WO2013146377A1 - コーティング組成物および医療機器 - Google Patents
コーティング組成物および医療機器 Download PDFInfo
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- WO2013146377A1 WO2013146377A1 PCT/JP2013/057495 JP2013057495W WO2013146377A1 WO 2013146377 A1 WO2013146377 A1 WO 2013146377A1 JP 2013057495 W JP2013057495 W JP 2013057495W WO 2013146377 A1 WO2013146377 A1 WO 2013146377A1
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- drug
- paclitaxel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M2025/1043—Balloon catheters with special features or adapted for special applications
- A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
Definitions
- the present invention relates to a coating composition for a drug-eluting medical device, a drug coating layer of the drug-eluting medical device, and / or a drug-eluting medical device coated with the coating composition.
- DES drug eluting stent
- PHA polylactic acid
- Rapid drug delivery technology does not require a polymer matrix such as PLA (polylactic acid) or PLGA (polylactic acid-glycolic acid copolymer) for sustained release, and is advantageous for avoiding complications .
- a drug-eluting balloon (DEB: Drug Eluting Ballon) in which a balloon catheter is coated with a drug has been actively developed and reported to be effective in the treatment and prevention of restenosis.
- the balloon is coated with a coating containing a drug and an additive, and when the blood vessel is expanded, the balloon is pressed against the blood vessel wall to deliver the drug to the target tissue.
- the drug is easily peeled off from the balloon in the process until the balloon is delivered to the target tissue, when the drug is delivered to the affected area, the drug will not remain in the balloon enough for the therapeutic effect. The therapeutic effect is not expected.
- the drug that has been easily peeled off during the delivery process is unnecessarily exposed to the blood, it is not preferable in terms of safety. Therefore, there is a demand for a drug-coated layer that allows a balloon catheter coated with a drug to be delivered to the affected area without peeling off the drug, and allows the balloon to be pressed against the blood vessel wall at the same time as dilatation to release the drug quickly.
- the hydrophobicity of the compound is too strong, the hydrophobic interaction with the water-insoluble drug will be strong, and these hydrophobic regions will have a strong affinity for the balloon surface. Therefore, even if the balloon comes into contact with the affected area (the inner surface of the blood vessel), it is difficult for the drug to be released (transferred) from the balloon to the affected area. Furthermore, if the low molecular weight compound mixed with the hydrophobic drug is strong, the hydrophobic interaction between the water-insoluble drugs will be strong, and it may be easy to aggregate on the surface of the medical device, making it difficult to coat uniformly. is there.
- the medicine coated on the surface of the medical device in an agglomerated state is easily removed from the balloon surface during handling, which is not preferable in terms of safety and function.
- the low-molecular compound is too hydrophilic, it may be difficult to mix with a water-insoluble drug, and it may be difficult to prepare a stable drug-coating layer solution. At the same time, there is a possibility that it will be easily carried into the bloodstream. Therefore, low molecular weight compounds that are coated with drugs have an affinity for water-insoluble drugs with a hydrophilic region that can alleviate hydrophobic interactions between water-insoluble drugs and disperse the drugs uniformly. It is desirable that hydrophobic regions also coexist, and their balance is important.
- the present invention can deliver the drug without being easily peeled off from the medical device in the process of delivery to the target tissue. It is an object of the present invention to provide a coating composition for a drug-eluting medical device that can release the drug and enhance the transfer of the drug to a target tissue.
- the present inventors have found that a water-insoluble drug, an amino acid ester compound having a hydrophobicity index (HI) of 0 or less, and an amino acid ester compound and salts thereof.
- a coating composition containing at least one selected from the group consisting of the above is used, the medical device can easily be delivered to a target tissue in order to treat a blood vessel affected area such as restenosis on the surface of the medical device. It was learned that a drug-coated layer can be formed that can be delivered without being peeled off, and the present invention has been completed.
- the present invention provides the following (1) to (13).
- a drug-eluting medical device comprising a water-insoluble drug and at least one selected from the group consisting of an ester compound of an amino acid whose hydrophobicity index of an amino acid side chain is 0 or less and a salt thereof Coating composition.
- ester compound at least one of the hydrogen atoms of the amino group at the ⁇ -position of glycine, serine, asparagine, aspartic acid, glutamine, glutamic acid, arginine, threonine, histidine, lysine, tyrosine, tryptophan, and these amino acids is carbon.
- the ester compound is represented by the following formula: [Wherein, R 1 represents a hydrogen atom, guanidinopropyl group, carbamoylmethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 2-carbamoyl-ethyl group, 2-carboxyethyl group, 2-methoxycarbonyl group.
- R 2 is a hydrogen atom, or a trimethylene group formed together with R 1
- R 3 is a hydrogen atom, having 5 or less carbon atoms
- An alkyl group, a benzyl group or a benzoyl group, and R 4 is an alkyl group having 5 or less carbon atoms. Kill group.
- the coating composition according to any one of (1) to (3) which is represented by: (5)
- the ester compound is benzylglycine ethyl ester, benzylglycine methyl ester, arginine ethyl ester, arginine methyl ester, benzoyl arginine ethyl ester, benzoyl arginine methyl ester, aspartic acid diethyl ester, aspartic acid methyl ester, aspartic acid dimethyl ester,
- the coating composition according to any one of the above (1) to (4) which is at least one selected from the group consisting of glycine ethyl ester, glycine methyl ester, serine ethyl ester and serine methyl ester.
- the water-insoluble drug is at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel and everolimus.
- the medical device is a medical device that is radially expandable within a lumen.
- the coating composition according to (9) above, wherein the medical device that is radially expandable within the lumen is a balloon catheter or a stent.
- the drug in order to treat a blood vessel affected area such as restenosis, can be easily delivered without being peeled off from the medical device in the process of delivery to the target tissue.
- a coating composition for drug-eluting medical devices can be provided that allows the drug to migrate to the target tissue.
- FIG. 1 is a schematic cross-sectional view of an experimental apparatus in a state in which a balloon catheter is inserted into a guiding catheter installed in a mimic blood vessel in a drug coat layer resistance evaluation test using the mimic blood vessel.
- FIG. 2 is a graph showing the residual rate of paclitaxel on the balloon after the delivery operation of the drug-eluting balloons of Examples 1 to 7 and Comparative Examples C1 to C4 in the drug coat layer resistance evaluation using mimic blood vessels.
- FIG. 3 is a graph showing the amount of paclitaxel in vascular tissue of Example 8, Comparative Examples C5 and C6 in the evaluation of drug tissue migration in rabbit iliac arteries.
- FIG. 1 is a schematic cross-sectional view of an experimental apparatus in a state in which a balloon catheter is inserted into a guiding catheter installed in a mimic blood vessel in a drug coat layer resistance evaluation test using the mimic blood vessel.
- FIG. 2 is a graph showing the residual rate of paclitaxel on the balloon after the delivery operation of the drug
- FIG. 4 is a graph showing the amount of paclitaxel in vascular tissue after 1 hour and 24 hours after intravascular dilation in Examples 9 and 10 in the evaluation of drug retention in tissues in rabbit abdominal aorta.
- FIG. 5 is a graph showing the stenosis rates of Examples 9 to 11 and Comparative Examples C6 and C7 in the efficacy evaluation in porcine coronary arteries.
- Coating composition The coating composition of the present invention comprises a water-insoluble drug and at least one selected from the group consisting of an ester compound of an amino acid whose amino acid side chain hydrophobicity index is 0 or less and a salt thereof.
- a coating composition for an eluting medical device comprises a water-insoluble drug and at least one selected from the group consisting of an ester compound of an amino acid whose amino acid side chain hydrophobicity index is 0 or less and a salt thereof.
- the coating composition of the present invention contains a water-insoluble drug and at least one selected from the group consisting of an ester compound of an amino acid whose amino acid side chain hydrophobicity index is 0 or less and a salt thereof, and these are mixed together. It is a mixture (blend) and a non-polymeric coating. These components are not covalently bonded to each other. Since it is desired that the coating composition of the present invention is uniformly coated, prevents dropping until delivery to the affected area, and efficiently releases the drug in the affected area, the low molecular weight compound mixed with the water-insoluble drug is Preferred are those that are miscible with water and water-miscible organic solvents and that have affinity for hydrophobic water-insoluble drugs.
- ester compounds of amino acids having side chains with a hydrophobicity index of 0 or less, and / Or a salt thereof is preferred.
- citrate ester has three carboxyl groups in one molecule, but it is presumed that the polarity is greatly lowered by esterification of the portion.
- the affinity with water-insoluble drugs is improved, but the polarity decreases and the hydrophobic interaction with water-insoluble drugs becomes stronger, so the drugs tend to aggregate and the drug is released from the balloon surface at the affected area. It becomes difficult to obtain a preferable coating composition.
- Water-insoluble drug means a drug that is insoluble or hardly soluble in water. Specifically, the solubility in water is less than 5 mg / mL at pH 5-8. Its solubility may be less than 1 mg / mL and even less than 0.1 mg / mL. Water-insoluble drugs include fat-soluble drugs.
- examples of some preferred water-insoluble drugs include immunosuppressants, such as cyclosporines including cyclosporine, immunoactive agents such as rapamycin, anticancer agents such as paclitaxel, antiviral or antibacterial agents, anti-neoplastic agents, Analgesics and anti-inflammatory agents, antibiotics, antiepileptics, anxiolytics, antiparalytic agents, antagonists, neuron blocking agents, anticholinergics and cholinergic agents, antimuscarinic and muscarinic agents, antiadrenergic agents, Contains antiarrhythmic, antihypertensive, hormonal and nutritional agents.
- immunosuppressants such as cyclosporines including cyclosporine, immunoactive agents such as rapamycin, anticancer agents such as paclitaxel, antiviral or antibacterial agents, anti-neoplastic agents, Analgesics and anti-inflammatory agents, antibiotics, antiepileptics, anxiolytics, antiparalytic agents, antagonist
- the water-insoluble drug is preferably at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel and everolimus.
- Rapamycin, paclitaxel, docetaxel and everolimus each include analogs and / or derivatives thereof as long as they have similar medicinal properties.
- paclitaxel and docetaxel are in an analog relationship
- rapamycin and everolimus are in a derivative relationship. Of these, paclitaxel is more preferred.
- the coating composition of the present invention contains the water-insoluble drug at a concentration of preferably 5 to 60 mg / mL, more preferably at a concentration of 20 to 50 mg / mL, and even more preferably at a concentration of 30 to 40 mg / mL. To do.
- hydrophobic index of amino acid side chain is the amino acid side It represents the hydrophobicity and hydrophilicity of the chain. The larger the number, the greater the hydrophobicity of the amino acid. Hereinafter, it may be simply referred to as “hydrophobic index”.
- the hydrophobicity index refers to the hydrophobicity index according to “Kyte and Doolittle, J. Mol. Biol., 157, 105-132 (1982)”. The hydrophobicity index is not particularly limited as long as it is 0 or less.
- Table 1 shows the hydrophobicity indices of representative amino acids.
- “Amino acid” means an amino acid
- CAS no Means a CAS registration number
- HI means a hydrophobicity index.
- the amino acids are not particularly limited as long as the hydrophobicity index of the side chain is 0 or less, but ⁇ -amino acids are preferred.
- the ester compound is not particularly limited as long as it is an ester compound of an amino acid having a side chain having a hydrophobicity index of 0 or less, but an ⁇ -amino acid ester compound is preferred, and glycine, serine, asparagine, aspartic acid, glutamine, Glutamic acid, arginine, threonine, histidine, lysine, tyrosine, tryptophan and an amino acid in which at least one hydrogen atom of the amino group at the ⁇ -position of these amino acids is substituted with an alkyl group having 5 or less carbon atoms, a benzyl group or a benzoyl group, and At least one amino acid selected from the group consisting of amino acids in which the hydrogen atom of proline and the imino group of proline
- R 2 is a hydrogen atom, or a trimethylene group formed together with R 1
- R 3 is a hydrogen atom, having 5 or less carbon atoms
- An alkyl group, a benzyl group or a benzoyl group, and R 4 is an alkyl group having 5 or less carbon atoms. Kill group.
