JP6880136B2 - Drug release coating for medical devices - Google Patents

Description

Reference of related applications
[001] This application is a partial continuation application of Application No. 12 / 121,986, May 16, 2008, which is a partial continuation application of the following: Application No. 11 / 942,452, November 2007 Filed on May 19, this claims priority based on US Provisional Application No. 60 / 860,084, filed November 20, 2006, US Provisional Application No. 60 / 880,742, filed January 17, 2007, US Provisional Application No. 60 / 897,427, filed January 25, 2007, US Provisional Application No. 60 / 903,529, filed February 26, 2007, US Provisional Application No. 60 / 904,473, filed March 2, 2007, US Provisional Application No. 60 / 926,850, filed April 30, 2007, US Provisional Application No. 60 / 981,380, filed October 19, 2007, and US Provisional Application No. 60 / 981,384, filed October 19, 2007; All of these disclosures are incorporated herein by reference.

Field of invention
[002] Aspects of the invention are coated medical devices, especially coated balloon catheters, as well as stenosis and particularly stenosis for treating diseases for rapid delivery of therapeutic agents to specific tissues or body cavities. With respect to their use to reduce late lumen loss of the body cavity. Aspects of the invention also include methods of making these medical devices, coatings applied to these medical devices, solutions for making these coatings, and arteries in particular with these coated medical devices. It relates to a method for treating a body cavity such as the vasculature.

[003] It has become increasingly common to treat a variety of pathological conditions by introducing medical devices into the vasculature or other body cavities of human or animal patients, such as the esophagus, trachea, colon, bile ducts or urinary tract. I came. For example, medical devices used in the treatment of vascular disease include stents, catheters, balloon catheters, guide wires, cannulas and the like. While these medical devices appear to be effective at first, their benefits are often compromised by the development of complications such as delayed thrombosis after such treatment or the recurrence of disease such as stenosis (restenosis). ..

[004] Restenosis, for example, involves a physiological response to angioplasty-induced vascular injury. Over time, de-endotheliaziation and damage to smooth muscle cells result in thrombosis, leukocyte and macrophage infiltration, smooth muscle cell proliferation / migration, fibrosis and extracellular matrix deposition. Inflammation plays a central role in linking early vascular injury to the end result of neointimal hyperplasia and luminal injury. In balloon-injured arteries, leukocyte recruitment is limited to early neutrophil infiltration, whereas in stented arteries, initial neutrophil recruitment is followed by persistent macrophage accumulation. Widespread use of coronary stents results in stronger persistent inflammatory conditions due to chronic irritation from implanted foreign bodies, and in the case of drug-eluting stents (DES), the biocompatibility of polymer coatings. Due to inadequacy, the vascular response to injury was altered.

[005] Over the last few years, a number of local drug delivery systems have been developed to treat and / or prevent restenosis after balloon angioplasty or stent placement. Examples include topical drug delivery catheters, delivery balloon catheters, and polymer-drug coated stents. Since many diseases affect specific local parts or organs in the body, it is advantageous to preferentially treat only the affected area. This avoids high systemic drug levels that can cause adverse side effects and concentrates the therapeutic agent in the local area where they are needed. By treating only the affected tissue, the total amount of drug used can be significantly reduced. In addition, topical drug delivery allows the use of certain effective therapeutic agents that were previously considered too toxic or non-selective for systemic use.

[006] An example of a local delivery system is a drug-eluting stent (DES). The stent is coated with a drug-impregnated polymer. When the stent is inserted into a blood vessel, the polymer breaks down and the drug is gradually released. Sustained drug release over weeks or months has been reported as one of the major benefits of DES use. However, sustained release may be advantageous when placing foreign bodies such as stents, which are responsible for chronic irritation and inflammation, and if foreign bodies are not implanted, inflammation and cell proliferation after acute injury. It is advantageous to deliver the drug rapidly to the vascular tissue during the procedure to prevent the disease. Therefore, a significant drawback of DES, or any other implantable medical device designed for sustained release of a drug, is the inability to rapidly release the drug into the blood vessel.

[007] Furthermore, although drug-eluting stents were initially shown to be effective techniques for reducing and preventing restenosis, their effectiveness and safety have recently been questioned. Late-onset thrombosis, a fatal complication of this approach, has emerged as a major concern. Drug-eluting stents cause substantial arterial healing disorders characterized by lack of complete endothelial remodeling and survival of fibrin compared to bare metal stents (BMS), which causes delayed DES thrombosis. Is interpreted as the source of. There is also concern that polymer matrices embedding antiproliferative agents on stents may exacerbate inflammation and thrombosis because the polymers used are not sufficiently biocompatible. These polymer systems are designed for long-lasting drug delivery over days, months or years rather than seconds or minutes. These polymer-drug coatings on medical devices do not release the polymer, which remains on the medical device even after the drug has been released. Even with biodegradable polymers, the polymer and drug are not released at the same time. Rapid drug release from these polymeric systems intended by aspects of the invention is not possible. Therefore, the combination of therapeutic agents and polymers in the coating of medical devices can have significant drawbacks.

[008] Another significant limitation of DES is the non-uniform distribution of water-insoluble drugs in the polymer matrix of the coating. In addition, the drug and polymer are concentrated on the strut of the stent, but not in the voids between the strut. This non-uniform drug distribution causes non-uniform drug release into the vascular wall of the tissue. This can cause tissue damage and thrombosis in areas exposed to excess drug, as well as hyperplasia and restenosis in poorly treated areas. Therefore, the solubility of the drug in the coating of the medical device is improved by increasing the compatibility of the drug with the carrier in the coating, such as the polymer matrix, thereby eliminating the drug crystal particles in the polymer matrix or other coatings. However, or by reducing its size, it is necessary to improve the uniformity of drug delivery to the target tissue by forming a uniform drug distribution in the drug coating on the medical device.

[009] Yet another significant limitation of DES is that the relatively small surface area of the stent can only be loaded with a limited amount of active agent.
[010] Local delivery systems that are not stented, such as balloon catheters, have also been effective in the treatment and prevention of restenosis. The balloon is coated with the active drug, and when the blood vessel is dilated, the balloon is pressed against the blood vessel wall to deliver the active drug. Therefore, when using a balloon catheter, it is advantageous that the drug in the coating is delivered rapidly and absorbed by the vascular tissue. Any coating component that inhibits rapid release, such as lipids or polymers, or encapsulated particles, is of course disadvantageous for the intended use of the balloon catheter, i.e., to inflate for a very short period of time and then withdraw from the body.

[011] Hydrophilic drugs, such as heparin, have been reported to be delivered by balloon catheters coated with polymeric hydrogels. However, polymer hydrogel coatings cannot effectively deliver water-insoluble drugs (eg, paclitaxel and rapamycin); they cannot be mixed with hydrogel coatings. In addition, as the drug is released, the crosslinked polymer hydrogel remains on the balloon after the drug is released. The iodine contrast agent iopromide has been used to coat balloon catheters with paclitaxel and has been somewhat successful in treating restenosis. Contrast media have been reported to improve paclitaxel adhesion to the balloon surface. However, iodinated contrast media have some well-known drawbacks. When used in diagnostic operations, they can have a complication rate of 5-30%. These agents carry the risk of bradycardia, ventricular arrhythmias, hypotension, heart block, sinus arrest, sinus tachycardia, and fibrillation. Iodine contrast agents can also induce renal failure, and as a result, significant efforts have been made to remove these contrast agents from the vascular system after diagnostic manipulation.

[012] In addition, the Food and Drug Administration (FDA) reported in 2006 that it was a serious condition known as Nephrogenic Systemic Fibrosis or Nephrogenic Fibrosing Dermopathy for contrast agents. A second public health advisory was issued for late-onset adverse reactions. Due to the wide range of adverse events associated with intravascular delivery of contrast media, there is a need for improved medical devices with coatings that do not inherently give patients additional contrast media to deliver the desired therapeutic agent. There is.

[013] Iodinated X-ray contrast agents are large hydrophilic spherical molecules. They are characterized by extracellular distribution and rapid glomerular filtration and renal excretion. Because they are large polar hydrophilic molecules, they cannot enter the cells of the vasculature through the membrane lipid bilayer. Therefore, they do not have the optimal ability to carry hydrophobic drugs such as paclitaxel into the cell, and the percentage of paclitaxel reported to be taken up by vascular tissue after placement of these devices is only 5-20%. In addition, paclitaxel and iopromide are not well compatible or miscible, and the coating is poorly integrated and uniform. Particles are easily peeled off and lost from the coating during handling. These drawbacks have a detrimental effect on the amount and uniformity of the drug delivered to the target tissue. Therefore, an improved coating, a coating that not only avoids unnecessary contrast administration, but also maintains integrity during handling, delivers the drug more effectively and uniformly, and facilitates its absorption by the tissue. Is required.

[014] Alternatively, it has been reported to coat a balloon catheter with a hydrophobic therapeutic agent mixed with oil or lipid or encapsulated in particles or polymers such as liposomes. All of these drug delivery formulations have significant drawbacks. Unlike hydrophilic contrast agents, oils and lipids mix well with water-insoluble drugs such as paclitaxel or rapamycin, but the particle size of the oil used to solubilize the therapeutic agent is relatively unstable, hundreds of nanometers in diameter. It covers a wide range of particle size distributions from meters to a few microns.

[015] Typical micelles have a low loading capacity. Another drawback of oily liposome formulations is
Drug absorption depends on the rate and degree of lipolysis. Lipolysis of oily triglycerides is difficult, depends on many factors, and the triglycerides must be digested to release the drug in order to be absorbed by the affected tissue. Liposomes and micelles cannot release hydrophobic drugs efficiently, thus carrying them away before they can be absorbed by the tissue, so the amount of hydrophobic drug delivered to the tissue by these agents will be low. Therefore, oils and lipids have no effect on promoting drug uptake of tissues quickly and efficiently during very short tool placement times, and there are no reports showing that these types of coatings are effective. The ratio of drug to lipid in these formulations is generally 0.2-0.3, as the drug is encapsulated in particles, micelles or liposomes, which requires significantly higher lipid concentrations than the drug. These techniques involve first forming drug / lipid particles and then coating the medical device with these prepared particles. There are several reports showing that drug release from these oil / lipid formulations occurs in the range of days to weeks or months. This property is not desirable in situations where drug release is in the range of seconds to minutes. Therefore, approaches to oil / lipid formulations need to be significantly improved to be useful in such situations.

[016] Drugs encapsulated in polymer particles may take longer to diffuse from the coating (reported range is months to years) and may be even more difficult to penetrate rapidly into the target tissue. .. Microspheres made of a polymeric material, such as polyester, cannot release the drug until the polymeric material has decomposed when used to enclose a water-insoluble drug. Therefore, while these polymer microspheres are useful for sustained long-term release of the drug, they cannot release the drug rapidly to promote tissue uptake.

[017] Combining drugs and medical devices is a complex technical area. It maintains the drug's adherence to the medical device until it reaches the target site, followed by delivery of the drug to the target tissue with the desired release and absorption kinetics, along with conventional formulation challenges such as oral or injectable medications. With the challenge of doing more. The drug coating of a medical device must also have the property that it will not be destroyed when the medical device, such as a balloon catheter or stent, expands and contracts. In addition, the coating must not compromise the rupture pressure of the balloon and its functional performance such as compliance or radial strength of the self-inflating or balloon inflatable stent. The coating thickness must also be kept to a minimum, as thick coatings increase the contours of medical devices and reduce tracking and delivery capabilities. These coatings generally contain very little liquid chemical compounds commonly used to stabilize drugs. Therefore, formulations that are effective for pills or injections may not work at all for coating medical devices. If the drug is released too easily from the medical device, it can be lost during delivery before the medical device can be placed at the target site, or the drug is explosively released from the medical device in the early stages of swelling and into the body cavity. May be washed away before pressure contact with target tissue on the wall. If the drug adheres too tightly, the medical device may be withdrawn before the drug is released and absorbed by the tissue of the target tissue.

[018] Therefore, to treat or prevent vascular and non-vascular diseases such as restenosis, therapeutic agents, drugs or bioactive substances are rapidly placed into a confined tissue area during or after a medical procedure. There is still a need to develop highly specialized coatings that can be delivered directly. Medical devices release the therapeutic agent quickly, effectively and efficiently at the desired target location, where the therapeutic agent rapidly penetrates the target tissue to treat the disease, eg, reduce stenosis, restenosis and slowing of the lumen. Idiopathic loss of lumen should be prevented.

[019] In addition, therapeutic agents have different structures and properties, and therefore different formulations are required to achieve the desired coating properties and optimal therapeutic benefit. Therapeutic agents react differently with different drug carriers, and the reaction between the drug and the additive can inactivate the therapeutic agent or produce potentially toxic degradation products. This is further complicated by the large surface area of drug-coated medical devices and by exposure to heat, moisture and oxidative conditions during sterilization. These are especially problematic if the therapeutic agent is sensitive to water or susceptible to hydrolysis or oxidation. Paractaxels can be hydrolyzed and react with many compound functional groups. Rapamycin and its derivatives are easily hydrolyzed and oxidized. Therefore, an object of a particular aspect of the invention is a medical device coating containing an additive and a therapeutic agent, which is not involved in the degradation of a therapeutic agent, such as rapamycin and a derivative thereof, or the sterilization and use of the medical device. It is to protect the therapeutic agent from oxidation and hydrolysis during pre-storage, while providing a coating that is still capable of delivering and penetrating the therapeutic dose of the drug into the target tissue. Aspects of the invention relate to compositions and methods of making coated medical devices that minimize oxidative and / or hydrolysis degradation of therapeutic agents such as rapamycin and derivatives thereof. The coating of aspects of the invention comprises a therapeutic agent and at least one additive, the therapeutic agent in the coating layer such that the degradation of the therapeutic agent is minimized based on the unique properties of each therapeutic agent. Combined with to provide safe and effective drug coated medical devices.

[020] We present the outer surface of medical devices, especially balloon catheters or stents.
For example, we have found that coating with a therapeutic agent and a layer containing an additive having both hydrophilic and drug-affinity moieties is useful in solving the problems associated with the coatings mentioned above. The drug-affinity moiety is a hydrophobic moiety and / or has an affinity for the therapeutic agent by hydrogen bonding and / or van der Waals interaction. Surprisingly, we found that at least one additive, including an affinity moiety and a drug affinity moiety according to aspects of the invention, is a medical device in combination with a therapeutic agent, without the use of oils and lipids. It has been found that an effective drug delivery coating is formed on top, which avoids the lipid degradation dependence and other drawbacks of common oil-based coating formulations. In addition, the additives according to aspects of the invention facilitate rapid drug elution and excellent drug permeation into the affected tissue. Therefore, coating according to aspects of the invention improves the rate and / or degree of absorption of the hydrophobic therapeutic agent in the affected tissue of the vasculature and other body cavities. In aspects of the invention, the coated medical device delivers the therapeutic agent to the tissue during a very short placement period of less than 2 minutes, reducing body cavity stenosis and delayed lumen loss.

[021] In one embodiment, the invention is a medical device for delivering a therapeutic agent to a tissue.
The present invention relates to a medical device including a layer covering the outer surface of the medical device. This medical device includes balloon catheters, perfusion balloon catheters, and infusion catheters, such as distal perforated drug infusion tubes, perforated balloons, spaced double balloons, perforated balloons, and weeping balloons. ), Cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, debulking catheters, stents, filters, stent grafts, coated stents, patches, wires, and One of the valves is included. In addition, tissues include one of the coronary, peripheral, cerebral, esophageal, respiratory, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract.

[022] In one aspect of a medical device, the coating layer overlying the surface of the medical device comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug affinity moiety, in which the drug affinity. The moiety is at least one of a hydrophobic moiety, an affinity for the therapeutic agent due to hydrogen bonding, and an affinity for the therapeutic agent due to van der Waals interaction, wherein the additive is water-soluble. Being sex, the additive is at least one of a surfactant and a chemical compound, wherein the chemical compound has a molecular weight of 80 to 750.

[023] In one aspect of a medical device, the coating layer covering the surface of the medical device is a therapeutic agent.
It contains an antioxidant and an additive, in which the additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety is a hydrophobic moiety, a moiety having an affinity for a therapeutic agent by hydrogen bonding. , And at least one of the moieties that have an affinity for the therapeutic agent by van der Waals interaction, where the additive is water soluble, in which case the additive is of a surfactant and a chemical compound. The chemical compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, the chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups is selected from: aminoalcohols, hydroxylcarboxylic acids, esters, amides, ethers. Kinds, acid anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitans, glycerol, polyalcohols, phosphates, sulfates, organic acids, Esters, salts, vitamins, soluble povidone, soluble polyvinylpyrrolidone with a molecular weight of less than 4000, Kollidon 12 PF, Kollidon 17 PF, urea, biuret, acetamide, lactic acid amide, amino acid amide, acetaminophen, uric acid, polyurea, Urethane, urea derivative, niacinamide, N-methylacetamide, N, N-dimethylacetamide, sodium sulfacetamide, versetamide (versetamide), diethanolamide laurate, diethanolamide laurate myristate, N, N-bis (2) -Hydroxyethyl stealamide), cocamide MEA, cocamide DEA, arginine, bis (2-ethylhexyl) phthalate, di-n-hexyl phthalate, diethyl phthalate, bis adipate (2-ethylhexyl), dimethyl adipate, Dioctyl adipate, dibutyl sebacate, dibutyl maleate, triethyl citrate, acetyltriethyl citrate, trioctyl citrate, trihexyl citrate, butyryl trihexyl citrate, trimethyl citrate, acetic acid and anhydride, benzoic acid and anhydride, Diethylenetriamine pentaacetate dianhydride, ethylenediaminetetraacetate dianhydride, maleic acid and anhydride, succinic acid and anhydride, diglycolic acid anhydride, glutaric anhydride, ascorbic acid, citric acid, tartrate acid, lactic acid, oxalic acid, aspartic acid, nicotine Acids, 2-pyrrolidone-5-carboxylic acids, aleuritic acid, shellolic acid, combinations of amino alcohols and organic acids, as well as their substituted molecules.

[024] In one aspect of a medical device, the coating layer covering the surface of the medical device is a therapeutic agent.
It contains an antioxidant and an additive, in which the additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety is a hydrophobic moiety, a moiety having an affinity for a therapeutic agent by hydrogen bonding. , And at least one of the moieties that have an affinity for the therapeutic agent by van der Waals interaction, where the additive is water soluble, in which case the additive is of a surfactant and a chemical compound. The chemical compound has a molecular weight of 20 to 750. In other embodiments, the layer covering the outer surface of the medical device consists essentially of therapeutic agents, antioxidants and additives.

[025] In one embodiment, the antioxidant is at least one of the following: oligomeric or polymeric proanthocyanidins, polyphenols, polyphosphates, polyazomethine, high sulfate agar oligomers, chito-oligosaccharides, poly. Functional oligomeric thioethers containing sterically hindered phenols, hindered phenols, p-phenylenediamine, trimethyldihydroquinolones, and alkylated diphenylamines, hindered phenols, t -Butyl, arylamines, phosphites, hydroxylamines, benzofuranones, p-phenylenediamine, diphenylamine, N, N'di-substituted p-phenylenediamines, butylated hydroxytoluene ("BHT"), butylated hydroxy Anisol (“BHA”), L-ascorbate (vitamin C), vitamin E, herb rosemary, sage extract, glutathione, resverator, ethoxyquin, rosmanol, isorosmanol, rosmaridiphenol ), Butyl propyl acid, chlorogenic acid, coffee acid, p-coumeric acid, p-hydroxybenzoic acid, astaxanthin, ferulic acid, dehydrozingerone, chlorogenic acid, ellagic acid ( ellagic acid), propylparaben, synapic acid, daidzin, glycitin, genistine, daidzein, glycitein, genistein, isoflavones, tert-butylhydroquinone, di (stearyl) pentaerythritol diphosphite, tris (2, 4-Di-tert-butylphenyl) phosphite, dilauryl thiodipropionate, bis (2,4-di-tert-butylphenyl) pentaerythritol diphosphite, octadecyl-3,5, di-tert-butyl-4 -Hydroxycinnamate, tetrakis-methylene-3- (3', 5'-di-tert-butyl-4-hydroxyphenyl) propionate methane 2,5-di-tert-butylhydroquinone, ionol, pyrogallol, retinol, octadecyl -3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate, glutathione, lipoic acid, melatonin, tocopherols, tocotrienols, thiols, beta-carotene, retinoic acid, cryptoxanthin, 2,6 -Di-tert-butylphenol, propyl gallate, catechin, catechin gallate, quercetin, and derivatives thereof.

[026] In another aspect of the medical device, the coating layer covering the outer surface of the medical device comprises a therapeutic agent, an antioxidant and an additive, the additive being selected from: p-isononylphenoxypolyglycidol. , PEG Laurate, Tween 20, Tween 21, Tween 40, Tween 60, Tween 61, Tween 80, Tween 81, Tween 85, PEG Oleate, PEG Sterate, PEG-15 12-Hydroxystearate (Solutol HS 15), Cremoph EL and ELP, Cremophor RH40, Polyester-PEG Block Copolymer, PLLA-PEG, PEG-PLLA-PEG, PEG-PPG, PEG-PPG-PEG, Polyethylene Glycol Graft Copolymer, Soluprus, Polyvinyl Caprolactam-Polyvinyl Acetate-Polyethylene Glycol Graft Copolymer, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl millistate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 millistate, polyglyceryl -6 Palmitate, Polyglyceryl-10 laurate, Polyglyceryl-10 oleate, Polyglyceryl-10 millistate, Polyglyceryl-10 Palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether , PEG Lauryl Ether, Laneth-5, Laneth-10, Laneth-15, Laneth-20, Laneth-25, Laneth-40), Laureth-5, laureth-10, Laureth-15, laureth-20, Laureth-25 , Laureth-40, Oleth-2, Oleth-5, Oleth-10, Oleth-12, Oleth-16, Oleth-20, and Oleth-25, Steareth-2, Steareth-7, Steareth-8, Steareth-10, Steareth-16, Steareth-20, Steareth-25, Steareth-8 0, Ceteth-5, Ceteth-10, Ceteth-15, Ceteth-20, Ceteth-25, Ceteth-30, Ceteth-40, PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij 30), Sodium lauryl sulfate, sodium dodecyl sulfate, sodium lauryl ether sulfate, sodium cetostearyl sulfate, sodium cetearyl sulfate, sodium tetradecyl sulfate, sulfated castor oil, sodium cholesteryl sulfate, sodium tetradecyl sulfate, sodium myristyl sulfate, sodium octyl sulfate, medium chain-branched Or non-branched alkyl sulphates, sodium doxate, sodium dioctyl sulfosuccinate, sodium lauryl sulfosulfate, sodium alkylbenzene sulfonate, sodium dodecylbenzene sulfonate, octoxinol, monoxinol, tyrosapol, sucrose monopalmitate, sucrose monolaurate, Decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyle- N-Methyl glucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β -D-glucopyranoside (n-noyl-β-D-glucopyranoside), octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine , Isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine; acetic acid anhydride, benzoic acid anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate, dianehydride ethylenediaminetetraacetate, maleic acid and anhydrides. , Succinic acid anhydride, Diglycolic acid anhydride, Glutaric acid anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; cycothiamine, dexpantenol, niacinamide, di Cotinic acid, pyridoxal 5-phosphate, ascorbic acid nicotine amide, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamins. U; albumin, immunoglobulins, caseins, hemoglobins, lysoteams, immunoglobins, a-2-macroglobulin, fibronectins, bitronectins, fibrinogens, lipases, benzalconium chloride, benzethonium chloride, docecil ( docecyl) Trialkyl ester of trimethylammonium bromide, sodium docecil sulfate, dialkylmethylbenzylammonium chloride, and sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, Diethanolamine, meglumin, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, ribbon acid Lactone, lactobionic acid, glucosamine, glutamate, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin, Methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin asbestosate, tiletamine, ketamine, Propofol, lactic acid, acetic acid, salts of any organic acid and organic amine, polyglycidol, glycerol, multiglycerols, galactitol, di (ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta ( Ethylene glycol), poly (ethylene glycol) oligomers, di (propylene glycol), tri (propylene glycol), tetra (propylene glycol), and penta (pu). Lopyrene glycol), poly (propylene glycol) oligomer, block copolymer of polyethylene glycol and polypropylene glycol, soluble povidone, soluble polyvinylpyrrolidone with a molecular weight of less than 4000, Kollidon 12 PF, Kollidon 17 PF, urea, biuret, acetamide, lactic acid amide, amino acid amide. , Acetaminophen, uric acid, polyurea, urethane, urea derivative, niacinamide, N-methylacetamide, N, N-dimethylacetamide, sulfacetamide sodium, vercetamide, laurate diethanolamide, laurate myristic acid diethanolamide, N , N-bis (2-hydroxyethyl stealamide), cocamide MEA, cocamide DEA, arginine, and derivatives and combinations thereof.

[027] In one embodiment, the coating layer covering the outer surface of the medical device comprises a therapeutic agent and one or more additives, wherein each additive comprises a hydrophilic moiety and a drug-affinity moiety, in which the drug The affinity portion is at least one of a hydrophobic portion, a portion having an affinity for a therapeutic agent due to hydrogen bonding, and a portion having an affinity for a therapeutic agent due to a van der Waals interaction, in which one type. One of the above additives is a liquid additive.

[028] In one embodiment, the coating layer covering the outer surface of the medical device comprises a therapeutic agent and at least one additive, wherein the at least one additive comprises a first additive and a second additive. , Each additive contains a hydrophilic moiety and a drug-affinity moiety, where the drug-affinity moiety is a hydrophobic moiety, an affinity for the therapeutic agent by hydrogen bonding, and a therapeutic agent by van der Waals interaction. At least one of the moieties having an affinity for, where the first additive is more compatible than the second additive.

[029] In one embodiment, the coating layer covering the outer surface of the medical device comprises a therapeutic agent and at least one additive, wherein the at least one additive comprises a first additive and a second additive. , Each additive contains a hydrophilic moiety and a drug-affinitive moiety, where the drug-affinitive moiety is a hydrophobic moiety, a moiety that has an affinity for the therapeutic agent by hydrogen binding, and van der Waals force interaction. It is at least one of the moieties having affinity for the drug, in which case the HLB value of the first additive is higher than that of the second additive.

[030] In one embodiment, the coating layer covering the outer surface of the medical device comprises a therapeutic agent and at least one additive, wherein the at least one additive comprises a first additive and a second additive. , Each additive contains a hydrophilic moiety and a drug-affinitive moiety, where the drug-affinitive moiety is a hydrophobic moiety, a moiety that has an affinity for the therapeutic agent by hydrogen binding, and a van der Waals interaction. At least one of the moieties having an affinity for, where the Log P of the first additive is lower than that of the second additive.

