: - n is an integer selected from 1 to 10; -R has the structure of formula (IIb): in: R1 and R2 are independently selected from the group consisting of: a linear or branched alkyl group optionally containing a heteroatom; and a cycloalkyl group optionally containing a heteroatom, R3, R4, R5 and R6 are independently selected from the group consisting of: a linear or branched alkyl group optionally containing heteroatoms, heteroatoms and hydrogen atoms, Dashed lines indicate the absence or presence of a double bond; and b) a hydrophobic substance, wherein the hydrophobic substance is encapsulated by the supramolecular polymer; The hydrophobic substance comprises a compound selected from the group consisting of carvacrol, thymol, p-cymene and limonene; or the hydrophobic substance is an essential oil.

2. The composition of claim 1, wherein R1, R2, R3 and R4 are straight or branched chain alkyl groups, and R5 and R6 are hydrogen atoms.

3. The composition of claim 1, wherein each of the plurality of monomeric units has a structure of formula (III):

4. The composition of claim 1, wherein the hydrophobic substance is a liquid.

5. The composition of claim 1, wherein the hydrophobic substance forms non-covalent bonds with the plurality of monomer units.

6. A self-healing sustained-release antimicrobial coating composition comprising the composition of claim 1, wherein the composition comprises an antimicrobial compound.

7. The composition of claim 1, wherein the composition has an elastic modulus of at least 50 MPa at 25°C and an elastic modulus of less than 5 MPa at 100°C.

8. A method for preparing a composition, the method comprising the steps of: (a) providing a plurality of monomeric units, wherein each monomeric unit in the plurality of monomeric units has a structure of formula (I): in: - n is an integer selected from 1 to 10; -R represents a substituted or unsubstituted cyclic group; (b) mixing the plurality of monomer units with a hydrophobic substance; and (c) obtaining a supramolecular polymer comprising the plurality of monomer units, wherein the hydrophobic substance is encapsulated in the supramolecular polymer; Wherein R of formula (I) has the structure of formula (IIb): in: R1 and R2 are independently selected from the group consisting of: a linear or branched alkyl group optionally containing a heteroatom; and a cycloalkyl group optionally containing a heteroatom; R3, R4, R5 and R6 are independently selected from the group consisting of: a linear or branched alkyl group optionally containing a heteroatom; a heteroatom; and a hydrogen atom; The dashed line indicates that there is no double bond or there is one double bond; The hydrophobic substance comprises a compound selected from the group consisting of carvacrol, thymol, p-cymene and limonene; or the hydrophobic substance is an essential oil.

9. The method of claim 8, wherein the monomer units in the plurality of monomer units in step (a) are prepared by reacting a compound having formula (IVa) with a compound having formula (IVb): in: - m is an integer selected from 1 to 10; -R7, R8, R9, R 10 are independently selected from the group consisting of: a straight or branched alkyl group optionally containing a heteroatom; a heteroatom; and a hydrogen atom; and - wherein the dotted line indicates that there is no double bond or one double bond in the cyclic group of formula (IVb).

10. The method of claim 8, wherein each monomer unit of the plurality of monomer units has a structure of formula (III):

11. The method of claim 8, wherein the hydrophobic substance is a liquid.

12. The method of claim 8, wherein the step (b) is performed by dissolving the plurality of monomer units in the hydrophobic substance at a temperature of 50°C to 150°C.

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