- Ester compounds represented by the following are more preferred: benzylglycine ethyl ester, benzylglycine methyl ester, arginine ethyl ester, arginine methyl ester, benzoyl arginine ethyl ester, benzoyl arginine methyl ester, aspartic acid diethyl ester, aspartic acid methyl ester, asparagine More preferred is at least one selected from the group consisting of acid dimethyl ester, glycine ethyl ester, glycine methyl ester, serine ethyl ester and serine methyl ester.
- the salt of the ester compound is not particularly limited, but hydrochloride or acetate is preferable, and hydrochloride is more preferable. Further, when a free carboxy group that is not part of the ester bond is present, it may be an alkali metal salt, and sodium is preferred as the alkali metal.
- the salt of an amino acid ester compound is improved in polarity (water solubility) by an amino group salt such as hydrochloride. Moreover, different properties such as hydrophilicity / hydrophobicity and basicity / acidity can be exhibited depending on the properties of the side chain of the amino acid.
- the ester compound of an amino acid and its salt are not particularly limited as long as the hydrophobicity index is a side chain of 0 or less, but is preferably polar, and hydrolysis of the water-insoluble drug coexisting with itself and / or coexisting with it. From the viewpoint of suppressing decomposition such as, it is more preferable that it is polar and neutral.
- ester compounds of amino acids and salts thereof can have polarity depending on the properties of the side chain and the polarity of the amino group, and they have different polarities depending on the type of side chain of the amino acid. And can provide a good coating composition.
- the total amount of the ester compound and / or salt thereof is preferably 5 to 200 parts by weight, more preferably 8 to 150 parts by weight, and more preferably 100 parts by weight of the water-insoluble drug.
- the content is preferably 12 to 120 parts by mass.
- the coating composition of the present invention preferably further contains a lower alcohol.
- a lower alcohol is contained, the vascular permeability of the water-insoluble drug can be enhanced, and the uniformity of the drug coat layer can be enhanced.
- the lower alcohol is not particularly limited as long as it is an alcohol having 5 or less carbon atoms, but a triol or tetraol having 5 or less carbon atoms is preferable, and glycerin (also referred to as “glycerol” or “propane-1,2,3-triol”).
- 1,2,4-butantole also referred to as “butane-1,2,4-triol”
- erythritol also referred to as “(2R, 3S) -butane-1,2,3,4-tetraol”.
- glycerin is more preferable.
- the content thereof is not particularly limited, but is preferably 10 to 500 parts by weight, more preferably 30 to 300 parts per 100 parts by weight of the water-insoluble drug. Part by mass, more preferably 50 to 200 parts by mass.
- the coating composition of the present invention may contain a solvent for the above components such as water, ethanol, acetone, and tetrahydrofuran in addition to the above components.
- a solvent for the above components such as water, ethanol, acetone, and tetrahydrofuran in addition to the above components.
- Other additives may be contained on the condition that the above is not disturbed.
- the drug coat layer of the present invention is a layer formed on at least a part of the surface of the medical device by the coating composition of the present invention, and the water-insoluble drug and the amino acid side chain hydrophobicity index are 0 or less. It is a layer containing at least one selected from the group consisting of an ester compound of an amino acid and a salt thereof.
- the above-mentioned drug coat layer can be formed by coating the surface of a medical device with the coating composition of the present invention and drying it, but is not limited to this method.
- the amount of drug in the drug coat layer is not particularly limited, but it is 0.1 ⁇ g / mm 2 to 10 ⁇ g / mm 2 , preferably 0.5 ⁇ g / mm 2 to 5 ⁇ g / mm 2 , more preferably 0.5 ⁇ g. / mm 2 ⁇ 3.5 ⁇ g / mm 2 , more preferably contains a density of 1.0 ⁇ g / mm 2 ⁇ 3.0 ⁇ g / mm 2.
- the drug-eluting medical device of the present invention has the above-mentioned drug coat layer directly on its surface or through pretreatment such as organic solvent, primer irradiation, UV irradiation and the like.
- the medical device is preferably a medical device that can be expanded in the radial direction (circumferential direction) in a lumen such as a blood vessel, and more preferably a balloon catheter or a stent.
- At least a part of the surface of the drug-eluting medical device of the present invention has at least one selected from the group consisting of a water-insoluble drug, an amino acid ester compound whose amino acid side chain hydrophobicity index is 0 or less, and salts thereof.
- a drug coat layer containing one is formed. This drug coat layer has a high affinity with the surface of the medical device, is difficult to peel off or fall off during the delivery process of the medical device, and has a high affinity with the diseased affected tissue. Is expected to elute.
- a drug coat layer is formed on at least a part of the outer surface of the expansion portion (balloon).
- a drug coat layer is formed on at least a part of the outer surface of the expanded portion.
- the material of the expansion part of the medical device preferably has a certain degree of flexibility and a certain degree of hardness so that the drug can be released from the drug coat layer on its surface when it reaches a blood vessel or tissue.
- the surface of the extended portion where the drug coat layer is provided is made of resin.
- resin which comprises the surface of an extended part Polyamide is mentioned suitably. That is, at least a part of the surface of the extended portion of the medical device that coats the drug is a polyamide.
- the polyamide is not particularly limited as long as it is a polymer having an amide bond.
- polytetramethylene adipamide nylon 46
- polycaprolactam nylon 6
- polyhexamethylene adipamide nylon 66
- Homopolymers such as polyhexamethylene sebamide (nylon 610), polyhexamethylene dodecamide (nylon 612), polyundecanolactam (nylon 11), polydodecanolactam (nylon 12), caprolactam / lauryl lactam co-polymer Polymer (nylon 6/12), caprolactam / aminoundecanoic acid copolymer (nylon 6/11), caprolactam / ⁇ -aminononanoic acid copolymer (nylon 6/9), caprolactam / hexamethylenediammonium adipate copolymer ( Nylon 6/66 Copolymers such as a copolymer of adipic acid and meta-xylylenediamine, or hexamethylene diamine and m, and
- a polyamide elastomer which is a block copolymer having nylon 6, nylon 66, nylon 11, nylon 12 or the like as a hard segment and polyalkylene glycol, polyether or aliphatic polyester as a soft segment is also a medical according to the present invention. It can be used as a base material for equipment.
- the polyamides may be used alone or in combination of two or more.
- other parts of the expanded part of the medical device include, for example, polyolefins such as polyethylene, polypropylene, ethylene-propylene copolymer, polyesters such as polyethylene terephthalate, polyvinyl chloride, ethylene-vinyl acetate copolymer, and cross-linked type.
- polyolefins such as polyethylene, polypropylene, ethylene-propylene copolymer
- polyesters such as polyethylene terephthalate, polyvinyl chloride, ethylene-vinyl acetate copolymer, and cross-linked type.
- An ethylene-vinyl acetate copolymer, a thermoplastic resin such as polyurethane, polyamide, polyamide elastomer, silicone rubber, latex rubber and the like can be used.
- treatment method using drug-eluting medical device includes a step of eluting the drug from a drug coat layer formed on at least a part of the surface of the medical device. More specifically, the treatment method using the drug-eluting medical device of the present invention includes a step of delivering the medical device into a lumen, and a step of radially expanding the medical device within the lumen; It is preferable that the method further comprises a step of eluting a drug from a drug coat layer formed on at least a part of the surface of the medical device and causing the drug to act on the lumen.
- the step of delivering the drug-eluting medical device of the present invention into the lumen can be performed in the same manner as a conventionally known balloon or stent.
- a guiding catheter having a cylindrical shape is inserted from the patient's wrist or crotch artery to the portal coronary artery entrance.
- the balloon or stent can be delivered to the stenosis by inserting a guide wire into the guiding catheter and inserting a balloon catheter along the guide wire.
- the step of radially expanding the drug-eluting medical device of the present invention in the lumen can be performed in the same manner as a conventionally known balloon or stent.
- the step of eluting the drug from the drug coat layer formed on at least a part of the surface of the drug-eluting medical device of the present invention and causing the drug to act on the lumen comprises: expanding the medical device in the lumen; This can be performed by holding the drug-eluting balloon in an expanded state for several tens of seconds to several minutes, or by placing a drug-eluting stent. Thereby, the lumen is expanded, and the drug in the drug coat layer acts on the lumen tissue.
- the treatment method using the drug-eluting medical device of the present invention can be applied to, for example, the treatment of vascular stenosis, and uses a drug that suppresses cell proliferation such as an anticancer drug such as paclitaxel or an immunosuppressant as the drug. By doing so, restenosis can be prevented.
- a drug that suppresses cell proliferation such as an anticancer drug such as paclitaxel or an immunosuppressant as the drug.
- An amino acid ester compound whose amino acid side chain has a hydrophobicity index of 0 or less and a salt thereof contained in the coating composition of the present invention have high biocompatibility such as not causing thrombus formation, and are rapidly biodegraded. Therefore, it is possible to provide a drug-eluting medical device that is preferable in terms of safety.
- N ⁇ -benzoyl-L-arginine ethyl ester hydrochloride (CAS No. 2645-08-1) (60 mg) is weighed and dissolved in an ethanol / water mixture consisting of absolute ethanol (1 mL) and RO water (1 mL). 30 mg / mL N ⁇ -benzoyl-L-arginine ethyl ester solution was prepared.
- L-Aspartic acid dimethyl ester hydrochloride (CAS No. 32213-95-9) (60 mg) is weighed and dissolved in an ethanol / water mixture consisting of absolute ethanol (1 mL) and RO water (1 mL), 30 mg / ML L-aspartic acid dimethyl ester solution was prepared.
- L-Aspartic acid dimethyl ester hydrochloride (50 mg) is weighed and dissolved in an ethanol / water mixture consisting of absolute ethanol (0.5 mL) and RO water (0.5 mL), and 50 mg / mL L-aspartic acid. A dimethyl ester solution was prepared.
- L-Serine ethyl ester hydrochloride (CAS No. 26348-61-8) (60 mg) is weighed and dissolved in an ethanol / water mixture consisting of absolute ethanol (1 mL) and RO water (1 mL) to give 30 mg / mL.
- a mL L-serine ethyl ester solution was prepared.
- L-Serine ethyl ester hydrochloride (140 mg) was weighed and dissolved in an ethanol / water mixture consisting of absolute ethanol (1 mL) and RO water (1 mL) to prepare a 70 mg / mL L-serine ethyl ester solution. .
- L-Serine ethyl ester hydrochloride 140 mg is weighed, dissolved in an ethanol / water mixture consisting of RO water (1.5 mL) and absolute ethanol (0.5 mL), and dissolved in 70 mg / mL L-serine ethyl ester. A solution was prepared.
- L-Serine ethyl ester hydrochloride (140 mg) was weighed and dissolved in RO water (2 mL) to prepare a 70 mg / mL L-serine ethyl ester solution.
- Glycine ethyl ester hydrochloride (CAS No. 623-33-6) (60 mg) is weighed and dissolved in an ethanol / water mixture consisting of absolute ethanol (1 mL) and RO water (1 mL) to give 30 mg / mL glycine An ethyl ester solution was prepared.
- N-benzylglycine ethyl ester hydrochloride (CAS No. 6344-42-9) (80 mg) is weighed and dissolved in an ethanol / water mixture consisting of absolute ethanol (1 mL) and RO water (1 mL) to give 40 mg / ML N-benzylglycine ethyl ester solution was prepared.
- L-alanine ethyl ester hydrochloride (CAS No. 1115-59-9) (80 mg) is weighed and dissolved in an ethanol / water mixture consisting of absolute ethanol (1 mL) and RO water (1 mL) to give 40 mg / A mL L-alanine ethyl ester solution was prepared.
- L-valine methyl ester hydrochloride (CAS No. 6306-52-1) (54 mg) is weighed and dissolved in an ethanol / water mixture consisting of absolute ethanol (1.5 mL) and RO water (0.3 mL). 30 mg / mL L-valine methyl ester solution was prepared.
- L-valine methyl ester hydrochloride (CAS No. 6306-52-1) (90 mg) is weighed and dissolved in an ethanol / water mixture consisting of absolute ethanol (1.5 mL) and RO water (0.3 mL). 50 mg / mL L-valine methyl ester solution was prepared.