[031] In one embodiment, the coating layer covering the outer surface of the medical device comprises a therapeutic agent and at least one additive, wherein the at least one additive has at least one ester group. Contains chemical compounds. The products of organic acids and alcohols are examples of chemical compounds with ester groups. Chemical compounds with ester groups are often used as plasticizers for polymeric materials. Chemical compounds having at least one ester group include sebates, adipates, glutarates, and phthalates. Examples of these chemical compounds are bis (2-ethylhexyl) phthalate, di-n-hexyl phthalate, diethyl phthalate, bis (2-ethylhexyl) adipate, dimethyl adipate, dioctyl adipate, dibutyl sebacate, Dibutyl maleate, triethyl citrate, acetyltriethyl citrate, trioctyl citrate, trihexyl citrate, butyryl trihexyl citrate, and trimethyl citrate.

[032] In one embodiment, the coating layer covering the outer surface of the medical device comprises a therapeutic agent and at least one additive, wherein the at least one additive comprises at least one chemical compound having at least one amide group. Including. In certain embodiments, chemical compounds with at least one amide group are important in the coating formulation. Urea is an example of a chemical compound having at least one amide group. Other examples of chemical compounds with at least one amide group include biuret, acetamide, lactic acid amide, amino acid amide, acetaminophen, uric acid, polyurea, urethane, urea derivatives, niacinamide, N-methylacetamide, N, N. -Dimethylacetamide, Sulfacetamide Sodium, Versetamide, Lauric Acid Diethanolamide, Lauric Acid Myristic Acid Diethanolamide, N, N-Bis (2-Hydroxyethyl Stealamide), Cocamide MEA, Cocamide DEA, Arginine, and Others Includes organic acid amides and derivatives thereof. Certain chemical compounds with at least one amide group also include one or more hydroxyl, amino, carbonyl, acid or ester moieties.

[033] One of the chemical compounds having at least one amide group is soluble low molecular weight povidone. Some examples of povidone include Kollidon 12 PF, Kollidon 17 PF, Kollidon 17, Kollidon 25, and Kollidon 30. Kollidon products include polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers of various molecular weights and particle sizes of soluble and insoluble grades, and blends of polyvinyl acetate and polyvinylpyrrolidone. The family products have the names Povidone, Crosspovidone and Copovidone. Low molecular weight soluble povidones and copovidones are important additives in aspects of the invention: for example, Kollidon 12 PF, Kollidon 17 PF, and Kollidon 17. Solid povidone can maintain the integrity of the coating on medical devices. Low molecular weight povidone can be absorbed or permeated into affected tissue. The preferred molecular weight range for povidone is less than 54,000, less than 11,000, 7,000, and less than 4000. Povidones can solubilize water-insoluble therapeutic agents. Povidones and copovidones are particularly useful in aspects of the invention because of their properties (solid, low molecular weight, and tissue absorption / permeability). Povidones can be used in combination with other additives of the embodiments of the present invention. In one embodiment, povidone and a nonionic surfactant (eg, PEG-15 12-hydroxystearate (Solutol HS 15), Tween 20, Tween 80, Cremophor RH40, Cremophor EL and ELP) are paclitaxel or rapamycin or theirs. Together with analogs, it can be formulated as a coating for medical devices, such as balloon catheters.

[034] In one embodiment, the coating layer covering the outer surface of the medical device comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety comprises. At least one of a hydrophobic moiety, an affinity for a therapeutic agent due to hydrogen bonds, and an affinity for a therapeutic agent due to van der Waals interactions, where the additive is a surfactant and At least one of the chemical compounds, where the chemical compound has more than four hydroxyl groups. In one embodiment, a chemical compound having more than four hydroxyl groups has a melting point of 120 ° C. or lower, and the chemical compound is an alcohol or an ester.

[035] In one embodiment, the layer covering the outer surface of the medical device consists essentially of a therapeutic agent and an additive. In one embodiment, the layer covering the outer surface of the medical device does not contain an iodine covalently bound contrast agent. In one embodiment, the chemical compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, the chemical compounds are aminoalcohols, hydroxylcarboxylic acids, esters, acid anhydrides, hydroxylketones, hydroxyllactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitans. , Gloxy, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids, and their substituted molecules. In other embodiments, the surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, PEG omega-3 fatty acid esters, ethers, and alcohols, glycerol fatty acid esters. , Polysorbate fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters, sugar fatty acid esters, PEG sugar esters, and derivatives thereof.

[036] In another embodiment, the coating layer overlying the surface of the medical device comprises a therapeutic agent and an additive, the additive being a surfactant. In other embodiments, the surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, PEG omega-3 fatty acid esters, ethers, amides, and alcohols, glycerol fatty acids. It is selected from esters, sorbitan fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters, sugar fatty acid esters, PEG sugar esters, and derivatives thereof.

[037] In other embodiments, the additive is a chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, the chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups is aminoalcohols, hydroxylcarboxylic acids, esters, amides, ethers, acid anhydrides, hydroxylketones. , Hydroxyllactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins, sorbitans, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, It is selected from combinations of amino alcohols and organic acids, and their substituted molecules.

[038] In other embodiments, the additive has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups and has a molecular weight of 5,000 to less than 10,000, preferably less than 1000 to 5,000. More preferably less than 750-1,000, or most preferably less than 750 hydrophilic chemical compounds. The molecular weight of the additive is preferably lower than that of the delivered drug. Small molecules can diffuse rapidly and they easily release from the surface of the delivery balloon and carry the drug with them. They rapidly diffuse and separate from the drug as it binds to the tissue. However, the molecular weight of the additive should not be too low; additives with a molecular weight of less than 80 are not desirable as they are prone to evaporation and are not stable coating components. The molecular weight of the additive may be less than 80, less than 50, and less than 20 if the additive has a low molecular weight but is not volatile (eg, paste or solid) and does not easily evaporate or react. In another embodiment, the additive is a combination of a surfactant and a chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In other embodiments, the additive is a combination of an aminoalcohol and an organic acid; this combination may otherwise result in instability due to the reactivity of the acid or amine with a drug such as paclitaxel. It is advantageous because it prevents. In other embodiments, the additive is a hydroxyl ketone, a hydroxyl lactone, a hydroxyl acid, a hydroxyl ester, or a hydroxyl amide. In another embodiment, the additive is a glucono lactone or a ribbon acid lactone thereof. In yet another embodiment, the additives are meglumine / lactic acid, meglumine / gentisic acid, meglumine / acetic acid, lactobionic acid, Tween 20 / sorbitol, Tween 20 / lactobionic acid, Tween 20 / sugar or sugar derivative and N-octanoyl N-methyl. Selected from glucamine. In other embodiments, the additive is a vitamin or a derivative thereof. In other embodiments, the additive is an amino acid or a derivative thereof. In other embodiments, the additive is a protein or derivative thereof. In another embodiment, the additive is albumin. In another embodiment, the additive is soluble in an aqueous solvent and soluble in an organic solvent. In other embodiments, the additive is an organic acid or an anhydride thereof. In yet another embodiment, the additive is selected from sorbitan oleate and sorbitan fatty acid ester.

[039] In another embodiment, the coating layer overlying the surface of the medical device comprises a therapeutic agent and an additive, wherein the additive is water soluble, wherein the additive has a molecular weight from 20 to 750. It is a chemical compound.

[040] In one embodiment, the layer covering the outer surface of the medical device is oil-free, lipid- or polymer-free. In another embodiment, the layer covering the outer surface of the medical device is oil-free. In another embodiment, the layer covering the outer surface of the medical device does not contain a polymer. In another embodiment, the layer covering the outer surface of the medical device does not contain a purely hydrophobic additive. In one embodiment, the additive is not a therapeutic agent. In other embodiments, the additive is not salicylic acid or salts thereof.

[041] In another embodiment, the coating layer overlying the surface of the medical device comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug-affinitive moiety, wherein the drug-affinitive moiety comprises. , Hydrophilic moiety, moiety having affinity for therapeutic agent due to hydrogen bonding, and moiety having affinity for therapeutic agent due to van der Waals interaction, in which case the additives are: Selected from: p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG steerate, PEG glyceryl laurate, Tween 20, Tween 40, Tween 60, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate. , Polyglyceryl oleate, polyglyceryl millistate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6
Millistate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 millistate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate , PEG oleyl ether, PEG lauryl ether, octoxinol, monoxinol, tyroxapole, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β -D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoid-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D -Thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, Octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, aspartic acid, aspartic acid, glutamate, and methionine; acetic anhydride, benzoic acid anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, Sodium pyrrolidone carboxylate, dianehydride ethylenediamine tetraacetate, maleic acid and anhydride, succinic anhydride, diglycolic acid anhydride, glutaric anhydride, acetylamine, benfothamine, pantothenic acid; setothiamine; sicothamine, dexpantenol, niacinamide, Nicotinic acid, pyridoxal 5-phosphate, ascorbic acid nicotinamide, riboflavin, riboflavin phosphate, thiamine, folic acid, menadione diphosphate, menadione sodium bicarbonate, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamins. U; albumin, immunoglobulins, caseins, hemoglobins, lysoteams, immunoglobins, a-2-macroglobulin, fibronectins, bitronectins, fibrinogens, lipases, benzalconium chloride, benzethonium chloride, docecil Trimethylammonium bromide, docecil Dialkyl esters of sodium sulfate, dialkylmethylbenzylammonium chloride, and sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, amines. Alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, ribbon acid lactone, lactobionic acid, glucosamine, glutamate, benzyl alcohol , Ascorbic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, gentic acid, lactobionic acid, lactitol, cinnapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, Hydroxypropyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid, lysine acetate, genticinic acid, catechin, catechin ascorbic acid, tyretamine, ketamine, propofol, lactic acid, acetic acid, salts of any organic acid and organic amine, Polyglycidol, glycerols, multiglycerols, galactitol, di (ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene glycol), poly (ethylene glycol) oligomer, di (propylene glycol), Tri (propylene glycol), tetra (propylene glycol), and penta (propylene glycol), poly (propylene glycol) oligomers, and derivatives and combinations thereof.

[042] In one embodiment, the therapeutic agent is paclitaxel and its analogs, rapamycin and its analogs, beta-lapachone and its analogs, biovitamin D and its analogs, and mixtures of these therapeutic agents. It is one of them. In another embodiment, the therapeutic agent is a combination with a second therapeutic agent, wherein the therapeutic agent is paclitaxel, rapamycin, and one of its analogs, the second therapeutic agent being beta-rapacon, living body. Vitamin D and one of its analogs.

[043] In one embodiment, the medical device comprising a layer covering the outer surface of the medical device further comprises an adhesive layer between the outer surface of the medical device and this layer. In another aspect, the medical device further comprises an upper layer covering the surface of the layer in order to reduce the loss of the drug as it travels through the body to the tissue. In another embodiment, the top layer covering the surface of the layer covering the outer surface of the medical device contains an additive having a lower hydrophilicity than the additive in the layer covering the outer surface of the medical device, and the top layer additive is as follows. Selected from: p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween 60, PEG oleate, PEG steerate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate. , Polyglyceryl oleate, polyglyceryl millistate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 millistate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 millistate Polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, octoxinol, monoxinol, tyroxapol, sucrose monopalmitate, monolaurine Acid sucrose, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside , Heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n- Noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, asparagine Acids, glutamates, and methionines; acetic acid anhydride, benzoic acid anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate, dianhydride ethylenediaminetetraacetate, maleic acid and anhydride, succinic anhydride, diglycol anhydride. Acids, glutaric anhydride, acetylamines, benfothamines, pantothenic acids; setothia Min; sicothamine, dexpantenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate, ascorbic acid nicotinamide, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, sodium bisulfite, menadoxime, vitamin B12, Vitamin K5, Vitamin K6, Vitamin K6, and Vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysoteams, immunoglobins, a-2-macroglobulin, fibronectins, bitronectins, fibrinogens, lipases , Benzalconium chloride, benzethonium chloride, docecil trimethylammonium bromide, sodium docecil sulfate, dialkylmethylbenzylammonium chloride, and dialkyl ester of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and it. Salts, tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, amine alcohols, glucoheptoic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, mannon Acid lactone, ribbon acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, genticinic acid, lactobionic acid, lactitol, cinnapic acid, vanillic acid, vanillin , Methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid, lysine acetate, gentic acid, catechin, ascorbic acid catechin, tyretamine, ketamine, propofol, Lactic acid, acetic acid, salts of any organic acid and organic amine, polyglycidol, glycerol, multiglycerols, galactitol, di (ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene glycol) ), Poly (ethylene glycol) oligomer, Di (propylene glycol), Tri (propylene glycol), Tetra (propylene glycol), and Penta (propylene glycol), Poly (propylene) Recall) Oligomers, block copolymers of polyethylene glycol and polypropylene glycol, as well as derivatives and combinations thereof.

[044] In another aspect, the medical device further comprises a dimethyl sulfoxide solvent layer, wherein the dimethyl sulfoxide solvent layer covers the surface of the layer.
[045] In one aspect of a medical device, the medical device can release the therapeutic agent and additives in about 0.1 to 2 minutes to deliver the therapeutic agent to the tissue. In one embodiment, the concentration of therapeutic agent in the layer is from 1 to 20 μg / mm ² . In one embodiment, the concentration of therapeutic agent in the layer is from 2 to 10 μg / mm ² . In one embodiment, the therapeutic agent is not water soluble.

[046] In one embodiment, the additive facilitates the release of the therapeutic agent from the balloon. In other embodiments, the additive promotes penetration and absorption of the therapeutic agent into the tissue. In other embodiments, the additive has at least 1 mg / ml water and ethanol solubility and the therapeutic agent is not water soluble.

[047] In another aspect of the medical device, the layer covering the outer surface of the medical device comprises a therapeutic agent and at least two types of additives, wherein each additive contains a hydrophilic moiety and a drug-affinity moiety thereof. In this case, the drug-affinity portion is at least one of a hydrophobic portion, a portion having an affinity for a therapeutic drug due to hydrogen bonding, and a portion having an affinity for a therapeutic drug due to a van der Waals interaction. , Each additive is soluble in polar organic solvents and soluble in water. In one aspect of this embodiment, the polar organic solvent is selected from methanol, ethanol, isopropanol, acetone, dimethylformamide, tetrahydrofuran, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, ethyl acetate, and chloroform, and mixtures of these polar organic solvents and water. To. In another aspect of this aspect, the medical device further comprises an uppermost layer covering the surface of a layer covering the outer surface of the medical device in order to reduce the loss in moving through the body to the target tissue.

[048] In another aspect of the medical device, the layer overlying the outer surface of the medical device comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug affinity moiety, in which the drug affinity. The moiety is at least one of a hydrophobic moiety, an affinity for the therapeutic agent due to hydrogen binding, and an affinity for the therapeutic agent due to van der Waals interaction, in which the additive is therapeutic. It reduces the crystal size and number of particles of the drug, in which the additive is water soluble and the therapeutic agent is not.

[049] In another aspect of the medical device, the layer covering the outer surface of the medical device comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic portion and a drug-affinity moiety, in which the drug-affinity. The moiety is at least one of a hydrophobic moiety, an affinity for the therapeutic agent due to hydrogen bonding, and an affinity for the therapeutic agent due to van der Waals interaction, wherein the additive is an acid. It has an aliphatic chain of ester, ether or alcohol, which can be inserted directly into the lipid membrane structure of the tissue, in which the therapeutic agent is not water soluble.

[050] In another aspect of the medical device, the layer overlying the outer surface of the medical device comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic portion and a drug-friendly moiety, wherein the additive is. It can penetrate into the lipid membrane structure of the tissue and rearrange it, where the therapeutic agent is not water soluble, is not encapsulated in micelles, or is encapsulated in polymer particles.

[051] In another aspect of the medical device, the layer overlying the outer surface of the medical device comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug-affinitive moiety, wherein the additive comprises. It has an aliphatic chain of acid, ester, ether or alcohol, which can be inserted directly into the lipid membrane structure of the tissue, where the additive is by hydrogen bonding and / or van der Waals interaction. It has one or more functional groups that have affinity for the drug (functional groups include hydroxyls, esters, amides, carboxylic acids, primary, secondary and tertiary amines, carbonyls, acid anhydrides, oxides, and Amino alcohol is included), in which case the therapeutic agent is not water soluble, is not encapsulated in micelles, or is not encapsulated in polymer particles, in which case the layer is polymer free and the layer is iodine. Does not contain covalently bound contrasting agents.

[052] In yet another aspect, the invention relates to a stent coating for delivering a therapeutic agent to a tissue, comprising a layer covering the surface of the stent. In one aspect of this aspect, the layer overlying the surface of the stent comprises a therapeutic agent, an additive, and a polymer matrix, where the therapeutic agent is dispersed as particles in the polymer matrix but not encapsulated. In that case, the additive contains a hydrophilic part and a drug-affinity part, in which the drug-affinity part is a hydrophobic part, a part having an affinity for a therapeutic drug by hydrogen bonding, and a van der Waals interaction. It is at least one of the parts that have an affinity for the drug. In one aspect of this aspect, the additive improves the compatibility of the therapeutic agent with the polymer matrix, the additive reduces the particle size of the therapeutic agent to improve the uniformity of distribution in the polymer matrix, and the additive is the polymer matrix. Promotes the rapid release of the drug from.

[053] In yet another aspect, the invention relates to a medical device coating made from a mixture for delivering a drug to a tissue. In one aspect of this aspect, the coating is made from a mixture containing an organic phase containing internally dispersed drug particles and an aqueous phase containing water soluble additives. In one aspect of this aspect, the water-soluble additive is selected from polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidinone, polypeptides, water-soluble surfactants, water-soluble vitamins, and proteins. In another aspect of this aspect, the preparation of the mixture comprises homogenization under high shear conditions and, in some cases, under pressure.

[054] In another aspect, the invention relates to a balloon catheter for delivering a therapeutic agent to a blood vessel, the catheter comprising a coating layer covering the outer surface of the balloon. In one embodiment of the balloon catheter, the coating layer comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety is a hydrophobic moiety, a hydrogen bond. At least one of the parts that have an affinity for the therapeutic agent due to the van der Waals interaction and the portion that has an affinity for the therapeutic agent due to the van der Waals interaction, in which case the additive is water soluble, in which case the additive Is at least one of a surfactant and a chemical compound, wherein the chemical compound has a molecular weight of 20 to 750.

[055] In another aspect of the balloon catheter, the coating layer comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety is hydrophobic. The moiety is at least one of a moiety that has an affinity for a therapeutic agent due to hydrogen bonding and a moiety that has an affinity for a therapeutic agent due to van der Waals interactions, where the additive is a surfactant and a chemical compound. At least one of them, in which the chemical compound has more than four hydroxyl groups. In one aspect of this embodiment, a chemical compound having more than four hydroxyl groups has a melting point of 120 ° C. or lower, and the chemical compound is an alcohol or an ester.

[056] In one aspect of a balloon catheter, the coating layer covering the outer surface of the medical device consists essentially of a therapeutic agent and an additive. In another embodiment, the layer covering the outer surface of the medical device does not contain an iodine covalently bound contrast agent.

[057] In one embodiment, the surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, PEG omega-3 fatty acid esters, ethers, and alcohols, glycerol fatty acids. It is selected from esters, sorbitan fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters, sugar fatty acid esters, PEG sugar esters, and derivatives thereof. In one embodiment, the chemical compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxylcarboxylic acids, esters and anhydrides, hydroxylketones, hydroxyllactones, hydroxyl esters, Sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins, sorbitans, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids , As well as their substituted molecules.

[058] In one aspect of a balloon catheter, the coating layer covering the outer surface of the balloon does not contain a purely hydrophobic additive. In another embodiment, the coating layer covering the surface of the balloon does not contain an iodinated contrast agent. In other embodiments, the additive is not a therapeutic agent. In other embodiments, the additive is not salicylic acid or salts thereof. In other embodiments, the coating layer covering the surface of the balloon is oil-free, lipid- or polymer-free. In yet another embodiment, the coating layer covering the surface of the balloon is oil-free. In another aspect of this aspect, the coating layer is polymer free.

[059] In one embodiment of the balloon catheter, the additives in the coating layer, including the therapeutic agent and the additives, are selected from: p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween 60, PEG oleate, PEG steerate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl millistate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate. , Polyglyceryl-6 millistate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 millistate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, octoxinol, monoxinol, tyroxalol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n -Decil-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl -Β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β- D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamate, and methionine; acetate, benzoic acid anhydride, ascorbic acid, 2-pyrrolidone-5 -Carboxylic acid, sodium pyrrolidone carboxylate, dianehydride ethylenediaminetetraacetate, maleic acid and anhydride, succinic anhydride, diglycolic acid anhydride, glutaric anhydride, acetylamine, benfotiamine, pantothenic acid; setothiamine; sicothamine, dexpantenol , Niacinamide, nicotinic acid, pyridoxal 5-phosphate, ascorbic acid nicotinamide, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 , And Vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysoteams, immunoglobins, a-2-macroglobulin, fibronectins, bitronectins, fibrinogens, lipases, benzalkonium chloride, benzethonium chloride , Dosecil trimethylammonium bromide, sodium docecil sulfate, dialkylmethylbenzylammonium chloride, and dialkyl ester of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine , Diethanolamine, meglumin, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, ribbon acid lactone, lactobion Acids, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, cinnapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, Xylitol, cyclodextrin, (2-hydroxypropyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid, lysine acetate, gentic acid, catechin, ascorbic acid catechin, tyretamine, ketamine, propofol, lactic acid, acetic acid, any of Salts of organic acids and amines, polyglycidole, glycerol, multiglycerols, galactitol, di (ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene glycol), poly (ethylene glycol) oligomers , Di (propylene glycol), tri (propylene glycol), tetra (propylene glycol), and penta (propylene glycol), poly (propylene glycol) oligomers, polyethylene glyco Block copolymers of polypropylene glycol and polypropylene, as well as derivatives and combinations thereof.

[060] In one embodiment, the therapeutic agent is one of paclitaxel and its analogs, rapamycin and its analogs, beta-rapacon and its analogs, biovitamin D and its analogs, and mixtures of these therapeutic agents. Is. In another embodiment, the therapeutic agent is a combination with a second therapeutic agent, wherein the therapeutic agent is paclitaxel, rapamycin, and one of its analogs, the second therapeutic agent being beta-rapacon, living body. Vitamin D and one of its analogs. In one embodiment, the therapeutic agent is not water soluble.

[061] In one embodiment, the additive is soluble in organic solvents and water. In other embodiments, the additive promotes penetration and absorption of the therapeutic agent into vascular tissue. In other embodiments, the therapeutic agent is not water soluble. In other embodiments, the additive has at least 1 mg / ml water and ethanol solubility and the therapeutic agent is not water soluble.

[062] In one aspect of a balloon catheter, the catheter further comprises an adhesive layer between the outer surface of the balloon and the coating layer. In another aspect, the catheter further comprises a top layer overlying the surface of the coating layer, which reduces the loss of therapeutic agent as it travels through the body to blood vessels. The top layer contains additives selected from the additives according to the aspects of the invention described herein. The top layer will gradually dissolve as it moves through the body to the body cavity at the target site for therapeutic intervention. This top layer will reduce drug loss on the move and increase the drug available to the tissue when the medical device of the embodiment of the invention is in pressure contact with the lumen tissue. In one embodiment, the additive in the top layer is less hydrophilic than the additive in the coating layer. In another embodiment, the catheter further comprises a dimethyl sulfoxide solvent layer, in which the dimethyl sulfoxide solvent layer covers the surface of the coating layer.

[063] In one embodiment, the balloon catheter is capable of releasing the therapeutic agent and additives in about 0.1 to 2 minutes to deliver the therapeutic agent to the blood vessel.
[064] In one embodiment of a balloon catheter, the concentration of therapeutic agent in the coating layer is 1.
To 20 μg / mm ² . In other embodiments, the concentration of therapeutic agent in the coating layer is from 2 to 10 μg / mm ² .

[065] In yet another aspect, the invention relates to a balloon catheter for delivering a therapeutic agent to a blood vessel. In one aspect of this aspect, the catheter is an elongated member with a lumen and a distal end, an inflatable balloon connected to the distal end of the elongated member and fluidized with the lumen, and an inflatable balloon. Includes a coating layer that covers the outer surface of the balloon. In one aspect of this aspect, the coating layer covering the surface of the balloon comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety is hydrophobic. At least one of the sex moiety, the moiety that has an affinity for the therapeutic agent due to hydrogen binding, and the moiety that has an affinity for the therapeutic agent due to van der Waals interactions, where the additive is water soluble. In that case, the additive is at least one of the surfactant and the chemical compound, in which the chemical compound has a molecular weight of 20 to 750, in which the catheter is the therapeutic agent and addition in less than about 2 minutes. The agent can be released to deliver the therapeutic agent to the tissue of the blood vessel. In one aspect of this aspect, the layer does not contain an iodinated contrast agent.

[066] In one embodiment, the balloon catheter further comprises a dimethyl sulfoxide solvent layer overlying the coating layer, where the dimethyl sulfoxide solvent layer enhances the ability of the therapeutic agent to penetrate into the blood vessel. In another aspect, the balloon catheter further comprises an adhesive layer between the outer surface of the balloon and the coating layer. In yet another embodiment, the catheter further comprises a top layer covering a coating layer, which maintains the integrity of the coating as it moves intravascularly to the target site for therapeutic intervention.

[067] In one embodiment, the concentration of therapeutic agent in the coating layer is 2.5 to 6 μg / mm.
Up to ^2. In one embodiment, the surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, PEG omega-3 fatty acid esters, ethers, and alcohols, glycerol fatty acid esters. , Polysorbate fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters, sugar fatty acid esters, PEG sugar esters, and derivatives thereof. In one embodiment, the chemical compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxylcarboxylic acids, esters, and acid anhydrides, hydroxylketones, hydroxyllactones, hydroxyl esters. , Sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins, sorbitans, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, amino alcohols and organic acids Selected from combinations, as well as their substituted molecules. In one embodiment, the chemical compound has more than four hydroxyl groups, has a melting point of 120 ° C. or lower, and the chemical compound is an alcohol or ester.

[068] In one embodiment of a balloon catheter, the additive is selected from:
p-Isononylphenoxypolyglycidole, PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl -6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 millistate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 millistate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate. Rate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, Tween 20, Tween 40, Tween 60, Octoxinol, Monoxinol, Tyroxapol, Monopalmitate sucrose, Monolaurate sucrose, Decanoyl- N-Methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopiranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyle-N- Methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D -Glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, aspartic acid, aspartic acid, glutamate, and Methionin: Acetic anhydride, benzoic acid anhydride, aspartic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate, dianhydride tetraacetate ethylenediamine, maleic acid and anhydride, succinic anhydride, diglycolic acid anhydride, glutaric anhydride , Acetiamine, Benfothamine, Pantothenic acid; Setothiamine; Sicothamine, Dexpantenol, Niacinamide, Nicotinic acid, Pyridoxal 5-phosphate, Aspartic acid nicotinamide, Riboflavin, Riboflavin phosphate, Chia Min, folic acid, menadiol diphosphate, sodium diosulfate, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysoteams, immunoglobins , A-2-macroglobulin, fibronectins, bitronectins, fibrinogens, lipases, benzalconium chloride, benzethonium chloride, doceciltrimethylammonium bromide, sodium docecil sulfate, dialkylmethylbenzylammonium chloride, and sodium sulfosuccinate. Dialkyl ester, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, Gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, ribbon acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, Lysine acetate salt, gentic acid, lactobionic acid, lactitol, cinnapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid , Lysine acetate, gentic acid, catechin, catechin ascorbic acid, chilletamine, ketamine, propofol, lactic acid, acetic acid, salts of any organic acid and organic amine, polyglycidol, glycerol, multiglycerols, galactitol, di (ethylene) Glyco), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene glycol), poly (ethylene glycol) oligomer, di (propylene glycol), tri (propylene glycol), tetra (propylene glycol), and penta (propylene). Glycol), poly (propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, and derivatives and combinations thereof.

