BR112014021641B1 - coating composition, drug eluting medical device and drug coating layer - Google Patents

Abstract

patent summary: "coating composition and medical device". The present invention provides a drug eluting device coating composition which enables a medical device to be delivered into a target tissue for the purpose of treating an affected part of a blood vessel such as a restenosis without easy drug separation. medical device during the release process. such a medical device coating composition contains a water-insoluble drug and at least one selected from the group consisting of amino acid ester compounds having an amino acid side chain hydrophobicity index of zero or less than zero, and their salts.

Description

Descriptive Report of the Invention Patent for COMPOSITION OF COATING, MEDICAL DEVICE WITH DRUG ELUTION AND DRUG COATING LAYER.

Technical Field [0001] The present invention relates to a coating composition for a drug eluting medical device, a drug coating layer of a drug eluting medical device and / or a coated drug eluting medical device. with the coating composition.

Background Technique [0002] As an example of therapy with local drug release there is a drug eluting stent (DES). DES is thus designed for the local release of a drug in a manner sustained for a long period of time, thereby preventing restenosis of a blood vessel. The prolonged release of a drug from the DES is achieved by a polymer conjugate such as polylactic acid (PLA). In this case, as the polymer remains in a living body for a long period of time, there is a problem with severe complications such as chronic inflammation or delayed thrombosis in the part affected by an injury.

[0003] Conventionally, it has been reported that the prolonged release of a drug over a long period of time is necessary to contain restenosis. Recently, however, it has become clear that the rapid transfer of a drug to a target tissue, even a drug with a sustained effect for a short period of time, is sufficient to prevent successful restenosis. Rapid drug release technology does not require a polymeric matrix, such as PLA (polylactic acid) or PLGA

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2/50 (polylactic acid-glycolic acid copolymer), for prolonged release and, therefore, is advantageous for avoiding complications.

[0004] In addition, recently, the development of DEBs (Drug Elution Balloons), in which a balloon catheter is coated with a drug, has been done positively and has been reported to be effective in the treatment and prevention of restenosis. The balloon is coated with a coating that contains a drug and additives, and when a blood vessel is dilated, the balloon is pressed against the blood vessel wall in order to release the drug into the target tissue.

Summary of the Invention Technical Problem [0005] If the drug is easily removed from the balloon in the process of releasing the balloon into the target tissue, however, the amount of drug remaining on the balloon can be reduced below the level sufficient for a therapeutic effect, before that the balloon is released to the affected part of the lesion. In such a situation, the expected therapeutic effect cannot be promised. In addition, the drug that is easily removed during the delivery process is unnecessarily exposed to blood, which is also undesirable from the point of view of safety. Therefore, there is a need for a drug coating layer that ensures that the drug-coated catheter balloon can be released to the affected part of an injury without removing the drug, the balloon can be pressed against a vessel wall. blood flow simultaneously with the expansion and, in this way, the drug can be released quickly.

[0006] Furthermore, if a low molecular weight compound used in the coating together with the drug is excessively hydrophobic, its hydrophobic interaction with the drug insoluble in

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3/50 water may be accentuated and its hydrophobic regions may have a high affinity for the surface of the balloon. As a result, the release (transfer) of the drug from the balloon to the affected part (internal surface of the blood vessel) may not occur easily, even after contact of the balloon with the affected part. In addition, if the hydrophobicity of the low molecular weight compound mixed with the hydrophobic drug is enhanced, the hydrophobic interaction between the molecules of the water-insoluble drug may be so enhanced that the drug can easily aggregate onto the surface of the medical device, making it difficult get a uniform coating. In addition, the drug applied to the surface of the medical device in an aggregate state can be easily detached from the surface of the balloon during handling, which is undesirable from the point of view of safety and function. If the low molecular weight compound is excessively hydrophilic, on the other hand, it can be difficult to mix the compound with the water-insoluble drug. In such a case, it may be difficult to prepare a stable drug coating layer solution or the low molecular weight compound can be easily fluidized into the bloodstream along with the drug due to its marked hydrophilicity. Therefore, the low molecular weight compound used in the coating together with the drug desirably should have a hydrophilic region to relax the hydrophobic interaction between the molecules of the water-insoluble drug and ensure uniform dispersion of the drug and a hydrophobic region that has an affinity for water-insoluble drug; in short, the balance between the hydrophilic region and the hydrophobic region is important.

[0007] In view of the foregoing, it is an object of the present invention to provide a coating composition for medical drug eluting devices that ensures that a drug can

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4/50 be released for the treatment of a part of an affected blood vessel such as restenosis, without the easy release of the drug from the medical device in the process of delivery to a target tissue, such that the drug can be quickly released in the part affected from the lesion after release and that the transfer of the drug to the target tissue can be intensified.

Technical Solution [0008] The present inventors made extensive and intense investigations to solve the problem mentioned above. As a result of their investigations, the present inventors found that when a coating composition containing a water-insoluble drug is at least one selected from the group consisting of amino acid ester compounds that have a hydrophobicity index (hydropathy index: HI) of a side chain of an amino acid of zero or less than zero, and its salts is used, it is possible to form a drug coating layer on the surface of a medical device, the drug coating layer ensuring that the drug can be released for the treatment of an affected part of a blood vessel such as restenosis, without easy release of the drug from the medical device during the process of delivery to the target tissue. Based on the finding, they completed the present invention.

[0009] Specifically, according to the present invention, the following from (1) to (13) are provided.

(1) A coating composition for a drug-eluting medical device, which contains a water-insoluble drug and at least one selected from the group consisting of amino acid ester compounds, which have a hydrophobicity index of an amino acid side chain zero or less than zero and its salts.

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5/50 (2) The coating composition according to paragraph (1), wherein the amino acid is an α-amino acid.

(3) The coating composition according to paragraph (1) or (2) above, wherein the ester compound is an ester compound of at least one amino acid and a monohydric alcohol of up to five carbon atoms, the at least one amino acid being selected from the group consisting of glycine, serine, asparagine, aspartic acid, glutamine, glutamic acid, arginine, threonine, histidine, lysine, tyrosine, tryptophan, amino acids obtained by replacing at least one of the hydrogen atoms of an amino group in the α position on the aforementioned amino acids with an alkyl group of up to five carbon atoms, a benzyl group or a benzoyl group, proline and amino acids obtained by replacing a hydrogen atom of an imine proline group with an alkyl group of up to five carbon atoms, a benzyl group or a benzoyl group.

(4) Coating composition according to any of paragraphs (1) to (3) above, in which the ester compound is represented by the following formula: [Chemical 1]

where Ri is a hydrogen atom, guanidinopropyl group, carbamoylmethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 2-carbamoyl-ethyl group, 2-carboxyethyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group, group (1Himidazol-4 -yl) methyl, 4-aminobutyl group, hydroxymethyl group, 1hydroxyethyl group, (1H-indol-3-yl) methyl group or 4-hydroxybenzyl group or

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6/50 forms a trimethylene group together with R2, R2 is a hydrogen atom or forms a trimethylene group together with R1, R3 is a hydrogen atom, an alkyl group with up to five carbon atoms, a benzyl group or benzoyl group and R4 is an alkyl group with up to five carbon atoms.

(5) Coating composition according to any of paragraphs (1) to (4) above, wherein the ester compound is at least one selected from the group consisting of ethyl benzylglycine ester, methyl benzylglycine ester, ethyl arginine ester, ester methyl arginine, benzoyl arginine ester, methyl benzoyl arginine ester, diethyl aspartate, methyl aspartate, dimethyl aspartate, ethyl glycine ester, methyl glycine ester, ethyl serine ester and methyl serine ester.

(6) Coating composition according to any of paragraphs (1) to (5) above, additionally containing a lower alcohol.

(7) The coating composition according to paragraph (6), wherein the lower alcohol is glycerin.

(8) Coating composition according to any of paragraphs (1) to (7) above, wherein the water-insoluble drug is at least one selected from the group consisting of paclitaxel, rapamycin, docetaxel and everolimus.

(9) Coating composition according to any of paragraphs (1) to (8) above, wherein the medical device is a medical device that is radially expandable in a vascular lumen.

(10) Coating composition according to paragraph (9), wherein the medical device that is radially expandable in a vascular lumen is a balloon catheter or a stent.

(11) A drug coating layer that is formed at least in part by a surface of a medical device by using

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7/50 of a coating composition according to any of paragraphs (1) to (10) above.

(12) Drug-eluting medical device that has an outer surface coated with the coating composition according to any of paragraphs (1) to (10) above.

(13) Treatment method that includes:

a step of releasing the medical device according to paragraph (12) in a vascular lumen;

a step of radially expanding the medical device in a vascular lumen; and a drug elution step from a drug coating layer formed, at least in part, on the surface of the medical device and which allows the drug to act on the vascular lumen.

Advantageous Effect [00010] According to the present invention, it is possible to provide a coating composition for medical drug eluting devices that ensures that the drug is released for the treatment of a part of an affected blood vessel such as restenosis, without the easy detachment of the drug from the medical device in the process of delivery to the target tissue, such that the drug can be rapidly released in the affected part of the lesion after release and that the transfer of the drug to the target tissue can be enhanced.

Brief Description of the Drawings [Fig. 1] [00011] Fig. 1 is a schematic section of an experimental device used in a test to assess the durability of a drug coating layer using a blood vessel imitation, in a state in which the balloon catheter is inserted in one

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8/50 guide catheter in imitation of blood vessel.