- L-arginine hydrochloride (CAS No. 1119-34-2) (80 mg) is weighed and dissolved in an ethanol / water mixture consisting of absolute ethanol (1 mL) and RO water (1 mL) to give 40 mg / mL L -Arginine solution was prepared.
- L-serine (70 mg / mL L-serine solution) L-serine (CAS No. 56-45-1) (70 mg) was weighed and dissolved in RO water (1 mL) to prepare a 70 mg / mL L-serine solution.
- paclitaxel solution (20 mg / mL paclitaxel solution)
- Paclitaxel (CAS No. 33069-62-4) (40 mg) was weighed and dissolved in an ethanol / acetone mixture composed of absolute ethanol (1 mL) and acetone (1 mL) to prepare a 20 mg / mL paclitaxel solution.
- Paclitaxel (CAS No. 33069-62-4) (80 mg) was weighed and dissolved in an ethanol / acetone mixture composed of absolute ethanol (1 mL) and acetone (1 mL) to prepare 40 mg / mL paclitaxel solution 1. .
- Paclitaxel (160 mg) was weighed out and dissolved in tetrahydrofuran (CAS No. 109-99-9) (4 mL) to prepare a 40 mg / mL paclitaxel solution 2.
- Paclitaxel (56 mg / mL paclitaxel solution 1)
- Paclitaxel (336 mg) was weighed out and dissolved in tetrahydrofuran (6 mL) to prepare 56 mg / mL paclitaxel solution 1.
- Paclitaxel (224 mg) was weighed and dissolved in a THF / ethanol mixture consisting of tetrahydrofuran (2.66 mL) and absolute ethanol (1.34 mL) to prepare 56 mg / mL paclitaxel solution 2.
- Paclitaxel (56 mg / mL paclitaxel solution 3)
- Paclitaxel (336 mg) was weighed out and dissolved in a THF / ethanol mixture consisting of tetrahydrofuran (4 mL) and absolute ethanol (2 mL) to prepare 56 mg / mL paclitaxel solution 3.
- Paclitaxel (224 mg) was weighed and dissolved in a THF / ethanol mixed solution composed of tetrahydrofuran (2 mL) and absolute ethanol (2 mL) to prepare 56 mg / mL paclitaxel solution 4.
- Paclitaxel (56 mg / mL paclitaxel solution 5)
- Paclitaxel (448 mg) was weighed and dissolved in an ethanol / acetone mixed solution composed of absolute ethanol (4 mL) and acetone (4 mL) to prepare 56 mg / mL paclitaxel solution 5.
- glycerin solution 50% glycerin solution 1
- Glycerin (CAS No. 56-81-5) (100 ⁇ L) and absolute ethanol (100 ⁇ L) were mixed to prepare 50% glycerin solution 1.
- Example 1 (1) Preparation of Coating Solution 1 40 mg / mL N-benzylglycine ethyl ester solution (25 ⁇ L), 40 mg / mL paclitaxel solution 1 (150 ⁇ L) and absolute ethanol (25 ⁇ L) were mixed to prepare coating solution 1 .
- the mass ratio (BnGly-OEt / PTX) of benzylglycine ethyl ester to paclitaxel in coating solution 1 was 0.50.
- Example 2 ⁇ Example 2> (1) Preparation of Coating Solution 2 30 mg / mL L-arginine ethyl ester solution (50 ⁇ L) and 40 mg / mL paclitaxel solution 1 (60 ⁇ L) were mixed to prepare coating solution 2. The mass ratio of L-arginine ethyl ester to paclitaxel in Coating Solution 2 (Arg-OEt / PTX) was 0.63. (2) Drug coating on balloon A drug-eluting balloon was prepared in the same manner as in Example 1 except that coating solution 2 was used instead of coating solution 1.
- Example 3 Preparation of Coating Solution 3 30 mg / mL N ⁇ -benzoyl-L-arginine ethyl ester solution (50 ⁇ L) and 40 mg / mL paclitaxel solution 1 (50 ⁇ L) were mixed to prepare coating solution 3. The mass ratio of N ⁇ -benzoyl-L-arginine ethyl ester to paclitaxel in coating solution 3 (BzArg-OEt / PTX) was 0.75. (2) Drug coating on balloon A drug-eluting balloon was prepared in the same manner as in Example 1 except that the coating solution 3 was used instead of the coating solution 1.
- Example 4 ⁇ Example 4> (1) Preparation of Coating Solution 4 30 mg / mL L-aspartic acid dimethyl ester solution (50 ⁇ L) and 40 mg / mL paclitaxel solution 1 (75 ⁇ L) were mixed to prepare coating solution 4. The mass ratio of L-aspartic acid dimethyl ester to paclitaxel in coating solution 4 (Asp-DiOMe / PTX) was 0.63. (2) Drug coating on balloon A drug-eluting balloon was prepared in the same manner as in Example 1 except that the coating solution 4 was used instead of the coating solution 1.
- Example 5 ⁇ Example 5> (1) Preparation of Coating Solution 5 30 mg / mL glycine ethyl ester solution (50 ⁇ L) and 40 mg / mL paclitaxel solution 1 (110 ⁇ L) were mixed to prepare coating solution 5. The mass ratio of glycine ethyl ester to paclitaxel in coating solution 5 (Gly-OEt / PTX) was 0.63. (2) Drug coating on balloon A drug-eluting balloon was prepared in the same manner as in Example 1 except that the coating solution 5 was used instead of the coating solution 1.
- Example 6 ⁇ Example 6> (1) Preparation of Coating Solution 6 30 mg / mL L-serine ethyl ester solution (50 ⁇ L) and 40 mg / mL paclitaxel solution 1 (90 ⁇ L) were mixed to prepare coating solution 6. The mass ratio of L-serine ethyl ester to paclitaxel in coating solution 6 (Ser-OEt / PTX) was 0.42. (2) Drug coating on balloon A drug-eluting balloon was prepared in the same manner as in Example 1 except that the coating solution 6 was used instead of the coating solution 1.
- Example 8 Preparation of Coating Solution 8 50 mg / mL L-aspartic acid dimethyl ester solution (90 ⁇ L) and 40 mg / mL paclitaxel solution 2 (240 ⁇ L) were mixed to prepare coating solution 8. The mass ratio of L-aspartic acid dimethyl ester to paclitaxel in coating solution 8 (Asp-DiOMe / PTX) was 0.47. (2) Drug coating on balloon Drug-eluting balloon in the same manner as in Example 1 except that coating solution 8 was used instead of coating solution 1 and coating was performed so that the amount of paclitaxel was about 3 ⁇ g / mm 2. Was made.
- Example 9 Preparation of coating solution 9 70 mg / mL L-serine ethyl ester solution 1 (80 ⁇ L), 56 mg / mL paclitaxel solution 1 (240 ⁇ L), and 50% glycerin solution 2 (16 ⁇ L) were mixed to form coating solution 9 Was prepared.
- the mass ratio (Ser-OEt / PTX) of L-serine ethyl ester to paclitaxel in coating solution 9 was 0.42.
- Drug coating on balloon Drug-eluting balloon in the same manner as in Example 1 except that coating solution 9 was used instead of coating solution 1 and coating was performed so that the amount of paclitaxel was about 3 ⁇ g / mm 2. Was made.
- Example 10 Preparation of coating solution 10 70 mg / mL L-serine ethyl ester solution 1 (80 ⁇ L) and 56 mg / mL paclitaxel solution 1 (240 ⁇ L) were mixed to prepare coating solution 10. The mass ratio of L-serine ethyl ester to paclitaxel in the coating solution 10 (Ser-OEt / PTX) was 0.42. (2) Drug coating on balloon Drug-eluting balloon in the same manner as in Example 1 except that coating solution 10 was used instead of coating solution 1 and coating was performed so that the amount of paclitaxel was about 3 ⁇ g / mm 2. Was made.
- Example 11 Preparation of Coating Solution 11 70 mg / mL L-serine ethyl ester solution 1 (800 ⁇ L) and 56 mg / mL paclitaxel solution 2 (2400 ⁇ L) were mixed to prepare coating solution 11. The mass ratio (Ser-OEt / PT) of L-serine ethyl ester to paclitaxel in coating solution 11 was 0.42. (2) Drug coating on balloon Drug-eluting balloon in the same manner as in Example 1 except that coating solution 11 was used in place of coating solution 1 and coating was performed so that the amount of paclitaxel was about 3 ⁇ g / mm 2. Was made.
- Example 12 Preparation of Coating Solution 12 70 mg / mL L-serine ethyl ester solution 1 (600 ⁇ L) and 56 mg / mL paclitaxel solution 5 (1800 ⁇ L) were mixed to prepare coating solution 12. The mass ratio (Ser-OEt / PTX) of L-serine ethyl ester to paclitaxel in coating solution 12 was 0.42. (2) Drug coating on balloon Drug-eluting balloon in the same manner as in Example 1 except that coating solution 12 was used in place of coating solution 1 and coating was performed so that the amount of paclitaxel was about 3 ⁇ g / mm 2. Was made.
- Example 13 Preparation of Coating Solution 13 70 mg / mL L-serine ethyl ester solution 1 (600 ⁇ L) and 56 mg / mL paclitaxel solution 3 (1800 ⁇ L) were mixed to prepare coating solution 13. The mass ratio (Ser-OEt / PTX) of L-serine ethyl ester to paclitaxel in coating solution 13 was 0.42. (2) Drug coating on balloon Drug-eluting balloon in the same manner as in Example 1 except that coating solution 13 was used in place of coating solution 1 and coating was performed so that the amount of paclitaxel was about 3 ⁇ g / mm 2. Was made.
- Example 14 Preparation of coating solution 14 70 mg / mL L-serine ethyl ester solution 2 (500 ⁇ L) and 56 mg / mL paclitaxel solution 4 (1500 ⁇ L) were mixed to prepare coating solution 14. The mass ratio of L-serine ethyl ester to paclitaxel in the coating solution 14 (Ser-OEt / PTX) was 0.42. (2) Drug coating on balloon Drug-eluting balloon in the same manner as in Example 1 except that coating solution 14 was used instead of coating solution 1 and coating was performed so that the amount of paclitaxel was about 3 ⁇ g / mm 2. Was made.
- Example 15 Preparation of Coating Solution 15 70 mg / mL L-serine ethyl ester solution 3 (500 ⁇ L) and 56 mg / mL paclitaxel solution 4 (1500 ⁇ L) were mixed to prepare coating solution 15. The mass ratio (Ser-OEt / PTX) of L-serine ethyl ester to paclitaxel in coating solution 15 was 0.42. (2) Drug coating on balloon Drug-eluting balloon in the same manner as in Example 1 except that coating solution 15 was used instead of coating solution 1 and coating was performed so that the amount of paclitaxel was about 3 ⁇ g / mm 2. Was made.
- paclitaxel solution 16 40 mg / mL L-alanine ethyl ester solution (60 ⁇ L) and 40 mg / mL paclitaxel solution 1 (50 ⁇ L) were mixed to prepare paclitaxel solution 16.
- the mass ratio of L-alanine ethyl ester to paclitaxel in the paclitaxel solution 16 (Ala-OEt / PTX) was 1.20.
- Drug coating on balloon A drug-eluting balloon was prepared in the same manner as in Example 1 except that paclitaxel solution 16 was used instead of coating solution 1.
- paclitaxel solution 17 30 mg / mL L-valine methyl ester solution (70 ⁇ L) and 40 mg / mL paclitaxel solution 1 (50 ⁇ L) were mixed to prepare paclitaxel solution 17.
- the mass ratio (Val-OME / PTX) of L-valine methyl ester to paclitaxel in paclitaxel solution 17 was 1.05.
- Drug coating on balloon A drug-eluting balloon was prepared in the same manner as in Example 1 except that paclitaxel solution 17 was used instead of coating solution 1.
- paclitaxel solution 18 40 mg / mL arginine solution (60 ⁇ L) and 40 mg / mL paclitaxel solution 1 (50 ⁇ L) were mixed to prepare paclitaxel solution 18.
- the mass ratio (Arg / PTX) of L-arginine to paclitaxel in the paclitaxel solution 18 was 1.05.