[069] In yet another aspect, the invention relates to a pharmaceutical composition comprising a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug affinity moiety, in which the drug affinity. The moiety is at least one of a hydrophobic moiety, an affinity for the therapeutic agent due to hydrogen binding, and an affinity for the therapeutic agent due to van der Waals interaction, wherein the additive is water-soluble. It is sex, in which the additive is at least one of a surfactant and a chemical compound, wherein the chemical compound has a molecular weight of 20 to 750. In one aspect of this aspect, the pharmaceutical composition does not contain an iodine covalent contrast agent or polymer, in which the therapeutic agent is not encapsulated in micelles or particles.

[070] In one embodiment, the chemical compound is one or more hydroxyl, amino, carbonyl,
It has a carboxyl, acid, amide or ester group. In one embodiment, chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxylcarboxylic acids, esters, and acid anhydrides, hydroxylketones, hydroxyllactones, hydroxyl esters. , Sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins, sorbitans, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, amino alcohols and organic acids Selected from combinations, as well as their substituted molecules. In one embodiment, the chemical compound has more than four hydroxyl groups, has a melting point of 120 ° C. or lower, and the chemical compound is an alcohol or ester. In one embodiment, the surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, PEG omega-3 fatty acid esters, ethers, and alcohols, glycerol fatty acid esters, It is selected from sorbitan fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters, sugar fatty acid esters, PEG sugar esters, and derivatives thereof.

[071] In one embodiment of the pharmaceutical composition, the additive is selected from: p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG Glyceryl Steerate, Polyglyceryl Laurate, Tween 20, Tween 40, Tween 60, Polyglyceryl Oleate, Polyglyceryl Millistate, Polyglyceryl Palmitate, Polyglyceryl-6 Laurate, Polyglyceryl-6 Oleate, Polyglyceryl-6 Millistate, Polyglyceryl-6 , Polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 millistate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG laura Il ether, octoxinol, monoxinol, tyroxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n- Dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl -Β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thio Glucopyranoside; cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamate, and methionine; acetic anhydride, benzoic acid anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate, ethylenediamine tetra Diane hydride acetate, maleic acid and anhydride, succinic anhydride, diglycolic acid anhydride, glutaric anhydride, acetylamine, benfothamine, pantothenic acid; setothiamine; sicothamine, dexpantenol, niacinamide, nicotinic acid, pyridoxal 5-li Acid, ascorbic acid nicotine amide, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, sodium diosulfate, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulin , Caseins, hemoglobins, lysoteams, immunoglobins, a-2-macroglobulin, fibronectins, bitronectins, fibrinogens, lipases, benzalkonium chloride, benzethonium chloride, doceciltrimethylammonium bromide, docecil sulfate Dialkyl esters of sodiums, dialkylmethylbenzylammonium chloride, and sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, amine alcohols. Kind, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, ribbon acid lactone, lactobionic acid, glucosamine, glutamate, benzyl alcohol, Ascorbic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid, lactitol, cinnapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxy) Propyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid, lysine acetate, genticinic acid, catechin, catechin ascorbic acid, tyretamine, ketamine, propofol, lactic acid, acetic acid, salts of any organic acid and organic amine, poly Glycidol, glycerol, multiglycerols, galactitol, di (ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene glycol), poly (ethylene glycol) oligomer, di (propylene glycol), tri ( (Propylene glycol), tetra (propylene glycol), and penta (propylene glycol), poly (propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, And its derivatives and combinations.

[072] In yet another embodiment, the invention is a method for treating an affected body cavity or cavity after a surgical or intervention procedure, in which the pharmaceutical composition is delivered by catheter injection or spraying into the surgical procedure site. In which the composition comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety comprises. At least one of a hydrophobic moiety, an affinity for a therapeutic agent due to hydrogen bonds, and an affinity for a therapeutic agent due to van der Waals interactions, where the additive is a surfactant and At least one of the chemical compounds, wherein the chemical compound has a molecular weight of 20 to 750. In one embodiment, the chemical compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, the additive is water soluble and the composition does not contain an iodine covalently bound contrast agent.

[073] In one embodiment, the surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, PEG omega-3 fatty acid esters, ethers, and alcohols, glycerol fatty acids. It is selected from esters, sorbitan fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters, sugar fatty acid esters, PEG sugar esters, and derivatives thereof. In one embodiment, chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxylcarboxylic acids, esters and anhydrides, hydroxylketones, hydroxyllactones, hydroxyl esters, Sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins, sorbitans, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids , As well as their substituted molecules.

[074] In yet other embodiments, the present invention relates to the ovaries, chest, lungs, esophagus, head and neck, bladder, and the like.
It relates to a pharmaceutical composition for treating cancers and lymphomas, including cancers of the prostate, brain, liver and colon, wherein the composition comprises a therapeutic agent and an additive, wherein the additive is hydrophilic. A portion and a drug-affinity moiety are included, wherein the drug-affinity moiety is a hydrophobic moiety, a moiety having an affinity for a therapeutic agent by hydrogen bonding, and a moiety having an affinity for a therapeutic agent due to van der Waals interaction. At least one of them, in which the therapeutic agent is not encapsulated in micelles or encapsulated in polymer particles, where the composition does not contain an iodine covalently bound contrast agent. In one aspect of this aspect, the therapeutic agent is selected from paclitaxel and its analogs as well as rapamycin and its analogs.

[075] In yet another aspect, the invention relates to a solution for coating a medical device. In one aspect of this embodiment, the solution comprises an organic solvent, a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety is a hydrophobic moiety. It is at least one of a portion that has an affinity for a therapeutic agent due to hydrogen bonding and a portion that has an affinity for a therapeutic agent due to van der Waals interaction, in which case the additive is water soluble, in which case. The additive is at least one of a surfactant and a chemical compound, wherein the chemical compound has a molecular weight of 20 to 750. In other embodiments, the solution for coating medical devices does not contain iodine covalently bound contrast agents, oils, lipids, or polymers.

[076] In one embodiment, the chemical compound is one or more hydroxyl, amino, carbonyl,
It has a carboxyl, acid, amide or ester group. In one embodiment, chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxylcarboxylic acids, esters and anhydrides, hydroxylketones, hydroxyllactones, hydroxyl esters, Sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins, sorbitans, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids , As well as their substituted molecules. In one embodiment, the surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, PEG omega-3 fatty acid esters, ethers, and alcohols, glycerol fatty acid esters. , Polysorbate fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters, sugar fatty acid esters, PEG sugar esters, and derivatives thereof. In one embodiment, the therapeutic agent is paclitaxel or rapamycin or an analog thereof.

[077] In other embodiments, the additives in the coating solution are selected from: p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG steerate, PEG glyceryl laurate, Tween 20, tween. 60, Tween 80, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl millistate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 millistate, polyglyceryl-6 Palmitate, Polyglyceryl-10 laurate, Polyglyceryl-10 oleate, Polyglyceryl-10 millistate, Polyglyceryl-10 Palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG Lauryl ether, octoxinol, monoxinol, tyroxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n -Dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n- Hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D- Thioglucopyranoside; cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoic acid anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate, ethylenediamine Dianhydride tetraacetate, maleic acid and anhydride, succinic anhydride, diglycolic acid anhydride, glutaric anhydride, acetylamine, benfothamine, pantothenic acid; setothiamine; sicothamine, dexpantenol, niacinamide, nicotinic acid, pyridoxer Lu 5-phosphate, ascorbic acid nicotine amide, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, sodium benzosulfate, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin , Immunoglobulins, caseins, hemoglobins, lysoteams, immunoglobins, a-2-macroglobulin, fibronectins, bitronectins, fibrinogens, lipases, benzalconium chloride, benzethonium chloride, doceciltrimethylammonium bromide , Sodium docecil sulfate, dialkylmethylbenzylammonium chloride, and dialkyl ester of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine , Amin alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, ribbon acid lactone, lactobionic acid, glucosamine, glutamic acid, Benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, gentic acid, lactobionic acid, lactitol, cinnapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, ( 2-Hydroxypropyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid, lysine acetate, genticinic acid, catechin, ascorbic acid catechin, thyretamine, ketamine, propofol, lactic acid, acetic acid, any organic acid and organic amine Salts, polyglycidol, glycerol, multiglycerols, galactitol, di (ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene glycol), poly (ethylene glycol) oligomer, di (propylene glycol) , Tri (propylene glycol), tetra (propylene glycol), and penta (propylene glycol), poly (propylene glycol) oligomers, polyethylene glycol and polypropylene glycol blockco Polymers, as well as their derivatives and combinations.

[078] In yet another aspect, the invention is a medical device for delivering a therapeutic agent to a tissue, including a first layer applied to the outer surface of the medical device and a second layer covering the first layer. Regarding medical equipment. In one aspect of this embodiment, the first layer comprises a therapeutic agent and the second layer comprises an additive, wherein the additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety comprises. , Hydrophobic moieties, moieties that have an affinity for therapeutic agents due to hydrogen bonds, and moieties that have an affinity for therapeutic agents due to van der Waals interactions. In one aspect of this aspect, the first layer further comprises an additive, where the additive is water soluble and this layer does not contain an iodinated contrast agent. In another aspect of this aspect, the second layer further comprises a therapeutic agent. In yet another aspect of this aspect, the first layer further comprises an additive and the second layer further comprises a therapeutic agent.

[079] In yet another aspect, the invention relates to a two-layer coating comprising a first layer containing a therapeutic agent and a top layer containing an additive. In one aspect of this aspect, the top layer may cover the first layer. In one aspect of this embodiment, in both the first layer and the top layer, the additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety is a hydrophobic moiety, a hydrogen bond to the therapeutic agent. It is at least one of an affinity moiety and an affinity for a therapeutic agent by van der Waals interaction, where the additive is water soluble, where the additive is a surfactant. And at least one of the chemical compounds, where the chemical compound has a molecular weight of 20 to 750. In one aspect of this aspect, the first layer does not contain an iodine covalently bound contrast agent. In another aspect of this aspect, the top layer further comprises a therapeutic agent.

[080] In yet another aspect, the invention relates to a method of making a medical device. In one aspect of this aspect, the method comprises: (a) preparing a coating solution containing an organic solvent, a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug-friendly moiety. At that time, the drug-affinitive moiety is at least one of a hydrophobic moiety, a moiety having an affinity for a therapeutic drug due to hydrogen binding, and a moiety having an affinity for a therapeutic drug due to a van der Waals interaction. In this case, the additive is water-soluble, wherein the additive is at least one of a surfactant and a chemical compound, wherein the chemical compound has a molecular weight of 80 to 750, (b) this. The coating solution is applied to the medical device and (c) the coating solution is dried to form a coating layer. In one aspect of this aspect, the coating layer does not contain an iodine covalently bound contrast agent. In one aspect of this aspect, the coating solution is applied by immersing a portion of the outer surface of the medical device in the coating solution. In another aspect of this aspect, the coating solution is applied by spraying the coating solution onto a portion of the outer surface of the medical device. In another aspect of this aspect, steps (b) and (c) are repeated until a therapeutically effective amount of therapeutic agent in the coating layer is deposited on the surface of the medical device. In another aspect of this aspect, the total thickness of the coating layer is from about 0.1 to 200 microns. In yet another aspect of this aspect, the method further comprises applying a dimethyl sulfoxide solvent to the dry coating layer obtained in step (c).

[081] In yet another aspect, the invention relates to a method of making a drug coated balloon catheter. In one aspect of this aspect, the method comprises: (a) preparing a coating solution containing an organic solvent, a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug affinity moiety. At that time, the drug-affinity moiety is at least one of a hydrophobic moiety, a moiety having an affinity for a therapeutic drug due to hydrogen binding, and a moiety having an affinity for a therapeutic drug due to van der Waals interaction. In this case, the additive is at least one of a surfactant and a chemical compound, wherein the chemical compound has a molecular weight of 20 to 750 and (b) applies this coating solution to an inflated balloon catheter. , And (c) the balloon catheter is deflated and folded to allow the coating solution to dry to increase the uniformity of the drug coating.

[082] In yet another aspect, the invention relates to a method of treating a blood vessel. In one aspect of this aspect, the method comprises inserting a medical device containing a coating layer into a vessel, wherein the coating layer comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and A drug-affinity moiety is included, wherein the drug-affinity moiety is of a hydrophobic moiety, a moiety having an affinity for a therapeutic agent due to hydrogen bonding, and a moiety having an affinity for a therapeutic agent due to van der Waals interaction. At least one, in which the additive is water soluble, in which the additive is at least one of a surfactant and a chemical compound, wherein the chemical compound has a molecular weight of 20 to 750. And deliver the therapeutic agent into the vascular tissue by releasing the therapeutic agent and additives in less than 2 minutes. In one aspect of this aspect, the coating layer does not contain an iodine covalently bound contrast agent.

[083] In yet another aspect, the invention relates to a method of treating a complete occlusion or stenosis of a body passage. In one aspect of this aspect, the method comprises removing plaque from the body tube and inserting a medical device containing a coating layer into the body tube, wherein the coating layer comprises a therapeutic agent and an additive. The additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety is a hydrophobic moiety, an affinity for the therapeutic agent by hydrogen bonding, and a van der Waals interaction with the therapeutic agent. At least one of the affinity moieties, where the additive is at least one of the surfactant and the chemical compound, wherein the chemical compound has a molecular weight of 80 to 750 and has a molecular weight of 80 to 750. Then, in less than 2 minutes, the therapeutic agent and the additive are released to deliver the therapeutic agent into the tissue of the blood vessel.

[084] In yet another aspect, the invention relates to a method of treating body tissue, comprising contacting a medical device containing a coating layer with body tissue, wherein the coating layer is a therapeutic agent and an addition. It comprises an agent, in which the additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety is a hydrophobic moiety, a moiety having an affinity for a therapeutic agent by hydrogen binding, and van der Waals. It is at least one of the moieties that have an affinity for the therapeutic agent by interaction, where the additive is water soluble, in which case the additive is at least one of a surfactant and a chemical compound. There, the chemical compound has a molecular weight of 20 to 750 and releases the therapeutic agent and additives in less than 2 minutes to deliver the therapeutic agent into the tissue of the blood vessel. In one aspect of this aspect, the coating layer does not contain an iodine covalently bound contrast agent. In one aspect of this aspect, the tissue includes one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. included.

[085] In yet another aspect, the present invention relates to a method of making a balloon catheter.
In one aspect of this aspect, the method prepares a solution containing an organic solvent, a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug-affinitive moiety, in which the drug-affinitive moiety. Is at least one of a hydrophobic moiety, a moiety that has an affinity for a therapeutic agent due to hydrogen binding, and a moiety that has an affinity for a therapeutic agent due to van der Waals interaction, in which the additive is water soluble. In that case, the additive is at least one of a surfactant and a chemical compound, wherein the chemical compound has a molecular weight of 20 to 750, imparts this solution to a balloon catheter, and a solvent. Including evaporating. In one embodiment, the coating layer does not contain an iodinated contrast agent.

[086] In yet another aspect, the invention relates to a medical device comprising a layer covering the outer surface of the medical device, wherein the layer comprises a therapeutic agent and an additive, wherein the additive is a PEG fatty acid ester, a PEG fatty acid. It is one of ether and PEG fatty alcohol. In one aspect of this embodiment, the additives are PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate. , PEG-15 oleate, PEG-20 laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20 diolate, PEG-20 distearate, PEG-23 dilaurate and PEG-32 laurate. In another aspect of this aspect, the tissue includes one of the coronary, peripheral, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. Is included. In yet another aspect of this aspect, medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[087] In yet another aspect, the invention relates to a medical device comprising a layer covering the outer surface of the medical device, wherein the layer comprises a therapeutic agent and an additive, wherein the additive is a glycerol and a polyglycerol fatty acid ester. And one of the PEGglycerol fatty acid esters. In one aspect of this embodiment, the additives are polyglyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate, polyglyceryl millistate, polyglyceryl palmitate, polyglyceryl linoleate, polyglyceryl-10 laurate, Polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10
Millistate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6 millistate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate, polyglyceryl polylysinolate, PEG-20. It is selected from glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate. In another aspect of this aspect, the tissue includes one of the coronary, peripheral, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. Is included. In yet another aspect of this aspect, medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[088] In yet another aspect, the invention relates to a medical device comprising a layer covering the outer surface of the medical device, wherein the layer comprises a therapeutic agent and an additive, wherein the additive is a sorbitan fatty acid ester and a PEG sorbitan. It is one of the esters. In one aspect of this aspect, the additives are sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitan. It is selected from monooleate and PEG-20 sorbitan monostearate. In another aspect of this aspect, the tissue includes one of the coronary, peripheral, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. Is included. In yet another aspect of this aspect, medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[089] In yet another aspect, the invention relates to a medical device comprising a layer covering the outer surface of the medical device, wherein the layer comprises a therapeutic agent and an additive, wherein the additive is a chemical compound containing a phenol moiety. Is. In one aspect of this aspect, the additive is selected from p-isononylphenoxypolyglycidol, octoxinol, monoxinol, tyroxapole, octoxinol-9, and monoxinol-9. In another aspect of this aspect, the tissue includes one of the coronary, peripheral, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. Is included. In yet another aspect of this aspect, medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[090] In yet another aspect, the invention relates to a medical device comprising a layer overlying the outer surface of the medical device, the layer comprising a therapeutic agent and an additive, the additives being sucrose monolaurate, decanoyl-N-methyl. Glucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyle-N-methylglucamide , N-Heptyl-β-D-Glucopyranoside, n-Heptyl-β-D-thioglucoside, n-Hexyl-β-D-Glucopyranoside, Nonanoyl-N-Methylglucamide, n-Noyl-β-D-Glucopyranoside, Octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, D-glucoascorbic acid and its salts, tromethamine, glucamine, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl It is selected from lactones, gluconolactones, glucoheptonolactones, glucooctanoic acid lactones, glonic acid lactones, mannonic acid lactones, ribbon acid lactones, lactobionic acid, and glucosamine. In another aspect of this aspect, the tissue includes one of the coronary, peripheral, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. Is included. In yet another aspect of this aspect, medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[091] In yet another aspect, the invention relates to a medical device comprising a layer covering the outer surface of the medical device, the layer comprising a therapeutic agent and an additive, wherein the additive is an ionic surfactant. is there. In one aspect of this aspect, the additives are benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, doceciltrimethylammonium bromide, sodium docecil sulfate, dialkylmethylbenzylammonium chloride, edrophosphonium chloride, domiphen bromide, It is selected from dialkyl esters of sodium sulfosuccinate, sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate. In another aspect of this aspect, the tissue includes one of the coronary, peripheral, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. Is included. In yet another aspect of this aspect, medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[092] In yet another aspect, the invention relates to a medical device comprising a layer covering the outer surface of the medical device, wherein the layer comprises a therapeutic agent and an additive, wherein the additive is a vitamin or a vitamin derivative. .. In one aspect of this aspect, the additives are acetylamine, benfotiamine, pantothenic acid, setothiamine, sicothamine, dexpantenol, niacinamide, nicotinic acid and salts thereof, pyridoxal 5-phosphate, ascorbic acid nicotine amide, riboflavin, phosphorus. Riboflavin acid, thiamine, folic acid, menadiol diphosphate, menadiol sodium bicarbonate, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, vitamin U, ergosterol, 1-alpha-hydroxycholecalciferol, vitamin D2, vitamins D3, alpha-carotene, beta-carotene, gamma-carotene, vitamin A, flusultiamine, methylolriboflavin, octothiamine, prosultiamine, riboflavin, vinciamol, dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, disulfate. It is selected from menadiol, menadiol, vitamin K1, vitamin K1 oxide, vitamin K2, and vitamin K-S (II). In another aspect of this aspect, the tissue includes one of the coronary, peripheral, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. Is included. In yet another aspect of this aspect, medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[093] In yet another aspect, the invention relates to a medical device comprising a layer covering the outer surface of the medical device, wherein the layer comprises a therapeutic agent and an additive, wherein the additive is an amino acid, an amino acid salt, or. It is an amino acid derivative. In one aspect of this aspect, the additives are alanine, arginine, aspartic acid, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, proline, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine. , And its derivatives. In another aspect of this aspect, the tissue includes one of the coronary, peripheral, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. Is included. In yet another aspect of this aspect, medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[094] In yet another aspect, the invention relates to a medical device for delivering a therapeutic agent to a tissue, the medical device comprising a layer covering the outer surface of the medical device, the layer comprising the therapeutic agent and additives. , The additive is a peptide, oligopeptide, or protein. In one aspect of this aspect, the additives are from albumin, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulins, fibronectins, vitronectins, fibrinogens, and lipases. Be selected. In another aspect of this aspect, the tissue includes one of the coronary, peripheral, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. Is included. In yet another aspect of this aspect, medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[095] In yet another aspect, the invention relates to a medical device for delivering a therapeutic agent to a tissue, the medical device comprising a layer covering the outer surface of the medical device, the layer comprising a therapeutic agent and an additive. , The additive comprises a combination or mixture of both a surfactant and a chemical compound, wherein the chemical compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one aspect of this aspect, the surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, PEG omega-3 fatty acid esters, ethers, and alcohols, glycerol fatty acids. It is selected from esters, sorbitan fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters, sugar fatty acid esters, PEG sugar esters, and derivatives thereof. In another aspect of this embodiment, a chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups has a molecular weight from 20 to 750. In another aspect of this aspect, the chemical compounds are aminoalcohols, hydroxylcarboxylic acids, esters, and anhydrides, hydroxylketones, hydroxyllactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, sorbitans. , Gloxy, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohols and organic acids, as well as their substituted molecules. In another aspect of this embodiment, the chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups is selected from: acetic acid and anhydride, benzoic acid and anhydride, Diethylenetriamine pentaacetate dianhydride, ethylenediaminetetraacetate dianhydride, maleic acid and anhydride, succinic acid and anhydride, diglycolic acid and anhydride, glutaric acid and anhydride, ascorbic acid, citric acid, tartrate acid, lactic acid, asparagine oxalate Acids, nicotinic acid, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl Lactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, ribbon acid lactone, lactobionic acid, glucosamine, glutamate, benzyl alcohol, benzoic acid, hydroxybenzoic acid, 4-hydroxybenzoic acid Propyl, lysine acetate salt, gentic acid, lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphates, glucopyranose phosphate, sugar sulfates, cinnapic acid, vanillic acid, vanillin, methylparaben, propylparaben, xylitol, 2-ethoxyethanol , Cyclodextrin, (2-hydroxypropyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin asbestosate, tyretamine, ketamine, propofol, lactic acid, acetic acid, any of the above Organic acids and amine salts, polyglycidol, glycerol, multiglycerols, galactitol, di (ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene glycol), poly (ethylene glycol) oligomers , Di (propylene glycol), tri (propylene glycol), tetra (propylene glycol), and penta (propylene glycol), poly (propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, and derivatives and combinations thereof. In another aspect of this aspect, the tissue includes one of the coronary, peripheral, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. Is included. In yet another aspect of this aspect, medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[096] In another aspect, the invention relates to a pharmaceutical formulation comprising paclitaxel or rapamycin or a derivative thereof and a combination of both a surfactant and a chemical compound for administration to a mammal. , Chemical compounds have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, the surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, PEG omega-3 fatty acid esters, ethers, and alcohols, glycerol fatty acid esters, It is selected from sorbitan fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters, sugar fatty acid esters, PEG sugar esters, and derivatives thereof. In one embodiment, a chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups has a molecular weight from 20 to 750. In one embodiment, chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are aminoalcohols, hydroxylcarboxylic acids, esters and anhydrides, hydroxylketones, hydroxyllactones, hydroxyl esters. Sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organic acids, esters, salts, vitamins, amino It is selected from combinations of alcohols and organic acids, as well as their substituted molecules. In one embodiment, the chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups is selected from: L-ascorbic acid and salts thereof, D-glucoascorbic acid and Salts of it, tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, Mannonic acid lactone, ribbon acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, genticinic acid, lactobionic acid, lactitol, cinnapic acid, vanillic acid, Vanillin, methylparaben, propylparaben, acetaminophen, ibprofen, retinoic acid, lysine acetate, genticinic acid, catechin, catechin ascorbic acid, thyretamine, ketamine, propofol, lactic acids, acetic acid, ribic acid lactone, meglumin / lactic acid, meglumin / genticin Acids, meglumin / acetic acid, sorbitol, xylitol, 2-ethoxyethanol, sugars, galactones, glucose, mannose, xylose, sucrose, lactones, maltose, cyclodextrin, (2-hydroxypropyl) -cyclodextrin, any organic acid and Organic amine salts, polyglycidol, glycerol, multiglycerols, galactitol, di (ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene glycol), poly (ethylene glycol) oligomer, di (di (ethylene glycol). (Propylene glycol), tri (propylene glycol), tetra (propylene glycol), and penta (propylene glycol), poly (propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, and derivatives and combinations thereof.

[097] In other embodiments, the present invention comprises paclitaxel or rapamycin or a derivative thereof for administration to a mammal, and a chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. Including, the chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups has a molecular weight from 20 to 750. In one embodiment, the chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups is hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone. , Mannonic Acid Lactone, Ribbon Acid Lactone, Sugar Phosphate, Sugar Sulfate, Catechin, Catechin Carbate, and Combinations of Amino Alcohol and Organic Acids. In one aspect of this embodiment, the amino alcohol is selected from tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, glucosamine, lysine, and derivatives thereof; the organic acids are glucoheptonic acid, glucomic acid, glutamic acid, benzoic acid, hydroxybenzoic acid. , Gentisic acid, lactobionic acid, vanillic acid, lactic acids, acetic acid, and derivatives thereof.

[098] In yet another aspect, the invention relates to a pharmaceutical formulation comprising paclitaxel or rapamycin or a derivative thereof, and a combination of an amino alcohol and an organic acid for administration to a mammal. Amino alcohols are selected from tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, glucosamine, lysine, and derivatives thereof; organic acids are glucoheptonic acid, glucomic acid, glutamic acid, benzoic acid, hydroxybenzoic acid, genticic acid, lactobionic acid, It is selected from vanillic acid, lactic acids, acetic acid, and derivatives thereof.