[Fig. 2] [00012] Fig. 2 is a graph representing the rate of paclitaxel remaining in the flask after the drug-eluting flask release operation in Examples 1 to 7 and Comparative Examples C1 to C4, in assessing the durability of a drug coating layer using blood vessel imitation. [Fig. 3] [00013] Fig. 3 is a graph representing the amount of paclitaxel contained in blood vessel tissue in Example 8 and Comparative Examples C5 and C6, in assessing the transfer of a drug to tissue in the iliac artery of Bunny.

[Fig. 4] [00014] Fig. 4 is a graph depicting the rate of paclitaxel remaining in a blood vessel tissue after one hour and after 24 hours of expansion of the blood vessel vascular lumen in Examples 9 and 10, in the evaluation the retention of a drug in the abdominal aorta tissue of rabbits.

[Fig. 5] [00015] Fig. 5 is a graph depicting the rate of stenosis in Examples 9 to 11 and Comparative Examples C6 and C7 in assessing efficacy in the porcine coronary artery.

Mode for Carrying Out the Invention

1. Coating Composition [00016] The coating composition according to the present invention is a coating composition for medical drug eluting devices, which contains a water insoluble drug and at least one selected from the group consisting of ester compounds amino acids, which have a hydrophobicity index of an amino acid side chain of zero or

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9/50 less than zero and its salts.

[00017] The coating composition of the present invention contains the insoluble drug and at least one selected from the group consisting of amino acid ester compounds, which have a hydrophobicity index of an amino acid side chain of zero or less than zero and its salts, is a mixture that has the ingredients mixed together and is not a polymeric coating. These ingredients are not linked to each other by a covalent bond.

[00018] The coating composition of the present invention is desired to be applied uniformly, to be contained from the separation during delivery to an affected part and to release the drug efficiently on the affected part. Therefore, it is preferable that the low molecular weight compound mixed with the water-insoluble drug is water-miscible and water-miscible organic solvents and also has an affinity for the hydrophobic water-insoluble drug. From that point of view, the low molecular weight compound is preferably an amino acid ester compound that has a side chain with a hydrophobicity index of zero or less than zero and / or its salts.

[00019] On the other hand, for example, a citric acid ester or the like that has three carboxyl groups in one molecule and esterification of the carboxyl group portion is supposed to significantly decrease the polarity of the citric acid ester or the like. As a result, although the affinity of the citric acid ester or the like for the water-insoluble drug is increased, the citric acid ester or the like is reduced in polarity and reinforced in hydrophobic interaction with the water-insoluble drug, such that the drug molecules are prone to aggregate. Additionally, it becomes difficult for the drug to be released

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10/50 of the balloon's surface in the affected part. Therefore, it is assumed that a favorable coating composition cannot be obtained.

(1) Water-insoluble drug [00020] The water-insoluble drug means a drug that is insoluble or hardly soluble in water, specifically a drug that has a water solubility of less than 5 mg / mL at pH 5 to 8. Solubility can be less than 1 mg / ml or it can be less than 0.1 mg / ml. The water-insoluble drug includes fat-soluble drugs.

[00021] Preferable examples of the water-insoluble drug include immunosuppressants, for example, cyclosporins including cyclosporine, immune adjuvants such as rapamycin, etc., carcinostatics such as paclitaxel, etc., antiviral and antibacterial agents, antineoplastic agents, analgesic agents and anti-inflammatory agents, antibiotics, antiepileptics, anxiolytic agents, antiparalysis agents, antagonists, agents that block neurons, anticholinergic and cholinergic agents, muscarinic antagonists and muscarinic agents, antiadrenergic agents, antiarrhythmic agents, antihypertensive agents, hormonal preparations and nutritional supplements.

[00022] The water-insoluble drug is preferably at least that selected from the group consisting of rapamycin, paclitaxel, docetaxel and everolimus. Rapamycin, paclitaxel, docetaxel, and everolimus include their analogs and / or derivatives, as long as the analogs and / or derivatives have an effect equivalent to the original. For example, paclitaxel and docetaxel are in an analogous relationship, while rapamycin and everolimus have a derivative relationship. Among these, most preferred is paclitaxel.

[00023] The coating composition of the present invention contains the water-insoluble drug preferably in a

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11/50 concentration of 5 to 60 mg / ml, more preferably 20 to 50 mg / ml and still preferably 30 to 40 mg / ml.

(2) Amino acid ester compounds that have a hydrophobicity index of an amino acid side chain of zero or less than zero and its salts

2-1) Amino acid side chain hydrophobicity index [00024] The hydrophobicity index (hydropathy index) of an amino acid side chain represents the hydrophobicity or hydrophilicity of an amino acid side chain. The higher the numerical value of the side chain hydrophobicity index of an amino acid, the more hydrophobic the amino acid is. Hereinafter, the side chain hydrophobicity index of an amino acid can be referred to simply as the "hydrophobicity index".

[00025] In the present invention, the hydrophobicity index is the hydrophobicity index according to "Kyte and Doolittle, J. Mol. Biol., 157, 105-132 (1982)".

[00026] The hydrophobicity index is not particularly limited, as it is zero or less than zero.

[00027] Table 1 shows hydrophobicity indexes of typical amino acids. In Table 1 “Amino acid” means amino acid, “Cas no.” Means CAS registration number and “H.I.” means hydrophobicity index.

[Table 1]

Amino Acid CAS no. H.I. Glycine 56-40-6 -0.4 Asparagine 70-47-3 -3.5 Serina 56-45-1 -0.8 Aspartic acid 56-84-8 -3.5 Glutamine 56-85-9 -3.5 Glutamic acid 56-86-0 -3.5

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12/50

Threonine 72-19-5 -0.7 Arginine 74-79-3 -4.5 Histidine 71-00-1 -3.2 Lysine 56-87-1 -3.9 Tyrosine 60-18-4 -1.3 Tryptophan 73-22-3 -0.9 Cysteine 52-90-4 2.5 Methionine 63-68-3 1.9 Proline 147-85-3 -1.6 Phenylalanine 63-91-2 2.8 Alanine 56-41-7 1.8 Valina 72-18-4 4.2 Leucine 61-90-5 3.8 Isoleucine 73-32-5 4.5 2-2) Ester compounds d and amino acids and their salts

[00028] Amino acids are not specifically restricted as they have a side chain hydrophobicity index of zero or less than zero; preferably, however, the amino acids are α-amino acids.

[00029] In addition, ester compounds are not particularly restricted since they are amino acid ester compounds, which have a hydrophobicity index of an amino acid side chain of zero or less than zero. Preferably, however, the ester compounds are α-amino acid ester compounds. More preferably, the ester compounds are ester compounds of at least one amino acid and a monohydric alcohol of up to five carbon atoms, the at least one amino acid being selected from the group consisting of glycine, serine, asparagine, aspartic acid, glutamine, glutamic acid , arginine, threonine, histidine, lysine, tyrosine, tryptophan, amino acids

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13/50 obtained by replacing at least one of the hydrogen atoms of an amino group in the α position in the aforementioned amino acids with an alkyl group of up to five carbon atoms, a benzyl group or a benzoyl group, proline and amino acids obtained by substitution of a hydrogen atom of an imine proline group with an alkyl group of up to five carbon atoms, a benzyl group or a benzoyl group. Preferably, the ester compounds are ester compounds represented by the following formula:

[Chemist 2]

Í? 1 where Ri is a hydrogen atom, guanidinopropyl group, carbamoylmethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 2-carbamoyl-ethyl group, 2-carboxyethyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group, group ( 1Himidazol-4-yl) methyl, 4-aminobutyl group, hydroxymethyl group, 1hydroxyethyl group, (1 H-indol-3-yl) methyl group or 4-hydroxybenzyl group or forms a trimethylene group together with R2, R2 is an atom of hydrogen or forms a trimethylene group together with R1, R3 is a hydrogen atom, an alkyl group of up to five carbon atoms, a benzyl group or a benzoyl group and R4 is an alkyl group of up to five carbon atoms. Even more preferably, the ester compound is at least that selected from the group consisting of ethyl benzylglycine ester, methyl benzylglycine ester, ethyl arginine ester, methyl arginine ester, ethyl benzoylginine ester, methyl benzoylarginine ester, diethyl aspartate, methyl aspartate, aspartate dimethyl, glycine ethyl ester, glycine methyl ester, serine ethyl ester and serine methyl ester.

[00030] Salts of ester compounds are not specifically

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Restricted 14/50; however, the salts are preferably hydrochlorides or acetate, more preferably hydrochlorides. In addition, in the case where there is a free carboxyl group that is not part of an ester bond, the salts of the ester compounds can be alkali metal salts, where the alkali metal is preferably sodium.

[00031] The salt of the amino acid ester compound is enhanced in polarity (water solubility) by a salt of an amino group, for example, hydrochloride of an amino group. In addition, the salt of the amino acid ester compound may exhibit different properties such as hydrophilic property or hydrophobic property and basic property or acidic property, depending on the properties of the amino acid chain or side chains. In the present invention, the amino acid ester compounds and their salts are not specifically restricted, as they have a side chain with a hydrophobicity index of zero or less than zero. Preferably, however, they are polar. More preferably, they are polar and neutral, from the point of view of suppression of decomposition, such as hydrolysis, of themselves and / or of the water-insoluble drug that coexists with them. Therefore, in the present invention, the amino acid ester compounds and their salts can have polarity, according to the properties of their side chains and the polarity of the amino group. In addition, they have different types of polarity, depending on the type of side chain of the amino acid and can provide favorable coating compositions.