- Drug coating on balloon A drug-eluting balloon was prepared in the same manner as in Example 1 except that paclitaxel solution 18 was used instead of coating solution 1.
- paclitaxel solution 19 The 20 mg / mL paclitaxel solution was used as paclitaxel solution 19.
- the paclitaxel solution 19 is a paclitaxel (PTX) solution containing no amino acid ester or amino acid.
- PTX paclitaxel
- paclitaxel solution 20 50 mg / mL L-valine methyl ester solution (80 ⁇ L) and 40 mg / mL paclitaxel solution 2 (240 ⁇ L) were mixed to prepare paclitaxel solution 20.
- the mass ratio of L-valine methyl ester to paclitaxel in the paclitaxel solution 20 (Val-OMe / PTX) was 0.42.
- Drug coating on balloon A drug-eluting balloon was prepared in the same manner as in Example 1 using the prepared paclitaxel solution 20.
- Comparative Example C6 > IN. Is a commercially available balloon catheter. PACT (Invatec) was prepared. The balloon of Comparative Example C6 is a drug eluting balloon with paclitaxel coated on the surface.
- Comparative Example C7 A balloon catheter (manufactured by Terumo Corporation, nylon elastomer material) having a diameter of 3.0 ⁇ 20 mm in length (expanded portion) was prepared.
- the balloon of Comparative Example C7 is a drug-uncoated balloon that is not coated with a drug.
- ⁇ Comparative Example C8> (1) Preparation of Coating Solution 21 70 mg / mL L-serine solution (300 ⁇ L) and 56 mg / mL paclitaxel solution 3 (900 ⁇ L) were mixed to prepare coating solution 20. The coating solution was cloudy. (2) Drug coating on the balloon Since the coating solution 21 was cloudy, the balloon could not be coated. Therefore, it became clear that a drug coating solution could not be prepared with an L-serine solution.
- Examples 1 to 15 and Comparative Examples C1 to C5 and C8 the prepared coating solution and the drug, amino acid ester hydrochloride / amino acid, amino acid ester hydrochloride or amino acid hydrophobicity index, lower alcohol contained in the coating solution
- Table 2 lists the solvents (only if used) and solvents.
- Examples 1 to 15 in the column of Examples / Comparative Examples are examples, and C1 to C5 and C8 are comparative examples.
- “PTX” in the drug column means paclitaxel
- Bn-Gly-Et in the amino acid ester / amino acid column means N-benzylglycine ethyl ester
- L-Arg-Et means L-arginine ethyl.
- “Bnz-Arg-Et” is N ⁇ -benzoyl-L-arginine ethyl ester
- “L-Asp-2Me” is L-aspartic acid dimethyl ester
- “Gly-Et” is glycine ethyl ester
- “L-Ser-Et” is L-serine ethyl ester
- “L-Ala-Et” is L-alanine ethyl ester
- “L-Val-Me” is L-valine methyl ester
- “L-Arg” is L-arginine means “L-Ser” means L-serine.
- “Glycerine” in the lower alcohol column means glycerin.
- “EtOH” means ethanol
- RO—W” means RO water
- “THF” means tetrahydrofuran
- “AC” means acetone.
- the prepared drug-eluting balloon was immersed in a methanol solution, and then shaken for 10 minutes using a shaker to extract paclitaxel coated on the balloon.
- the absorbance at 227 nm of the methanol solution from which paclitaxel was extracted was measured by high performance liquid chromatography using a UV-visible absorptiometer to determine the amount of paclitaxel per balloon ([ ⁇ g / ballon]).
- the amount of paclitaxel per unit area of the balloon [ ⁇ g / mm 2 ]) was calculated from the obtained amount of paclitaxel and the surface area of the balloon.
- the amount of paclitaxel coated on the balloon was about 2 ⁇ g / mm 2 (Examples 1 to 7, Comparative Examples C1 to C3) or about It was 3 ⁇ g / mm 2 (Examples 8 to 15, Comparative Examples C4 and C5), and the target paclitaxel amount could be coated on the balloon surface.
- Method (1) A hollow mimic blood vessel 1 having an angle of 90 degrees was prepared, and a guiding catheter 2 (outer diameter: 5 Fr.) was passed therethrough (see FIG. 1). (2) The inside of the guiding catheter 2 was filled with PBS heated at 37 ° C. (3) The produced drug-eluting balloon (expanded size 3.0 mm diameter ⁇ 20 mm length) was folded with a lapping machine. (4) The balloon catheter 3 after wrapping was inserted into a guiding catheter filled with PBS, and the delivery operation of the balloon 4 was performed for 1 minute toward the outlet of the guiding catheter. (5) The balloon after delivery in the guiding catheter was collected, and the amount of paclitaxel remaining on the balloon (residual PTX amount) was quantified by liquid chromatography. Further, the residual rate of paclitaxel on the balloon (PTX residual rate) was calculated from the amount of paclitaxel coated on the drug-eluting balloon (mounting PTX amount) and the residual PTX amount.
- PTX residual rate
- FIG. 2 is a graph showing the residual rate of paclitaxel on the balloon after the delivery operation of the drug-eluting balloons of Examples 1 to 7 and Comparative Examples C1 to C4 in the drug coat layer resistance evaluation using a mimic blood vessel.
- the horizontal axis represents an example or a comparative example
- numerals 1 to 7 mean Examples 1 to 7, respectively
- numerals C1 to C4 with alphabets mean comparative examples C1 to C4, respectively.
- the vertical axis represents the residual rate of paclitaxel on the balloon after the delivery operation (unit: mass%). “Mass%” means “mass%”.
- the amount of paclitaxel remaining in the balloon after the delivery operation of the drug eluting balloon produced in Examples 1 to 7 was 60% by mass or more based on the coating amount.
- the amount of paclitaxel remaining in the balloon was 50% by mass or less.
- an ester hydrochloride compound of an amino acid whose side chain hydrophobicity index is larger than 1 and has a relatively high hydrophobicity has been difficult to enhance the drug retention ability in the delivery operation. Further, as shown in Comparative Example C3, even when the side chain hydrophobicity index was 0 or less, in the case of an unesterified amino acid, preferable drug resistance was not obtained.
- Example 8 [Evaluation of drug tissue migration in rabbit iliac arteries]
- the drug-eluting balloons of Example 8 and Comparative Examples C5 and C6 were evaluated for paclitaxel tissue transfer to the blood vessel 1 hour after balloon dilatation in the rabbit iliac artery by the following procedure.
- Method (1) A guide wire was inserted into the right iliac artery or the left iliac artery under fluoroscopy in a rabbit. Subsequently, a drug-eluting balloon (expansion size diameter 3.0 ⁇ length 20 mm (expansion part)) was transferred to the iliac artery along the guide wire. (2) The balloon was expanded at 7 atm for 1 minute. Immediately thereafter, the balloon was removed. (3) A blood vessel (a range of about 3.5 cm from the branch) was collected 60 minutes after balloon expansion. (4) Methanol was added to the collected blood vessel and homogenized to obtain tissue homogenate.
- the tissue homogenate was analyzed using a high performance liquid chromatograph, and the amount of paclitaxel in the tissue (the amount of paclitaxel per gram of tissue) was quantified. Further, the residual rate of paclitaxel on the balloon (PTX residual rate on the balloon) was calculated from the amount of paclitaxel coated on the drug-eluting balloon and the amount of paclitaxel remaining on the balloon.
- FIG. 3 is a graph showing the amount of paclitaxel in the vascular tissue of Example 8 and Comparative Examples C5 and C6 in the evaluation of drug tissue migration in rabbit iliac arteries.
- the horizontal axis represents an example or a comparative example
- the numeral 8 represents the example 8
- the alphabetic numbers C5 and C6 represent the comparative examples C5 and C6, respectively.
- the vertical axis represents the amount of paclitaxel (unit: ⁇ g / g tissue) contained in 1 g of vascular tissue. “ ⁇ g / g tissue” means “ ⁇ g / g tissue”.
- Example 8 the amount of paclitaxel per unit area of the balloon was 3.2 ⁇ g / mm 2 , and the IN. Less than 4.1 ⁇ g / mm 2 of PACT (manufactured by Invatec). However, as shown in Table 5 and FIG. 3, the amount of paclitaxel in the tissue recovered after 60 minutes of intravascular expansion exceeded 500 ⁇ g per gram of tissue, exceeded Comparative Example C6, and the transition of paclitaxel to good vascular tissue Suggested.
- Method (1) After wrapping the drug-eluting balloon, the stent was premounted. A drug-eluting balloon after stent premount was used. (2) After inserting the guide wire into the rabbit into the abdominal aorta under X-ray fluoroscopy, the guiding catheter was removed while maintaining the position of the guide wire. Next, a stent-mounted drug-eluting balloon (expanded size diameter 3.0 ⁇ length 20 mm (expanded portion)) was transferred to the abdominal aorta along the guide wire. (3) The balloon was expanded at 7 atm for 1 minute. Immediately thereafter, the balloon was removed. (4) Blood vessels (in the range of about 3.5 cm from the branch) were collected 1 hour and 24 hours after balloon expansion.
- tissue homogenate was analyzed using a high performance liquid chromatograph, and the amount of paclitaxel in the tissue (the amount of paclitaxel per gram of tissue) after 1 hour and 24 hours after balloon expansion was quantified. Further, the amount of paclitaxel coated on the drug-eluting balloon and the amount of paclitaxel in the tissue after 1 hour and 24 hours after balloon dilatation, the rate of migration of paclitaxel to the tissue after 1 hour and 24 hours after balloon dilatation (to the tissue). PTX transfer rate) was calculated, and the residual rate (PTX residual rate on the balloon) was calculated from the amount of paclitaxel remaining on the balloon.
- PTX amount in tissue is the amount of paclitaxel contained in 1 g of blood vessel tissue (unit: ⁇ g / g tissue), and “PTX transfer rate to tissue” is transferred from the balloon into the blood vessel tissue.
- the ratio (unit: mass%) of paclitaxel, and “PTX residual ratio on balloon” represent the ratio (unit: mass%) of paclitaxel remaining on the balloon.
- “1H” and “24H” in the columns of “amount of PTX in tissue” and “PTX transfer rate to tissue” mean 1 hour and 24 hours after intravascular dilation, respectively.
- FIG. 4 is a graph showing the amount of paclitaxel in vascular tissue after 1 hour and 24 hours after intravascular dilation in Examples 9 and 10 in evaluation of drug retention in tissue in rabbit abdominal aorta.
- the horizontal axis represents an embodiment, and numerals 9 and 10 represent the embodiments 9 and 10, respectively.
- the vertical axis represents the amount of paclitaxel (unit: ⁇ g / g tissue) contained in 1 g of vascular tissue.
- the legends “1H” and “24H” mean 1 hour and 24 hours after intravascular dilation, respectively.
- “ ⁇ g / g tissue” means “ ⁇ g / g tissue”.
- the stent (stent diameter 3 mm ⁇ length 15 mm) was expanded to 1.2 times for 30 seconds, and then the stent placement balloon catheter was removed.
- the drug-eluting balloon (balloon diameter: 3 mm ⁇ length 20 mm) was expanded at the stent placement site for 1 minute so as to be 1.3 times the blood vessel diameter, and then the catheter was removed.
- After expanding the drug-eluting balloon remove the guiding catheter and sheath, ligate the central side of the carotid artery, and then suture the cervical wound with the surgical suture between the peeled muscles. The skin was sutured.
- An autopsy was performed 28 days after balloon expansion.
- stenosis rate stenosis rate
- FIG. 5 is a graph showing the vascular stenosis rates of Examples 9 to 11 and Comparative Examples C6 and C7 in the efficacy evaluation in porcine coronary arteries.
- the horizontal axis represents an example or a comparative example
- numerals 9 to 11 represent Examples 9 to 11, respectively
- numbers C6 and C7 with alphabets represent Comparative Examples C6 and C7, respectively.
- the vertical axis represents the stenosis rate (unit:%) of the blood vessel.
- Comparative Example C7 the stenosis rate of blood vessels treated with a drug-uncoated balloon as a drug-untreated control was 35.0%.