[099] In yet another aspect, the invention relates to a medical device for delivering a therapeutic agent to a tissue, wherein the medical device comprises a layer covering the outer surface of the medical device, the layer comprising the therapeutic agent and an additive. At that time, the additive is selected from hydroxyl ketone, hydroxyl lactone, glucono lactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, ribbon acid lactone and lactobionic acid.

[0100] In yet another aspect, the invention relates to a medical device for delivering a therapeutic agent to a tissue, the medical device comprising a layer covering the outer surface of the medical device, the layer comprising the therapeutic agent and an additive. In that case, the therapeutic agent is paclitaxel and its analogs or rapamycin and its analogs, and the additives are sorbitol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol oligomer, polypropylene glycol oligomer, polyethylene glycol and polypropylene glycol. Block copolymer oligomers, xylitol, 2-ethoxyethanol, sugars, galactose, glucose, mannose, xylose, sucrose, lactose, maltose, Tween
20, Tween 40, Tween 60, and derivatives thereof, the weight ratio of the drug to the additive being from 0.5 to 3, in which the therapeutic agent and the additive are released simultaneously.

[0101] Many aspects of the invention are particularly useful in the treatment of vascular disease and in the reduction of stenosis and delayed luminal loss, or in the preparation of tools for that purpose.
[0102] It is construed that the above general description and the following detailed description are merely examples and explanations and do not limit the present invention described in the claims.

[0103] FIG. 1 is a perspective view of an exemplary embodiment of a balloon catheter according to the present invention. [0104] FIGS. 2A-2C are cross-sectional views obtained along lines AA of the distal portions of different aspects of the balloon catheter of FIG. 1 showing an example of a coating layer.

[0105] Aspects of the present invention relate to medical devices having a rapid release coating, particularly including balloon catheters and stents, and methods for making such coated devices. The therapeutic agents according to aspects of the invention do not require delayed release or long-term release, but preferably release the therapeutic agent and additives in a very short period of time upon contact with tissue to provide a therapeutic effect. An object of the present invention is to facilitate the rapid and effective uptake of a drug by a target tissue while the device is temporarily placed at the target site.

[0106] As shown in FIG. 1, in one embodiment, the medical device is a balloon catheter. The balloon catheter may be any catheter suitable for the desired application and includes common balloon catheters known to those of skill in the art. For example, the balloon catheter 10 is an inflatable balloon 12 at the distal end of the catheter 10, a handle assembly 16 at the proximal end of the catheter 10, and an elongated extension between the proximal and distal ends. The flexible member 14 can be included. The handle assembly 16 can connect to and / or receive a source of one or more suitable medical devices, such as an inflatable medium (eg, air, saline, or contrast agent). The flexible member 14 may be a tube made of a suitable biocompatible material and having one or more lumens inside. At least one lumen is constructed to receive an expansion medium and send that medium to the balloon 12 for expansion. Balloon catheters may be rapid exchange or over-the-wire catheters and are made of either suitable material.

[0107] In one aspect, the invention provides a medical device for delivering a therapeutic agent to a tissue. The medical device includes a layer applied to the outer surface of the medical device, such as a balloon catheter or stent. This layer contains therapeutic agents and additives. For example, as shown in the embodiment described in FIG. 2A, the balloon 12 is coated with a layer 20 containing a therapeutic agent and an additive. In some embodiments, this layer consists essentially of therapeutic agents and additives, i.e., this layer contains essentially only therapeutic agents and additives and no other significant material components. In some embodiments, the medical device may include an adhesive layer. For example, as shown in the embodiment described in FIG. 2B, the balloon 12 is coated with an adhesive layer 22. A layer 24 containing the therapeutic agent and additives covers the adhesive layer. An adhesive layer, which is a separate layer beneath the drug coating layer, improves the adhesion of the drug coating layer to the outer surface of the medical device and protects the coating integrity. For example, if the adherence of the drug to the additive to the medical device is different, the adhesive layer will prevent the difference in component loss as it travels to the target site for therapeutic intervention and the drug-to-additive ratio in the coating. Can be maintained. In addition, the adhesive layer can serve to facilitate the rapid release of the coating layer component off the surface of the medical device upon contact with the tissue at the target site. In other embodiments, the medical device can include a top layer. The top layer is in direct contact with the coating layer 20 pressed against the target tissue before the drug layer contacts the target tissue, for example when the balloon 12 moves to the therapeutic intervention site, or at the moment of the first expansion of the balloon 12. It is possible to reduce the loss of the drug layer before the treatment.

[0108] In one embodiment, the concentration density of at least one therapeutic agent applied to the surface of the medical device is from about 1 to 20 μg / mm ² , or more preferably from about 2 to 6 μg / mm ² . The weight ratio of the therapeutic agent to the additive is from about 0.5 to 100, for example from about 0.1 to 5, from 0.5 to 3, and even from about 0.8 to 1.2. If the ratio (weight) of the therapeutic agent to the additive is too low, the drug may be released prematurely, and if this ratio is too high, the drug will not elute quickly enough when placed at the target site. It may not be absorbed by the tissue.

[0109] In other embodiments, the layer comprises a therapeutic agent and an additive, wherein the therapeutic agent is paclitaxel and its analogs or rapamycin and its analogs, the additives being sorbitol, diethylene glycol, triethylene glycol, tetra. Select from ethylene glycol, xylitol, 2-ethoxyethanol, saccharides, galactose, glucose, mannose, xylose, sucrose, lactose, maltose, Tween 20, Tween 40, Tween 60, and derivatives thereof, with therapies for additives. The weight ratio of the drug is from 0.5 to 3. If the ratio (weight) of the therapeutic agent to the additive is less than 0.5, the drug may be released prematurely, and if this ratio exceeds 3, the drug will be released sufficiently quickly when placed at the target site. May not elute or be absorbed by the tissue. In other embodiments, the layer may comprise a therapeutic agent and more than one additive. For example, one additive can act to improve the adhesion of other additives (s) that are superior in facilitating drug release or tissue drug uptake to the balloon.

[0110] Current drug-containing stent coatings include drug and polymer carriers. The drug is dispersed in the polymer matrix, sometimes as particles. In the case of durable polymers, the drug is released over a long period of time. The durable polymer stays permanently in the body with the stent. In the case of biodegradable polymers such as PLLA, the drug is released in 1-3 months, after which the polymer is degraded in approximately 1 year or more. The drug is released as a pure drug. Pure drug particles increase the risk of toxicity in tissues. However, the additives of the embodiments of the present invention will mitigate this risk when used as a stent coating in combination with a polymer carrier. In aspects of the invention, the drugs and additives in the polymeric stent coating are different but are simultaneously released into the tissue. This will reduce the risk of drug toxicity to tissues.

[0111] In other embodiments, as a coating for medical devices such as stents or balloons, the layer may comprise at least one therapeutic agent, at least one additive, and at least one polymer carrier. The additive used in combination with the polymer carrier during stent coating may be at least one additive according to the aspects of the invention discussed herein. The additives in the layer improve the compatibility of the drug with the polymer carrier. It reduces or eliminates the size of drug crystal particles in the polymer matrix of the coating. Uniform drug distribution in the coating improves clinical outcome by delivering the drug more uniformly to the target tissue.

[0112] In another aspect, the medical device comprises two layers applied to the outer surface of the medical device, particularly, for example, a balloon catheter. The first layer contains the therapeutic agent. The first layer may contain additives (s). The second layer contains the additive (s). The second layer may contain at least one therapeutic agent. When both the first layer and the second layer contain a therapeutic agent, the content of the therapeutic agent in the second layer is lower than the content of the therapeutic agent in the first layer. In one embodiment, the second layer covers the first layer. In this mode, the second layer causes drug loss as the medical device is placed into the body duct, for example, as the balloon catheter moves through a tortuous anatomical structure to a tissue site within the vasculature. It can be stopped.

[0113] In another aspect, the medical device comprises two layers applied to the outer surface of the medical device, particularly, for example, a balloon catheter. The first layer contains the therapeutic agent. The first layer may contain additives (s). The second layer contains the additive (s). The second layer may contain at least one therapeutic agent. When both the first layer and the second layer contain a therapeutic agent, the content of the therapeutic agent in the first layer is lower than the content of the therapeutic agent in the second layer. In one embodiment, the second layer covers the first layer. This mode is useful, for example, for therapeutic agents that adhere too tightly to the surface of the balloon and cannot be rapidly eluted from the balloon when inflated at the target site. In this mode, the first layer facilitates the rapid release of large amounts of the drug in the second layer off the surface of the medical device while the medical device is swelling at the target site of the therapeutic intervention. Fulfill the function of

[0114] In other embodiments, two or more therapeutic agents are used in combination in the drug-additive layer.
[0115] In yet another embodiment, the medical device comprising a two-layer coating may include an adhesive layer. This adhesive layer does not contain therapeutic agents. For example, the balloon 12 is coated with the adhesive layer 22 as shown in the embodiment shown in FIG. 2C. A first layer 26 containing a therapeutic agent and optionally additives (s) covers the adhesive layer 22. A second layer 28 of additives, including additives and optionally therapeutic agents, covers the first layer 26. The adhesive layer improves the adhesion of the first layer to the outer surface of the medical device and protects the integrity of the first layer. For example, if the adhesive strength of the drug and the additive (s) in the first layer to the medical device are different, the adhesive layer will prevent the loss difference of the component when moving to the target site for therapeutic intervention. The drug-to-additive ratio and the additive-to-additive ratio can be maintained. In addition, the adhesive layer can serve to facilitate the rapid elution of the coating layer from the surface of the medical device upon contact with the tissue at the target site. In one embodiment, the first layer, the second layer and the adhesive layer each contain an additive.

[0116] In some cases treatment with dimethyl sulfoxide (DMSO) or other solvent is advantageous; because DMSO can further enhance the penetration and absorption of the drug into the tissue. DMSO removes water from the lipid head groups and protein domains of the membrane lipid bilayer of target cells and indirectly loosens the lipid structure to promote drug absorption and penetration.

[0117] In yet another embodiment, the invention treats an affected body cavity or cavity after a surgical or intervention procedure (PTCA, PTA, stent placement, excision of affected tissue such as cancer, and reduction or treatment of stenosis). The pharmaceutical composition comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug-affinitive moiety, in which the drug-affinitive moiety. Is a hydrophobic moiety and / or has an affinity for the therapeutic agent by hydrogen bonding and / or van der Waals interaction, where the therapeutic agent is not encapsulated in micelles or encapsulated in polymer particles. Not.

[0118] Complications or disease recurrence (by focal reduction, atherectomy or laser treatment) after other embodiments, ie surgical or interventional procedures, such as PTCA, PTA, stent placement, stenosis or plaque removal (by focal reduction, atherectomy or laser treatment). For example, in a method of preventing cancer or restenosis), the pharmaceutical composition is topically applied to or near the intervention site by a coated medical device (eg, a drug-coated balloon), by spraying, by injection, or by deposition. Deliver. For example, the pharmaceutical composition can be delivered by spray, injection, balloon or other deposition method to reduce the risk of recurrence into the cavity formed by surgical removal of the cancerous tissue. As another example, a method of delivering a pharmaceutical composition involves vascular intervention, such as PTCA, PTA, stent placement, followed by blood treatment of a medical device (eg, a guide catheter or drug infusion catheter) to prevent re-stenosis. Injecting the pharmaceutical composition by inserting into, wherein the pharmaceutical composition comprises a therapeutic agent and an additive, in which the additive comprises a hydrophilic moiety and a drug-affinitive moiety, in which the drug. The affinity moiety is a hydrophobic moiety and / or has affinity for the therapeutic agent by hydrogen binding and / or van der Waals interaction, where the therapeutic agent is not encapsulated in micelles or polymer particles. Not enclosed in.

[0119] Many aspects of the invention are particularly useful for treating vascular disease and reducing stenosis and delayed luminal loss, or making tools for that purpose or treating the disease. Useful for the method.

[0120] Additives
[0121] The additive of aspects of the present invention has two parts. One part is the hydrophobic part and the other part is the drug affinity part. The drug-affinity moiety is a hydrophobic moiety and / or has an affinity for the therapeutic agent by hydrogen bonding and / or van der Waals interaction. The drug-affinity portion of the additive can bind lipophilic drugs such as rapamycin or paclitaxel. The hydrophilic moiety promotes diffusion and enhances the penetration of the drug into the tissue. It increases the solubility of the drug in the interstitial space by preventing mutual aggregation of hydrophobic drug molecules or aggregation into medical devices, and / or the drug passes through the polar head group of the cell membrane of the target tissue. By facilitating reaching the lipid bilayer, the drug can be facilitated to move quickly away from the medical device when placed at the target site. The additive of the embodiment of the invention has two parts that function together, facilitating the rapid separation of the drug from the surface of the medical device and uptake into the target tissue when placed (as opposed to the high affinity of the drug). (By facilitating contact between the sex tissue and the drug), while preventing the drug from being released prematurely from the medical device before it is placed at the target site.

[0122] In aspects of the invention, the therapeutic agent is rapidly released and immediately absorbed after contacting the medical device with the tissue. For example, certain aspects of the medical device of the invention include a drug-coated balloon catheter, which provides short-term direct compression contact of a lipophilic antiproliferative drug (eg, paclitaxel or rapamycin) during balloon angioplasty. Deliver to vascular tissue at high drug concentrations. Lipophilic drugs are preferentially retained in the target tissue at the delivery site, where they prevent hyperplasia and restenosis and still allow endothelium formation. In these embodiments, the coating formulations of the present invention not only allow the drug to be rapidly released from the balloon surface upon placement, facilitating the transfer of the drug into the target tissue, but also through a tortuous arterial structure. Prevents the drug from diffusing from the medical device before reaching the target tissue while migrating, and the drug from the medical device before the drug coating comes into direct compressive contact with the surface of the vessel wall in the early stages of balloon swelling. Prevents explosive release.

[0123] Additives according to a particular embodiment have a drug-affinity moiety and a hydrophilic moiety. The drug-affinity moiety is a hydrophobic moiety and / or has an affinity for the therapeutic agent by hydrogen bonding and / or van der Waals interaction. Drug-affinity moieties include aliphatic and aromatic hydrocarbon compounds such as benzene, toluene, and alkanes in particular. These parts are not water soluble. They can bind both hydrophobic drugs and cell membrane lipids with which they share structural similarities. They do not have covalently bound iodine. The drug affinity moiety can include functional groups capable of forming hydrogen bonds with the drug and itself. Hydrophilic moieties include, among other things, hydroxyl groups, amine groups, amide groups, carbonyl groups, carboxylic acids and anhydrides, ethyl oxide, ethyl glycol, polyethylene glycol, ascorbic acid, amino acids, aminoalcohol, glucose, sucrose, sorbitan, glycerol, Polyalcohols, phosphates, sulfates, organic salts, and their substituted molecules can be included. For example, one or more hydroxyl, carboxyl, acid, amide or amine groups may be advantageous; they can easily eliminate water molecules hydrogen bonded to the polar head groups and surface proteins of cell membranes. Because it can serve to remove this barrier between hydrophobic drugs and cell membrane lipids. These moieties can be dissolved in water and polar solvents. These additives are not oils, lipids or polymers. Therapeutic agents are not encapsulated in micelles or liposomes, or encapsulated in polymer particles. The additive of aspects of the invention has both a component that binds the drug and a component that, when placed, facilitates the drug to quickly move away from the medical device and into the target tissue.

[0124] The additives of the embodiments of the present invention are surfactants and chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties. Surfactants include ionic, nonionic, aliphatic, and aromatic surfactants. Chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties are amino alcohols, hydroxylcarboxylic acids and anhydrides, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sugars, glucose. , Sculose, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, and their substituted molecules.

[0125] As is well known in the art, the terms "hydrophilic" and "hydrophobic" are relative terms. To function as an additive in an exemplary embodiment of the invention, the compound comprises a polar or hydrophilic moiety and a non-polar hydrophobic (lipophilic) moiety.

[0126] An empirical parameter commonly used in pharmaceutical chemistry to characterize the relative hydrophilicity and hydrophobicity of pharmaceutical compounds is the partition coefficient P, i.e. two immiscible solvents (usually octanol and water). The ratio of the concentrations of the unionized compounds in the two phases of the mixture of, and thus ([solute] octanol / [solute] water). Compounds with higher log P are more hydrophobic, while compounds with lower log P are more hydrophilic. Lipinski's rule suggests that pharmaceutical compounds with log P <5 are generally more membrane permeable. For the purposes of a particular aspect of the invention, the additive preferably has a log P lower than the log P of the drug to be blended (for example, paclitaxel has a log P of 7.4). The greater the log P difference between the drug and the additive, the easier the phase separation of the drug may be. For example, if the log P of the additive is much lower than the log P of the drug, the additive promotes the release of the drug from the surface of the device in an aqueous environment, where the drug would otherwise be tightly attached. This can facilitate drug delivery to the tissue when placed at the intervention site for a short period of time. In certain aspects of the invention, the log P of the additive is negative. In other embodiments, the log P of the additive is lower than the log P of the drug. The octanol-water partition coefficient P, or log P, is useful as a measure of relative hydrophilicity and hydrophobicity, but it is useful in determining suitable additives for use in aspects of the invention. It's just a rough indicator.

[0127] The coating of aspects of the invention comprises a therapeutic agent and at least one additive, the additive being combined with the therapeutic agent in the coating layer based on the unique properties of each therapeutic agent to provide the therapeutic agent. Provide safe and effective drug-coated medical devices with minimal degradation. The additives of the embodiments of the present invention do not chemically react with the functional groups of therapeutically effective agents. Each therapeutically effective drug has its own chemical structure and properties, reacts differently with different drug carrier additives, and the reaction between the drug and the additive inactivates the therapeutic agent or is a potentially toxic degradation product. May generate. The additive is selected so that it does not have a functional group that chemically reacts with the functional group of the therapeutically effective agent. Otherwise, such a reaction between the drug and the additive would inactivate the therapeutic agent or produce potentially toxic degradation products. It is important to harmonize the therapeutic agent with the selected additive (s) in order to minimize the degradation of the therapeutic agent and for the drug-coated medical device to be safe and effective. Paclitaxel reacts with many functional groups such as acids, water, oxygen, and amines. Rapamycin and its derivatives can be easily hydrolyzed or oxidized. Due to the large surface area of coated medical devices, optimizing the stability of the active drug in the coating becomes even more important. Drug-coated medical devices are exposed to high heat, moisture, and oxidative conditions during sterilization, and they are often stored for extended periods of time prior to use. The additives of the embodiments of the present invention are carefully selected to minimize the degradation of the therapeutic agent when exposed to harsh conditions and when stored for extended periods of time. Certain drugs, such as rapamycin and its derivatives, are sensitive to oxygen and water and are susceptible to oxidation and hydrolysis. We have found that antioxidants are additives that protect drugs such as rapamycin from oxidation and hydrolysis. Aspects of the present invention are coatings for medical devices containing additives and active agents, wherein the additives are not involved in the decomposition of the active agent or-like an additive which is an antioxidant-decompose the active agent. Provide a coating that protects against.

[0128] Aspects of the invention are also methods for making coated medical devices (preparation of coating compositions) that minimize oxidative and / or hydrolysis degradation of sensitive therapeutic agents such as rapamycin and derivatives thereof. And methods for processing). Processing, packaging and storage of coated medical devices are particularly important for drug stability, and in aspects of the invention, reducing oxygen and water during packaging will oxidize and hydrolyze the therapeutic agent over time during long-term storage. Is further suppressed. Certain embodiments of the method provide processing and packaging of coated medical devices to minimize the degradation of the therapeutic agent.

Suitable additives that can be used in aspects of the invention include, but are not limited to, organic and inorganic pharmaceutical excipients, natural products and derivatives thereof (eg, sugars, vitamins, amino acids, peptides, proteins, and (Amino acids), low molecular weight oligomers, surfactants (anionic, cationic, nonionic, and ionic), and mixtures thereof. The following detailed list useful in the present invention is presented for illustrative purposes and is not intended to be comprehensive. Many other additives can be used for the purposes of the present invention.

[0130] Surfactant
[0131] The surfactant may be any surfactant suitable for use in pharmaceutical compositions. Such surfactants may be anionic, cationic, zwitterionic or nonionic. Mixtures of surfactants are also included within the scope of the invention, including combinations of surfactants and other additives. Surfactants often have one or more long aliphatic chains, such as fatty acids, which can be inserted directly into the lipid bilayer of cell membranes to form part of the lipid structure, while surfactants Other components loosen the lipid structure and enhance the penetration and absorption of the drug. The contrast agent iopmemid does not have these properties.

[0132] A commonly used empirical parameter to characterize the relative hydrophilicity and hydrophobicity of surfactants is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values are more hydrophobic and have greater solubility in oil, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solution. Have. Using HLB values as a rough indicator, hydrophilic surfactants are generally compounds with HLB values greater than about 10 and generally anionic, cationic, or amphoteric compounds to which HLB values cannot be applied. Conceivable. Similarly, hydrophobic surfactants are compounds with an HLB value of less than about 10. In certain aspects of the invention, higher HLB values are preferred as high hydrophilicity can facilitate the release of hydrophobic drugs from the surface of medical devices. In one embodiment, the HLB of the surfactant is higher than about 10. In other embodiments, the HLB of the additive is higher than about 14. Alternatively, the surface activity with a lower HLB, for example when used in a topcoat covering a drug layer containing highly hydrophilic additives, to prevent drug loss prior to placement of the medical device at the target site. Agents may be preferred. The HLB value of the surfactant-based additive in a particular embodiment is in the range of 0.0-40.

[0133] It should be understood that the HLB value of a surfactant is only a rough indicator commonly used to allow the formulation of emulsions for, for example, industrial, pharmaceutical and cosmetic products. For many important surfactants, including some polyethoxylated surfactants, HLB values can vary by as much as about 8 HLB units depending on the empirical method chosen to measure HLB values. (Schott, J. Pharm. Sciences, 79 (1), 87-88 (1990)). Considering these inherent difficulties, the HLB value as an index is used to identify a hydrophilic or hydrophobic surfactant suitable for use in aspects of the invention as described herein. Can be done.

[0134] PEG-fatty acids and PEG-fatty acid monoesters and diesters
[0135] Polyethylene glycol (PEG) itself does not function as a surfactant, but a variety of PEG-fatty acid esters have useful surfactant properties. Among the PEG-fatty acid monoesters, the esters of lauric acid, oleic acid, and stearic acid, myristoleic acid, palmitoleic acid, linoleic acid, linolenic acid, eicosapentaenoic acid, erucic acid, ricinoleic acid, and docosahexaenoic acid are of the present invention. Most useful for aspects. Preferred hydrophilic surfactants include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, Includes PEG-15 oleate, PEG-20 laurate and PEG-20 oleate. PEG-15 12-Hydroxystearate (Solutol HS 15) is a nonionic surfactant used in injections. Solutol HS 15 is a preferred additive in certain embodiments of the invention because it is a white paste at room temperature and becomes liquid at about 30 ° C., which is above room temperature but below body temperature. HLB values range from 4 to 20.

[0136] This additive (eg, Solutol HS 15) is in paste, solid or crystalline state at room temperature and liquid at body temperature. Certain additives that are liquid at room temperature can make it difficult to make uniformly coated medical devices. Certain liquid additives may prevent the solvent from evaporating or may not stay in place on the surface of the medical device during the coating process of the device at room temperature, eg, on the balloon portion of a balloon catheter. In certain embodiments of the invention, paste and solid additives are preferred; they can remain localized on the medical device as a uniform coating and can be dried at room temperature. .. In some embodiments, when the solid coating on a medical device is exposed to a higher physiological temperature of about 37 ° C. when placed in the human body, it becomes a liquid. In these embodiments, the liquid coating is very easily released from the surface of the medical device and easily migrates into the affected tissue. Additives with changes in temperature-induced state under physiological conditions are of great importance in certain aspects of the invention, especially in drug-coated balloon catheters. In certain embodiments, both solid and liquid additives are used in combination during the drug coating of the present invention. This combination improves the integration of medical device coatings. In certain aspects of the invention, at least one solid additive is used during drug coating.

[0137] Polyethylene glycol fatty acid diesters are also suitable for use as surfactants in the compositions of aspects of the present invention. The most preferred hydrophilic surfactant is PEG-20.
Includes dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-23 dioleate. HLB values range from 5 to 15.

[0138] In general, mixtures of surfactants are also useful in aspects of the invention, including mixtures of two or more commercially available surfactants, and surfactants and other additives (s). Contains a mixture. Several PEG-fatty acid esters are commercially available as a mixture of monoesters and diesters.

[0139] Polyethylene glycol glycerol fatty acid ester
[0140] Preferred hydrophilic surfactants are PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate.

[0141] Alcohol-Oil Transesterification Product
Reactions of alcohols or polyalcohols with various natural and / or hydrogenated oils can produce a large number of surfactants with varying degrees of hydrophobicity or hydrophilicity. Most commonly, the oil used is castor oil or hydrogenated castor oil, or edible vegetable oils such as corn oil, olive oil, lacquer oil, palm kernel oil, apricot oil or tongue oil (almond oil). Preferred alcohols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, and pentaerythritol. Of these alcohol-oil ester exchange type surfactants, the preferred hydrophilic surfactants are PEG-35 castor oil, glycerol polyethylene glycol-lysinolate (Incrocas-35, and Cremophor EL and ELP), and PEG-40 hydrogenated castor oil. (Cremophor RH 40), PEG-15 hydrogenated castor oil (Solutol HS 15), PEG-25 trioleate (TAGAT.RTM.TO), PEG-60 corn glycols (Crovol M70), PEG-60 tongue oil (Crovol A70). , PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 capricyl / capric acid glyceride (Labrasol), and PEG-6 caprylic acid / capric acid glyceride (Softigen 767). Preferred hydrophobic surfactants in this class include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil. RTM. M 2125 CS), PEG- 6 Castor oil (Labrafil. RTM. M 1966 CS), PEG-6 apricot oil (Labrafil. RTM. M 1944 CS), PEG-6 olive oil (Labrafil. RTM. M 1980 CS), PEG-6 Lacrafil. RTM. M 1969 CS), PEG-6 hydrogenated palm kernel oil (Labrafil. RTM. M 2130 BS), PEG-6 palm kernel oil (Labrafil. RTM. M 2130 CS), PEG-6 triorain (Labrafil. RTM) .B M 2735 CS), PEG-8 corn oil (Labrafil. RTM. WL 2609 BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 castor glycerides (Crovol A40).

[0143] Fatty Acid Polyglyceryl A fatty acid polyglyceryl ester is also a suitable surfactant for use in aspects of the present invention. Among the fatty acid polyglyceryl esters, preferred hydrophobic surfactants include polyglyceryl oleicue, polyglyceryl-2 dioleate (Nikkol DGDO), polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate, polyglyceryl myristate, and polyglyceryl. Includes palmitate, and polyglyceryl linoleate. Preferred hydrophilic surfactants are polyglyceryl-10 laurate (Nikkol Decaglin 1-L), polyglyceryl-10 oleate (Nikkol Decaglin 1-O), and polyglyceryl-10 mono, dioleate (Caprol. RTM. PEG 860), polyglyceryl. -10 stearate, polyglyceryl-10 laurate, polyglyceryl-10 millistate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6 millistate, polyglyceryl-6 palmitate, and polyglyceryl-6 -6 linoleate is included. Polyglyceryl polyricinolates (Polymuls) are also preferred surfactants.