[00032] The coating composition of the present invention contains the ester compound and / or its salts in a total amount of preferably 5 to 200 parts by weight, more preferably 8 to 150 parts by weight and most preferably 12 to 120 parts by weight , based on 100 parts by weight of the water-insoluble drug.

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15/50 (3) Other preferred ingredients [00033] Preferably, the coating composition of the present invention additionally contains a lower alcohol. When the coating composition contains a lower alcohol, the drug's water-insolubility property for penetration into blood vessels can be enhanced and the uniformity of the drug coating layer can be enhanced. The lower alcohol is not specifically restricted, as it is an alcohol with up to five carbon atoms. Preferably, the lower alcohol is a triol or tetraol of up to five carbon atoms. Most preferably, the lower alcohol is glycerin (also referred to as "glycerol" or "propane-1,2,3triol"), 1,2,4-butanotriol (also referred to as "butane-1,2,4-triol") or erythritol (also referred to as “(2R, 3S) -butane-1,2,3,4-tetraol”).

Preferably, the lower alcohol is glycerin.

[00034] In the case where the coating composition of the present invention contains the lower alcohol, its content is not particularly limited. The lower alcohol content is preferably 10 to 500 parts by weight, more preferably 30 to 300 parts by weight, and even more preferably 50 to 200 parts by weight based on 100 parts by weight of the water-insoluble drug.

(4) Other ingredients that may be contained [00035] In addition to the ingredients mentioned above, the coating composition of the present invention may contain solvent for those ingredients, such as water, ethanol, acetone, tetrahydrofuran, etc. In addition, the coating composition may contain other additives with the proviso that the additives are not harmful for the purpose of the present invention.

2. Drug Coating Layer [00036] The drug coating layer in the present invention is a layer formed on at least part of a

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16/50 surface of a medical device by using the coating composition of the present invention. The drug coating layer is a layer containing the water-insoluble drug and at least one selected from the group consisting of amino acid ester compounds, which have a hydrophobicity index of an amino acid side chain of zero or less than zero and its salts.

[00037] The drug coating layer can be formed by coating a medical device with the coating composition of the present invention, followed by drying. This method, however, is not restrictive.

[00038] The amount of the drug contained in the drug coating layer is not particularly limited. The drug is preferably contained in the drug coating layer at a density of 0.1 to 10 pg / mm ² , more preferably 0.5 to 5 pg / mm ² , more preferably 0.5 to 3.5 pg / mm ² and more preferably 1.0 to 3.0 pg / mm ² .

3. Drug-eluting medical device [00039] The drug-eluting medical device in the present invention has the drug coating layer, directly on its surface or on the surface that has been pre-treated with an organic solvent, irradiation of initiator, irradiation with UV rays or the like. The medical device is preferably a medical device that is radially (circumferentially) expandable in a vascular lumen, such as a blood vessel, more preferably a balloon catheter or stent.

[00040] On at least part of a drug-eluting medical device surface in the present invention, the drug coating layer containing the water-insoluble drug and at least one selected from the group consisting of

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17/50 amino acid ester compounds, which have a side chain hydrophobicity index of zero or less than zero and its salts. The drug coating layer has a high affinity for the surface of the medical device, such that it is not susceptible to detachment or separation from the surface of the medical device during the process of releasing the medical device. In addition, the coating layer also has a high affinity for the tissue of an affected part of the lesion, such that the drug is expected to be rapidly eluted in the target tissue. In the case of a balloon catheter, the drug coating layer is formed on at least part of the outer surface of an expandable portion (balloon). In addition, in the case of a stent, the drug coating layer is formed on at least part of an outer surface of an expandable portion.

[00041] The material of the expandable portion of the medical device is preferably a material that has a certain degree of flexibility and has a certain degree of stiffness such that after reaching the blood vessel, tissue or the like, the expandable portion is expanded such that the drug can be released from the drug coating layer present on the surface of the expandable portion. Specifically, the surface of the expandable portion on which the drug coating layer is provided, is formed by a resin. The resin that forms the surface of the expandable portion is not specifically restricted and preferred examples of the material include polyamides. In other words, at least part of the surface of the expandable portion of the medical device to be coated with the drug is made of a polyamide. Polyamide is not specifically restricted, as it is a polymer that has an amide bond. Examples of polyamide include aromatic polyamides, for example, homopolymers such as polytetramethylene adipamide

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18/50 (nylon 46), polycaprolactam (nylon 6), polyhexamethylene adipamide (nylon 66), polyhexamethylene sebacamide (nylon 610), polyhexamethylene dodecamide) (nylon 612), polyundecanolactam (nylon 11) , polydodecanolactam (nylon 12), etc., copolymers such as caprolactam / laurylactam copolymer (nylon 6/12), caprolactam / aminoundecanoic acid copolymer (nylon 6/11), caprolactam / ω-aminonanoic acid copolymer (nylon 6 / 9), caprolactam / hexamethylene diamine adipate (nylon 6/66), etc., adipic acid copolymer with metaxylenediamine and hexamethylenediamine copolymers with m, p-phthalic acids. In addition, polyamide elastomers that are block copolymers that have nylon 6, nylon 66, nylon 11, nylon 12 or the like as a rigid segment and that have a polyalkylene glycol, a polyether, an aliphatic polyester or the like as a soft segment as well can be used as a base material for the medical device in the present invention. Polyamides can be used alone or in combination with two or more of them.

[00042] In addition, for other portions other than the expandable portion of the medical device, thermoplastic resins can be used, for example, polyolefins such as polyethylene, polypropylene, ethylene-propylene copolymer, etc., polyesters such as polyethylene terephthalate, etc., polyvinyl chloride, ethylene-vinyl acetate copolymer, cross-linked ethylene-vinyl acetate copolymer, polyurethane, etc., polyamides, polyamide elastomers, silicone rubbers, latex rubbers and etc.

4. Method of treatment in which the drug-eluting medical device is used [00043] The method of treatment in which the drug-eluting medical device of the present invention is used includes a step of eluting the drug from the drug coating layer formed by

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19/50 less on part of the surface of the medical device. To be more specific, the treatment method in which the drug-eluting medical device according to the present invention is used, preferably includes: a step of releasing the medical device in a vascular light; a step of radially expanding the medical device within the vascular lumen; and a step of eluting the drug from the drug coating layer formed at least in part of the surface of the medical device, thereby allowing the drug to act on the vascular light.

[00044] The step of releasing the drug-eluting medical device of the present invention into the vascular lumen can be carried out in the same manner as in the case of conventionally known balloons and stents. For example, in the case where the drug-eluting balloon or stent in the present invention is to be released into a stenosed part of a coronary artery, a tube-shaped guide catheter is inserted through the patient's femoral artery or carpus to an internal portion of a cardiac coronary artery, a guide wire is inserted into the guide catheter and the balloon catheter is inserted together with the guide wire, through which the balloon or stent can be released in the stenosed part.

[00045] The step of radially expanding the drug-eluting medical device of the present invention in vascular light can be performed in the same manner as in the case of conventionally known balloons and stents.

[00046] The drug elution step of the drug coating layer formed on at least part of the drug eluted medical device surface of the present invention to allow the drug to act on the vascular lumen, can be performed by the method in which the expanded medical device within the vascular lumen is maintained for a period of several tenths of a second at

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20/50 several minutes while holding the expanded drug-eluting balloon or in which the drug-eluting stent is placed intimately in the vascular lumen. This ensures that the vascular lumen is expanded and the drug's coating layer acts on the vascular lumen tissue.

[00047] The treatment method in which the drug-eluting medical device of the present invention is used can be applied, for example, for the treatment of angiostenosis. According to the method of treatment, it is possible to prevent restenosis by using a cell proliferation suppressing agent such as a carcinostatic (e.g., paclitaxel) or an immunosuppressant such as the drug.

[00048] The amino acid ester compounds, which have a hydrophobicity index of an amino acid side chain of zero or less than zero and their salts to be contained in the coating composition according to the present invention are highly biocompatible (for example, example, they do not induce thrombus formation) and are readily biodegradable. Therefore, it is possible to provide a drug-eluting medical device that is favorable, also from the point of view of safety.

EXAMPLES [00049] Now, the present invention will be described in more detail below, when showing the examples. It should be noted, however, that the present invention is not restricted to the following examples.

[00050] Manufacture of a drug-eluting flask or marketed flask preparation [00051] Examples of preparation of an amino acid ester solution (30 mg / mL solution of arginine ethyl ester) [00052] L ethyl ester dihydrochloride -arginine (CAS No. 36589

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21/50

29-4) in an amount of 60 mg was weighed and added and dissolved in a mixture of ethanol and water containing 1 ml of anhydrous ethanol and 1 ml of RO water, to prepare a solution of 30 mg / ml of ethyl ester of L-arginine.

(30 mg / mL solution of zoα-benzoyl-L arginine ethyl ester) [00053] Nα-benzoyl-L arginine ethyl ester dihydrochloride (CAS No. 2645-08-1) in an amount of 60 mg and was added and dissolved in a mixture of ethanol and water containing 1 ml of anhydrous ethanol and 1 ml of RO water, to prepare a solution of 30 mg / ml of Nα-benzoyl-L arginine ethyl ester.

(30 mg / mL solution of dimethyl L-aspartate) [00054] Dimethyl L-aspartate hydrochloride (CAS No. 32213-95-9) in an amount of 60 mg was weighed and added and dissolved in a mixture of ethanol and water containing 1 ml of anhydrous ethanol and 1 ml of RO water, to prepare a 30 mg / ml solution of dimethyl Laspartate.