- the stenosis ratio of the blood vessel treated with a commercially available drug-eluting balloon (IN.PACT) in Comparative Example C6 was 17.1%.
- the stenosis rates of the blood vessels treated with the drug release balloons of Examples 9 to 11 were 16.1%, 6.5%, and 7.3%, respectively. From the above, it was clarified that the drug coating layer containing amino acid ester hydrochloride (and glycerin) and paclitaxel having a hydrophobicity index of amino acid side chain of 0 or less shows a good stenosis inhibiting effect.
- the drug can be efficiently delivered to the lesioned part while suppressing the drop of the drug coat layer during the delivery to the lesioned part.
- rapid drug release from the medical device in the affected area can be promoted, and the tissue transferability of the drug can be enhanced.
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Abstract
Description
(1)水不溶性薬剤と、アミノ酸側鎖の疎水性指標が0以下であるアミノ酸のエステル化合物およびその塩からなる群から選択される少なくとも1つとを含有する、薬剤溶出性の医療機器のためのコーティング組成物。
(2)前記アミノ酸がαアミノ酸である、上記(1)に記載のコーティング組成物。
(3)前記エステル化合物が、グリシン、セリン、アスパラギン、アスパラギン酸、グルタミン、グルタミン酸、アルギニン、トレオニン、ヒスチジン、リシン、チロシン、トリプトファンおよびこれらのアミノ酸のα位のアミノ基の水素原子の少なくとも1つが炭素数5以下のアルキル基、ベンジル基またはベンゾイル基で置換されたアミノ酸、ならびにプロリンおよびプロリンのイミノ基の水素原子が炭素数5以下のアルキル基、ベンジル基またはベンゾイル基で置換されたアミノ酸からなる群から選択される少なくとも1つのアミノ酸と、炭素数5以下の一価アルコールとのエステル化合物である、上記(1)または(2)に記載のコーティング組成物。
(4)前記エステル化合物が下記式
で表される、上記(1)~(3)のいずれかに記載のコーティング組成物。
(5)前記エステル化合物がベンジルグリシンエチルエステル、ベンジルグリシンメチルエステル、アルギニンエチルエステル、アルギニンメチルエステル、ベンゾイルアルギニンエチルエステル、ベンゾイルアルギニンメチルエステル、アスパラギン酸ジエチルエステル、アスパラギン酸メチルエステル、アスパラギン酸ジメチルエステル、グリシンエチルエステル、グリシンメチルエステル、セリンエチルエステルおよびセリンメチルエステルからなる群から選択される少なくとも1つである、上記(1)~(4)のいずれかに記載のコーティング組成物。
(6)さらに低級アルコールを含有する、上記(1)~(5)のいずれかに記載のコーティング組成物。
(7)前記低級アルコールがグリセリンである、上記(6)に記載のコーティング組成物。
(8)前記水不溶性薬剤がラパマイシン、パクリタキセル、ドセタキセルおよびエベロリムスであるからなる群から選択される少なくとも1つである、上記(1)~(7)のいずれかに記載のコーティング組成物。
(9)前記医療機器が管腔内で径方向に拡張可能な医療機器である、上記(1)~(8)のいずれかに記載のコーティング組成物。
(10)前記管腔内で径方向に拡張可能な医療機器がバルーンカテーテルまたはステントである、上記(9)に記載のコーティング組成物。
(11)上記(1)~(10)のいずれかに記載のコーティング組成物により医療機器の表面の少なくとも一部に形成される薬剤コート層。
(12)上記(1)~(10)のいずれかに記載のコーティング組成物で外面がコートされた薬剤溶出性の医療機器。
(13)上記(12)に記載の医療機器を管腔内に送達するステップと、上記管腔内で上記医療機器を径方向に拡張させるステップと、上記医療機器の表面の少なくとも一部に形成された薬剤コート層から薬剤を溶出させ、上記管腔に薬剤を作用させるステップとを備える治療方法。
本発明のコーティング組成物は、水不溶性薬剤と、アミノ酸側鎖の疎水性指標が0以下であるアミノ酸のエステル化合物およびその塩からなる群から選択される少なくとも1つとを含有する、薬剤溶出性の医療機器のためのコーティング組成物である。
本発明のコーティング組成物は、均一にコーティングされ、患部に送達するまでの脱落を抑え、かつ患部で薬剤を効率良く放出することが望まれるため、水不溶性薬剤と混合される低分子化合物は、水および水混和性有機溶剤と混和することができ、かつ疎水性の水不溶性薬剤とも親和性を有するものが好ましく、この点から、疎水性指標が0以下の側鎖を有するアミノ酸のエステル化合物および/またはその塩が好ましい。
一方、例えば、クエン酸エステルなどは、カルボキシル基を1分子中に3個有するが、その部分がエステル化されることにより極性が大きく低下すると推測される。その結果、水不溶性薬剤との親和性は向上するが、極性が下がり水不溶性薬剤との疎水性相互作用が強くなるため、薬剤同士が凝集しやすくなり、また患部で薬剤がバルーン表面から放出しにくくなり、好ましいコーティング組成物は得られないと推測される。
水不溶性薬剤とは、水に不溶または難溶性である薬剤を意味し、具体的には、水に対する溶解度が、pH5~8で5mg/mL未満である。その溶解度は、1mg/mL未満、さらに、0.1mg/mL未満でもよい。水不溶性薬剤は脂溶性薬剤を含む。
2-1)アミノ酸側鎖の疎水性指標
アミノ酸側鎖の疎水性指標(hydropathy index)とは、アミノ酸の側鎖の疎水性、親水性を表し、数字が大きいほど、アミノ酸の疎水性が大きい。以下、単に「疎水性指標」という場合がある。
本発明において、疎水性指標は、“Kyte and Doolittle, J. Mol. Biol., 157, 105-132(1982)”による疎水性指標をいう。
疎水性指標は0以下であれば特に限定されない。
表1に、代表的なアミノ酸の疎水性指標を示す。表1中、“Amino acid”はアミノ酸を、“CAS no.”はCAS登録番号を、“H.I.”は疎水性指標を、それぞれ意味する。
上記アミノ酸は、側鎖の疎水性指標が0以下であれば特に限定されるものではないが、αアミノ酸が好ましい。
また、上記エステル化合物は、疎水性指標が0以下である側鎖を有するアミノ酸のエステル化合物であれば特に限定されないが、αアミノ酸のエステル化合物が好ましく、グリシン、セリン、アスパラギン、アスパラギン酸、グルタミン、グルタミン酸、アルギニン、トレオニン、ヒスチジン、リシン、チロシン、トリプトファンおよびこれらのアミノ酸のα位のアミノ基の水素原子の少なくとも1つが炭素数5以下のアルキル基、ベンジル基またはベンゾイル基で置換されたアミノ酸、ならびにプロリンおよびプロリンのイミノ基の水素原子が炭素数5以下のアルキル基、ベンジル基またはベンゾイル基で置換されたアミノ酸からなる群から選択される少なくとも1つのアミノ酸と、炭素数5以下の一価アルコールとのエステル化合物がより好ましく、下記式
本発明のコーティング組成物は、さらに低級アルコールを含有することが好ましい。低級アルコールを含有すると、水不溶性薬剤の血管浸透性を増強することができ、また、薬剤コート層の均一性を高めることができる。低級アルコールは、炭素数5以下のアルコールであれば特に限定されないが、炭素数5以下のトリオールまたはテトラオールが好ましく、グリセリン(「グリセロール」または「プロパン-1,2,3-トリオール」ともいう。)、1,2,4-ブタントリール(「ブタン-1,2,4-トリオール」ともいう。)またはエリトリトール(「(2R,3S)-ブタン-1,2,3,4-テトラオール」ともいう。)がより好ましく、グリセリンがさらに好ましい。
本発明のコーティング組成物は、上記成分の他に、水、エタノール、アセトン、テトラヒドロフラン等の、上記成分の溶媒を含んでもよく、さらに、本発明の効果を妨げないことを条件に、その他の添加剤を含有してもよい。
本発明の薬剤コート層は、本発明のコーティング組成物により医療機器の表面の少なくとも一部に形成された層であり、水不溶性薬剤と、アミノ酸側鎖の疎水性指標が0以下であるアミノ酸のエステル化合物およびその塩からなる群から選択される少なくとも1つとを含有する、層である。
本発明の薬剤溶出性の医療機器は、その表面上に直接、または有機溶剤、プライマー照射、UV照射等の前処理を介して上記薬剤コート層を有する。医療機器としては、血管等の管腔内で径方向(周方向)に拡張可能な医療機器が好ましく、バルーンカテーテルまたはステントがより好ましい。
本発明の薬剤溶出性の医療機器を用いる治療方法は、当該医療機器の表面の少なくとも一部に形成された薬剤コート層から薬剤を溶出するステップを備える。より詳細には、本発明の薬剤溶出性の医療機器を用いる治療方法は、当該医療機器を管腔内に送達するステップと、前記管腔内で前記医療機器を径方向に拡張させるステップと、前記医療機器の表面の少なくとも一部に形成された薬剤コート層から薬剤を溶出させ、前記管腔に薬剤を作用させるステップとを備えることが好ましい。
上記本発明の薬剤溶出性の医療機器を管腔内に送達するステップは、従来公知のバルーンやステントと同様に行うことができる。例えば、本発明の薬剤溶出性のバルーンまたはステントを冠動脈の狭窄部に送達する場合には、患者の手首または太股の動脈から筒状になっているガイディングカテーテルを心臓冠動脈の入口部まで挿入し、ガイディングカテーテルの中にガイドワイヤーを挿入し、バルーンカテーテルをガイドワイヤーに沿って挿入することで、バルーンまたはステントを狭窄部に送達することができる。
本発明の薬剤溶出性の医療機器を管腔内で径方向に拡張させるステップは、従来公知のバルーンやステントと同様に行うことができる。
本発明の薬剤溶出性の医療機器の表面の少なくとも一部に形成された薬剤コート層から薬剤を溶出させ、前記管腔に薬剤を作用させるステップは、管腔内で拡張させた医療機器を、薬剤溶出バルーンを拡張したまま数十秒間~数分間保持したり、薬剤溶出ステントを留置したりすることによって行うことができる。これにより、管腔が拡張され、薬剤コート層の薬剤が管腔組織に作用する。
本発明の薬剤溶出性の医療機器を用いる治療方法は、例えば、血管狭窄症の治療に適用することができ、薬剤としてパクリタキセル等の抗がん剤や免疫抑制剤など細胞増殖を抑える薬剤を利用することで、再狭窄を防止することができる。
〈アミノ酸エステル溶液の調製例〉
(30mg/mL アルギニンエチルエステル溶液)
L-アルギニンエチルエステル二塩酸塩(CAS No.36589-29-4)(60mg)を量りとり、無水エタノール(1mL)およびRO水(1mL)からなるエタノール/水混合液に加えて溶解し、30mg/mL L-アルギニンエチルエステル溶液を調製した。
Nα-ベンゾイル-L-アルギニンエチルエステル塩酸塩(CAS No.2645-08-1)(60mg)を量りとり、無水エタノール(1mL)およびRO水(1mL)からなるエタノール/水混合液に加えて溶解し、30mg/mL Nα-ベンゾイル-L-アルギニンエチルエステル溶液を調製した。
L-アスパラギン酸ジメチルエステル塩酸塩(CAS No.32213-95-9)(60mg)を量りとり、無水エタノール(1mL)およびRO水(1mL)からなるエタノール/水混合液に加えて溶解し、30mg/mL L-アスパラギン酸ジメチルエステル溶液を調製した。
L-アスパラギン酸ジメチルエステル塩酸塩(50mg)を量りとり、無水エタノール(0.5mL)およびRO水(0.5mL)からなるエタノール/水混合液に加えて溶解し、50mg/mL L-アスパラギン酸ジメチルエステル溶液を調製した。
L-セリンエチルエステル塩酸塩(CAS No.26348-61-8)(60mg)を量りとり、無水エタノール(1mL)およびRO水(1mL)からなるエタノール/水混合液に加えて溶解し、30mg/mL L-セリンエチルエステル溶液を調製した。
L-セリンエチルエステル塩酸塩(140mg)を量りとり、無水エタノール(1mL)およびRO水(1mL)からなるエタノール/水混合液に加えて溶解し、70mg/mL L-セリンエチルエステル溶液を調製した。
L-セリンエチルエステル塩酸塩(140mg)を量りとり、RO水(1.5mL)および無水エタノール(0.5mL)からなるエタノール/水混合液に加えて溶解し、70mg/mL L-セリンエチルエステル溶液を調製した。
L-セリンエチルエステル塩酸塩(140mg)を量りとり、RO水(2mL)に加えて溶解し、70mg/mL L-セリンエチルエステル溶液を調製した。
グリシンエチルエステル塩酸塩(CAS No.623-33-6)(60mg)を量りとり、無水エタノール(1mL)およびRO水(1mL)からなるエタノール/水混合液に加えて溶解し、30mg/mL グリシンエチルエステル溶液を調製した。
N-ベンジルグリシンエチルエステル塩酸塩(CAS No.6344-42-9)(80mg)を量りとり、無水エタノール(1mL)およびRO水(1mL)からなるエタノール/水混合液に加えて溶解し、40mg/mL N-ベンジルグリシンエチルエステル溶液を調製した。
L-アラニンエチルエステル塩酸塩(CAS No.1115-59-9)(80mg)を量りとり、無水エタノール(1mL)およびRO水(1mL)からなるエタノール/水混合液に加えて溶解し、40mg/mL L-アラニンエチルエステル溶液を調製した。
L-バリンメチルエステル塩酸塩(CAS No.6306-52-1)(54mg)を量りとり、無水エタノール(1.5mL)およびRO水(0.3mL)からなるエタノール/水混合液に加えて溶解し、30mg/mL L-バリンメチルエステル溶液を調製した。
L-バリンメチルエステル塩酸塩(CAS No.6306-52-1)(90mg)を量りとり、無水エタノール(1.5mL)およびRO水(0.3mL)からなるエタノール/水混合液に加えて溶解し、50mg/mL L-バリンメチルエステル溶液を調製した。
(40mg/mL L-アルギニン溶液)