[0144] Propylene glycol fatty acid ester
[0145] Esters of propylene glycol and fatty acids are suitable surfactants for use in aspects of the present invention. In this surfactant class, preferred hydrophobic surfactants include propylene glycol monolaurate (Lauroglycol FCC), propylene glycol lysinolate (Propymuls), propylene glycol monooleate (Myverol P-O6), and propylene glycol di. Caprilate / dicaplate (Captex. RTM. 200), and propylene glycol dioctanoate (Captex. RTM. 800) are included.

[0146] Sterols and sterol derivatives
[0147] Sterols and sterol derivatives are surfactants suitable for use in aspects of the invention. Preferred derivatives include polyethylene glycol derivatives. A preferred surfactant in this class is PEG-24 cholesterol ether (Solulan C-24).

[0148] Polyethylene glycol sorbitan fatty acid ester
[0149] A variety of PEG-sorbitan fatty acid esters are available and are suitable for use as surfactants in aspects of the invention. Among the PEG-sorbitan fatty acid esters, preferred surfactants are PEG-20 sorbitan monolaurate (Tween-20), PEG-4 sorbitan monolaurate (Tween-21), and PEG-20.
Sorbitan Monopalmitate (Tween-40), PEG-20 Sorbitan Monostearate (Tween-60), PEG-4 Sorbitan Monostearate (Tween-61), PEG-20 Sorbitan Monooleate (Tween-80), PEG -4 Sorbitan monooleate (Tween-81), PEG-20 sorbitan trioleate (Tween-85) are included. Lauric acid ester is preferable because it has a shorter lipid chain than oleic acid ester and enhances drug absorption.

[0150] Polyethylene glycol alkyl ether
[0151] Polyethylene glycol and alkyl alcohol ethers are surfactants suitable for use in aspects of the present invention. Preferred ethers include laureths (Laneth-5, laureth-10, laureth-15, laureth-20, laureth-25, and laureth-40), laureths (Laureth-5, laureth-10, laureth-15, laureth). -20, Laureth-25, and Laureth-40), Ethers (Oleth-2, Oleth-5, Oleth-10, Oleth-12, Oleth-16, Oleth-20, and Oleth-25), Ethereths (Steareth) -2, Steareth-7, Steareth-8, Steareth-10, Steareth-16, Steareth-20, Steareth-25, and Steareth-80), Ethers (Ceteth-5, Ceteth-10, Ceteth-15, Ceteth- 20, Ceteth-25, Ceteth-30, and Ceteth-40), PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij 30).

[0152] Sugars and derivatives thereof
[0153] Sugar derivatives are surfactants suitable for use in aspects of the present invention. Preferred surfactants in this class include sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl. -Β-D-Glucopyranoside, n-dodecyl-β-D-Maltside, Heptanoyl-N-Methylglucamide, n-Heptyl-β-D-Glucopyranoside, n-Heptyl-β-D-thioglucoside, n-hexyl- β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, and octyl-β-D-thio Contains glucopyranoside.

[0154] Polyethylene glycol alkylphenol
[0155] Several PEG-alkylphenol-based surfactants, such as PEG-10-100 nonylphenol and PEG-15-100 octylphenol ether, Tyroxapol, octoxinol, nonoxinol, are available and are surface active in aspects of the invention. Suitable for use as an agent.

[0156] Polyoxyethylene-Polyoxypropylene (POE-POP) Block Copo
Rimmer
[0157] POE-POP block copolymers are a unique class of polymeric surfactants. The unique structure of these surfactants, including the hydrophilic POE moiety and the hydrophobic POP moiety in well defined proportions and positions, provides a wide variety of surfactants suitable for use in aspects of the invention. To do. These surfactants are available under a variety of trade names, including the Synperonic PE Series (ICI); Pluronic. RTM. Included are Series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Puracare, and Purodac. The generic name for these polymers is "poloxamer" (CAS 9003-11-6). These polymers have the following equation:
[0158] HO (C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) _a H: “a” and “b” in the equation are polyoxyethylene units and polyoxy, respectively. Represents the number of propylene units.

[0159] Preferred hydrophilic surfactants in this class include Poloxamer 108, 188, 217, 238, 288, 338, and 407. Preferred hydrophobic surfactants of this class include Poloxamer 124, 182, 183, 212, 331, and 335.

[0160] Polyester-Polyethylene Glycol Block Copolymer
[0161] Polyethylene glycol-polyester block copolymers are a unique class of polymeric surfactants. The unique structure of these surfactants, which include hydrophilic polyethylene glycol (PEG) moieties and hydrophobic polyester moieties in well-defined proportions and positions, is a wide variety of interfaces suitable for use in aspects of the invention. Provide an activator. Polyesters in these block polymers include: poly (L-lactide) (PLLA), poly (DL-lactide) (PDLLA), poly (D-lactide) (PDLA), polycaprolactone (PDLA). PCL), polyesteramide (PEA), polyhydroxyalkanoates, polyhydroxybutyrate (PHB), polyhydroxybutyrate-co-hydroxyvalerates (PHBV), polyhydroxybutyrate-co-hydroxyhexanoate (PHBV) PHBHx), polyamino acids, polyglycolides or polyglycolic acids (PGA), polyglycolides and copolymers thereof (poly with lactic acid (lactic acid-co-glycolic acid), poly with ε-caprolactone (glycolide-co-caprolactone), Poly (glycolide-co-trimethylene carbonate) with trimethylene carbonate, and their copolyesters. Examples are PLA-b-PEG, PLLA-b-PEG, PLA-co-PGA-b-PEG, PCL-co-PLLA-b-PEG, PCL-co-PLLA-b-PEG, PEG-b-PLLA- b-PEG, PLLA-b-PEG-b-PLLA, PEG-b-PCL-b-PEG, and other di, tri, and multiblock copolymers. The hydrophilic block may be other hydrophilic or water soluble polymers such as polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, and polyacrylic acid.

[0162] Polyethylene Glycol Graft Copolymer
[0163] An example of a graft copolymer is Soluplus (BASF, Germany). Soluplus is a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. This copolymer is a solubilizer with an amphipathic chemical structure that can solubilize poorly soluble drugs such as paclitaxel, rapamycin and derivatives thereof in aqueous media. The molecular weight of this copolymer is in the range of 90,000 to 140000 g / mol.

[0164] Polymers, copolymers, block copolymers, and graft copolymers with amphipathic chemical structures are used as additives in the present invention. Polymers with amphipathic chemical structures are block or graft copolymers. Many segments (at least two segments) of different repeating units are in these copolymers. In some embodiments, one of the segments is more hydrophilic than the other segments in their copolymer. Similarly, one of the segments is more hydrophobic than the other segments in their copolymers. For example, in Soluplus (BASF, Germany), polyethylene glycol segments are more hydrophilic than polyvinylcaprolactam-polyvinyl acetate segments. Polyester segments in polyethylene glycol-polyester block copolymers are more hydrophobic than polyethylene glycol segments. In PEG-PLLA, PEG is more hydrophilic than PLLA. In PEG-b-PCL-b-PEG, PCL is more hydrophobic than PEG. The hydrophilic segment is not limited to polyethylene glycol. Other water-soluble polymers, such as soluble polyvinylpyrrolidone and polyvinyl alcohol, can form hydrophilic segments in polymers with amphipathic structures. These copolymers can be used in combination with other additives in the present invention.

[0165] Sorbitan fatty acid ester
[0166] The sorbitan ester of fatty acid is a surfactant suitable for use in aspects of the present invention. Among these esters, preferred hydrophobic surfactants include sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate (Span-80), and sorbitan monostearate. included.

[0167] The amphipathic derivative of vitamin C, sorbitan monopalmitate, which has vitamin C activity, can perform two important functions in the solubilization system. First, it possesses effective polar groups that can regulate the microenvironment. These polar groups are the same groups that form organic vitamin C itself (ascorbic acid), one of the most water-soluble organic solid compounds available: ascorbic acid up to about 30 wt / wt% in water. Dissolves (eg, very close to the solubility of sodium chloride). Second, as the pH rises, some of the ascorbyl palmitate is converted to more soluble salts, such as sodium ascorbyl palmitate.

[0168] Ionic surfactant
[0169] Ionic surfactants, including cationic, anionic and amphoteric surfactants, are hydrophilic surfactants suitable for use in aspects of the invention.

[0170] Anionic surfactants carry a negative charge in the hydrophilic moiety. The major classes of anionic surfactants used as additives in aspects of the invention include carboxylates, sulfates and sulfonate ions. Preferred cations used in aspects of the invention are sodium, calcium, magnesium and zinc. The straight chain is generally a saturated or unsaturated C8-C18 aliphatic group. Anionic surfactants containing carboxylate ions include aluminum stearate, sodium stearate, calcium stearate, magnesium stearate, zinc stearate, sodium oleate, zinc and potassium, sodium stearyl fumarate, sodium lauroyl sarcosinate. , And sodium myritoyl sarcosinate. Anionic surfactants with sulfate groups include sodium lauryl sulfate, sodium dodecyl sulfate, mono- and di-lauryl sulfate, and triethanolamine, sodium lauryl ether sulfate, sodium cetostearyl sulfate, sodium cetearyl sulfate, and sodium tetradecyl sulfate. Includes, sulfated castor oil, sodium cholesteryl sulfate, sodium tetradecyl sulfate, sodium myristyl sulfate, sodium octyl sulfate, other medium-chain-branched or unbranched alkyl sulfates, and ammonium lauryl sulfate. Anionic surfactants having a sulfonate group include sodium doxate, sodium dioctyl sulfosuccinate, sodium lauryl sulfonate, sodium alkylbenzene sulfonate, sodium dodecylbenzene sulfonate, sodium diisobutyl sulfosuccinate, sodium diamyl sulfosuccinate, sulfosuccinate. Includes di (2-ethylhexyl) acid and sodium bis (1-methylamyl) sulfosuccinate.

[0171] The most common cationic surfactant used in aspects of the present invention is a quaternary ammonium compound having _{the general formulas R 1} , R ₂ , R ₃ , R ₄ N ⁺ X ^{− and formula.} X ^{− in it} is usually a chlorine or bromine ion, and R represents an alkyl group containing C8-18 atoms. These types of surfactants are of pharmaceutical importance due to their bacterial killing properties. The major cationic surfactant used in the preparation of pharmaceuticals and medical devices in the present invention is a quaternary ammonium salt. These surfactants include cetrimid, cetrimonium bromide, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, hexadecyltrimethylammonium chloride, stearalconium chloride, lauralconium chloride, tetradecylammonium chloride, myristylpicoli. Includes nium chloride, and dodecylpicolinium chloride. These surfactants may react with certain therapeutic agents in the formulation or coating. These surfactants may be preferred if they do not react with the therapeutic agent.

[0172] Zwitteric or amphoteric surfactants include, among other things, dodecyl betaine, cocamidopropyl betaine, cocoampho clycinate.
[0173] Preferred ionic surfactants include sodium lauryl sulphate, sodium dodecyl sulphate, sodium lauryl ether sulphate, sodium cetostearyl sulphate, sodium cetearyl sulphate, sodium tetradecyl sulphate, sulfated castor oil, sodium cholesteryl sulphate, sodium tetradecyl sulphate, Sodium myristyl sulphate, sodium octyl sulphate, other medium-branched or non-branched alkyl sulfates, sodium doxate, sodium dioctyl sulfosuccinate, sodium lauryl sulfosuccinate, sodium alkylbenzene sulfonate, sodium dodecylbenzene sulfonate, benzalconium chloride , Benzethonium Chloride, Cetylpyridinium Chloride, Doseciltrimethylammonium Bromide, Sodium Dosecil Sulfate, Dialkylmethylbenzylammonium Chloride, Edrophonium Chloride, Domiphen Bromide, Dialkylester of Sodium Sulfosuccinate, Sodium Dioctyl Sulfosuccinate, Sodium Dodecyl Sulfate, and Taurocol Includes sodium sulphate. These quaternary ammonium salts are preferred additives. They can be dissolved in both organic solvents (eg ethanol, acetone, and toluene) and water. It is particularly useful for medical device coatings as it simplifies the preparation and coating process and has good adhesive properties. Water-insoluble drugs are generally dissolved in organic solvents. The HLB values of these surfactants are generally in the range of 20-40, for example sodium dodecyl sulfate (SDS) has an HLB value of 38-40.

[0174] Certain surfactants described herein are extremely stable under heating. They survive the ethylene oxide sterilization process. They do not react with drugs such as paclitaxel or rapamycin in the bactericidal process. Hydroxy, ester, and amide groups are preferred because they are not considered to react with the drug, while amines and acid groups often actually react with paclitaxel or rapamycin during the sterilization process. In addition, surfactant-based additives improve the integrity and quality of the coating layer, so particles do not fall off during handling. When the surfactants described herein are formulated with paclitaxel, it experimentally protects the drug from premature release in the medical device delivery process, while placing it at the target site for a very short period of 0.2-2 minutes. To facilitate the rapid release and elution of paclitaxel. Drug absorption by tissues at the target site is unexpectedly high according to experiments.

[0175] Chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties
Chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties include aminoalcohols, hydroxylcarboxylic acids, esters, and anhydrides, hydroxylketones, hydroxyllactones, hydroxylesters, Sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins, sorbitans, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids , As well as their substituted molecules. Hydrophilic chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties having a molecular weight of 5,000 to less than 10,000 are preferred for certain embodiments. In other embodiments, the molecular weight of the additive having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties is preferably less than 1000-5,000, or more preferably less than 750-1,000. Or most preferably less than 750. In these embodiments, the molecular weight of the additive is preferably smaller than that of the delivered drug. In addition, the molecular weight of the additive is preferably greater than 80; molecules with a molecular weight less than 80 are extremely prone to evaporation and do not remain in the coating of medical devices. If the additive is volatile or liquid at room temperature, it is important that its molecular weight exceeds 80 so that the additive is not lost when the solvent is evaporated during the coating process. However, in certain aspects where the additive is not volatile, such as solid additives such as alcohols, esters, amides, acids, amines, and derivatives thereof, the additive easily evaporates from the coating. The molecular weight of the additive may be less than 80, less than 60, and less than 20. The solid additive may be crystalline, semi-crystalline, and amorphous. Small molecules can diffuse rapidly. They themselves can easily elute from the delivery balloon to facilitate the release of the drug, and they can withdraw and diffuse from the drug as it binds to the tissues of the body cavity. In certain embodiments, for example in the case of high molecular weight additives, more than four hydroxyl groups are preferred. Large molecules are slow to diffuse. If the molecular weight of the additive or chemical compound is high, for example greater than 800, greater than 1000, greater than 1200, greater than 1500, or greater than 2000, the macromolecules will elute from the surface of the medical device. It may be too late to release the drug in less than 2 minutes. When these large molecules contain more than four hydroxyl groups, they become more hydrophilic, which is necessary for the relatively large molecules to release the drug rapidly. Increased hydrophilicity aids the coating to elute from the balloon, facilitates drug release, improves drug migration through the water barrier and polar head groups of the lipid bilayer and penetrates the tissue. Or make it easier. Hydroxy groups are preferred as hydrophilic moieties as they are not believed to react with water-insoluble drugs such as paclitaxel or rapamycin. In some embodiments, a chemical compound containing more than four hydroxyl groups has a melting point of 120 ° C. or lower. In some embodiments, chemical compounds containing more than four hydroxyl groups have three adjacent hydroxyl groups, all of which are on one side of the molecule in configuration. For example, sorbitol and xylitol all have three adjacent hydroxyl groups on one side of the molecule in the configuration, while galactitol does not. This difference affects the physical properties of the isomers, such as the melting temperature. This configuration of three adjacent hydroxyl groups can enhance drug binding. This will improve the compatibility of the water-insoluble drug with the hydrophilic additive and improve the uptake and absorption of the drug by the tissue.

[0177] Chemical compounds with amide moieties are important in coating formulations in certain aspects of the invention. Urea is an example of a chemical compound having an amide group. In addition, biuret, acetamide, lactic acid amide, amino acid amide, acetaminophen, uric acid, polyurea, urethane, urea derivative, niacinamide, N-methylacetamide, N, N-dimethylacetamide, sulfacetamide sodium, versetamide, Includes lauric acid diethanolamide, lauric acid myristic acid diethanolamide, N, N-bis (2-hydroxyethylstealamide), cocamide MEA, cocamide DEA, arginine, and other organic acid amides, as well as their derivatives. .. Some chemical compounds with an amide group also have one or more hydroxyl, amino, carbonyl, carboxyl, acid, or ester moieties.

[0178] One of the chemical compounds with an amide group is soluble low molecular weight povidone. Povidone includes Kollidon 12 PF, Kollidon 17 PF, Kollidon 17, Kollidon 25, and Kollidon 30. Kollidon products consist of soluble and insoluble grades of polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers of various molecular weights and particle sizes, and blends of polyvinyl acetate and polyvinylpyrrolidone. Family products are labeled Povidone, Crosspovidone and Copovidone. Low molecular weight soluble povidones and copovidones are particularly important additives in the present invention. For example, Kollidon 12 PF, Kollidon 17 PF, and Kollidon 17 are extremely important. Solid povidone can maintain the integrity of the coating on medical devices. Low molecular weight povidone can be absorbed or permeated into affected tissue. The preferred molecular weight range of povidone is less than 54,000, less than 11,000, less than 7,000 and less than 4000. They can solubilize water-insoluble therapeutic agents. Due to these solid, low molecular weight and tissue absorption / permeation properties, povidone and copovidone are particularly useful in the present invention. Povidone can be used in combination with other additives in the present invention. In one embodiment, povidone and a nonionic surfactant (eg, PEG-15 12-hydroxystearate (Solutol HS 15), Tween 20, Tween 80, Cremophor RH40, Cremophor EL and ELP) are paclitaxel or rapamycin or theirs. Together with analogs, it can be formulated as a coating for medical devices such as balloon catheters.

[0179] Chemical compounds with ester moieties are of particular importance for coating formulations of certain embodiments. The products of organic acids and alcohols are chemical compounds with ester groups. Chemical compounds with ester groups are often used as plasticizers for polymeric materials. A wide range of ester chemical compounds include sebates, adipates, gluterates, and phthalates. Examples of these chemical compounds are bis (2-ethylhexyl) phthalate, di-n-hexyl phthalate, diethyl phthalate, bis (2-ethylhexyl) adipate, dimethyl adipate, dioctyl adipate, dibutyl sebacate, Dibutyl maleate, triethyl citrate, acetyltriethyl citrate, trioctyl citrate, trihexyl citrate, butyryl trihexyl citrate, and trimethyl citrate.

[0180] Some of the chemical compounds with one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties described herein are extremely stable under heating. They survive the ethylene oxide sterilization process and do not react with the water-insoluble drug paclitaxel or rapamycin during the sterilization process. In contrast, L-ascorbic acid and its salts as well as diethanolamine do not necessarily survive in such bactericidal processes, and they react with paclitaxel. Therefore, different sterilization methods are preferred for L-ascorbic acid and diethanolamine. Hydroxy, ester, and amide groups are preferred as they are unlikely to react with therapeutic agents such as paclitaxel or rapamycin. Amines and acid groups sometimes actually react with paclitaxel; for example, benzoic acid, gentisic acid, diethanolamine, and ascorbic acid are not stable under ethylene oxide sterilization, heating, and aging processes and have reacted with paclitaxel, for example. .. When the chemical compounds described herein are formulated with paclitaxel, hydrophilic small molecules sometimes release the drug too easily, thus preventing premature drug loss prior to placement at the target site during the delivery process of the medical device. Therefore, the top coat layer may be advantageous. The chemical compounds herein cause the drug to elute rapidly from the balloon when placed at the target site. Surprisingly, if the coating contains these additives, even if some drug is lost when moving the medical device to the target site, experiments have shown that tissue absorption of the drug is, for example, ribbon acid lactone and Additives such as gluconolactone Hydroxyllactones are unexpectedly high, only 0.2 to 2 minutes after placement.

[0181] Antioxidants
[0182] Antioxidants are molecules that can delay or prevent the oxidation of other molecules. The oxidative reaction can generate free radicals, which can initiate a chain reaction and cause the degradation of sensitive therapeutic agents such as rapamycin and its derivatives. Antioxidants terminate these chain reactions by removing free radicals, and they further inhibit the oxidation of the active agent by oxidizing themselves. Antioxidants are, in certain embodiments, used as additives to prevent or delay the oxidation of therapeutic agents in the coating of medical devices. Antioxidants are a type of free radical scavenger. Antioxidants can be used alone or in combination with other additives in certain embodiments of the invention to prevent the degradation of effective therapeutic agents during sterilization or storage prior to use.

[0183] Some representative examples of antioxidants that can be used in the methods of the invention are, but are not limited to, oligomeric or polymeric proanthocyanidins, polyphenols, polyphosphates, polyazomethins, high sulfate agar oligomers, chitosan. Chitooligosaccharides obtained by partial hydrolysis of, polyfunctional oligomeric thioethers, including sterically damaged phenols, hindered amines, for example, but not limited to p-phenylenediamine, trimethyldihydroquinolones, and alkylated diphenylamines. , Substituted phenolic compounds (hindered phenols) containing one or more bulky functional groups such as tert-butyl, arylamines, phosphites, hydroxylamines, and benzofuranones. Aromatic amines such as p-phenylenediamine, diphenylamine, and N, N'di-substituted p-phenylenediamine can also be used as free radical scavengers. Other examples include, but are not limited to, butylated hydroxytoluene (“BHT”), butylated hydroxyanisole (“BHA”), L-ascorbate (vitamin C), vitamin E, herb rosemary, sage extract, glutathione. , Resverator, ethoxyquin, rosmanol, isolosmanol, rosmaridiphenol, propyl gallic acid, gallic acid, caffeic acid, p-coumeric acid, p-hydroxybenzoic acid, astaxanthin, ferulic acid, dehydrozingerone , Chlorogenic acid, ellagic acid, propylparaben, synapic acid, daidin, glycitin, genistine, daizein, glycitein, genistain, isoflavones, and tert-butylhydroquinone. Examples of some phosphites include di (stearyl) pentaerythritol diphosphite, tris (2,4-di-tert-butylphenyl) phosphite, dilauryl thiodipropionate and bis (2,4-di-). tert-Butylphenyl) Pentaerythritol diphosphite is included. Some examples of hindered phenols include, but are not limited to, octadecyl-3,5, di-tert-butyl-4-hydroxycinnamate, tetrakis-methylene-3- (3', 5'-di-tert-butyl). -4-Hydroxyphenyl) propionate methane includes 2,5-di-tert-butylhydroquinone, ionol, pyrogallol, retinol, and octadecyl-3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate. .. Antioxidants include glutathione, lipoic acid, melatonin, tocopherols, tocotrienols, thiols, beta-carotene, retinoic acid, cryptoxanthin, 2,6-di-tert-butylphenol, propyl gallate, catechin, propylate. Cathetin, and quercetin can be included. Preferred antioxidants are butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).

[0184] Fat-soluble vitamins and their salts
[0185] Vitamins A, D, E and K are considered fat-soluble vitamins in their various forms and in the form of provitamins, and many other vitamins and vitamin sources or related vitamins. It is also lipophilic, with polar groups and a relatively high octanol-water partition coefficient. Obviously, such compounds in the general class have a safe history of use and a high profit / loss ratio, which makes them useful as additives in aspects of the invention.

Examples of fat-soluble vitamin derivatives and / or vitamin sources below are also useful as additives: alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, tocopherol acetate, ergosterol, 1-alpha- Hydroxycholeciferol, Vitamin D2, Vitamin D3, Alpha-Caroten, Beta-Caroten, Gamma-Caroten, Vitamin A, Flusultiamine, Methylrolriboflavin, Octothamine, Prosultiamine, Riboflavin, Vinthiamol, Dihydrovitamin K1, 2 Menadiol acetate, menadiol dibutyrate, menadiol disulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamin K2, and vitamin K-S (II). Folic acid is also of this type, which is water soluble at physiological pH but can be formulated in the form of free acid. Other derivatives of fat-soluble vitamins useful in aspects of the present invention can be readily obtained by well-known chemical reactions with hydrophilic molecules.

[0187] Water-soluble vitamins and their amphipathic derivatives
[0188] Vitamins B, C, U, pantothenic acid, folic acid, and some menadione-related vitamins / provitamins, in their various forms, are considered water-soluble vitamins. They can also be conjugated or complexed with hydrophobic moieties or polyvalent ions to form amphipathic forms with relatively high octanol-water partition coefficients and polar groups. Again, such compounds can have low toxicity and high profit / loss ratios, which makes them useful as additives in aspects of the invention. These salts can also be useful as additives in aspects of the present invention. Examples of water-soluble vitamins and derivatives include, but are not limited to, acetylamine, benfothamine, pantothenic acid, setothiamine, sicothamine, dexpantenol, niacinamide, nicotinamide, pyridoxal 5-phosphate, ascorbic acid nicotinamide, riboflavin, Includes riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, sodium menadione bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U. Similarly, as mentioned above, folic acid is water soluble as a salt over a wide pH range, including physiological pH.

[0189] Compounds in which amino or other basic groups are present are acids containing hydrophobic groups, such as fatty acids (particularly lauric acid, oleic acid, myristic acid, palmitic acid, stearic acid, or 2-ethylhexanoic acid). Can be easily modified by a simple acid-base reaction with a poorly soluble amino acid, benzoic acid, salicylic acid, or an acidic fat-soluble vitamin (eg, riboflavin). Other compounds can be obtained by reacting such acids with other groups on the vitamin, such as hydroxyl groups, to form bonds such as ester bonds. Derivatives of water-soluble vitamins containing acid groups can be produced by reaction with reactants containing hydrophobic groups, such as stearylamine or riboflavin, to form compounds useful in aspects of the invention. Binding of the palmitate chain to vitamin C gives ascorbyl palmitate.

[0190] Amino acids and their salts
[0191] Alanine, arginine, aspartic acid, aspartic acid, cysteine, cysteine, glutamic acid, glutamine, glycine, histidine, proline, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, and derivatives thereof. Is another additive useful in aspects of the invention.

[0192] Certain amino acids, in their zwitterionic form and / or in the form of salts with monovalent or polyvalent ions, have polar groups and have a relatively high octanol-water partition coefficient. It is useful for aspects of the present invention. With respect to the disclosure of the present invention, "poorly soluble amino acid" is meant to mean an amino acid having a solubility of less than about 4% (40 mg / ml) in unbuffered water. These include cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine.

[0193] Amino acid dimers, sugar conjugates, and other derivatives are also useful. By a simple reaction well known in the art, hydrophilic molecules can be attached to hydrophobic amino acids, or hydrophobic molecules can be attached to hydrophilic amino acids to produce yet other additives useful in aspects of the invention.