(50 mg / mL solution of dimethyl L-aspartate) [00055] Dimethyl L-aspartate hydrochloride in an amount of mg was weighed and added and dissolved in a mixture of ethanol and water containing 0.5 ml of ethanol anhydrous and 0.5 mL of RO water, to prepare a 50 mg / mL solution of dimethyl L-aspartate. (L-serine ethyl ester solution 30 mg / mL) [00056] L-serine ethyl ester hydrochloride (CAS No. 26348-61-8) in an amount of 60 mg was weighed and added and dissolved in a mixture of ethanol and water containing 1 ml of anhydrous ethanol and 1 ml of RO water, to prepare a solution of 30 mg / ml of L-serine ethyl ester.

(70 mg / mL solution 1 of L-serine ethyl ester) [00057] L-serine ethyl ester hydrochloride in an amount of 140 mg was weighed and added and dissolved in a mixture of

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22/50 ethanol and water containing 1 ml of anhydrous ethanol and 1 ml of RO water, to prepare a solution of 70 mg / ml of L-serine ethyl ester. (70 mg / mL solution 2 of L-serine ethyl ester) [00058] L-serine ethyl ester hydrochloride in an amount of 140 mg was weighed and added and dissolved in a mixture of ethanol and water containing 1, 5 ml of RO water and 0.5 ml of anhydrous ethanol, to prepare a solution of 70 mg / ml of L-serine ethyl ester. (70 mg / ml L-serine ethyl ester solution 3) [00059] L-serine ethyl ester hydrochloride in an amount of 140 mg was weighed and added and dissolved in 2 ml of RO water, to prepare a 70 mg / mL solution of Lserine ethyl ester.

(30 mg / mL solution of glycine ethyl ester) [00060] Glycine ethyl ester hydrochloride (CAS No. 623-33-6) in an amount of 60 mg was weighed and added and dissolved in an ethanol mixture and water containing 1 ml of anhydrous ethanol and 1 ml of RO water, to prepare a 30 mg / ml solution of glycine ethyl ester.

(40 mg / mL N-benzylglycine ethyl ester solution) [00061] N-Benzylglycine ethyl ester hydrochloride (CAS No. 634442-9) in an amount of 80 mg was weighed and added and dissolved in a mixture of ethanol and water containing 1 ml of anhydrous ethanol and 1 ml of RO water, to prepare a 40 mg / ml solution of N-benzylglycine ethyl ester.

(L-alanine ethyl ester 40 mg / mL solution) [00062] L-alanine ethyl ester hydrochloride (CAS No. 1115-59-9) in an amount of 80 mg was weighed and added and dissolved in a mixture of ethanol and water containing 1 ml of anhydrous ethanol and 1 ml of RO water, to prepare a 40 mg / ml solution of L-alanine ethyl ester.

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23/50 (L-valine methyl ester solution 30 mg / mL) [00063] L-valine methyl ester hydrochloride (CAS No. 6306-52-

1) in an amount of 54 mg it was weighed and was added and dissolved in a mixture of ethanol and water containing 1.5 ml of anhydrous ethanol and 0.3 ml of RO water, to prepare a solution of 30 mg / ml of ester methyl of L-valine.

(50 mg / mL L-valine methyl ester solution) [00064] L-Valine methyl ester hydrochloride (CAS No. 6306-52-

1) in an amount of 90 mg it was weighed and was added and dissolved in a mixture of ethanol and water containing 1.5 ml of anhydrous ethanol and 0.3 ml of RO water, to prepare a solution of 50 mg / ml of ester methyl of L-valine.

[00065] Examples of preparation of amino acid solution (40 mg / ml L-arginine solution) [00066] L-arginine hydrochloride (CAS No. 1119-34-2) in an amount of 80 mg was weighed and added and dissolved in a mixture of ethanol and water containing 1 ml of anhydrous ethanol and 1 ml of RO water, to prepare a 40 mg / ml solution of L-arginine. (70 mg / ml L-serine solution) [00067] L-serine (CAS No. 56-45-1) in an amount of 70 mg was weighed and added and dissolved in 1 ml of RO water, to prepare a 70 mg / mL solution of L-serine.

[00068] Examples of preparation of paclitaxel solution (20 mg / mL solution of Paclitaxel) [00069] Paclitaxel (CAS No. 33069-62-4) in an amount of 40 mg was weighed and added and dissolved in a mixture of ethanol and acetone containing 1 ml of anhydrous ethanol and 1 ml of acetone, to prepare a solution of 20 mg / ml of paclitaxel.

(40 mg / mL solution 1 of Paclitaxel) [00070] Paclitaxel (CAS No. 33069-62-4) in an amount of 80

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24/50 mg was weighed and was added and dissolved in a mixture of ethanol and acetone containing 1 ml of anhydrous ethanol and 1 ml of acetone, to prepare a solution 1 of 40 mg / ml of paclitaxel.

(40 mg / ml solution 2 of Paclitaxel) [00071] Paclitaxel in an amount of 160 mg was weighed and added and dissolved in 4 ml of tetrahydrofuran (CAS No. 10999-9) to prepare a solution 2 of 40 mg / ml paclitaxel.

(Paclitaxel 56 mg / mL solution 1) [00072] Paclitaxel in an amount of 336 mg was weighed and added and dissolved in 6 mL of tetrahydrofuran to prepare a 56 mg / mL solution 1 of paclitaxel.

(Paclitaxel 56 mg / mL solution 2) [00073] Paclitaxel in an amount of 224 mg was weighed and added and dissolved in a THF-ethanol mixture containing 2.66 mL of tetrahydrofuran and 1.34 mL of anhydrous ethanol to prepare a 56 mg / mL solution 2 of paclitaxel.

(Paclitaxel 56 mg / ml solution 3) [00074] Paclitaxel in an amount of 336 mg was weighed and added and dissolved in a THF-ethanol mixture containing 4 ml of tetrahydrofuran and 2 ml of anhydrous ethanol to prepare a 56 mg / ml solution 3 of paclitaxel.

(Paclitaxel 56 mg / mL solution 4) [00075] Paclitaxel in an amount of 224 mg was weighed and added and dissolved in a THF-ethanol mixture containing 2 mL of tetrahydrofuran and 2 mL of anhydrous ethanol to prepare a 56 mg / ml solution 4 of paclitaxel.

(Paclitaxel 56 mg / mL solution 5) [00076] Paclitaxel in an amount of 448 mg was weighed and added and dissolved in an ethanol-acetone mixture containing 4 mL of anhydrous ethanol and 4 mL of acetone to prepare a solution 5

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25/50 of 56 mg / ml paclitaxel.

[00077] Examples of preparation of glycerin solution (50% glycerin solution 1) [00078] Glycerin (CAS No. 56-81-5) in an amount of 100 pL and anhydrous ethanol in an amount of 100 pL were mixed to prepare a 50% glycerin solution 1.

(50% glycerin solution 2) [00079] Glycerin in an amount of 500 pL and anhydrous ethanol in an amount of 500 pL were mixed together to prepare a solution of 50% glycerin 2.

EXAMPLE 1 (1) Preparation of coating solution 1 [00080] The solution of 40 mg / ml of benzylglycine ethyl ester in an amount of 25 pL was mixed with 150 pL of solution 1 of 40 mg / ml of paclitaxel and 25 pL of anhydrous ethanol, to prepare a coating solution 1. The mass ratio of benzylglycine ethyl ester to paclitaxel in coating solution 1 (BnGlyOEt / PTX) was 0.50.

(2) Lining the balloon with the drug [00081] A balloon catheter (produced by Terumo Corporation, the balloon material (expandable portion) is a nylon elastomer), whose expandable portion is 3.0 mm in diameter and 20 mm in diameter. length when expanded, was prepared. The expanded flask was coated with coating solution 1, such that the amount of paclitaxel will be about 2 pg / mm ² , using a pipette, followed by drying to make a drug-eluting flask.

EXAMPLE 2 (1) Preparation of coating solution 2 [00082] The solution with 30 mg / ml of L-arginine ethyl ester in an amount of 50 pL was mixed with 60 pL of solution 1 of 40

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26/50 mg / ml paclitaxel to prepare a coating solution 2. The weight ratio of glycine ethyl ester to paclitaxel in coating solution 2 (Arg-OEt / PTX) was 0.63.

(2) Coating the drug flask [00083] A drug eluting flask was manufactured in the same manner as in Example 1, except that coating solution 2 was used in place of coating solution 1.

EXAMPLE 3 (1) Preparation of coating solution 3 [00084] The 30 mg / mL solution of Na-benzoyl-Larginine ethyl ester in an amount of 50 pL was mixed with 50 pL of solution 1 of 40 mg / mL of paclitaxel to prepare a coating solution 3. The mass ratio of Nα-benzoylL-arginine ethyl ester to paclitaxel in coating solution 3 (BzArgOEt / PTX) was 0.75.

(2) Coating the drug flask [00085] A drug-eluting flask was manufactured in the same manner as in Example 1, except that coating solution 3 was used in place of coating solution 1.

EXAMPLE 4 (1) Preparation of coating solution 4 [00086] The solution with 30 mg / ml of dimethyl L-aspartate in an amount of 50 pL was mixed with 75 pL of solution 1 of 40 mg / ml of paclitaxel to prepare a coating solution 4. The mass ratio of dimethyl L-aspartate to paclitaxel in coating solution 4 (Asp-DiOMe / PTX) was 0.63.