L-アルギニン塩酸塩(CAS No.1119-34-2)(80mg)を量りとり、無水エタノール(1mL)およびRO水(1mL)からなるエタノール/水混合液に加えて溶解し、40mg/mL L-アルギニン溶液を調製した。
L-セリン(CAS No.56-45-1)(70mg)を量りとり、RO水(1mL)に加えて溶解し、70mg/mL L-セリン溶液を調製した。
(20mg/mL パクリタキセル溶液)
パクリタキセル(CAS No.33069-62-4)(40mg)を量りとり、無水エタノール(1mL)およびアセトン(1mL)からなるエタノール/アセトン混合液に加えて溶解し、20mg/mL パクリタキセル溶液を調製した。
パクリタキセル(CAS No.33069-62-4)(80mg)を量りとり、無水エタノール(1mL)およびアセトン(1mL)からなるエタノール/アセトン混合液に加えて溶解し、40mg/mL パクリタキセル溶液1を調製した。
パクリタキセル(160mg)を量りとり、テトラヒドロフラン(CAS No.109-99-9)(4mL)に加えて溶解し、40mg/mL パクリタキセル溶液2を調製した。
パクリタキセル(336mg)を量りとり、テトラヒドロフラン(6mL)に加えて溶解し、56mg/mL パクリタキセル溶液1を調製した。
パクリタキセル(224mg)を量りとり、テトラヒドロフラン(2.66mL)および無水エタノール(1.34mL)からなるTHF/エタノール混合液に加えて溶解し、56mg/mL パクリタキセル溶液2を調製した。
パクリタキセル(336mg)を量りとり、テトラヒドロフラン(4mL)および無水エタノール(2mL)からなるTHF/エタノール混合液に加えて溶解し、56mg/mL パクリタキセル溶液3を調製した。
パクリタキセル(224mg)を量りとり、テトラヒドロフラン(2mL)および無水エタノール(2mL)からなるTHF/エタノール混合液に加えて溶解し、56mg/mL パクリタキセル溶液4を調製した。
パクリタキセル(448mg)を量りとり、無水エタノール(4mL)およびアセトン(4mL)からなるエタノール/アセトン混合液に加えて溶解し、56mg/mL パクリタキセル溶液5を調製した。
(50% グリセリン溶液1)
グリセリン(CAS No.56-81-5)(100μL)と、無水エタノール(100μL)とを混合し、50% グリセリン溶液1を調製した。
グリセリン(500μL)と、無水エタノール(500μL)とを混合し、50% グリセリン溶液2を調製した。
(1)コーティング溶液1の調製
40mg/mL N-ベンジルグリシンエチルエステル溶液(25μL)と、40mg/mL パクリタキセル溶液1(150μL)と、無水エタノール(25μL)とを混合し、コーティング溶液1を調製した。コーティング溶液1中のパクリタキセルに対するベンジルグリシンエチルエステルの質量比(BnGly-OEt/PTX)は0.50であった。
(2)バルーンへの薬剤コーティング
拡張時サイズが直径3.0×長さ20mm(拡張部)のバルーンカテーテル(テルモ社製、バルーン(拡張部)の素材はナイロンエラストマー)を準備した。パクリタキセル量が約2μg/mm2となるように、コーティング溶液1を拡張したバルーンにピペットでコートし、バルーンを乾燥させ、薬剤溶出バルーンを作製した。
(1)コーティング溶液2の調製
30mg/mL L-アルギニンエチルエステル溶液(50μL)と、40mg/mL パクリタキセル溶液1(60μL)とを混合し、コーティング溶液2を調製した。コーティング溶液2中のパクリタキセルに対するL-アルギニンエチルエステルの質量比(Arg-OEt/PTX)は0.63であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液2を用いた点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液3の調製
30mg/mL Nα-ベンゾイル-L-アルギニンエチルエステル溶液(50μL)と、40mg/mL パクリタキセル溶液1(50μL)とを混合し、コーティング溶液3を調製した。コーティング溶液3中のパクリタキセルに対するNα-ベンゾイル-L-アルギニンエチルエステルの質量比(BzArg-OEt/PTX)は0.75であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液3を用いた点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液4の調製
30mg/mL L-アスパラギン酸ジメチルエステル溶液(50μL)と、40mg/mL パクリタキセル溶液1(75μL)とを混合し、コーティング溶液4を調製した。コーティング溶液4中のパクリタキセルに対するL-アスパラギン酸ジメチルエステルの質量比(Asp-DiOMe/PTX)は0.63であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液4を用いた点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液5の調製
30mg/mL グリシンエチルエステル溶液(50μL)と、40mg/mLパクリタキセル溶液1(110μL)とを混合し、コーティング溶液5を調製した。コーティング溶液5中のパクリタキセルに対するグリシンエチルエステルの質量比(Gly-OEt/PTX)は0.63であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液5を用いた点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液6の調製
30mg/mL L-セリンエチルエステル溶液(50μL)と、40mg/mL パクリタキセル溶液1(90μL)とを混合し、コーティング溶液6を調製した。コーティング溶液6中のパクリタキセルに対するL-セリンエチルエステルの質量比(Ser-OEt/PTX)は0.42であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液6を用いた点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液7の調製
30mg/mL L-アルギニンエチルエステル溶液(160μL)と、40mg/mL パクリタキセル溶液1(200μL)と、50%グリセリン溶液1(20μL)とを混合し、コーティング溶液7を調製した。コーティング溶液7中のパクリタキセルに対するL-アルギニンエチルエステルの質量比(Arg-OEt/PTX)は0.60であった。
コーティング溶液7は、L-アルギニンエチルエステル(Arg-OEt、アミノ酸側鎖の疎水性指標=-4.5)およびパクリタキセル(PTX)に加えて、さらにグリセリンを含有するコーティング溶液である。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液7を用いた点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液8の調製
50mg/mL L-アスパラギン酸ジメチルエステル溶液(90μL)と、40mg/mL パクリタキセル溶液2(240μL)とを混合し、コーティング溶液8を調製した。コーティング溶液8中のパクリタキセルに対するL-アスパラギン酸ジメチルエステルの質量比(Asp-DiOMe/PTX)は0.47であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液8を用いた点およびパクリタキセル量が約3μg/mm2となるようにコートした点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液9の調製
70mg/mL L-セリンエチルエステル溶液1(80μL)と、56mg/mL パクリタキセル溶液1(240μL)と、50% グリセリン溶液2(16μL)とを混合し、コーティング溶液9を調製した。コーティング溶液9中のパクリタキセルに対するL-セリンエチルエステルの質量比(Ser-OEt/PTX)は0.42であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液9を用いた点およびパクリタキセル量が約3μg/mm2となるようにコートした点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液10の調製
70mg/mL L-セリンエチルエステル溶液1(80μL)と、56mg/mL パクリタキセル溶液1(240μL)とを混合し、コーティング溶液10を調製した。コーティング溶液10中のパクリタキセルに対するL-セリンエチルエステルの質量比(Ser-OEt/PTX)は0.42であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液10を用いた点およびパクリタキセル量が約3μg/mm2となるようにコートした点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液11の調製
70mg/mL L-セリンエチルエステル溶液1(800μL)と、56mg/mL パクリタキセル溶液2(2400μL)とを混合し、コーティング溶液11を調製した。コーティング溶液11中のパクリタキセルに対するL-セリンエチルエステルの質量比(Ser-OEt/PT)は0.42であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液11を用いた点およびパクリタキセル量が約3μg/mm2となるようにコートした点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液12の調製
70mg/mL L-セリンエチルエステル溶液1(600μL)と、56mg/mL パクリタキセル溶液5(1800μL)とを混合し、コーティング溶液12を調製した。コーティング溶液12中のパクリタキセルに対するL-セリンエチルエステルの質量比(Ser-OEt/PTX)は0.42であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液12を用いた点およびパクリタキセル量が約3μg/mm2となるようにコートした点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液13の調製
70mg/mL L-セリンエチルエステル溶液1(600μL)と、56mg/mL パクリタキセル溶液3(1800μL)とを混合し、コーティング溶液13を調製した。コーティング溶液13中のパクリタキセルに対するL-セリンエチルエステルの質量比(Ser-OEt/PTX)は0.42であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液13を用いた点およびパクリタキセル量が約3μg/mm2となるようにコートした点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液14の調製
70mg/mL L-セリンエチルエステル溶液2(500μL)と、56mg/mL パクリタキセル溶液4(1500μL)とを混合し、コーティング溶液14を調製した。コーティング溶液14中のパクリタキセルに対するL-セリンエチルエステルの質量比(Ser-OEt/PTX)は0.42であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液14を用いた点およびパクリタキセル量が約3μg/mm2となるようにコートした点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)コーティング溶液15の調製
70mg/mL L-セリンエチルエステル溶液3(500μL)と、56mg/mL パクリタキセル溶液4(1500μL)とを混合し、コーティング溶液15を調製した。コーティング溶液15中のパクリタキセルに対するL-セリンエチルエステルの質量比(Ser-OEt/PTX)は0.42であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにコーティング溶液15を用いた点およびパクリタキセル量が約3μg/mm2となるようにコートした点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)パクリタキセル溶液16の調製
40mg/mL L-アラニンエチルエステル溶液(60μL)と、40mg/mL パクリタキセル溶液1(50μL)とを混合し、パクリタキセル溶液16を調製した。パクリタキセル溶液16中のパクリタキセルに対するL-アラニンエチルエステルの質量比(Ala-OEt/PTX)は1.20であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにパクリタキセル溶液16を用いた点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)パクリタキセル溶液17の調製
30mg/mL L-バリンメチルエステル溶液(70μL)と、40mg/mL パクリタキセル溶液1(50μL)とを混合し、パクリタキセル溶液17を調製した。パクリタキセル溶液17中のパクリタキセルに対するL-バリンメチルエステルの質量比(Val-OME/PTX)は1.05であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにパクリタキセル溶液17を用いた点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)パクリタキセル溶液18の調製
40mg/mL アルギニン溶液(60μL)と、40mg/mL パクリタキセル溶液1(50μL)とを混合し、パクリタキセル溶液18を調製した。パクリタキセル溶液18中のパクリタキセルに対するL-アルギニンの質量比(Arg/PTX)は1.05であった。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにパクリタキセル溶液18を用いた点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)パクリタキセル溶液19の調製
20mg/mL パクリタキセル溶液をパクリタキセル溶液19とした。パクリタキセル溶液19は、アミノ酸エステルまたはアミノ酸を含有しない、パクリタキセル(PTX)溶液である。
(2)バルーンへの薬剤コーティング
コーティング溶液1の代わりにパクリタキセル溶液19を用いた点およびパクリタキセル量が約3μg/mm2となるようにコートした点を除き、実施例1と同様にして薬剤溶出バルーンを作製した。
(1)パクリタキセル溶液20の調製