[0194] Catecholamines such as dopamine, levodopa, carbidopa, and DOPA are also useful as additives.
[0195] Oligopeptides, peptides and proteins
[0196] Oligopeptides and peptides are useful as additives because hydrophobic and hydrophilic amino acids are easily coupled, and various amino acid sequences can be tested to maximize the tissue permeation of the drug. ..

[0197] Proteins are also useful as additives in aspects of the invention. Serum albumin, for example, is a particularly preferred additive because it is water-soluble and contains a significant hydrophobic moiety that binds the drug: paclitaxel is 89% -98% protein-bound after intravenous injection into humans. Rapamycin binds 92% to proteins, primarily (97%) albumin. In addition, the solubility of paclitaxel in PBS is increased by more than 20-fold with the addition of BSA. Albumin is naturally present in high concentrations in serum and is therefore extremely safe for use in human blood vessels.

[0198] Other useful proteins include, but are not limited to, other albumins, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulins, fibronectins, vitronectins, Includes fibrinogens, lipases, etc.

[0199] Organic acids and their esters, amides and anhydrides
[0200] Examples include acetic acid and anhydride, benzoic acid and anhydride, diethylenetriamine pentaacetate dianhydride, ethylenediaminetetraacetate dianhydride, maleic acid and anhydride, succinic acid and anhydride, diglycolic acid anhydride, glutaric anhydride, Ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic anhydride aspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, alloyric acid, shelophosphoric acid, and 2-pyrrolidone. Aleuritic acid and shelophosphoric acid can form a resin called shellac. Paclitaxel, aleuritic acid, and shelophosphate can be used together as a drug release coating for balloon catheters.

[0201] These esters and acid anhydrides are soluble in organic solvents such as ethanol, acetone, methyl ethyl ketone, ethyl acetate. Water-insoluble drugs can be dissolved in organic solvents containing these esters, amides and acid anhydrides, then readily coated on medical devices and then hydrolyzed under high pH conditions. Hydrolyzed acid anhydrides or esters are acids or alcohols, which are water soluble and can effectively carry the drug away from the medical device and into the vascular wall.

[0202] Other chemical compounds with one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties
[0203] Additives according to aspects of the invention include both cyclic and linear aliphatic and aromatic amino alcohols, alcohols, amines, acids, amides and hydroxyl acids. Examples are: L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxyl. Ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, ribbon acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, 4- Chrysoxybenzoate propyl, lysine acetate salt, gentic acid, lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphates, glucopyranose phosphate, sugar sulfates, cinnapic acid, vaniphosphate, vanillin, methylparaben, propylparaben, xylitol, 2 -Ethoxyethanol, sugars, galactose, glucose, ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose, fructose, cyclodextrin, (2-hydroxypropyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid, Lysine acetate, gentisic acid, catechin, ascorbic acid catechin, chilletamine, ketamine, propofol, lactic acid, acetic acid, salts of any of the above organic acids and amines, polyglycidole, glycerol, multiglycerols, galactitol, di (ethylene) Glycol), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene glycol), poly (ethylene glycol) oligomer, di (propylene glycol), tri (propylene glycol), tetra (propylene glycol), and penta (propylene). Glycol), poly (propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, and derivatives and combinations thereof.

[0204] Combinations of additives are also useful for the purposes of the present invention.
[0205] One embodiment comprises a combination or mixture of two additives, eg, the first additive comprises a surfactant and the second additive is one or more hydroxyls, amines, carbonyls, carboxyls, acids, amides. Alternatively, it contains a chemical compound having an ester moiety.

[0206] Combinations or mixtures of surfactants and water-soluble small molecules (chemical compounds with one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties) have advantages. Formulations containing a mixture of two additives and a water-insoluble drug are, in certain cases, superior to mixtures containing any of the additives alone. Hydrophobic drugs bind extremely water-soluble small molecules weaker than they bind surfactants. They are often phase separated from water-soluble small molecules, which can lead to non-optimal coating uniformity and integrity. Water-insoluble drugs have higher Log P than both those of surfactants and those of small water-soluble molecules. However, the Log P of surfactants is generally higher than that of chemical compounds having one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties. Surfactants have a relatively high Log P (usually greater than 0) and water-soluble molecules have a low Log P (usually less than 0). When used as an additive in aspects of the invention, certain surfactants adhere significantly strongly to the surface of water-insoluble drugs and medical devices, so that the drug cannot be rapidly released from the surface of the medical device at the target site. In contrast, some water-soluble small molecules (chemical compounds with one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties) bind significantly weakly to medical devices before they reach the target site. In addition, the coated balloon catheter releases the drug, for example, into the serum as it travels to the target site for intervention. Surprisingly, by adjusting the concentration ratio of hydrophilic small molecules to surfactants in the formulation, the coating stability during migration and the swelling are pressed against the tissue of the lumen wall at the target site of the therapeutic intervention. We have found that the rapid release of the drug on occasion is in some cases superior to formulations containing any of the additives alone. In addition, the miscibility and compatibility of water-insoluble drugs with highly water-soluble molecules is enhanced by the presence of surfactants. Surfactants also improve coating uniformity and integrity due to their good adhesion to drugs and small molecules. The long-chain hydrophobic portion of the detergent binds the drug tightly, while the hydrophilic portion of the surfactant binds small water-soluble molecules.

[0207] Surfactants in mixtures or combinations include all surfactants described herein for use in aspects of the invention. The surfactant in the mixture can be selected from: PEG fatty acid esters, PEG omega-3 fatty acid esters and alcohols, glycerol fatty acid esters, sorbitan fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters. , Sugar fatty acid esters, PEG sugar esters, Tween 20, Tween 40, Tween 60, p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG steerate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl Steerate, Polyglyceryl Laurate, Polyglyceryl Oleate, Polyglyceryl Millistate, Polyglyceryl Palmitate, Polyglyceryl-6 Laurate, Polyglyceryl-6 Oleate, Polyglyceryl-6 Millistate, Polyglyceryl-6 Palmitate, Polyglyceryl-10 Laurate, Polyglyceryl-10 Oleate Polyglyceryl-10 millistate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, Tween 20, Tween 40, Tween 60, Tween 80, Octoxinol, Monoxinol, Tyroxapol, Monopalmitate sucrose, Monolaurate sucrose, Decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n -Hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D -Thioglucopyranoside, and derivatives thereof.

[0208] A chemical compound having one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties in a mixture or combination is one or more described herein for use in aspects of the invention. Includes all chemical compounds with hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties. A chemical compound having one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties in the mixture has at least one hydroxyl group in one of aspects of the invention. In certain embodiments, more than four hydroxyl groups are preferred, for example in the case of high molecular weight additives. In some embodiments, a chemical compound having more than four hydroxyl groups has a melting point of 120 ° C. or lower. Large molecules are slow to diffuse. If the molecular weight of the additive or chemical compound is high, for example greater than 800, greater than 1000, greater than 1200, greater than 1500, or greater than 2000, the macromolecules will elute from the surface of the medical device. It may be too late to release the drug in less than 2 minutes. When these large molecules contain more than four hydroxyl groups, they become more hydrophilic, which is necessary for the relatively large molecules to release the drug rapidly. Increased hydrophilicity helps the coating elute away from the balloon, facilitates drug release, and improves drug migration through the water barrier and the polar head groups of the lipid bilayer to penetrate the tissue. Make or make it easier. Hydroxy groups are preferred as hydrophilic moieties as they are not believed to react with water-insoluble drugs such as paclitaxel or rapamycin.

[0209] Chemical compounds having one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties in the mixture are selected from: L-ascorbic acid and salts thereof, D-glucoascorbic. Acids and salts thereof, tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid Lactone, mannonic acid lactone, ribbon acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, gentic acid, lactobionic acid, lactitol, sorbitol, glucitol, Sugar phosphates, glucopyranose phosphate, sugar sulfates, cinnapic acid, vaniphosphate, vanillin, methylparaben, propylparaben, xylitol, 2-ethoxyethanol, sugars, galactose, glucose, ribose, mannose, xylose, sucrose, lactose, maltose , Arabinose, Lixose, Fluctose, Cyclodextrin, (2-Hydroxypropyl) -Cyclodextrin, Acetaminophen, Ibuprofen, Retinoic acid, Lysine acetate, Genticinic acid, Catequin, Catergic acid catechin, Tyretamine, Ketamine, Propofol, Lactic acid, Acetic acid, salts of any of the above organic acids and amines, polyglycidole, glycerol, multiglycerols, sorbitol, di (ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene glycol), Poly (ethylene glycol) oligomers, di (propylene glycol), tri (propylene glycol), tetra (propylene glycol), and penta (propylene glycol), poly (propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, and their components. Derivatives and combinations.

[0210] Mixtures or combinations of surfactants and water-soluble small molecules provide the benefits of both additives. Water-insoluble drugs often have poor compatibility with highly water-soluble chemical compounds, and surfactants improve compatibility. Surfactants also improve coating quality, uniformity and integrity, and particles do not fall out of the balloon during handling. Surfactants reduce drug loss as they move to the target site. Water-soluble chemical compounds improve drug release from balloons and drug absorption into tissues. Experiments have shown that this combination was surprisingly effective in blocking drug release during migration and achieving high drug levels in tissues after a very short deployment of 0.2-2 minutes. .. In addition, in animal studies, it effectively reduced arterial stenosis and delayed lumen loss.

[0211] Mixtures or combinations of surfactants and water-soluble small molecules are extremely stable under heating. They survive the ethylene oxide sterilization process and do not react with the water-insoluble drug paclitaxel or rapamycin during the sterilization process. Hydroxy, ester, and amide groups are preferred as they are not considered to react with drugs such as paclitaxel or rapamycin. Amines and acid groups sometimes actually react with paclitaxel under ethylene oxide sterilization, heating and aging and are not stable. When the mixtures or combinations described herein are formulated with paclitaxel, the topcoat layer may be advantageous in order to protect the drug layer and protect it from premature drug loss between devices.

[0212] Liquid additives
[0213] Solid additives are often used in drug-coated medical devices. The iodine contrast agent, iopromide, is used with paclitaxel to coat balloon catheters. These types of coatings do not contain liquid chemical compounds. The coating is an agglomeration of paclitaxel solid and iopromide solid on the surface of a balloon catheter. This coating is non-adhesive to medical devices and coating particles fall off during handling and intervention operations. Water-insoluble drugs such as paclitaxel, rapamycin, and their analogs are often solid chemical compounds. In aspects of the invention, liquid additives can be used in medical device coatings to improve coating integrity. It is preferred to use liquid additives that can improve the compatibility of solid drugs and / or other solid additives. It is preferred to use a liquid additive that can form a solid coating solution that is not an agglomerate of two or more solid particles. If the other additives and drugs are solid, the use of at least one liquid additive is preferred.

[0214] The liquid additive used in aspects of the present invention is not a solvent. Solvents such as ethanol, methanol, dimethyl sulfoxide, and acetone will evaporate after the coating has dried. In other words, the solvent will not remain in the coating after it has dried. In contrast, the liquid additive in aspects of the invention will remain in the coating after it has dried. Liquid additives are liquid or semi-liquid at room temperature and 1 atmosphere. Liquid additives can form gels at room temperature. The liquid additive comprises a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety is a hydrophobic moiety, an affinity for the therapeutic agent by hydrogen bonding, and a van der Waals interaction with the therapeutic agent. It is at least one of the parts having affinity. Liquid additives are not oils.

[0215] Nonionic surfactants are often liquid additives. Examples of liquid additives include the PEG-fatty acids and esters mentioned above, PEG-oil ester exchange products, polyglyceryl fatty acids and esters, propylene glycol fatty acid esters, PEG sorbitan fatty acid esters, and PEG alkyl ethers. Some examples of liquid additives are Tween 80, Tween 81, Tween 20, Tween 40, Tween 60, Solutol HS 15, Cremophor RH40, and Cremophor EL and ELP.

[0216] More than one additive
[0217] In one embodiment, the layer or coating covering the outer surface of the medical device comprises more than one additive, such as a few or four additives. In one embodiment, the coating layer comprises at least one additive, the at least one additive comprising a first additive and a second additive, the first additive being more hydrophilic than the second additive. .. In another embodiment, the coating layer comprises at least one additive, the at least one additive comprising a first additive and a second additive, the first additive different from that of the second additive. Has a structure. In another embodiment, the coating layer comprises at least one additive, the at least one additive comprising a first additive and a second additive, the HLB value of the first additive being that of the second additive. Higher than the one. In yet another embodiment, the coating layer comprises at least one additive, the at least one additive comprising a first additive and a second additive, the Log P value of the first additive being the second additive. Lower than that of the agent. For example, sorbitol (Log P -4.67) is more hydrophilic than Tween 20 (Log P about 3.0). PEG fatty acid esters are more hydrophilic than fatty acids. Butylated hydroxyanisole (BHA) (Log P 1.31) is more hydrophilic than butylated hydroxytoluene (BHT) (Log P 5.32).

[0218] In other embodiments, the layer or coating covering the outer surface of the medical device comprises more than one type of surfactant, such as a few or four types of surfactant. In one embodiment, the coating layer comprises at least one surfactant, the at least one surfactant comprising a first surfactant and a second surfactant, the first surfactant being a second surfactant. It is more hydrophilic than the agent. In another embodiment, the coating layer comprises at least one surfactant, the at least one surfactant comprising a first surfactant and a second surfactant, the HLB value of the first surfactant. Higher than that of the second surfactant. For example, Tween 80 (HLB 15) is more hydrophilic than Tween 20 (HLB 16.7). Tween 80 (HLB 15) is more hydrophilic than Tween 81 (HLB 10). Pluronic F68 (HLB 29) is more hydrophilic than Solutol HS 15 (HLB 15.2). Sodium dodecyl sulfate (HBL 40) is more hydrophilic than sodium doxate (HLB 10). Tween 80 (HBL 15) is more hydrophilic than Creamophor EL (HBL 13).

[0219] Preferred additives include: p-isononylphenoxypolyglycidol, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl. -6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 millistate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 millistate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan mono Laurate, PEG sorbitan monooleate, PEG sorbitan stearate, octoxinol, monoxinol, tyroxalol, sucrose monopalmitate, sucrose monolaurate, decanoyle-N-methylglucamide, n-decyl-β-D-glucopyranoside, n -Decil-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyle-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl -Β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β- D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine (amino acid); setothiamine; sicothamine, dexpantenol, niacinamide, nicotin Acid and its salts, pyridoxal 5-phosphate, ascorbic acid nicotinamide, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bicarbonate, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 , And vitamin U (vitamins); albumin, immunoglobulins, caseins, hemoglobins, lysoteams, immunoglobins, a-2-macroglobulin, fibronectins, bitronectins, fibrinogens, lipase Dialkyl esters of benzalkonium chloride, benzethonium chloride, doceciltrimethylammonium bromide, sodium docecil sulfate, dialkylmethylbenzylammonium chloride, and sodium sulfosuccinate, L-ascorbic acid and salts thereof, D-glucoascorbic acid and Salts of it, tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone Mannon acid lactone, ribbon acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, genticinic acid, lactobionic acid, lactitol, cinnapic acid, vanillic acid, Vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid, lysine acetate, genticic acid, catechin, catechin caricate, tyretamine, ketamine, propofol , Lactic acid, acetic acid, salts of any organic acid and organic amine, polyglycidol, glycerol, multiglycerols, galactitol, di (ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene) Glycol), poly (ethylene glycol) oligomers, di (propylene glycol), tri (propylene glycol), tetra (propylene glycol), and penta (propylene glycol), poly (propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol. , And derivatives and combinations thereof (chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups). Some of these additives are water-soluble and organic solvent-soluble. They have good adhesive properties and adhere to the surface of polyamide medical devices, such as balloon catheters. Therefore, they can be used in the adhesive layer, top layer, and / or drug layer of aspects of the invention. Aromatic and aliphatic groups increase the solubility of water-insoluble drugs in the coating solution, and polar groups of alcohols and acids promote tissue permeation of the drug.

Other preferred additives according to aspects of the invention include combinations or mixtures of aminoalcohols and organic acids or amide reaction products. Examples are lysine / glutamate, lysine acetate, lactobionic acid / meglumin, lactobionic acid / tromethanemine, lactobionic acid / diethanolamine, lactic acid / meglumin, lactic acid / tromethanemin, lactic acid / diethanolamine, gentisic acid / meglumin, gentisic acid / tromethanemin, Gencitic acid / diethanolamine, vanillic acid / meglumin, vanillic acid / tromethanemin, vanillic acid / diethanolamine, benzoic acid / meglumin, benzoic acid / tromethanemin, benzoic acid / diethanolamine, acetic acid / meglumin, acetic acid / tromethanemin, and acetic acid / diethanolamine.

Other preferred additives according to aspects of the invention include hydroxyl ketones, hydroxyl lactones, hydroxyl acids, hydroxyl esters, and hydroxyl amides. Examples are gluconolactone, D-glucoheptono-1,4-lactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, erythronic acid lactone, ribbon acid lactone, glucuronic acid, gluconic acid, gentic acid, lactobionic acid, Lactic acid, acetaminophen, vanillic acid, cinnapic acid, hydroxybenzoic acid, methylparaben, propylparaben, and derivatives thereof.

[0222] Other preferred additives that can be used in aspects of the invention include riboflavin, sodium riboflavin phosphate, vitamin D3, folic acid (vitamin B9), vitamin 12, diethylenetriamine pentaacetate dianhydride, ethylenediaminetetraacetate dianhydride, maleine. Acids and anhydrides, succinic acid and anhydride, diglycolic acid anhydride, glutaric anhydride, L-aspartic acid, thiamine, nicotinamide, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, cysteine, tyrosine, tryptophan, leucine, Includes isoleucine, phenylalanine, asparagine, aspartic acid, glutamate, and methionine.

[0223] From a structural point of view, these additives share structural similarities and are compatible with water-insoluble drugs (eg, paclitaxel and rapamycin). They often contain double bonds, such as C = C, C = N, C = O in aromatic or aliphatic structures. These additives also include amines, alcohols, esters, amides, acid anhydrides, carboxylic acids, and / or hydroxyl groups. They can form hydrogen bonds and / or van der Waals interactions with the drug. They are also useful in the top layer of the coating. For example, a compound containing one or more hydroxyl, carboxyl, or amine groups promotes drug release from the surface of the medical device, facilitating the elimination of water in contact with the polar head groups and surface proteins of the cell membrane, thereby providing a hydrophobic drug. It is particularly useful as an additive because it can remove this barrier to the permeability of the protein. They promote the hydrophobic drug away from the balloon and the drug's migration to the lipid layers of cell membranes and tissues with very high affinity. They can also carry or facilitate the movement of the drug away from the balloon into a more aqueous environment, such as within the interstitial cavity of vascular tissue damaged by balloon angioplasty or stent swelling. Additives such as polyglyceryl fatty acid esters, ascorbic acid esters of fatty acids, sugar esters of fatty acids, alcohols and ethers provide fatty chains that can be integrated into the lipid structure of the membrane of the target tissue to carry the drug to the lipid structure. Have. Some of the amino acids, vitamins and organic acids have an aromatic C = N group and amino, hydroxyl, and carboxylic acid components in their structure. They have structural moieties that can bind or complex with hydrophobic drugs such as paclitaxel or rapamycin, which allow tissue permeation by removing the hydrophobic barrier between the hydrophobic drug and the lipid structure of the cell membrane. It also has a structural part that facilitates it.

[0224] For example, isononylphenyl polyglycidol (Olin-10 G and Surfactant-10 G), PEG glyceryl monooleate, sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate. (Span-80), Sorbitan Monostearate, Polyglyceryl-10 Oleate, Polyglyceryl-10 Laurate, Polyglyceryl-10
Palmitate, and polyglyceryl-10 stearate, all have more than four hydroxyl groups in their hydrophilic moiety. These hydroxyl groups have a very good affinity for the vessel wall and can eliminate hydrogen-bonded water molecules. At the same time, they have long-chain fatty acids, alcohols, ethers and esters that can complex with hydrophobic drugs and integrate into the lipid structure of cell membranes to form part of the lipid structure. This deformation or loosening of the lipid membrane of the target cell can further promote the permeation of the hydrophobic drug into the tissue.

[0225] As another example, L-ascorbic acid, thiamine, maleic acids, niacinamide, and 2-pyrrolidone-5-carboxylic acid all have extremely high water solubility and ethanol solubility, as well as low molecular weight and small size. .. They also have structural components that include aromatic C = N, amino, hydroxyl, and carboxylic acid groups. These structures have very good compatibility with paclitaxel and rapamycin, which can increase the solubility of these water-insoluble drugs in water and enhance their absorption into tissues. However, they often have poor adhesion to the surface of medical devices. Therefore, they are preferably used in the drug layer and top layer in combination with other additives to help enhance drug absorption. Vitamins D2 and D3 are particularly useful because they themselves have an anti-restenosis effect and reduce thrombosis, especially when used in combination with paclitaxel.

[0226] In aspects of the invention, the additive is soluble in aqueous solvents and soluble in organic solvents. Examples of hydrophobic compounds that do not have sufficient hydrophilic moieties and are insoluble in aqueous solvents, such as Sudan Red, are not useful as additives in these embodiments. Sudan red is also genetically toxic.

[0227] In one embodiment, the concentration density of at least one therapeutic agent applied to the surface of the medical device is from about 1 to 20 μg / mm ² , or more preferably from about 2 to 6 μg / mm ² . In one embodiment, the concentration of at least one additive applied to the surface of the medical device is from about 1 to 20 μg / mm ² . The weight ratio of additive to drug in the coating layer according to aspects of the invention is about 20: 0.05, preferably about 10: 0.5, or more preferably about 5: 0.8.

[0228] The relative amount of therapeutic agent and additive in the coating layer can be varied depending on the environment in which it may be applied. The optimum amount of additive is, for example, the individual therapeutic agent and additive selected, the critical micelle concentration of the surface modifier if it forms micelles, the hydrophilicity-lipophilicity-balance (HLB) of the surfactant. , Or the octonol-water partition coefficient (P) of the additive, the melting point of the additive, the water solubility of the additive and / or the therapeutic agent, the surface tension of the aqueous solution of the surface modifier, and the like.

[0229] In the example of the coating composition of aspects of the invention, the additive is a clear aqueous dispersion or emulsion or solution containing a hydrophobic therapeutic agent in an aqueous solution or organic solution when diluted in aqueous solution. Exists in such an amount that If the relative amount of surfactant is too large, the resulting dispersion will be visually "turbid".

[0230] The optical clarity of the aqueous dispersion can be measured using standard quantification methods for turbidity assessment. One simple method for measuring turbidity is to measure the amount of light of a specific wavelength that has passed through the solution, for example, with a UV-visible spectrophotometer. Optical clarity corresponds to higher transmission, as a more turbid solution will scatter more incident light and produce lower transmission measurements using this method.

[0231] Another method for measuring optical clarity and carrier diffusivity through the aqueous boundary layer is to quantitatively measure the size of the particles that make up the dispersion. These measurement methods can be carried out with a commercially available particle size analyzer.

[0232] Other considerations will provide further information on the choice of relative ratios for the various additives. These considerations include the biotolerance of the additive and the target dose of the hydrophobic therapeutic agent to be supplied.

[0233] Therapeutic agents
[0234] The drug or bioactive substance that can be used in aspects of the invention may be any therapeutic agent or substance. The drug may be in a variety of physical states, such as molecular distribution, crystalline or clustered form. Examples of drugs particularly useful in aspects of the invention are lipophilic, substantially water-insoluble drugs such as paclitaxel, rapamycin, daunorubicin, doxorubicin, lapacon, vitamins D2 and D3, And its analogs and derivatives. These drugs are particularly suitable for use during coatings on balloon catheters used to treat vascular tissue.

Other drugs that can be used in aspects of the invention include, but are not limited to, glucocorticoids (eg, dexamethasone, betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisense drugs, anticancer drugs, etc. Included are anti-proliferative agents, oligonucleotides, and more generally antiplatelet agents, anticoagulants, anti-cell division agents, antioxidants, anti-metamethasones, anti-cytogenic agents, and anti-inflammatory agents.

[0236] Also useful in aspects of the invention are, for example, polynucleotides, antisense, RNAi, or siRNA that inhibit inflammation and / or proliferation of smooth muscle or fibroblasts.

[0237] Antiplatelet drugs can include drugs such as aspirin and dipyridamole. Aspirin is classified as an analgesic, antipyretic, anti-inflammatory and antiplatelet drug. Dipyridamole is a drug similar to aspirin in that it has antiplatelet properties. Dipyridamole is also classified as a coronary vasodilator. Anticoagulants used in aspects of the invention can include drugs such as heparin, protamine, hirudin and tick anticoagulant proteins. Antioxidants can include probucol. Antiproliferative agents can include drugs such as amlodipine and doxazosin. Cell division inhibitors and metabolic antagonists that can be used in aspects of the invention include methotrexate, azathioprine, vincristine, vinblastine, 5-fluorouracil, adriamycin and mutamycin ( Drugs such as mutamycin) can be included. Antibiotics for use in aspects of the invention include penicillin, cefoxitin, oxacillin, tobramycin and gentamicin. Antioxidants suitable for use in aspects of the invention include probucol. In addition, genes or nucleic acids or parts thereof can be used as therapeutic agents in aspects of the invention. In addition, collagen synthesis inhibitors, such as tranilast, can be used as therapeutic agents in aspects of the invention.

[0238] Photosensitizers for photodynamic or radiotherapy, including various porphyrin compounds, such as porfimer, are also useful as drugs in aspects of the invention.