(2) Coating the drug flask [00087] A drug eluting flask was manufactured in the same manner as in Example 1, except that coating solution 4 was used in place of coating solution 1.

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27/50

EXAMPLE 5 (1) Preparation of coating solution 5 [00088] The solution with 30 mg / ml of glycine ethyl ester in an amount of 50 pL was mixed with 110 pL of solution 1 of 40 mg / ml of paclitaxel to prepare a coating solution 5. The mass ratio of glycine ethyl ester to paclitaxel in coating solution 5 (Gly-OEt / PTX) was 0.63.

(2) Coating the drug flask [00089] A drug eluting flask was manufactured in the same manner as in Example 1, except that coating solution 5 was used in place of coating solution 1.

EXAMPLE 6 (1) Preparation of coating solution 6 [00090] The solution of 30 mg / ml of L-serine ethyl ester in an amount of 50 pL was mixed with 90 pL of solution 1 of 40 mg / ml of paclitaxel for prepare a coating solution 6. The mass ratio of L-serine ethyl ester to paclitaxel in coating solution 6 (Ser-OEt / PTX) was 0.42.

(2) Coating the flask with the drug [00091] A drug-eluting flask was manufactured in the same manner as in Example 1, except that coating solution 6 was used in place of coating solution 1.

EXAMPLE 7 (1) Preparation of coating solution 7 [00092] The solution of 30 mg / ml of L-arginine ethyl ester in an amount of 160 pL was mixed with 200 pL of solution 1 of 40 mg / ml of paclitaxel and 20 µl of 50% glycine solution 1 to prepare a coating solution 7. The mass ratio of L-arginine ethyl ester to paclitaxel in coating solution 7 (Arg-OEt / PTX) was 0.60.

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28/50 [00093] Coating solution 7 is a coating solution containing glycerin in addition to the Larginine ethyl ester (Arg-OEt; which has a hydrophobicity index of an amino acid side chain of -4.5) and paclitaxel (PTX).

(2) Coating the drug flask [00094] A drug eluting flask was manufactured in the same manner as in Example 1, except that coating solution 7 was used in place of coating solution 1.

EXAMPLE 8 (1) Preparation of coating solution 8 [00095] The solution with 50 mg / ml of dimethyl L-aspartate in an amount of 90 pL was mixed with 240 pL of solution 2 of 40 mg / ml of paclitaxel to prepare a coating solution 8. The mass ratio of dimethyl L-aspartate to paclitaxel in coating solution 8 (Asp-DiOMe / PTX) was 0.47.

(2) Coating the drug flask [00096] A drug-eluting flask was manufactured in the same manner as in Example 1, except that coating solution 8 was used in place of coating solution 1 and coating was conducted such that the amount of paclitaxel will be about 3 pg / mm ² .

EXAMPLE 9 (1) Preparation of coating solution 9 [00097] Solution 1 with 70 mg / ml of L-serine ethyl ester in an amount of 80 pL was mixed with 240 pL of solution 1 of 56 mg / ml of paclitaxel and 16 µl of 50% glycerin solution 2 to prepare a coating solution 9. The weight ratio of L-serine ethyl ester to paclitaxel in coating solution 9 (Ser-OEt / PTX) was 0.42.

(2) Coating the balloon with the drug

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29/50 [00098] A drug-eluting flask was manufactured in the same manner as in Example 1, except that coating solution 9 was used in place of coating solution 1 and the coating was conducted in such a way that the amount of paclitaxel will be about 3 pg / mm ² .

EXAMPLE 10 (1) Preparation of coating solution 10 [00099] Solution 1 with 70 mg / ml of L-serine ethyl ester in an amount of 80 pL was mixed with 240 pL of solution 1 of 56 mg / ml of paclitaxel to prepare a coating solution 10. The mass ratio of L-serine ethyl ester to paclitaxel in coating solution 10 (Ser-OEt / PTX) was 0.42.

(2) Coating the drug flask [000100] A drug-eluting flask was manufactured in the same manner as in Example 1, except that coating solution 10 was used in place of coating solution 1 and coating was conducted such that the amount of paclitaxel will be about 3 pg / mm ² .

EXAMPLE 11 (1) Preparation of coating solution 11 [000101] Solution 1 with 70 mg / ml of L-serine ethyl ester in an amount of 800 pL was mixed with 2400 pL of solution 2 of 56 mg / ml of paclitaxel to prepare a coating solution

11. The weight ratio of L-serine ethyl ester to paclitaxel in coating solution 11 (Ser-OEt / PTX) was 0.42.

(2) Coating the drug flask [000102] A drug-eluting flask was manufactured in the same manner as in Example 1, except that coating solution 11 was used in place of coating solution 1 and coating was conducted such that the amount of paclitaxel will be about

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30/50 of 3 pg / mm ² .

EXAMPLE 12 (1) Preparation of coating solution 12 [000103] Solution 1 with 70 mg / ml of L-serine ethyl ester in an amount of 600 pL was mixed with 1800 pL of solution 5 of 56 mg / ml of paclitaxel to prepare a coating solution

12. The weight ratio of L-serine ethyl ester to paclitaxel in coating solution 12 (Ser-OEt / PTX) was 0.42.

(2) Coating the drug flask [000104] A drug-eluting flask was manufactured in the same manner as in Example 1, except that coating solution 12 was used in place of coating solution 1 and coating was conducted such that the amount of paclitaxel will be about 3 pg / mm ² .

EXAMPLE 13 (1) Preparation of coating solution 13 [000105] Solution 1 with 70 mg / ml of L-serine ethyl ester in an amount of 600 pL was mixed with 1800 pL of solution 3 of 56 mg / ml of paclitaxel to prepare a coating solution

13. The weight ratio of L-serine ethyl ester to paclitaxel in coating solution 13 (Ser-OEt / PTX) was 0.42.

(2) Drug flask coating [000106] A drug elution flask was manufactured in the same manner as in Example 1, except that coating solution 13 was used in place of coating solution 1 and coating was conducted such that the amount of paclitaxel will be about 3 pg / mm ² .

EXAMPLE 14 (1) Preparation of coating solution 14 [000107] Solution 2 with 70 mg / mL of L-serine ethyl ester in

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31/50 a quantity of 500 pL was mixed with 1500 pL of solution 4 of 56 mg / mL of paclitaxel to prepare a coating solution

14. The weight ratio of L-serine ethyl ester to paclitaxel in coating solution 14 (Ser-OEt / PTX) was 0.42.

(2) Coating the drug flask [000108] A drug-eluting flask was manufactured in the same manner as in Example 1, except that coating solution 14 was used in place of coating solution 1 and coating was conducted such that the amount of paclitaxel will be about 3 pg / mm ² .

EXAMPLE 15 (1) Preparation of coating solution 15 [000109] Solution 3 with 70 mg / ml of L-serine ethyl ester in an amount of 500 pL was mixed with 1500 pL of solution 4 of 56 mg / ml of paclitaxel to prepare a coating solution

15. The weight ratio of L-serine ethyl ester to paclitaxel in coating solution 15 (Ser-OEt / PTX) was 0.42.

(2) Coating the drug flask [000110] A drug eluting flask was manufactured in the same manner as in Example 1, except that coating solution 15 was used in place of coating solution 1 and coating was conducted such that the amount of paclitaxel will be about 3 pg / mm ² .

COMPARATIVE EXAMPLE C1 (1) Preparation of paclitaxel solution 16 [000111] The solution with 40 mg / ml of L-alanine ethyl ester in an amount of 60 pL was mixed with 50 pL of solution 1 of paclitaxel with 40 mg / ml , to prepare paclitaxel solution 16. The mass ratio of L-alanine ethyl ester to paclitaxel in solution 16 of paclitaxel (Ala-OEt / PTX) was 1.20.

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32/50 (2) Drug lining the flask [000112] A drug elution flask was manufactured in the same manner as in Example 1, except that paclitaxel 16 solution was used in place of lining solution 1.

COMPARATIVE EXAMPLE C2 (1) Preparation of solution 17 of paclitaxel [000113] The solution with 30 mg / ml of methyl ester of L-valine in an amount of 70 pL was mixed with 50 pL of solution 1 of paclitaxel with 40 mg / ml , to prepare paclitaxel solution 17. The mass ratio of L-valine methyl ester to paclitaxel in solution 17 of paclitaxel (Val-OMe / PTX) was 1.05.

(2) Coating the drug flask [000114] A drug eluting flask was manufactured in the same manner as in Example 1, except that paclitaxel solution 17 was used in place of coating solution 1.

COMPARATIVE EXAMPLE C3 (1) Preparation of paclitaxel solution 18 [000115] The solution with 40 mg / ml of arginine in an amount of 60 pL was mixed with 50 pL of solution 1 of paclitaxel with 40 mg / ml, to prepare the solution 18 of paclitaxel. The mass ratio of L-arginine to paclitaxel in solution 18 of paclitaxel (ArgOEt / PTX) was 1.05.

(2) Coating the drug flask [000116] A drug eluting flask was manufactured in the same manner as in Example 1, except that paclitaxel 18 solution was used in place of coating solution 1.

COMPARATIVE EXAMPLE C4 (1) Preparation of paclitaxel solution 19 [000117] The solution with paclitaxel 20 mg / ml was made to be paclitaxel solution 19. Paclitaxel solution 19 is a solution of

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33/50 paclitaxel (PTX) that does not contain an amino acid ester or an amino acid.