50mg/mL L-バリンメチルエステル溶液(80μL)と、40mg/mL パクリタキセル溶液2(240μL)とを混合し、パクリタキセル溶液20を調製した。パクリタキセル溶液20中のパクリタキセルに対するL-バリンメチルエステルの質量比(Val-OMe/PTX)は0.42であった。
(2)バルーンへの薬剤コーティング
調製したパクリタキセル溶液20を用いて、実施例1と同様にして薬剤溶出バルーンを作製した。
市販品のバルーンカテーテルであるIN.PACT(Invatec社)を準備した。比較例C6のバルーンは、パクリタキセルが表面にコートされた薬剤溶出バルーンである。
拡張時サイズが直径3.0×長さ20mm(拡張部)のバルーンカテーテル(テルモ社製、ナイロンエラストマー素材)を準備した。比較例C7のバルーンは、薬剤がコートされていない薬剤無塗布バルーンである。
(1)コーティング溶液21の調製
70mg/mL L-セリン溶液(300μL)と、56mg/mL パクリタキセル溶液3(900μL)とを混合し、コーティング溶液20を調製した。コーティング溶液は白濁していた。
(2)バルーンへの薬剤コーティング
コーティング溶液21は白濁していたため、バルーンにコートすることができなかった。従って、L-セリン溶液では、薬剤コーティング溶液を調製できないことが明らかとなった。
実施例1~15および比較例C1~C5の薬剤溶出バルーンについて、バルーンにコートされたパクリタキセル量を、以下の手順により測定した。
調製した薬剤溶出バルーンをメタノール溶液に浸して、その後、10分間、振とう機を用いて振とうし、バルーンにコートされたパクリタキセルを抽出した。パクリタキセルを抽出したメタノール溶液の227nmでの吸光度を、紫外可視吸光光度計を用いて高速液体クロマトグラフィーにて測定し、バルーンあたりのパクリタキセル量([μg/balloon])を求めた。さらに、求めたパクリタキセル量と、バルーン表面積とから、バルーンの単位面積あたりのパクリタキセル量([μg/mm2])を算出した。
表3に示す結果を得た。表3中、実施例/比較例の列の1~15は実施例であり、C1~C5は比較例である。また、表3中、「バルーン表面積」はバルーンの拡張時表面積(単位:mm2)を、「バルーン上のPTX量」の「バルーンあたり」はバルーン1個あたりのパクリタキセル量(単位:μg/バルーン)を、「バルーン上のPTX量」の「単位面積あたり」はバルーンの表面積1mm2あたりのパクリタキセル量(単位:μg/mm2)を、それぞれ表す。
実施例1~7および比較例C1~C4の薬剤溶出バルーンについて、病変患部に送達する過程でどれだけ薬剤コート層が脱落するかを評価するために、模倣血管を用いてデリバリー操作を行い、デリバリー後のバルーン上に残存するパクリタキセルを定量することで薬剤コート層耐性試験を行った。
(1)90度の角度がついている中空の模倣血管1を準備し、その中にガイディングカテーテル2(外径:5Fr.)を通した(図1を参照)。
(2)ガイディングカテーテル2の内部を37℃で加温したPBSで満たした。
(3)作製した薬剤溶出バルーン(拡張時サイズ 直径3.0×長さ20mm)を、ラッピング機で折りたたんだ。
(4)ラッピング後のバルーンカテーテル3を、PBSで満たしたガイディングカテーテル内に挿入し、ガイディングカテーテルの出口に向かって1分間にわたりバルーン4のデリバリー操作を行った。
(5)ガイディングカテーテル内をデリバリー後のバルーンを回収し、液体クロマトグラフによってバルーン上に残存したパクリタキセル量(残存PTX量)を定量した。さらに、薬剤溶出バルーンにコートされたパクリタキセル量(搭載PTX量)と残存PTX量とから、バルーン上のパクリタキセルの残存率(PTX残存率)を算出した。
表4に示す結果を得た。表4中、実施例/比較例の列の1~7は実施例であり、C1~C4は比較例である。また、表4中、「搭載PTX量」は薬剤溶出バルーン1個当たりにコートされたパクリタキセル量(単位:μg/バルーン)を、「バルーン上残存PTX量」はデリバリー操作後のバルーン1個あたりに残存したパクリタキセル量(単位:μg/バルーン)を、「バルーン上PTX残存率」はデリバリー操作後にバルーン上に残存していたパクリタキセルの割合(単位:質量%)を、それぞれ表す。
実施例8、比較例C5およびC6の薬剤溶出バルーンについて、以下の手順により、ウサギ腸骨動脈におけるバルーン拡張1時間後の血管へのパクリタキセル組織移行性を評価した。
(1)ウサギにガイドワイヤーをX線透視下で右腸骨動脈または左腸骨動脈まで挿入した。次いで、薬剤溶出バルーン(拡張時サイズ直径3.0×長さ20mm(拡張部))を、ガイドワイヤーに沿わせて、該腸骨動脈まで移行させた。
(2)7atmで1分間バルーンを拡張させた。その後、直ちに、バルーンを抜去した。
(3)バルーン拡張60分後に、血管(分枝より約3.5cmの範囲)を採取した。
(4)採取した血管にメタノールを添加し、ホモジネイトして、組織ホモジネイトとした。
(5)組織ホモジネイトを、高速液体クロマトグラフを用いて分析し、組織中パクリタキセル量(組織1gあたりのパクリタキセル量)を定量した。さらに、薬剤溶出バルーンにコートされたパクリタキセル量と、バルーン上に残存したパクリタキセル量とから、バルーン上のパクリタキセルの残存率(バルーン上PTX残存率)を算出した。
表5に示す結果を得た。表5中、実施例/比較例の列の8は実施例であり、C5およびC6は比較例である。また、表5中、「組織中PTX量」は血管組織1g中に含まれるパクリタキセル量(単位:μg/g組織)を、「組織へのPTX移行率」はバルーン上から血管組織中に移行したパクリタキセルの割合(単位:質量%)を、「バルーン上PTX残存率」はバルーン上に残存したパクリタキセルの割合(単位:質量%)を、それぞれ表す。
実施例9および10の薬剤溶出バルーンについて、以下の手順により、ウサギ腹大動脈におけるバルーン拡張1時間後および24時間後の組織中パクリタキセル量を求め、薬剤滞留性を評価した。
(1)薬剤溶出バルーンをラッピング後、ステントをプレマウントした。ステントプレマウント後の薬剤溶出バルーンを用いた。
(2)ウサギにガイドワイヤーをX線透視下で腹大動脈まで挿入した後、ガイドワイヤーの位置を保持しながら、ガイディングカテーテルを抜去した。次いで、ステントプレマウントした薬剤溶出バルーン(拡張時サイズ直径3.0×長さ20mm(拡張部))を、ガイドワイヤーに沿わせながら、該腹大動脈まで移行させた。
(3)7atmで1分間バルーンを拡張させた。その後、直ちに、バルーンを抜去した。
(4)バルーン拡張1時間後および24時間後に、血管(分枝より約3.5cmの範囲)を採取した。
(5)採取した血管にメタノールを添加し、ホモジネイトして、組織ホモジネイトとした。
(6)組織ホモジネイトを、高速液体クロマトグラフを用いて分析し、バルーン拡張1時間後および24時間後の組織中パクリタキセル量(組織1gあたりのパクリタキセル量)を定量した。さらに、薬剤溶出バルーンにコートされたパクリタキセル量と、バルーン拡張1時間後および24時間後の組織中パクリタキセル量とから、バルーン拡張1時間後および24時間後のパクリタキセルの組織への移行率(組織へのPTX移行率)を算出し、バルーン上に残存したパクリタキセル量から残存率(バルーン上PTX残存率)を算出した。
表6に示す結果を得た。表6中、実施例の列の9、10は実施例である。また、表6中、「組織中PTX量」は血管組織1g中に含まれるパクリタキセル量(単位:μg/g組織)を、「組織へのPTX移行率」はバルーン上から血管組織中に移行したパクリタキセルの割合(単位:質量%)を、「バルーン上PTX残存率」はバルーン上に残存したパクリタキセルの割合(単位:質量%)を、それぞれ表す。さらに、「組織中PTX量」および「組織へのPTX移行率」の列の「1H」および「24H」は、それぞれ血管内拡張1時間後および24時間後を意味する。
実施例9~11および比較例C6の薬剤溶出バルーンならびに比較例C7の薬剤無塗布バルーンについて、ブタ冠動脈における有効性評価を、以下の手順により行った。
(1)ガイドワイヤーとともにガイディングカテーテルを8Fr.シースより挿入し、エックス線透視下でブタの左および右冠動脈開口部まで誘導した。
(2)各冠動脈の造影を行い(冠動脈:左冠動脈前下行枝(LAD)、右冠動脈(RCA)、左冠動脈回旋枝(LCX))、造影で得られた冠動脈の血管経をQCAソフトにより測定した。
(3)血管径に対しステントの径が1.2倍、かつ薬剤溶出バルーンの径が1.3倍になる部位を選択し、ステント留置以降の作業を実施した。
(4)選択した冠動脈内でステント(ステント径3mm×長さ15mm) を1.2倍になるように30秒間拡張した後、ステント留置用バルーンカテーテルを抜去した。ステント留置部位にて薬剤溶出バルーン(バルーン径:3mm×長さ20mm)を血管径に対し1.3倍になるように1分間拡張させた後、カテーテルを抜去した。
(5)薬剤溶出バルーン拡張終了後、ガイディングカテーテルおよびシースを抜去し、頚動脈の中枢側を結紮した後、頚部の創口は剥離した筋肉間を手術用縫合糸で縫合し、皮膚縫合用ステープラーで皮膚を縫合した。
(6)バルーン拡張28日後に、剖検を実施した。剖検時には冠動脈造影検査を行い、ステント留置部位の開存性(狭窄率)を確認し、血管径を測定した。バルーン拡張直後の平均血管径と28日後の平均血管径より狭窄率(%)を算出した。
表7に示す結果を得た。表7中、実施例/比較例の列の9~11は実施例であり、C6およびC7は比較例である。
これに対して、実施例9~11の本発明の薬剤放出バルーンで処置した血管の狭窄率は、それぞれ、16.1%、6.5%、7.3%であった。
以上のことから、アミノ酸側鎖の疎水性指標が0以下であるアミノ酸エステル塩酸塩(およびグリセリン)とパクリタキセルとを含む薬剤コーティング層は、良好な狭窄抑制効果を示すことが明らかとなった。
2 ガイディングカテーテル
3 バルーンカテーテル
4 バルーン
Claims (13)
- 水不溶性薬剤と、アミノ酸側鎖の疎水性指標が0以下であるアミノ酸のエステル化合物およびその塩からなる群から選択される少なくとも1つとを含有する、薬剤溶出性の医療機器のためのコーティング組成物。
- 前記アミノ酸がαアミノ酸である、請求項1に記載のコーティング組成物。
- 前記エステル化合物が、グリシン、セリン、アスパラギン、アスパラギン酸、グルタミン、グルタミン酸、アルギニン、トレオニン、ヒスチジン、リシン、チロシン、トリプトファンおよびこれらのアミノ酸のα位のアミノ基の水素原子の少なくとも1つが炭素数5以下のアルキル基、ベンジル基またはベンゾイル基で置換されたアミノ酸、ならびにプロリンおよびプロリンのイミノ基の水素原子が炭素数5以下のアルキル基、ベンジル基またはベンゾイル基で置換されたアミノ酸からなる群から選択される少なくとも1つのアミノ酸と、炭素数5以下の一価アルコールとのエステル化合物である、請求項1または2に記載のコーティング組成物。
- 前記エステル化合物が下記式
で表される、請求項1~3のいずれかに記載のコーティング組成物。 - 前記エステル化合物がベンジルグリシンエチルエステル、ベンジルグリシンメチルエステル、アルギニンエチルエステル、アルギニンメチルエステル、ベンゾイルアルギニンエチルエステル、ベンゾイルアルギニンメチルエステル、アスパラギン酸ジエチルエステル、アスパラギン酸メチルエステル、アスパラギン酸ジメチルエステル、グリシンエチルエステル、グリシンメチルエステル、セリンエチルエステルおよびセリンメチルエステルからなる群から選択される少なくとも1つである、請求項1~4のいずれかに記載のコーティング組成物。
- さらに低級アルコールを含有する、請求項1~5のいずれかに記載のコーティング組成物。
- 前記低級アルコールがグリセリンである、請求項6に記載のコーティング組成物。
- 前記水不溶性薬剤がパクリタキセル、ラパマイシン、ドセタキセルおよびエベロリムスからなる群から選択される少なくとも1つである、請求項1~7のいずれかに記載のコーティング組成物。
- 前記医療機器が管腔内で径方向に拡張可能な医療機器である、請求項1~8のいずれかに記載のコーティング組成物。
- 前記管腔内で径方向に拡張可能な医療機器がバルーンカテーテルまたはステントである、請求項9に記載のコーティング組成物。
- 請求項1~10のいずれかに記載のコーティング組成物により医療機器の表面の少なくとも一部に形成される薬剤コート層。
- 請求項1~10のいずれかに記載のコーティング組成物で外面がコートされた薬剤溶出性の医療機器。
- 請求項12に記載の医療機器を管腔内に送達するステップと、
前記管腔内で前記医療機器を径方向に拡張させるステップと、
前記医療機器の表面の少なくとも一部に形成された薬剤コート層から薬剤を溶出させ、前記管腔に薬剤を作用させるステップと
を備える治療方法。
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US (2) | US9603974B2 (ja) |
EP (2) | EP2813250B1 (ja) |
JP (3) | JP6042876B2 (ja) |
CN (2) | CN104203297B (ja) |
AU (1) | AU2013238160B2 (ja) |
CA (1) | CA2867429C (ja) |
ES (1) | ES2636251T3 (ja) |
HK (1) | HK1205002A1 (ja) |
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WO (1) | WO2013146377A1 (ja) |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2013146376A1 (ja) * | 2012-03-27 | 2015-12-10 | テルモ株式会社 | コーティング組成物および医療機器 |
WO2018169052A1 (ja) * | 2017-03-16 | 2018-09-20 | テルモ株式会社 | バルーンカテーテルの製造方法 |
JPWO2019059347A1 (ja) * | 2017-09-21 | 2020-09-03 | テルモ株式会社 | 薬剤コート層およびその形成方法 |
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US11529331B2 (en) | 2020-05-29 | 2022-12-20 | Boulder Bioscience Llc | Methods for improved endovascular thrombectomy using 3,3′-diindolylmethane |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008502376A (ja) * | 2004-05-25 | 2008-01-31 | バイオインターアクションズ リミテッド | 吸収性生物適合性材料 |