Drugs for use in aspects of the invention also include: everolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin. ), Ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, trolleyandomycin, Folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, blastine vinblastine ), Viscristine, vindesine, vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine, cyclophosfamide, 4- Hydroxycyclophosphamide, etoposide, melphalan, ifosfamide, trofosfamide, chlorambucil, bendamustine, decarbazine, busulfan, procarbazine (procarbazine), treosulfan, temozolomide, thiotepa, daunorubicin, doxorubicin, aclarubisi Aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, 5 '-Dihydrogen phosphate fludalabine, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel doceta (carboplatin), cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesroykin (carboplatin), cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide aldesleukin), tretinoin,
Asparaginase, pegaspargase, anastrozole, exemestane, letrozole, formestane, aminoglutethimide, adriamycin, azithromycin, spirothromycin Mycin (spiramycin), cepharantin, smc growth inhibitor-2w, epothilone A and B, mitoxantrone, azathioprine, mycophenol atmofetil, c-myc-anti Sense, b-myc-antisense, betulinic acid, camptothecin, lapachol, beta-lapachone, podophyllotoxin, betulin, podophile 2-ethylhydrazide (podophyllic acid 2-ethylhydrazide), molgramostim (rhuGM-CSF), peginterferon a-2b, lenograstim (r-HuG-CSF), filgrastim , Macrogol, dacarbazine, basiliximab, daclizumab, selectin (selectin (cytosan antagonist)), CETP inhibitors, cadherins, cytokinin inhibitors, COX-2 inhibitors, NFkB , Angiopeptin, ciprofloxacin, camptothecin, fluoroblastin, monoclonal antibody that inhibits muscle cell proliferation, bFGF antagonists, probecol, prostaglandins , 1,11-dimethoxycantin-6-one (1,11-dimet) hoxycanthin-6-on), 1-hydroxy-11-methoxycantin-6-one, scopoletin, corhitin, NO donors such as pentaerythritol tetranitrate and syndnoeimine, S-nitroso derivatives, tamoxyphene (tamoxifen), staurosporine, beta-estradiol, a-estradiol, estriol, estron, ethynyl estradiol, fosfestrol, medroxyprogesterone, estradiol cypionate , Estradiols benzoate, tranilast, kamebakaurin and other teniposides for cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostines), cyclosporin A, 6 -A-Hydroxy-pacritaxel, baccatin, taxotere and other carbon suboxide macrocyclic oligomers of carbon suboxide (MCS) and their derivatives, mofebutazone, acemetacin , Diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, phosphorus Chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, beta-cytosterin (beta.-sitosterin), Ademethio Ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, ellipticine, D-24851 (Calbiochem) colcemid, cytochalasin A to E, indanocine, nocodazole, S100 protein, bacitracin, vitronectin receptor antagonists, azelastine, metal proteinase-1 and -2 Guanidylcyclase stimulator Tissue inhibitor, free nucleic acid, nucleic acid incorporated into viral mediator, DNA and RNA fragments, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense Oligonucleotides, VEGF inhibitors, IGF-1, active drugs in the antibiotic group, such as cefadroxil, cefazolin, cefaclor, cefotaxim, tobramycin, gentamycin, penicillin Classes such as dichloroxacillin, oxacillin, sulfonamides, metronidazol, antithrombotic agents such as algatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, hirudin (coumadin), enoxaparin, desulfated and N-reacetylated heparin, tissue plasminogen activator, GpIIb / IIIa thrombocytopenic receptor, Xa factor inhibitory antibody, heparin, hirudin, r-hirudin , PPACK, protamin, prourokinase, streptoxine, warfarin, urokinase, vasodilator, etc. Speaking of dipyramidole, trapidil, nitroplside, PDGF antagonists such as triazolopyrimidine and seramin, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril (enalapril), losartan, thiol protease inhibitors, prostacyclin, vapiprost, interferon a, beta and y, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, eg p65 NF-kB or Bcl-xL antisense oligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, tea polyphenols, epigalolic acid epicatechins, epigalolic acid benzoates, bosswellic acid ( Boswellic acids and their derivatives, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacillin, tetracyclin, triamcinolone, triamcinolone , Procainamide, retinoic acid, quinidine, disopyramide, flecainide, propafenone, sotalol, amidorone, natural and synthetic steroids such as briophyllin A (bryophyllin A), inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexa Metazone (dexamethasone), non-steroidal substances (NSAID), such as fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviral drugs, such as Acyclovir, ganciclovir and zidovudine, antifungal agents such as clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin ), Terbinafine, antigenic pesticides such as chloroquine, mefloquine, quinine, other natural terpenoids such as hippocaesculin, barringtogenol- C21-angelate), 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelin Acid (4,7-oxycycloanisomelic acid), baccharinoid B1, B2, B3 and B7, tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanzioside ) N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, C and D, ursolic acid,
Hyptatic acid A, zeorin, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B , Sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-a-senecioyloxychaparrin, taxamyrin (taxamairin) A and B, regenilol, triptolide, and other cymarin, apocymarin, aristolochic acid, anopterin, hydroxyanopterin, Anemonin, protoanemonin, berberine, cheliburin chloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavone A, Curcumin, dihydronitidine, nitidine chloride, 12-beta-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid , Helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, glycoside 1a, podophyllotoxin, justicidin A and B, lareatin ( larreatin), malloterin, malotochromanol (mallo) tochromanol, isobutyrylmallotochromanol, maquiroside A, marchantin A, maytansine, lycoridicin, margetine, pancratistatin, liriodenine ), Bisparthenolidine, oxoushinsunine, Aristolactam-AII, bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid. ), Deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, sphatheliachromen, Stizophyllin, mansonine, strebloside, akagerine, dihydrousambarensine, hydroxyusambarine, strychnopentamine, strychnopentamine, strychnopentamine , Usambarine, usambarensine, berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol, methoxylariciresinol Sinol (syringare sinol), umbelliferon, afro moson), acetylvismione B, desacetylvismione A, and vismione A and B.

[0240] Drug combinations can also be used in aspects of the invention. Some of the combinations have additive effects because they have different mechanisms; for example, paclitaxel and rapamycin, paclitaxel and active vitamin D, paclitaxel and rapacon, rapamycin and active vitamin D, rapamycin and rapacon. Due to the additive effect, the dose of the drug can also be reduced. These combinations can reduce complications from the use of high doses of drugs.

[0241] Adhesive layer
[0242] The adhesive layer, which is an optional layer beneath the drug coating layer, enhances the adhesion of the drug coating layer to the outer surface of the medical device and protects the integrity of the coating. If the adherence of the drug and the additive to the medical device is different, the adhesive layer will have a constant drug-to-additive ratio or drug-to-drug ratio in the drug layer and upon delivery of the therapeutic agent at the target site of the intervention. Differences in drug layer component loss (on the move) or elution (at the target site) can be prevented in order to maintain. In addition, the adhesive layer can serve to facilitate the release of coating layer components that may otherwise adhere too strongly to the medical device to elute during short-term contact with the tissue at the target site. it can. For example, when a particular drug binds tightly to a medical device, a more hydrophilic component is incorporated into the adhesive layer to reduce the drug's affinity for the surface of the medical device.

[0243] As mentioned above, the adhesive layer comprises a polymer or additive or a mixture of both. Polymers useful for the formation of adhesive layers are biocompatible and avoid irritation of body tissues. Some examples of polymers useful for forming adhesive layers are in vivo stable polymers such as polyurethanes, silicones, and polyesters. Other polymers useful in forming the adhesive layer include polymers that can be dissolved and polymerized on medical devices.

[0244] Some examples of polymers useful in the adhesive layer of aspects of the invention include: polyolefins, polyisobutylenes, ethylene-α-olefin copolymers, acrylic acid polymers and copolymers, polyvinyl chlorides. , Polyvinylmethyl ether, polyvinylidene fluoride and vinylidene chloride, polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinyl acetate, ethylene-methyl methacrylate copolymer, acrylonitrile-styrene copolymer, ABS resin, nylon 12 and its block copolymer, poly Caprolactone, polyoxymethylene, polyethers, epoxy resin, polyurethanes, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ether, carboxymethyl cellulose, chitins, polylactic acid, Polyglycolic acid, polylactic acid-cellulose oxide copolymers, polyethylene glycols, polypropylene glycols, polyvinyl alcohols, and mixtures and block copolymers thereof.

[0245] Since medical devices undergo mechanical manipulation, i.e. expansion and contraction, examples of useful polymers in the adhesive layer include elastic polymers such as silicones (eg polysiloxanes and substituted polysiloxanes), polyurethanes. Included, thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefin elastomers, and EPDM rubbers. Due to the elasticity of these polymers, the coating adheres better to the surface of the medical device when the medical device is subjected to force or stress when using these polymers.

[0246] The adhesive layer maintains the integrity and adhesion of the coating layer to the medical device and promotes both the attachment of moving drugs and additives and the rapid elution when placed at the site of therapeutic intervention. Therefore, it can also contain one or more of the additives mentioned above, or other components.

[0247] Top layer
[0248] To further protect the integrity of the drug layer, in some cases a top layer is added to move through the meandering anatomy to the target site, or early in the swelling of the medical device. The drug can be prevented from being lost before the coating comes into direct contact with the target tissue. The top layer can be gradually released into the body cavity while protecting the drug layer. If the top layer is composed of more hydrophobic high molecular weight additives, it will erode more slowly. Surfactants, such as Tween 20 and polyglyceryl oleate, are examples of more hydrophobic structures with long fatty chains. High molecular weight additives include polyethylene oxide, polyethylene glycol, and polyvinylpyrrolidone. The hydrophobic drug itself can act as the top layer component. For example, paclitaxel or rapamycin is hydrophobic. They can be used in the top layer. On the other hand, the top layer should not erode too slowly or may actually delay the release of the drug when placed at the target site. Other additives useful in the top layer include those that interact strongly with the drug or coating layer, such as the following additives: p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40. , Tween 60, PEG oleate, PEG steerate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl millistate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 Oleate, Polyglyceryl-6 millistate, Polyglyceryl-6 palmitate, Polyglyceryl-10 laurate, Polyglyceryl-10 oleate, Polyglyceryl-10 millistate, Polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate , PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, octoxinol, monoxinol, tyroxalol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyle-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n- Heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β -D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamate, and methionine; acetate, benzoic acid anhydride, ascorbic acid, 2-pyrrolidone- 5-Carboxylic Acid, Sodium Pyrrolidone Carboxylic Acid, Dianehydride, Ethylenediaminetetraacetate, Maleic Acid and Anhydrous, Succinochloride, Diglycolic Acid Anhydrous, Glutaric Acid Anhydrous, Acetiamine, Benfothamine, Pantothenic Acid; Setothiamine; Sicothamine, Dexpan Tenor, Niacinah Mid, nicotinic acid, pyridoxal 5-phosphate, ascorbic acid nicotine amide, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, And Vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysoteams, immunoglobins, a-2-macroglobulin, fibronectins, bitronectins, fibrinogens, lipases, benzalconium chloride, benzethonium chloride, Dialkyl ester of docecil trimethylammonium bromide, sodium docecil sulfate, dialkylmethylbenzylammonium chloride, and sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, Diethanolamine, meglumin, glucamine, amine alcohols, glucoheptoic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonollactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, ribonic acid lactone, lactobionic acid , Glucosamine, glutamate, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, gentic acid, lactobionic acid, lactitol, cinnapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol , Cyclodextrin, (2-hydroxypropyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid, lysine acetate, gentisic acid, catechin, ascorbic acid catechin, tyretamine, ketamine, propofol, lactic acid, acetic acid, any organic Acid and organic amine salts, polyglycidol, glycerol, multiglycerols, galactitol, di (ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta (ethylene glycol), poly (ethylene glycol) oligomers, Di (propylene glycol), tri (propylene glycol), tetra (propylene glycol), and penta (propylene glycol), poly (propylene glycol) oligomers, polyethylene glycol and polyp. Block copolymers of ropylene glycol, as well as derivatives and combinations thereof.

[0249] Solvent
[0250] Solvents for preparing the coating layer can include, for example, any combination of one or more of the following: (a) water, (b) alcohols such as hexane, octane, cyclohexane, and Heptane, (c) aromatic solvents such as benzene, toluene and xylene, (d) alcohols such as ethanol, propanol and isopropanol, diethylamine, ethylene glycol monoethyl ether, Trascitol, and benzyl alcohol, (e) ethers. For example dioxane, dimethyl ether and tetrahydrofuran, (f) esters / acetates such as ethyl acetate and isobutyl acetate, (g) ketones such as acetone, acetonitrile, diethyl ketone, and methyl ethyl ketone, and (h) water and organic solvents. Mixtures such as water / ethanol, water / acetone, water / methanol, water / tetrahydrofuran. The preferred solvent in the top layer is acetone.

[0251] Organic solvents such as short chain alcohols, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, dimethyl sulfoxide and the like are preferred solvents particularly useful in aspects of the invention; these organic solvents generally disintegrate colloidal aggregates. This is because all the components in the coating solution are solubilized together.

[0252] Therapeutic agents and additives (s) can be dispersed, solubilized, or otherwise mixed in a solvent. The weight% of the drug and the additive in the solvent may be in the range of 0.1 to 80% by weight, preferably 2 to 20% by weight.

[0253] Other aspects of the invention relate to methods of making medical devices, particularly balloon catheters or stents. First, a coating solution or suspension containing at least one solvent, at least one therapeutic agent, and at least one additive is prepared. In at least one embodiment, the coating solution or suspension contains only these three components. The content of the therapeutic agent in the coating solution may be 0.5 to 50% by weight based on the total weight of the solution. The content of the additive in the coating solution may be 1 to 45% by weight, 1 to 40% by weight, or 1 to 15% by weight based on the total weight of the solution. The amount of solvent used depends on the coating method and viscosity. It will affect the uniformity of the drug-additive coating, but will evaporate.

[0254] In other embodiments, two or more solvents, two or more therapeutic agents, and / or two or more additives can be used in the coating solution.
[0255] In other embodiments, therapeutic agents, additives, and polymeric materials can be used in coating solutions, such as stent coatings. In this coating, the therapeutic agent is not encapsulated in polymer particles.

[0256] A variety of techniques can be used to apply the coating solution to medical devices, such as casting, spinning, spraying, dipping (immersing), inkjet printing, electrostatic methods, and combinations of these methods. The choice of application method depends mainly on the viscosity and surface tension of the solution. Immersion and spraying are preferred for aspects of the invention, as this makes it easier to control the uniformity of the coating layer thickness and the concentration of the therapeutic agent applied to the medical device. Regardless of whether the coating is applied by spraying or dipping or by any other method or combination method, each layer is usually medically treated to control the uniformity and concentration of therapeutic substances and additives applied to the medical device. It is deposited on the tool in a number of application steps.

[0257] Each layer to be applied is about 0.1 micron to 15 micron thick. The total number of layers applied to the medical device ranges from about 2 to 50. The total thickness of the coating is from about 2 to 200 microns.

[0258] As mentioned above, spraying and dipping are particularly useful coating methods for use in aspects of the invention. In the spraying method, a coating solution or suspension of aspects of the invention is prepared and then transferred to an application tool for applying the coating solution or suspension to a balloon catheter.

An application instrument that can be used is a paint jar connected to an airbrush, such as the Badger Model 150, which is provided with a source of pressurized air by a regulator (Nogren, 0-160 psi). When using such application instruments, connecting the brush hose to a source of compressed air downstream of the regulator provides air. Adjust the pressure to about 15-25 psi and lower the trigger to check the nozzle condition.

[0260] Prior to spraying, both ends of the relaxed balloon are secured to the attachment with two elastic retainers, i.e. alligator clips, and the balloon is contracted and folded, or inflated or partially inflated. Adjust the distance between the clips so that they remain absent. The rotor is then actuated to adjust the rotation speed to the desired coating speed of about 40 rpm.

[0261] Adjust the spray nozzle so that the distance from the nozzle to the balloon is about 1 to 4 inches while rotating the balloon substantially in a horizontal plane. First, a sweeping motion of the brush along the balloon from the distal end to the proximal end of the balloon, and then from the proximal end to the distal end, at a rate at which one spray cycle is performed in about three balloon rotations. , Spray the coating solution substantially horizontally. The coating solution is repeatedly sprayed onto the balloon until an effective amount of drug is deposited on the balloon, followed by drying.

[0262] In one embodiment of the invention, the balloon is inflated or partially inflated, the coating solution is applied to the inflated balloon, for example by spraying, then the balloon is deflated, folded and then dried. Drying can be carried out under vacuum.

[0263] It should be understood that the description of this application fixture, fixture, and spraying method is only an example. Any other suitable spraying method or other technique can be used for coating medical devices, especially balloons for balloon catheters, or stent delivery systems or stent coatings.

[0264] After spraying the coating solution onto the medical device, the coated balloon is dried, at which time the solvent in the coating solution evaporates. This gives a coating matrix on the balloon containing the therapeutic agent. An example of the drying method is to put the coated balloon in an oven at about 20 ° C. or higher for about 24 hours. Any other suitable method of drying the coating solution can be used. The time and temperature can be varied depending on the individual additives and therapeutic agents.

[0265] Optimal post-processing
[0266] The drug-additive-containing layer is deposited on a medical device of a particular aspect of the invention and then the final surface of the coating is dipped or sprayed with dimethyl sulfoxide (DMSO) or other solvent or otherwise applied. You may. DMSO can immediately dissolve the drug, easily penetrate the membrane and enhance tissue absorption.

[0267] The medical device of an aspect of the present invention is particularly applicable to treat obstruction or blockage of any of the internal ducts, including: the vasculature, including the coronal, peripheral and cerebral vasculature. , Gastrointestinal tract including esophagus, stomach, small intestine and colon, trachea, bronchi, pulmonary airway including fine bronchi, sinus, bile duct, urinary tract, prostatic and cerebral tract. They are particularly suitable for treating vascular tissue, for example with balloon catheters or stents.

[0268] Yet another aspect of the invention relates to a method of treating blood vessels. The method involves inserting a medical device, including a coating, into a blood vessel. The coating layer contains therapeutic agents and additives. In this embodiment, the medical device can be constructed to have at least one inflatable portion. Some examples of such devices include balloon catheters, perfused balloon catheters, infusion catheters such as distal perforated drug infusion catheters, perforated balloons, separate double balloons, perforated balloons, and sweep balloons, cutting balloon catheters, scores. Included are ring balloon catheters, self-inflating and balloon inflatable stents, guide catheters, guide wires, embolization protective equipment, and various imaging devices.

[0269] As mentioned above, an example of a medical device that is particularly useful in the present invention is a coated balloon catheter. Balloon catheters generally have a long, thin hollow tube with a small deflated balloon. In aspects of the invention, the balloon is coated with a drug solution. The balloon is then manipulated through the cardiovascular system to reach blockages, obstructions, and other sites that require therapeutic agents. When in place, the balloon is inflated to contact the vessel wall and / or block or block. An object of the present invention is to deliver a drug to a target tissue rapidly and facilitate absorption by the tissue. It is advantageous to effectively deliver the drug to the tissue in the shortest possible time while the medical device is placed at the target site. Drug coating with a balloon expansion time of, for example, about 0.1 to 30 minutes, or preferably about 0.1 to 10 minutes, or more preferably about 0.2 to 2 minutes, or most preferably about 0.1 to 1 minute. Is in close contact with the affected vascular tissue to release the therapeutic agent into those tissues, such as the vascular wall.

[0270] The ability to deliver a therapeutically effective amount of a drug according to aspects of the invention, eg, into the arterial wall, can eliminate the need for stents in some cases and prevent the associated damage and complications of thrombosis.

[0271] If the placement of the stent is still desired, a particularly preferred use in aspects of the invention is to fasten the stent, eg, a bare metal stent (BMS), onto, for example, a drug-coated balloon as described in aspects herein. is there. When the balloon is inflated and a stent is placed at the affected vascular site, an effective amount of drug is delivered into the arterial wall to prevent restenosis and other complications or reduce their severity. Alternatively, the stent and balloon may be coated together, or the stent may be coated and then fastened to the balloon.

[0272] In addition, balloon catheters can be used alone or in combination with other methods for treating the vasculature, such as photodynamic therapy or atherectomy, to treat vascular tissue / disease. Atherosctomy is a procedure for removing plaque from an artery. Specifically, atherectomy removes plaque from the peripheral and coronary arteries. The medical device used for peripheral and coronary atherectomy may be a laser catheter or rotablator, or a direct atherectomy device at the end of the catheter. A catheter is inserted into the body and the artery is advanced to the stenosis. After the plaque is partially removed by atherectomy, balloon angioplasty using the coated balloon of the embodiment of the present invention can be performed. In addition, stent placement can be performed thereafter or at the same time as the inflating of the coated balloon. Photodynamic therapy is a method of using light or radiant energy to kill target cells in a patient. Photoactivated photosensitizers can be delivered to specific tissue regions according to aspects of the invention. A targeted light source or radioactivity selectively activates the drug to generate a cytotoxic response and mediate antiprolotherapy effects.

[0273] In some embodiments of coatings and layers containing drugs according to the invention, the coatings or layers do not contain polymers, oils, or lipids. Furthermore, the therapeutic agent is not encapsulated in polymer particles, micelles, or liposomes. As mentioned above, such formulations have significant drawbacks and can inhibit the intended effective and rapid drug release and tissue penetration, especially in the environment of affected tissue of the vasculature.

[0274] Although various aspects have been specifically described and described herein, modifications and modifications of the invention that do not deviate from the spirit and intended scope of the invention are included in the teachings and are within the scope of the claims. It will be recognized that it is included in the authority.

[0275] Except for operating examples, or unless otherwise indicated, all numerical values representing the amounts of components in the layers, reaction conditions, etc. used herein and in the claims are all in all cases. It should be interpreted as being modified by the term "about". Therefore, unless otherwise indicated otherwise, the numerical parameters described herein and in the claims are approximate and may vary depending on the characteristics of interest sought by the disclosure of the present invention.

[0276] Preparation
[0277] The medical device and coating layer of aspects of the present invention can be made in a variety of ways. For example, a coating solution can be prepared by simultaneously mixing all components, such as therapeutic agents, additives and solvents, together by dispersion, dissolution, diffusion or other means. The coating solution can also be prepared by adding each component in sequence based on solubility or some other parameter. For example, a coating solution can be prepared by first adding a therapeutic agent to a solvent and then an additive. Alternatively, the additive may be added first to the solvent and then the therapeutic agent later. Since the additive will increase the drug solubility of the solvent, it is preferable to first add the additive to the solvent and then the drug if the solvent used does not sufficiently dissolve the drug.

[0278] Example
[0279] The following examples include aspects of medical devices and coating layers within the scope of the present invention. The following examples are considered examples of the present invention, but these examples should not be construed as limitations to the present invention.

[0280] Example A
Preparation of coating solution (if necessary, add a small amount of water not exceeding 10% by volume, sufficient to dissolve all solutes):
Formulation 1.1: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) butylated hydroxytoluene (BHT), 15-90 mg Tween
80, 30-90 mg of sodium doxate (sodium dioctyl sulfosuccinate) and 1-3 ml of ethanol were mixed.

Formulation 1.2: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) butylated hydroxyanisole (BHA), 15-90 mg Tween 80, 30-90 mg sodium doxate (dioctyl). Sodium sulfosuccinate) and 1-3 ml of ethanol were mixed.

Formulation 1.3: 30-90 mg rapamycin, no BHT or BHA added, 15-90 mg Tween 80, 30-90 mg sodium doxate (sodium dioctylsulfosuccinate), and 1-3 ml ethanol mixed. did.

Formulation 1.4: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 15-90 mg Solutol HS 15, 5-30 mg sodium dodecyl sulfate, and 1-3 ml. Ethanol was mixed.

Formulation 1.5: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 15-90 mg Eth-20, 15-90 mg sodium doxate (sodium dioctylsulfosuccinate). , And 1-3 ml of ethanol were mixed.

Formulation 1.6: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 15-90 mg polyethylene glycol-b-poly (lactide) (PEG-b-PLA). , 30-120 mg of sodium doxate (sodium dioctylsulfosuccinate), and 1-3 ml of ethanol were mixed.

Formulation 1.7: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 15-90 mg Tween 81, 30-90 mg Oleth 20, and 1-3 ml ethanol. Was mixed.

Formulation 1.8: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHA, 45-225 mg polyethylene glycol-b-poly (lactide) (PEG-b-PLA). , And 1-3 ml of ethanol were mixed.

Formulation 1.9: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHA, 30-180 mg sodium doxate (sodium dioctyl sulfosuccinate), and 1-3 ml ethanol. Was mixed.

Formulation 1.10: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHA, 15-45 mg Oleth 10, 15-45 mg Oleth 20, and 1-3 ml ethanol. Was mixed.

Formulation 1.11: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 15-90 mg Solutol HS 15, 15-90 mg sodium doxate (sodium dioctylsulfosuccinate). ), And 1 to 3 ml of ethanol were mixed.

Formulation 1.12: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BTA or BHT, 15-90 mg Solutol HS 15, 15-90 mg polyethylene glycol-b-poly (lactide). ) (PEG-b-PLA) and 1-3 ml of ethanol were mixed.

Formulation 1.13: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHA, 3-135 mg Solutol HS 15, and 1-3 ml ethanol were mixed.

Formulation 1.14: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-135 mg Solutol HS 15, 3-90 mg Tween 81, and 1-3 ml. Ethanol was mixed.

Formulation 1.15: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-135 mg Solutol HS 15, 3-90 mg soluble polyvinylpyrrolidone (povidone or Kollidon 12PF) ), And 1 to 3 ml of ethanol were mixed.

Formulation 1.16: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-90 mg soluble polyvinylpyrrolidone (povidone or Kollidon 12PF), and 1-3 ml ethanol. Was mixed.

Formulation 1.17: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-90 mg Cremophor EL (PEG-35 castor oil or polyethylene glycol-glycinoleic acid glycerol), And 1-3 ml of ethanol were mixed.

Formulation 1.18: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-135 mg Cremophor EL (PEG-35 castor oil or polyethylene glycol-ricinoleic glycerol), 3 to 90 mg of Tween 81 and 1 to 3 ml of ethanol were mixed.

[0300] Formulation 1.19: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-90 mg Soluplus (polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), and. 1-3 ml of ethanol was mixed.

[0301] Formulation 1.20: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-90 mg Sorbitol HS 15, 3-90 mg sorbitol, and 1-3 ml ethanol. Was mixed.

[0302] Formulation 1.21: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-90 mg soluble polyvinylpyrrolidone (povidone or Kollidon 12 PF), 3-90 mg Tween 20 (polysorbate 20) and 1-3 ml of ethanol were mixed.

Formulation 1.22: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-90 mg Tween 20 (polysorbate 20), 3-90 mg Tween 81 (polysorbate 81). ), And 1 to 3 ml of ethanol were mixed.

Formulation 1.23: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-90 mg soluble polyvinylpyrrolidone (povidone or Kollidon 12 PF), 3-90 mg Tween 20 (polysorbate 20), 3 to 90 mg of Tween 81 (polysorbate 81), and 1 to 3 ml of ethanol were mixed.

Formulation 1.24: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-90 mg soluble polyvinylpyrrolidone (povidone or Kollidon 12 PF), 3-90 mg Solutol HS 15, 3-90 mg of Tween 81 (polysorbate 81), and 1-3 ml of ethanol were mixed.

Formulation 1.25: 30-90 mg rapamycin, 1-2% (% by weight based on rapamycin) BHA or BHT, 3-90 mg soluble polyvinylpyrrolidone (povidone or Kollidon 12 PF), 3-90 mg Cremophor EL (PEG-35 castor oil or polyethylene glycol-glycinoleic acid glycerol), 3 to 90 mg of lecithin, and 1 to 3 ml of ethanol were mixed.

[0307] Example B
[0308] Five PTCA balloon catheters (3 mm diameter and 20 mm length) coated using the method described in US Patent Application Publication No. 2010-0055294-A1 (incorporated herein by reference). did. These PTCA balloon catheters were inflated at 1 to 3 atmospheres. The inflated balloon was loaded with the formulation of Example A (1.1-1.3) and sprayed or immersed in it. The balloon was then dried and reloaded, sprayed or soaked until a sufficient amount of drug (3 μg / mm ^{2) was obtained on the balloon.} The coated balloon was folded, then repackaged and sterilized for analytical testing. The recovered rapamycin content was as follows: formulation 1.1 79% for BHT addition, formulation 1.2 100% for BHA addition, formulation 1.3 14% for BHT or no BHA addition ~ 50%. Antioxidants (BHT or BHA) protect rapamycin from oxidation or degradation.