(2) Coating the drug flask [000118] A drug-eluting flask was manufactured in the same manner as in Example 1, except that paclitaxel solution 19 was used in place of coating solution 1 and the coating was conducted such that the amount of paclitaxel will be about 3 pg / mm ² .

COMPARATIVE EXAMPLE C5 (1) Preparation of solution 20 of paclitaxel [000119] The solution with 50 mg / ml of methyl ester of L-valine in an amount of 80 pL was mixed with 240 pL of solution 2 of paclitaxel with 40 mg / ml , to prepare paclitaxel solution 20. The mass ratio of L-valine methyl ester to paclitaxel in solution 20 of paclitaxel (Val-OMe / PTX) was 0.42.

(2) Drug lining of the flask [000120] A drug elution flask was manufactured in the same manner as in Example 1, using the paclitaxel 20 solution prepared above.

COMPARATIVE EXAMPLE C6 [000121] A balloon catheter marketed IN.PACT (produced by Invatec) was prepared. The flask in Comparative Example C6 is a drug-eluting flask with the paclitaxel coated surface.

COMPARATIVE EXAMPLE C7 [000122] A balloon catheter (produced by Terumo C; formed from a nylon elastomer), whose expandable portion is 3.0 mm in diameter and 20 mm long when expanded, was prepared. The flask in COMPARATIVE EXAMPLE C7 is a non-drug coated flask that is not drug coated.

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34/50

COMPARATIVE EXAMPLE C8 (1) Preparation of coating solution 21 [000123] The solution with 70 mg / ml of L-serine in an amount of 300 pL was mixed with 900 pL of solution 3 of paclitaxel with 56 mg / ml, to prepare the coating solution 21. The solution appeared cloudy.

(2) Coating the flask with the drug [000124] Since the coating solution 21 was cloudy, the flask cannot be coated with it. Consequently, it has been found that the drug coating solution cannot be prepared using the L-serine solution.

[000125] The prepared coating solution, the drug and the amino acid ester hydrochloride contained in the coating solution, the hydrophobicity index of the amino acid ester hydrochloride or amino acid, the lower alcohol (only in cases where a lower alcohol is used) and the solvents for Examples 1 to 15 and Comparative Examples C1 to C5 and C8 are described in Table 2. In Table 2, 1 to 15 in the “Example / Comparative Example” column are Examples, while C1 a C5 and C8 are Comparative Examples. "PTX" in the "Drug" column means paclitaxel. In the “amino acid / amino acid ester” column, “Bn-Gly-Et” means Nbenzylglycine ethyl ester, “L-Arg-Et” means L-arginine ethyl ester, “Bnz-Arg-Et” means ethyl ester of Να-benzoyl-L-arginine, “L-Asp-2Me” means dimethyl laspartate, “Gly-Et” means glycine ethyl ester, “L-Ser-Et” means L-serine ethyl ester, “L-Ala -Et ”means Lalanine ethyl ester,“ L-Val-Me ”means L-valine methyl ester,“ L-Arg ”means L-arginine, and“ L-Ser ”means L-serine, respectively. "Glycerin" in the "Lower alcohol" column means glycerin. In the "Solvents" column, "EtOH" means ethanol, "RO-W" means water RO, "THF" means tetrahydrofuran and "AC" means acetone, respectively.

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35/50

Table 2

Examples / Examples Comparatives Coating Solution At the. Drug Ester of amino acid / Amino acid Lower alcohol Solvents Abbreviation Index of Hydropathy 1 1 PTX Bn-Gly-Et -0.4 - EtOH / RO-W 2 2 PTX L-Arg-Et -4.5 - EtOH / RO-W 3 3 PTX Bnz-L-Arg-Et -4.5 - EtOH / RO-W 4 4 PTX L-Asp-2Me -3.5 - EtOH / RO-W 5 5 PTX Gly-Et -0.4 - EtOH / RO-W 6 6 PTX L-Ser-Et -0.8 - EtOH / RO-W 7 7 PTX L-Arg-Et -4.5 Glycerin EtOH / RO-W 8 8 PTX L-Asp-2Me -3.5 - EtOH / RO-W 9 9 PTX L-Ser-Et -0.8 Glycerin THF / EtOH / RO-W 10 10 PTX L-Ser-Et -0.8 - THF / EtOH / RO-W 11 11 PTX L-Ser-Et -0.8 - THF / EtOH / RO-W 12 12 PTX L-Ser-Et -0.8 - THF / AC / RO-W 13 13 PTX L-Ser-Et -0.8 - THF / EtOH / RO-W 14 14 PTX L-Ser-Et -0.8 - THF / EtOH / RO-W 15 15 PTX L-Ser-Et -0.8 - THF / EtOH / RO-W C1 16 PTX L-Ala-Et 1.8 - EtOH / RO-W C2 17 PTX L-Val-Me 4.2 - EtOH / RO-W C3 18 PTX L-Arg -4.5 - EtOH / RO-W C4 19 PTX - - - EtOH / RO-W C5 20 PTX L-Val-Me 4.2 - EtOH / RO-W C8 21 PTX L-Ser -0.8 - THF / EtOH / RO-W

[000126] Measurement of the amount of paclitaxel in the lining of the flask [000127] For the drug-eluting flasks in Examples 1 to

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36/50 and Comparative Examples C1 to C5, the amount of paclitaxel in the balloon liner was measured by the following procedure.

1. Method [000128] The prepared drug elution flask was immersed in a methanol solution, followed by stirring using a stirring machine for 10 minutes, whereby paclitaxel in the flask coating was extracted. The absorption capacity of the methanol solution in which paclitaxel was extracted was measured by high performance liquid chromatography using a visible ultraviolet light absorptometer and the amount of paclitaxel per balloon ([pg / balloon]) was determined. In addition, from the amount of paclitaxel so determined and the surface area of the balloon, the amount of paclitaxel per unit area ([pg / mm ² ]) was determined.

2. Results [000129] The results were obtained as described in Table 3. In Table 3, 1 to 15 in the “Example / Comparative Example” column are Examples, while C1 to C5 in the column are Comparative Examples. In addition, in Table 3, “Surface area of a balloon” represents the surface area of an expanded balloon (unit: mm ² ), “for each” under “Quantity of PTX in a balloon” represents the amount of paclitaxel per each balloon (unit: pg / balloon) and "per unit area" under "Quantity of PTX over a balloon" represents the amount of paclitaxel per 1 mm ² of the balloon's surface area (unit: pg / mm ² ), respectively .

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37/50

Table 3

Examples / Examples Comparatives Coating Solution At the. Surface area of a balloon [mm ² ] Quantity of PTX from a balloon in each (pg / balloon) per unit area (pg / mm ² ) 1 1 188.4 305.8 1.6 2 2 188.4 278.3 1.5 3 3 188.4 290.4 1.5 4 4 188.4 342.5 1.8 5 5 188.4 294.3 1.6 6 6 188.4 285.4 1.5 7 7 188.4 333.1 1.8 8 8 188.4 597.2 3.2 9 9 188.4 504.5 2.7 10 10 188.4 560.2 3.0 11 11 188.4 588.9 3.1 12 12 188.4 489.2 2.6 13 13 188.4 523.0 2.8 14 14 188.4 653.2 3.5 15 15 188.4 652.6 3.5 C1 16 188.4 321.7 1.7 C2 17 188.4 367.0 2.0 C3 18 188.4 342.5 1.8 C4 19 188.4 492.4 2.6 C5 20 188.4 579.5 3.1

[000130] As shown in Table 3, in each of Examples 1 to 15 and Comparative Examples C1 to C5, the amount of paclitaxel in the coating on a balloon was about 2 pg / mm ² (Examples 1 to 7 and Comparative Examples C1 to C3) or about 3 pg / mm ² (Examples 8 to 15 and Comparative Examples C4 and C5), which means

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38/50 that the desired amount of paclitaxel can be supplied in the coating on the surface of a balloon.

[000131] Evaluation of the durability of the drug coating layer by using an imitation blood vessel [000132] In order to assess how much of the drug coating layer is separated from the balloon in the process of releasing the balloon to an affected part of an injury, for the drug eluting flasks in Examples 1 to 7 and Comparative Examples C1 to C4, a drug coating layer durability test was performed by performing a release operation using a blood vessel imitation and determining the amount of paclitaxel remaining on the flask after release.

1. Method (1) A hollow blood vessel imitation 1 with a 90 degree angle was prepared and a guide catheter 2 (outside diameter: 5 Fr.) was inserted and passed through the blood vessel imitation 1 (see FIG. 1).

(2) The interior of the guide catheter 2 was filled with PBS heated to 37 ° C.

(3) The manufactured drug elution flask (3 mm in diameter and 20 mm in length when expanded) was folded using a packaging machine.

(4) The balloon catheter 3 after packaging was inserted into the guide catheter filled with PBS and the balloon 4 release operation towards an exit of the guide catheter was performed for one minute.

(5) The balloon, having been released in the guide catheter, was recovered and the amount of paclitaxel remaining on the balloon (amount of PTX remaining) was determined by liquid chromatography. In addition, from the amount of paclitaxel in the drug lining of the flask (amount of PTX coated on the flask) and the remaining amount, the rate of remaining paclitaxel

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39/50 over the balloon (remaining PTX rates) was calculated.