JP2008509722A (ja) * | 2004-08-13 | 2008-04-03 | ラトガース,ザ ステート ユニバーシティ | 放射線不透過性の高分子ステント |
JP2010509991A (ja) * | 2006-11-20 | 2010-04-02 | ルトニックス・インコーポレ−テッド | 医療装置のための薬物放出コーティング |
JP2010516307A (ja) * | 2007-01-21 | 2010-05-20 | ヘモテック アーゲー | 身体管腔の狭窄の治療および切迫再狭窄の予防のための医療器具 |
JP2010540159A (ja) * | 2007-10-19 | 2010-12-24 | ルトニックス・インコーポレ−テッド | 医療装置のための薬物放出コーティング |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5102402A (en) | 1991-01-04 | 1992-04-07 | Medtronic, Inc. | Releasable coatings on balloon catheters |
JPH04270227A (ja) * | 1991-02-26 | 1992-09-25 | Yamanouchi Pharmaceut Co Ltd | ヒト組織プラスミノーゲン活性化因子含有組成物 |
US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
JPH0827002A (ja) * | 1994-07-20 | 1996-01-30 | Sankyo Co Ltd | 塩基性薬物の角質層への貯留を解消する製剤 |
US6774278B1 (en) | 1995-06-07 | 2004-08-10 | Cook Incorporated | Coated implantable medical device |
US6306166B1 (en) | 1997-08-13 | 2001-10-23 | Scimed Life Systems, Inc. | Loading and release of water-insoluble drugs |
US7803149B2 (en) | 2002-07-12 | 2010-09-28 | Cook Incorporated | Coated medical device |
DE10115740A1 (de) | 2001-03-26 | 2002-10-02 | Ulrich Speck | Zubereitung für die Restenoseprophylaxe |
DE10244847A1 (de) | 2002-09-20 | 2004-04-01 | Ulrich Prof. Dr. Speck | Medizinische Vorrichtung zur Arzneimittelabgabe |
US8430055B2 (en) | 2008-08-29 | 2013-04-30 | Lutonix, Inc. | Methods and apparatuses for coating balloon catheters |
US8414526B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising oils, fatty acids, and/or lipids |
US8998846B2 (en) | 2006-11-20 | 2015-04-07 | Lutonix, Inc. | Drug releasing coatings for balloon catheters |
US8414910B2 (en) * | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US8425459B2 (en) | 2006-11-20 | 2013-04-23 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent |
US8414525B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US9192697B2 (en) | 2007-07-03 | 2015-11-24 | Hemoteq Ag | Balloon catheter for treating stenosis of body passages and for preventing threatening restenosis |
DE102007036685A1 (de) | 2007-08-03 | 2009-02-05 | Innora Gmbh | Verbesserte arzneimittelbeschichtete Medizinprodukte deren Herstellung und Verwendung |
IT1394522B1 (it) * | 2009-01-09 | 2012-07-05 | Invatec Technology Ct Gmbh | Dispositivo medicale con rilascio di farmaco |
-
2013
- 2013-03-15 JP JP2014507711A patent/JP6042876B2/ja active Active
- 2013-03-15 ES ES13768084.9T patent/ES2636251T3/es active Active
- 2013-03-15 WO PCT/JP2013/057495 patent/WO2013146377A1/ja active Application Filing
- 2013-03-15 RU RU2014143070/15A patent/RU2605291C2/ru active
- 2013-03-15 AU AU2013238160A patent/AU2013238160B2/en active Active
- 2013-03-15 EP EP13768084.9A patent/EP2813250B1/en active Active
- 2013-03-15 CA CA2867429A patent/CA2867429C/en active Active
- 2013-03-15 CN CN201380015727.0A patent/CN104203297B/zh active Active
- 2013-03-15 CN CN201610141379.7A patent/CN105797218B/zh active Active
- 2013-03-15 EP EP17156660.7A patent/EP3219335B1/en active Active
-
2014
- 2014-09-25 US US14/496,058 patent/US9603974B2/en active Active
-
2015
- 2015-06-08 HK HK15105449.9A patent/HK1205002A1/xx unknown
-
2016
- 2016-05-24 JP JP2016103250A patent/JP6499120B2/ja active Active
-
2017
- 2017-02-01 US US15/421,645 patent/US10045960B2/en active Active
-
2018
- 2018-02-07 JP JP2018020129A patent/JP6584545B2/ja active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008502376A (ja) * | 2004-05-25 | 2008-01-31 | バイオインターアクションズ リミテッド | 吸収性生物適合性材料 |
JP2008509722A (ja) * | 2004-08-13 | 2008-04-03 | ラトガース,ザ ステート ユニバーシティ | 放射線不透過性の高分子ステント |
JP2010509991A (ja) * | 2006-11-20 | 2010-04-02 | ルトニックス・インコーポレ−テッド | 医療装置のための薬物放出コーティング |
JP2010516307A (ja) * | 2007-01-21 | 2010-05-20 | ヘモテック アーゲー | 身体管腔の狭窄の治療および切迫再狭窄の予防のための医療器具 |
JP2010540159A (ja) * | 2007-10-19 | 2010-12-24 | ルトニックス・インコーポレ−テッド | 医療装置のための薬物放出コーティング |
Non-Patent Citations (7)
Title |
---|
FARHAT M.Y. ET AL.: "Endothelium-mediated effects of N-substituted arginines on the isolated perfused rat kidney", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 255, no. 2, 1990, pages 473 - 477, XP008174302 * |
FARHAT M.Y. ET AL.: "Vasodilatory property of N-alpha benzoyl-L-arginine ethyl ester in the rat isolated pulmonary artery and perfused lung", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 254, no. 1, 1990, pages 289 - 293, XP008174301 * |
KIM B.S. ET AL.: "MAD (multiagent delivery) nanolayer: delivering multiple therapeutics from hierarchically assembled surface coatings.", LANGMUIR, vol. 25, no. 24, 2009, pages 14086 - 14092, XP055159426 * |
KYTE; DOOLITTLE, J. MOL. BIOL., vol. 157, 1982, pages 105 - 132 |
See also references of EP2813250A4 |
THOMAS G. ET AL.: "Effect of N alpha-benzoyl-L- arginine ethyl ester on coronary perfusion pressure in isolated guinea pig heart", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 178, no. 2, 1990, pages 251 - 254, XP025545111 * |
THOMAS G.: "Vasodilatory properties of mono-L- arginine-containing compounds", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 154, no. 1, 1988, pages 332 - 338, XP024837339 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2013146376A1 (ja) * | 2012-03-27 | 2015-12-10 | テルモ株式会社 | コーティング組成物および医療機器 |
WO2018169052A1 (ja) * | 2017-03-16 | 2018-09-20 | テルモ株式会社 | バルーンカテーテルの製造方法 |
JPWO2018169052A1 (ja) * | 2017-03-16 | 2020-01-16 | テルモ株式会社 | バルーンカテーテルの製造方法 |
JP7073337B2 (ja) | 2017-03-16 | 2022-05-23 | テルモ株式会社 | バルーンカテーテルの製造方法 |
JPWO2019059347A1 (ja) * | 2017-09-21 | 2020-09-03 | テルモ株式会社 | 薬剤コート層およびその形成方法 |
JP7246311B2 (ja) | 2017-09-21 | 2023-03-27 | テルモ株式会社 | 薬剤コート層およびその形成方法 |
Also Published As
Publication number | Publication date |
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CA2867429A1 (en) | 2013-10-03 |
JP2016198521A (ja) | 2016-12-01 |
JPWO2013146377A1 (ja) | 2015-12-10 |
JP2018114288A (ja) | 2018-07-26 |
EP3219335B1 (en) | 2018-12-19 |
JP6584545B2 (ja) | 2019-10-02 |
CN105797218B (zh) | 2019-06-21 |
RU2605291C2 (ru) | 2016-12-20 |
US9603974B2 (en) | 2017-03-28 |
US20150056265A1 (en) | 2015-02-26 |
HK1205002A1 (en) | 2015-12-11 |
EP2813250A1 (en) | 2014-12-17 |
JP6499120B2 (ja) | 2019-04-10 |
US20170143663A1 (en) | 2017-05-25 |
CN105797218A (zh) | 2016-07-27 |
EP2813250A4 (en) | 2015-08-12 |
US10045960B2 (en) | 2018-08-14 |
CA2867429C (en) | 2018-11-27 |
ES2636251T3 (es) | 2017-10-05 |
AU2013238160A1 (en) | 2014-08-21 |
CN104203297A (zh) | 2014-12-10 |
RU2014143070A (ru) | 2016-05-20 |
EP2813250B1 (en) | 2017-05-03 |
JP6042876B2 (ja) | 2016-12-14 |
AU2013238160B2 (en) | 2016-03-31 |
CN104203297B (zh) | 2016-04-06 |
EP3219335A1 (en) | 2017-09-20 |
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