2. Results [000133] The results were obtained as described in Table 4. In Table 4, 1 to 7 in the “Example / Comparative Example” column are Examples, while C1 to C5 in the column are Comparative Examples. In addition, in Table 4, "Quantity of PTX coated on the balloon" represents the amount of paclitaxel remaining per each balloon after the release operation (unit: pg / balloon), "Quantity of PTX remaining on the balloon" represents the amount of paclitaxel remaining for each balloon after the release operation (unit: pg / balloon) and “PTX rates remaining on the balloon” represent the paclitaxel rates remaining on the balloon after the release operation (unit:% mass).

[000134] Additionally, FIG. 2 shows a graph representing the paclitaxel rates remaining on the flask after the drug elution flask release operation in Examples 1 to 7 and Comparative Examples C1 to C4, in assessing the durability of the drug coating layer using imitation blood vessel. In FIG. 2, the abscissa axis represents Examples or Comparative Examples, where the numerals 1 to 7 mean Examples 1 to 7, respectively, and the numerals accompanied by the letter C1 to C4 mean Comparative Examples C1 to C4, respectively. In addition, the ordinate axis represents the rate of paclitaxel remaining on the balloon after the release operation (unit:% mass). “% By mass” means “% by mass”.

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40/50

Table 4

Examples / Examples Comparatives Quantity of PTX coated on the balloon (pg / balloon) Quantity of PTX remaining on the balloon (pg / balloon) PTX rates remaining on the balloon (% mass) 1 306 284 93 2 278 225 81 3 290 209 72 4 343 243 71 5 294 212 72 6 285 200 70 7 333 257 77 C1 322 106 33 C2 367 187 51 C3 343 171 50 C4 492 227 46

[000135] In this evaluation system, in the case where the amount of drug remaining on the flask after the release operation is equal to or more than 60% by mass, the ability to maintain the drug during the release operation is good and very drug can be released to the affected part of an injury. When the amount is below 60% by mass, on the other hand, most of the drug is released during the release operation, which is also undesirable from a safety point of view. In this case, moreover, the amount of drug that can be released to the affected part of an injury is small and, therefore, the transfer of the drug to the tissue cannot be expected. Consequently, in this evaluation system, when the amount remaining on the balloon after the release operation is equal to or greater than 60% by mass, it can be judged that the good ability to retain the

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41/50 drug during the release process is assured.

[000136] As shown in Table 4, for the drug eluting flasks manufactured in Examples 1 to 7, the amount of paclitaxel remaining on the flask after the release operation was equal to or greater than 60% by weight based on the amount of coating. On the other hand, the drug elution balloons manufactured in Comparative Examples C1 to C4, the amount of paclitaxel remaining on the balloon was equal to or less than 50% by weight. From the above results, it has been found that amino acid ester hydrochloride compounds that have an amino acid side chain hydrophobicity index of zero or less than zero that were used in Examples 1 to 7 ensure uniform coating with paclitaxel, intensifies the adhesion of paclitaxel to the balloon and enhances the ability to retain the drug during the release operation. On the other hand, in the case of amino acid ester hydrochloride compounds that have an amino acid side chain hydrophobicity index greater than 1 and that have comparatively higher hydrophobicity, it was difficult to enhance the ability to retain the drug during the operation. release. In addition, as shown in Comparative Example C3, in the case of an amino acid that has a side chain hydrophobicity index of zero or less than zero, but not yet esterified, a favorable drug durability performance cannot be obtained.

[000137] Evaluation of drug transfer to tissue in the rabbit's iliac artery [000138] For drug elution balloons in Example 8 and Comparative Examples C5 and C6, transfer of paclitaxel to blood vessel tissue after one hour from the balloon expansion in the rabbit iliac artery was evaluated by the following

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42/50 procedure.

1. Method (1) A guidewire was inserted into the right iliac artery or left iliac artery of a rabbit under radioscopic observation. Then, the drug-eluting flask (which has an expandable portion sized to be 3.0 mm in diameter and 20 mm long when expanded) was transferred along with the guidewire to the iliac artery.

(2) The balloon was expanded by 7 atm for one minute. Immediately afterwards, the balloon was removed.

(3) After 60 minutes of balloon expansion, a blood vessel (about 3.5 cm in length from the branch) was sampled.

(4) Methanol was added to the blood vessel sample, followed by homogenization, to obtain a tissue homogenate.

(5) The tissue homogenate was analyzed by high performance liquid chromatography, to determine the amount of paclitaxel contained in the tissue (the amount of paclitaxel per 1 g of tissue). In addition, from the amount of paclitaxel in the drug lining of the flask and the amount of paclitaxel remaining on the flask, the remaining rate of paclitaxel on the flask (PTX rate remaining on the flask) was calculated.

2. Results [000139] The results were obtained as described in Table 5. In Table 5, 8 in the “Examples / Comparative Examples” column is Example 8 and C5 and C6 in the column are Comparative Examples. In Table 5, “Amount of PTX contained in the tissue” represents the amount of paclitaxel contained in 1 g of blood vessel tissue (unit pg / g of tissue). “PTX fees transferred to the fabric” represents the paclitaxel fees transferred from the coating

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43/50 over the balloon in the blood vessel tissue (unit:% mass), and "PTX rates remaining on the balloon" represent the rates of paclitaxel remaining on the balloon (unit:% mass), respectively.

[000140] Additionally, FIG. 3 shows a graph representing the amount of paclitaxel contained in the blood vessel tissue in Example 8 and Comparative Examples C5 and C6, in assessing the ability of drug to transfer to tissue in the rabbit's iliac artery. In FIG. 3, the abscissa axis represents the Example or Comparative Examples, where the numeral 8 represents Example 8 and the numerals accompanied by the letter C5 and C6 mean Comparative Examples C5 and C6, respectively. In addition, the ordinate axis represents the amount of paclitaxel contained in 1 g of blood vessel tissue (unit: pg / g of tissue). pg / g of tissue ”means micrograms per gram of tissue.

Table 5

Examples / Examples Comparatives Quantity of PTX coated contained in fabric (pg / g of fabric) PTX rates transferred to the tissue (% mass) PTX rates remaining on the balloon (% mass) 8 530.1 2.5 21.8 C5 126.9 0.6 37.1 C6 398.2 1.5 19.5

[000141] In Example 8, the amount of paclitaxel per unit area of the balloon was 3.2 pg / mm ² , less than the 4.1 pg / mm ^{2 value} for IN.PACT (produced by Invatec) in Comparative Example C6. As shown in Table 5 in FIG.3, however, the amount of paclitaxel contained in the tissue recovered after 60 minutes of blood vessel expansion was above 500 pg per 1 g of tissue, the value of which was greater than the value for the Example

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44/50

Comparative C6 and suggested a favorable transfer of paclitaxel to the blood vessel tissue. On the other hand, in the case of the drug elution flask in Comparative Example C5 where the L-valine methyl ester (which has an amino acid side chain hydrophobicity index of 4.2) was used as the ester ester hydrochloride. hydrophobic amino acid, the amount of paclitaxel remaining on the balloon was large, showing a low rate of transfer of paclitaxel to the blood vessel tissue. From the above results, it was found that the paclitaxel present in the coating together with the amino acid ester hydrochloride which has an amino acid side chain hydrophobicity index of zero or less than zero shows efficient drug transfer to tissue, that is, good drug transfer capacity. [000142] Assessment of drug retention in rabbit abdominal aorta tissue [000143] For the drug-eluting balloons of Examples 9 and 10, the amount of paclitaxel contained in the tissue was determined after one hour and after 24 hours of balloon expansion in the rabbit abdominal aorta and drug retention was assessed using the following procedure.

1. Method (1) The drug-eluting flask was subjected to packaging, followed by pre-assembly of a stent. The drug-eluting flask with the pre-assembled stent was put to use.

(2) After a guide wire was inserted into the abdominal aorta of a rabbit under radioscopic observation, a guide catheter was removed while maintaining the position of the guide wire. Then, the drug-eluting flask (which has an expandable portion sized to be 3.0 mm in diameter and 20 mm long when expanded) with the pre-assembled stent was transferred along with the wire

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45/50 guide to the abdominal aorta.

(3) The balloon was expanded by 7 atm for one minute. Immediately afterwards, the balloon was removed.

(4) After one hour and after 24 hours of balloon expansion, a blood vessel (about 3.5 cm in length from the branch) was sampled.

(5) Methanol was added to the blood vessel sample, followed by homogenization, to obtain a tissue homogenate.

(6) The tissue homogenate was analyzed by high performance liquid chromatography, to determine the amount of paclitaxel contained in the tissue (the amount of paclitaxel per 1 g of tissue) after one hour and after 24 hours of balloon expansion. In addition, from the amount of paclitaxel present in the drug-eluting flask lining and the amounts of paclitaxel contained in the tissue after one hour and after 24 hours of expansion of the flask, the rates of transferring paclitaxel to the tissue (rate of PTX transferred to the tissue) after one hour and after 24 hours of balloon expansion were calculated and the remaining rate (PTX rate remaining on the balloon) was calculated from the amount of paclitaxel remaining on the balloon.

2. Results [000144] The results were obtained as described in Table 6. In Table 6, 9 and 10 in the “Examples” column are Examples. In addition, in Table 6, “Quantity of PTX contained in the tissue” represents the amount of paclitaxel contained in 1 g of blood vessel tissue (unit: pg / g of tissue). "PTX rates transferred to tissue" represent paclitaxel rates transferred from the coating on the balloon to the blood vessel tissue (unit:% mass), and "PTX rates remaining on the balloon" represent the remaining paclitaxel rates over the balloon

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46/50 (unit:% mass). Additionally, “1H and“ 24H ”in the“ Quantity of PTX contained in the tissue ”and“ PTX rates transferred to the tissue ”columns mean one hour after the expansion of the blood vessel light and 24 hours after the expansion of the vessel light blood, respectively.

[000145] FIG. 4 shows a graph representing the amount of paclitaxel remaining in the blood vessel tissue after one hour and after 24 hours of the expansion of the blood vessel light in Examples 9 and 10, in the assessment of drug retention in the tissue in the abdominal aorta of Bunny. In FIG. 4, the abscissa axis represents the Examples, where the numerals 9 and 10 mean Examples 9 and 10, respectively. The ordinate axis represents the amount of paclitaxel contained in 1 g of blood vessel tissue (unit: pg / g of tissue). In the caption, “1H” and “24H” mean one hour after the expansion of the blood vessel light and 24 hours after the expansion of the blood vessel light, respectively. "Pg / g of tissue" means micrograms per gram of tissue.

Table 6

Examples Quantity of PTX contained in the tissue (pg / g of tissue) PTX rates transferred to the tissue (% mass) Taxes of remaining the balloon (% pasta) PTX on 1H 24H 1H 24H 9 945.0 1106.1 5.6 5.1 10.4 10 1126.4 1338.9 4.9 7.1 8.2

[000146] As shown in Table 6, in Examples 9 and 10, the amounts of paclitaxel contained in blood vessel tissue after one hour and after 24 hours of blood vessel expansion, had approximately equal values, suggesting that the amount of paclitaxel does not decrease significantly over time. From

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47/50 above results, it was found that a drug coating layer containing an amino acid ester hydrochloride that has an amino acid side chain hydrophobicity index of zero or less than zero (specifically, ethyl ester hydrochloride L-serine, which has a hydrophobicity index of an amino acid side chain of -0.8) and paclitaxel, ensures that a sufficient amount of drug is maintained in the tissue for a long period of time after drug transfer. for the fabric. When glycerin is contained in the drug coating layer, sufficient drug retention in the tissue can also be achieved.

[000147] Evaluation of effectiveness in the porcine coronary artery [000148] For the drug-eluting balloons in Examples 9 to 11 and Comparative Example C6, as well as the uncoated drug balloon in Comparative Example C7, the effectiveness in a coronary artery swine was assessed by the following procedure.

1. Method (1) A guide catheter was inserted through a 2.7 mm sheath (8 Fr.), along with a guide wire and was guided to the orifices of the left and right coronary artery of a pig under radioscopic observation .

(2) Angiography was performed on each coronary artery (coronary artery: left anterior descending coronary artery (LAD), right coronary artery (RCA), left circumflex coronary artery (LCX) and the diameter of the blood vessel was measured with a QCA program .

(3) A part where the diameter of the stent was 1.2 times the diameter of the blood vessel and the diameter of the drug-eluting balloon was 1.3 times the diameter of the blood vessel was selected and the procedure for the operation of placing the stent was performed.

(4) The stent (stent sized to be 3 mm in diameter and 15 mm in length) was expanded to 1.2 times the size in the artery

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48/50 coronary artery was selected for 30 seconds and then the balloon catheter for placement of the resident stent was removed. At the resident stent site, the drug-eluting balloon (balloon sized to be 3 mm in diameter and 20 mm in length) was expanded to 1.3 times the size in the selected coronary artery for one minute and then the catheter was removed.

(5) After the expansion of the drug-eluting balloon ended, the guide catheter and sheath were removed and the central side of the carotid artery was ligated. Then, in an external opening of an injury to a cervical part, the dissected muscles were sutured with a surgical suture and the skin was sutured with a skin suture clamp.

(6) After 28 days of balloon expansion, necropsy was performed. At necropsy, coronary angiography was performed, whereby the patency (rate of stenosis) at the site of the resident stent was assessed and the diameter of the blood vessel was measured. The rate of stenosis (%) was calculated from the mean diameter of the blood vessel immediately after expansion of the balloon and the mean diameter of the blood vessel after 28 days.

2. Results [000149] The results were obtained as described in Table 7. In Table 7, 9 to 11 in the column “Examples / Examples

Comparative ”are Examples and C6 and C7 are Comparative Examples. [000150] FIG. 5 shows a graph representing the rate of stenosis of a blood vessel in Examples 9 to 11 and in Comparative Example C6 and C7, in evaluating the efficacy in a porcine coronary artery. In FIG. 5, the abscissa axis represents Examples or Comparative Examples, where the numerals 9 to 11 mean Examples 9 to 11, respectively and the numerals accompanied by the letter C6 and C7 mean Comparative Examples

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49/50

C6 and C7, respectively. In addition, the ordinate axis represents the Stenosis rate (unit:%).

Table 7

Examples / Examples Comparatives Stenosis rate (%) S.D. 9 16.1 6.88 10 6.5 10.82 11 7.3 2.68 C6 17.1 5.48 C7 35.0 14.28

[000151] The rate of stenosis of a blood vessel treated with an uncoated drug balloon prepared as an untreated drug control in Comparative Example C7 was 35.0%. In addition, the rate of stenosis of a blood vessel treated with the commercial drug elution (IN.PACT) balloon prepared in Comparative Example C6 was 17.1%.

[000152] On the other hand, the rates of stenosis of the blood vessels treated with the drug eluting balloons of the present invention manufactured in Examples 9 to 11 were 16.1%, 6.5% and 7.3%, respectively.

[000153] From the above results, it was found that a drug coating layer that contains an amino acid ester hydrochloride that has a hydrophobicity index of an amino acid side chain of zero or less than zero (and glycerin) and paclitaxel shows a good effect of restraint or suppression of stenosis.

[000154] When a medical device (e.g., a balloon catheter) coated with the coating composition according to the present invention is used, a drug can be efficiently

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50/50 released to the affected part of an injury while containing or suppressing the separation of the drug coating layer from the medical device during the release process to the affected part of the injury. In addition, the rapid release of the drug from the medical device in the affected part of the lesion can be promoted and the ability to transfer the drug to the tissue can be enhanced.

Description of Reference Numbers

1. Imitation of blood vessel

2. Guide catheter

3. Balloon catheter

4. Balloon

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Claims (12)

1. Coating composition for a drug-eluting medical device, characterized by the fact that it contains a water-insoluble drug and at least one selected from the group consisting of amino acid ester compounds, which have a hydrophobicity index of a side chain of amino acid of zero or less than zero and its salts, in which the water-insoluble drug is at least one selected from the group consisting of paclitaxel, rapamycin, docetaxel and everolimus. 2. Coating composition according to claim 1, characterized by the fact that the amino acid is an αamino acid. Coating composition according to claim 1 or 2, characterized in that the ester compound is an ester compound of at least one amino acid and a monohydric alcohol of up to five carbon atoms, the at least one amino acid being selected of the group consisting of glycine, serine, asparagine, aspartic acid, glutamine, glutamic acid, arginine, threonine, histidine, lysine, tyrosine, tryptophan, amino acids obtained by replacing at least one of the hydrogen atoms of an amino group in the α position in the aforementioned amino acids with an alkyl group of up to five carbon atoms, a benzyl group or a benzoyl group, proline and amino acids obtained by replacing a hydrogen atom of an imine proline group with an alkyl group of up to five carbon atoms , a benzyl group or a benzoyl group. Coating composition according to any one of claims 1 to 3, characterized in that the ester compound is represented by the following formula: [Chemist 1] Petition 870190080089, of 8/19/2019, p. 7/64 2/3 where Ri is a hydrogen atom, guanidinopropyl group, carbamoylmethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 2-carbamoyl-ethyl group, 2-carboxyethyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group, group (1Himidazol-4 -yl) methyl, 4-aminobutyl group, hydroxymethyl group, 1hydroxyethyl group, (1H-indol-3-yl) methyl group or 4-hydroxybenzyl group or forms a trimethylene group together with R2, R2 is a hydrogen atom or forms a hydrogen trimethylene group together with R1, R3 is a hydrogen atom, an alkyl group with up to five carbon atoms, a benzyl group or benzoyl group and R4 is an alkyl group with up to five carbon atoms. Coating composition according to any one of claims 1 to 4, characterized in that the ester compound is at least one selected from the group consisting of ethyl benzylglycine ester, methyl benzylglycine ester, ethyl arginine ester, methyl arginine ester , benzoyl arginine ethyl ester, benzoyl arginine methyl ester, diethyl aspartate, methyl aspartate, dimethyl aspartate, ethyl glycine ester, glycine methyl ester, ethyl serine ester and methyl serine ester. Coating composition according to any one of claims 1 to 5, characterized in that it additionally contains a lower alcohol. Coating composition according to claim 6, characterized by the fact that the lower alcohol is glycerin. Petition 870190080089, of 8/19/2019, p. 8/64 3/3 Coating composition according to any one of claims 1 to 7, characterized in that the water-insoluble drug is at least one selected from the group consisting of paclitaxel, rapamycin, docetaxel and everolimus. Coating composition according to any one of claims 1 to 8, characterized in that the medical device is a medical device that is radially expandable in a vascular lumen. Coating composition according to claim 9, characterized in that the medical device that is radially expandable in a vascular light is a balloon catheter or a stent. 11. Drug coating layer, characterized in that it is formed at least in part by a surface of a medical device that is radially expandable in a vascular light, by the use of a coating composition, as defined in any one of claims 1 to 10. 12. Drug-eluting medical device, characterized in that it has an outer surface coated with the coating composition, as defined in any of claims 1 to 10 and is radially expandable in a vascular light.