[0309] Example C
[0310] Six PTCA balloon catheters (3.5 and 3.0 mm diameter and 20 mm length) were inflated at 1-3 atmospheres. The inflated balloon was loaded with formulations 1.1-1.25 of Example A. A sufficient amount of drug (3-4 μg / mm ² ) was obtained on the balloon. The inflated balloon was folded and then dried. The coated and folded balloons were then repackaged, sterilized for animal testing and, in some cases vacuum dried.

[0311] Procedure : A coated PTCA balloon catheter was inserted into a 25-45 lb porcine coronary vasculature target site (LAD, LCX and RCA). The balloon was inflated to about 12 atmospheres. The overdilation ratio (the ratio of the diameter of the balloon to the diameter of the blood vessel) was about 1.15 to 1.40. During the swelling period of 30-60 seconds, the drug was delivered into the target tissue. The balloon catheter was then deflated and pulled out of the animal's body. Target vessels were collected 0.25 to 24 hours after this procedure. The drug content in the target tissue and the residual drug remaining on the balloon were analyzed by tissue extraction and HPLC.

[0312] In some of these animal studies, stents were clamped to drug-coated balloon catheters prior to placement. In long-term animal studies, angiography was performed before and after all interventions and 28-35 days after the procedure (above). The lumen diameter was measured and delayed lumen loss was calculated. Delayed lumen loss is the minimum lumen diameter measured after the follow-up period (usually weeks or months after interventions such as angioplasty and stent placement in this case) and the minimum lumen measured immediately after the intervention. The difference in diameter. Restenosis can be quantified by diameter stenosis, which is the difference between the mean lumen diameter after follow-up and immediately after manipulation divided by the mean lumen diameter immediately after manipulation. The animal test results for formulations 1.1-1.25 are reported below. All data are the average of 5 or 6 experimental data points.

[0313] An 18 mm stent was placed with an uncoated balloon. A coated balloon catheter was then inserted into a 25-45 lb porcine coronary target site (LAD, LCX and RCA). The drug content of formulation 1.1 on a 3.5 mm coated balloon catheter was approximately 3-4 μg / mm ² . After performing the above procedure, the residual drug on the balloon was 21 μg, or 4% of the total drug loaded on the balloon. The drug content of the tissue collected 15-30 minutes after the operation was 40.2 μg, or 7.6% of the total drug initially loaded into the balloon. The expansion ratio during operation is 1.2 to 1.4. Delayed lumen loss after 28-35 days was 0.76 (sd 0.22) mm.

[0314] An 18 mm stent was placed from an uncoated balloon. A coated balloon catheter was then inserted into a 25-45 lb porcine coronary target site (LAD, LCX and RCA). The drug content of formulation 1.4 on a 3.5 mm coated balloon catheter was approximately 3.0-4.0 μg / mm ² . After performing the above procedure, the residual drug on the balloon was 5.0 μg, i.e. 1% of the total loaded drug. The drug content of the tissue collected 15-30 minutes after the operation was 6.3 μg, i.e. 1-3.0% of the total drug loaded. After 28-35 days, the delayed lumen loss was 0.76 (sd 0.28) mm.

[0315] The drug content (control arm) of the uncoated balloon on the 3.5 mm balloon catheter was 0.0 μg / mm ² . An 18 mm stent was placed with an uncoated balloon. After performing the above procedure, the residual drug on the balloon was 0.0 μg, i.e. 0% of the total loaded drug. The drug content of the tissue collected 15-30 minutes after the operation was 0.0 μg, or 0.0% of the total loaded drug. After 28-35 days, the delayed lumen loss was 1.14 (sd 0.28) mm.

The drug content of formulation 1.5 on a 3.5 mm balloon catheter was 2.88 μg / mm ² . After performing the above procedure, the residual drug on the balloon was 6.29 μg, or 1.0% of the total loaded drug. The drug content of the tissue collected 15-30 minutes after the operation was 16 μg, or 8.9% of the total loaded drug. The drug content of the tissue collected 28 days after the procedure was 7.7 ng / mg tissue. After 28-35 days, the delayed lumen loss was 0.9 (sd 0.18) mm.

[0317] The drug content of formulation 1.6 on a 3.5 mm balloon catheter was 3.31 μg / mm ² . After performing the above procedure, the residual drug on the balloon was 37.0 μg, or 6.0% of the total loaded drug. The drug content of the tissue collected 15-30 minutes after the operation was 51.8 μg, or 9.0% of the total drug loaded. The drug content of the tissue collected 28 days after the procedure was 6.15 ng / mg tissue. After 28-35 days, the delayed lumen loss was 0.90 (sd 0.07) mm.

[0318] The drug content of formulation 1.7 on a 3.5 mm balloon catheter was 3.03 μg / mm ² . After performing the above procedure, the residual drug on the balloon was 4.41 μg, or 0.8% of the total loaded drug. The drug content of the tissue collected 15-30 minutes after the operation was 11.3 μg, i.e. 1.9% of the total drug loaded.

[0319] The drug content of formulation 1.8 on a 3.5 mm balloon catheter was 3-4 μg / mm ² . After performing the above procedure, the residual drug on the balloon was 95.0 μg, i.e. 13.0% of the total loaded drug. The drug content of the tissue collected 28 days after the procedure was 0.7 ng / mg tissue. After 28-35 days, the delayed lumen loss was 1.11 (sd 0.24) mm.

[0320] The drug content of formulation 1.9 on a 3.5 mm balloon catheter was 3-4 μg / mm ² . After performing the above procedure, the residual drug on the balloon was 57.0 μg, or 6.4% of the total loaded drug. The drug content of the tissue collected 28 days after the procedure was 35.2 ng / mg tissue.

[0321] The drug content of formulation 1.10 on a 3.5 mm balloon catheter was 3-4 μg / mm ² . After performing the above procedure, the residual drug on the balloon was 13.0 μg, or 2.5% of the total loaded drug. The drug content of the tissue collected 28 days after the procedure was 10.75 ng / mg tissue. After 28-35 days, the delayed lumen loss was 0.73 (sd 0.09) mm.

[0322] Example 1
[0323] Preparation of coating solution
[0324] Formulation 1: 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 25-100 mg ascorbyl palmitate, 25-100 mg L-ascorbic acid, and 0.5 ml of ethanol was mixed.

[0325] Formulation 2: 50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (or ethanol), 50-200 mg polyglyceryl-10 oleate, and 0.5 ml ethanol were mixed. ..

[0326] Formulation 3: Mix 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 50-200 mg Octoxinol-9, and 0.5 ml ethanol. did.

Formulation 4: 50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (or ethanol), 50-200 mg p-isononylphenoxypolyglycidol, and 0.5 ml ethanol. Was mixed.

[0328] Formulation 5: 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 50-200 mg Tyroxapol, and 0.5 ml ethanol were mixed.

Formulation 6: 50-150 mg (0.05-0.16 mmole) rapamycin (in 2-6 ml acetone (or ethanol)), and 50-150 mg L-ascorbic acid (1 ml water or ethanol, Or in both) was mixed.

[0330] Formulation 7: 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 50-150 mg niacinamide (in 1 ml water or ethanol) were mixed.

Formulation 8: 50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (or ethanol), and 50-200 mg nicotinic acid (in 1 ml water or ethanol) were mixed. ..

[0332] Formulation 9: 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml ethanol (or acetone), 150 mg thiamine hydrochloride (1 ml water), and 0.5 ml were mixed.

[0333] Formulation 10: 50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone or ethanol, and 150 mg 2-pyrrolidone-5-carboxylic acid (in 1 ml water or ethanol). Mixed.

Formulation 11: 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg niacinamide (1 ml water). Or in ethanol), and 0.5 ml of ethanol were mixed.

Formulation 12: 50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (or ethanol), 75 mg octoxinol-9
, 75 mg thiamine hydrochloride (in 1 ml water or ethanol), and 0.5 ml ethanol were mixed.

Formulation 13: 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg 2-pyrrolidone-5- Carboxylic acid (in 1 ml water or ethanol) and 0.5 ml ethanol were mixed.

Formulation 14: 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg nicotinic acid (1 ml water). Or in ethanol), and 0.5 ml of ethanol were mixed.

Formulation 15: 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg L-ascorbic acid (1 ml). In water or ethanol), and 0.5 ml of ethanol were mixed.

[0339] Formulation 16: 50-150 mg (0.06-0.18 mmole) of paclitaxel was dissolved in 5-10 ml methylene chloride. This solution was added to 30 ml of human serum albumin solution (5% w / v). The solution was then homogenized at low speed for 5 minutes to form an emulsion. The emulsion was then sonicated at 40 kHz, 50-90% power, 0-5 ° C. for 1-5 minutes.

[0340] Formulation 17: 50-150 mg (0.05-0.16 mmole) of rapamycin was dissolved in 5-10 ml methylene chloride and 10-30 mg p-isononylphenoxypolyglycidol. This solution was added to 30 ml of human serum albumin solution (5% w / v). The solution was then homogenized at low speed for 5 minutes to form an emulsion. The emulsion was then sonicated at 40 kHz, 50-90% power, 0-5 ° C. for 1-5 minutes.

Formulation 18: 50-100 mg (0.06-0.12 mmole) paclitaxel, 1-1.6 ml acetone, 1-1.6 ml ethanol, 0.4-1.0 ml water, and 50. ~ 200 mg of gluconolactone was mixed.

Formulation 19: 35-70 mg (0.042-0.084 m mmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 ml ethanol, 35-70 mg Tween 20, and. 35-70 mg of N-octanoyl N-methylglucamine was mixed.

Formulation 20: 35-70 mg (0.042-0.084 m mmole) paclitaxel, 0.4-1.0 ml acetone, 0.4-1.0 ml ethanol, 0.2-0.4 ml. Water, 35-70 mg of Tween 20, and 35-70 mg of sorbitol were mixed.

Formulation 21: 40-80 mg (0.048-0.096 m mmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 ml ethanol, 40-80 mg meglumine, and 32. ~ 64 mg of gencitonic acid (equal molar ratio to meglumine) was mixed.

Formulation 22: 35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.4-0.8 ml acetone, 0.4-0.8 ml ethanol, 0.25-0.50 ml. Water, 35 to 70 mg of lactobionic acid, and 10 to 20 mg of diethanolamine (equal molar ratio to lactobionic acid) were mixed.

Formulation 23: 35-70 mg (0.042-0.084 m mmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 ml ethanol, and 70-140 mg N-octanoyl. N-Methylglucamine was mixed.

Formulation 24: 35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.4-0.8 ml acetone, 0.4-0.8 ml ethanol, 0.2-0.4 ml. Water, 35-70 mg of meglumine, and 18-36 mg of lactic acid (equal molar ratio to meglumine) were mixed.

Formulation 25: 50-100 mg (0.06-0.12 mmole) paclitaxel, 0.8-1.6 ml acetone, 0.8-1.6 ml ethanol, 0.4-1.0 ml. Water, 50-100 mg of gencitic acid, and 30-60 mg of diethanolamine (equal molar ratio to gencitic acid) were mixed.

Formulation 26: Comparative Solution-50 mg (0.06 mmole) of paclitaxel, 1 ml of ethanol, 0.2 ml of acetone, and 0.042 ml of Ultravist 370 were mixed.

Formulation 27: Comparative Solution-40 mg (0.048 mmole) of paclitaxel, 0.5 ml of ethanol, and 0.5 ml of acetone were mixed.
Formulation 28: 35-70 mg (0.042-0.084 m mmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 ml ethanol, 35-70 mg Triton X-100. , And 35-70 mg of N-heptanoyl N-methylglucamine were mixed.

[0352] Example 2
[0353] Five PTCA balloon catheters (3 mm diameter and 20 mm length) were folded under vacuum with three wings. Example 1 on a balloon folded under vacuum
Formulation (1-17) of was sprayed or soaked in it. The folded balloon was then dried and sprayed or soaked again until a sufficient amount of drug (3 μg / mm ² ) was obtained on the balloon, dried and then sprayed or soaked again. The coated and folded balloons were then repackaged and sterilized for animal testing.

[0354] Example 3
[0355] Five PTCA balloon catheters (3 mm diameter and 20 mm length) were folded under vacuum with three wings. The formulation (1-5) of Example 1 was sprayed on or immersed in a balloon folded under vacuum. The folded balloon is then dried and the formulation (6-10) is sprayed again or soaked in it, dried and sprayed or soaked again until a ^{sufficient amount of drug (3 μg / mm 2) is obtained on the balloon.} did. The coated and folded balloons were then repackaged and sterilized for animal testing.

[0356] Example 4
[0357] Five PTCA balloon catheters (3 mm diameter and 20 mm length) to which a bare metal coronary stent was fastened were sprayed with or immersed in the formulation of Example 1 (1-5). These stent delivery systems were then dried and formulated (6-1).
0) was sprayed or soaked in it again, dried and sprayed or soaked again until a ^{sufficient amount of drug (3 μg / mm 2) was obtained on the balloon.} The coated and folded stent delivery system was then sterilized for animal testing.

[0358] Example 5
A drug-coated and uncoated balloon catheter (as a control) was inserted into the porcine coronary arteries. The balloon was over-expanded (1: 1.2) and the inflated balloon was held in the blood vessel for 60 seconds to release the drug and additives, then contracted and withdrawn from the pig. Animals were angiographically imaged 3 days, 31 days, 3 months, 6 months, 9 months and 12 months later. The amount of drug in the arterial tissue of the killed animal was measured after 60 minutes, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months.

[0360] Example 6
[0361] Five coronary stents (3 mm diameter and 18 mm length) were sprayed or immersed coated with the formulation of Example 1 (1-17). These stents were then dried and sprayed or soaked again until a sufficient amount of drug (3 μg / mm ^{2) was obtained on the stents and dried again.} The coated stent was then fastened to a PTCA balloon catheter (3 mm diameter and 20 mm length). These coated stents with balloon catheters were then sterilized for animal testing.

[0362] Example 7
[0363] Drug-coated and uncoated stents (as a control) were inserted into the porcine coronary arteries and then the balloon was overdilated (1: 1.2). Stents were implanted, drugs and additives were released, and the balloon was deflated and withdrawn from the pig. The animals were then angiographically imaged after 5, 30, 60 minutes, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months. The amount of drug in the arterial tissue of the killed animal was measured at 60 minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months.

[0364] Example 8
[0365] Five PTCA balloon catheters were sprayed with or soaked in the formulation of Example 1 (1-17), dried and again until a ^{sufficient amount of drug (3 μg / mm 2) was obtained on the balloon.} It was sprayed or soaked and dried again. Bare metal coronary stents (3 mm diameter and 20 mm length) were fastened to each coated balloon.
These coated balloons with bare metal coronary stents were packaged and sterilized for animal testing.

[0366] Example 9
[0367] Five PTCA balloon catheters were sprayed with or soaked in the formulation of Example 1 (1-5), dried and the formulation (6-10) was sprayed again or soaked in it. The balloon was then dried and sprayed or soaked again until a sufficient amount of drug (3 μg / mm ^{2) was obtained on the balloon.} Bare metal coronary stents (3 mm diameter and 20 mm length) were fastened to each coated balloon. These coated balloons with bare metal coronary stents were packaged and sterilized for animal testing.

[0368] Example 10
[0369] Drug-coated balloon inflatable bare metal stents and plain balloon inflatable bare metal stents (as a control) from Examples 8 and 9 were inserted into the porcine coronary arteries to over-expand the balloon (1: 1). .2). A stent was implanted and the balloon was held in an inflated state for 60 seconds to release the drug and additives, then the balloon was deflated and withdrawn from the pig. The animals were then angiographically imaged after 5, 30, 60 minutes, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months. After 60 minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months, the amount of drug in the arterial tissue of the killed animal is measured.

[0370] Example 11
[0371] 150 mg (0.18 mmole) of paclitaxel, 5 ml of acetone (or ethyl acetate or methyl ethyl ketone), 150 mg of acetic anhydride or maleic anhydride or diglycolic acid anhydride, and 0.5 ml of ethanol are mixed, and then the solution is prepared. Stirred until obtained. The solution was sprayed or soaked in 5 PTCA balloon catheters, dried and re-sprayed or soaked until a ^{sufficient amount of drug (3 μg / mm 2) was obtained on the balloon.} The coated balloon was then treated under high pH (pH 8-11.5 range) conditions to hydrolyze the acid anhydride. This can be confirmed by the IR method. At this point, the hydrophilicity of the coating had increased. The coated balloon was then sterilized for animal testing.

[0372] Example 12
A drug-coated and uncoated balloon catheter (as a control) was bronchoscopically inserted into the pulmonary airways of pigs. The balloon was inflated and the inflated balloon was held in the lumen for 60 seconds in an inflated state to release the drug and additives. The balloon was deflated and pulled out of the pig. Animals were then bronchoscopically examined 3 days, 31 days, 3 months, 6 months, 9 months and 12 months later, and tissue samples were taken for pathophysiological examination and quantification of drug uptake.

[0374] Example 13
An uncoated stent delivery catheter was inserted into the porcine lumen. The balloon was inflated, a stent was placed, and the inflated balloon was withdrawn. The pharmaceutical formulations of Example 1 (1 to 15 (10 to 100 ml)) were injected into the stent implantation site (about 5 to 15 mg of drug per pig). The drug was then absorbed into the injured tissue. Animals were then examined and tissue samples were taken for pathophysiological examination.

[0376] Example 14
[0377] Affected tissue (breast cancer or prostate or atheroma or stenosis) was surgically removed from the human body. Pharmaceutical formulations 1-15 (10-100 ml) of Example 1 were injected into or above the surgical cavity formed by this surgical intervention (approximately 5-20 mg drug). Topical drug delivery included injection with long needles, guide catheters, induction sheaths, drug infusion tubes, and other drug delivery catheters. The drug was then absorbed into the tissue at the target site.

[0378] Example 15
[0379] Six PTCA balloon catheters (3.5 and 3.0 mm diameter and 20 mm length) were inflated at 1-3 atmospheres. The inflated balloon was loaded with formulations 18-28 of Example 1. A sufficient amount of drug (3 μg / mm ² ) was obtained on the balloon. The inflated balloon was folded and then dried. The coated and folded balloons were then repackaged and sterilized for animal testing.

[0380] A coated PTCA balloon catheter was inserted into a 25-45 lb porcine coronary target site (LAD, LCX and RCA). The balloon was inflated to about 12 atmospheres. The overexpansion ratio (the ratio of the diameter of the balloon to the diameter of the blood vessel) is about 1.15 to 1.
.. It was 40. During the swelling period of 30-60 seconds, the drug was delivered into the target tissue. The balloon catheter was then deflated and pulled out of the animal's body. Target vessels were collected 0.25 to 24 hours after this procedure. The drug content in the target tissue and the residual drug remaining on the balloon were analyzed by tissue extraction and HPLC.

[0381] In some of these animal studies, the stent was fastened to a drug-coated balloon catheter prior to placement. In long-term animal studies, angiography was performed before and after all interventions and 28-35 days after the procedure. The lumen diameter was measured and delayed lumen loss was calculated. Delayed lumen loss is the minimum lumen diameter measured after the follow-up period (usually weeks or months after interventions such as angioplasty and stent placement in this case) and the minimum measured immediately after the intervention. The difference in lumen diameter. Restenosis can be quantified by diameter stenosis, which is the difference between the mean lumen diameter after follow-up and immediately after manipulation divided by the mean lumen diameter immediately after manipulation. The animal test results for formulations 18-28 are reported below. All data are the average of 5 or 6 experimental data points.

[0382] The drug content of formulation 18 on a 3.5 mm balloon catheter was 3.26 μg / mm ² . After the procedure, the residual drug on the balloon was 15.92 μg, or 2.3% of the total drug loaded on the balloon. The drug content of the tissue collected 15-30 minutes after the operation was 64.79 μg, or 9.2% of the total drug initially loaded into the balloon. When the 18 mm stent was placed with a coated balloon, the residual drug on the balloon was 31.96 μg, or 4.5% of the loaded drug, and the drug content of the tissue collected 15-30 minutes after the operation was 96. It was 49 μg, or 13.7% of the loaded drug. The expansion ratio in operation is 1.3. Delayed lumen loss after 28-35 days was 0.10 (sd 0.2) mm. The diameter stenosis is 3.3%.

[0383] The drug content of formulation 19 on a 3.5 mm balloon catheter was 3.08 μg / mm ² . After the operation, the residual drug on the balloon was 80.58 μg, or 11.4% of the total loaded drug. The drug content of the tissue collected 15-30 minutes after the operation was 42.23 μg, or 6.0% of the total drug loaded. After 28-35 days, the delayed lumen loss was 0.30 (sd 0.23) mm. The diameter stenosis was 5.4%.

The drug content of formulation 20 on a 3.5 mm balloon catheter was 3.61 μg / mm ² . After the operation, the residual drug on the balloon was 174.24 μg, or 24.7% of the total loaded drug. The drug content of the tissue collected 15-30 minutes after the operation was 83.83 μg, i.e. 11.9% of the total drug loaded. When a pre-tightened 18 mm stent was placed, the residual drug on the balloon was 114.53 μg, or 16.1% of the total drug loaded, and the drug content of the tissue collected 15-30 minutes after the operation was 147. It was 95 μg, or 18.1% of the total drug loaded. The expansion ratio in operation was 1.3. Delayed lumen loss after 28-35 days was 0.10 (sd 0.1) mm. The diameter stenosis was 3.4%.

The drug content of formulation 21 on a 3.5 mm balloon catheter was 4.71 μg / mm ² . After the operation, the residual drug on the balloon was 44.39 μg, or 6.3% of the total loaded drug. The drug content of the tissue collected 15-30 minutes after the operation was 77.87 μg, i.e. 11.0% of the total drug loaded. After 28-35 days, the delayed lumen loss was 0.23 (sd 0.44) mm. The diameter stenosis was 7.3%.

The drug content of formulation 22 on a 3.5 mm balloon catheter was 3.85 μg / mm ² . After the operation, the residual drug on the balloon was 24.59 μg, or 3.5% of the total loaded drug. The drug content of the tissue collected 15-30 minutes after the operation was 37.97 μ.
It was g, or 5.4% of the total drug loaded. After 28-35 days, the delayed lumen loss was 0.33 (sd 0.14) mm. The diameter stenosis was 6.7%.

The drug content of formulation 23 on a 3.5 mm balloon catheter was 3.75 μg / mm ² . After the procedure, the residual drug on the balloon was 0.82 μg, or 0.1% of the total drug loaded. The drug content of the tissue collected 60 minutes after the operation was 45.23 μg, or 5.5% of the total drug loaded. After 28-35 days, the delayed lumen loss was 0.49 (sd 0.26) mm. The diameter stenosis was 11.3%.

The drug content of formulation 24 on a 3.5 mm balloon catheter was 3.35 μg / mm ² . After the operation, the residual drug on the balloon was 62.07 μg, or 7.5% of the total loaded drug. The drug content of the tissue collected 60 minutes after the operation was 40.55 μg, or 4.9% of the total drug loaded. After 28-35 days, the delayed lumen loss was 0.47 (sd 0.33) mm. The diameter stenosis was 9.9%.

The drug content of formulation 25 on a 3.5 mm balloon catheter was 3.41 μg / mm ² . After the procedure, the residual drug on the balloon was 50.0 μg, or 6.0% of the total drug loaded. The drug content of the tissue collected 60 minutes after the operation was 26.72 μg, ie 3.2% of the total drug loaded. After 28-35 days, the delayed lumen loss was 0.36 (sd 0.41) mm. The diameter stenosis was 9.3%.

The drug content of formulation 28 on a 3.5 mm balloon catheter was 3.10 μg / mm ² . After the operation, the residual drug on the balloon was 1.9% of the total drug loaded. The drug content of the tissue collected 2 hours after the operation was 34.17 μg, or 5.0% of the total loaded drug. In the tissue collected 24 hours after the operation, the drug content of the tissue was 28.92 μg, or 4.2% of the total drug loaded.

The drug content of the control formulation (uncoated balloon) on a 3.5 mm balloon catheter was 0.0 μg / mm ² . After the operation, the residual drug on the balloon was 0% of the total drug loaded. The drug content of the tissue collected 15 minutes after the operation was 0 μg. In the tissue collected 24 hours after the operation, the drug content of the tissue was 0 μg. After 28-35 days, the delayed lumen loss was 0.67 (sd 0.27) mm. The diameter stenosis is 20.8%. In the second repeat experiment, the expansion ratio was 1.3. The delayed lumen loss was 1.1 (sd 0.1) mm. The diameter stenosis was 37.5%.

[0392] The drug content of Comparative Formulation 26 on a 3.5 mm balloon catheter was 3.21 μg / mm ² . After the operation, the residual drug on the balloon was 13.52 μg, i.e. 1.9% of the total drug loaded. The drug content of the tissue was 28.32 μg, or 4.0% of the total drug loaded. When a balloon with a pre-tightened 18 mm stent was placed, the residual drug on the balloon was 26.45 μg, or 3.7% of the total loaded drug. The drug content of the tissue was 113.79 μg, or 16.1% of the loaded drug. After 28-35 days, the delayed lumen loss was 0.27 (sd 0.15) mm. The diameter stenosis was 7.1%.

[0393] The drug content of formulation 27 (without additives) on a 3.5 mm balloon catheter was 4.22 μg / mm ² . After the operation, the residual drug on the balloon was 321.97 μg, or 45.6% of the total loaded drug. The drug content of the tissue was 12.83 μg, or 1.8% of the total drug loaded.

[0394] Surprisingly, after placing balloons coated with formulations 18-25 and 28 according to aspects of the invention, the concentration of drug absorbed by porcine coronary tissue is delivered by balloons coated with comparative formulation 26. It was higher than the one coated with the drug-only formulation 27. Delayed lumen loss after 28-35 days of follow-up was less than in controls (uncoated balloons).

[0395] Example 16
[0396] Six PTCA balloon catheters (3.5 and 3.0 mm diameter and 20 mm length) were inflated at 1-3 atmospheres. The inflated balloon was loaded with the formulations 18-25 and 28 of Example 1. A sufficient amount of drug (3 μg / mm ² ) was obtained on the surface of the balloon. The inflated balloon was dried. This drug-coated balloon was followed by a topcoat. Top coating formulations in acetone or ethanol were selected from gentisic acid, methylparaben, acetic acid, Tween 20, vanillin and aspirin. The coated and folded balloons were dried, then repackaged and sterilized for animal testing.

[0397] A floating experiment was designed to determine the amount of drug lost before inflating during insertion and transfer of a balloon catheter to the target site. A control balloon catheter was coated with Formulation 18. A top-coated catheter with a propylparaben top coating was also created. For top-coated catheters, the balloon catheter was coated with Formulation 18, then dried and coated with 25-50 mg of propylparaben in acetone (about 50% by weight of paclitaxel) on the coating of Formulation 18. A control and top coated balloon catheter was inserted into the porcine artery. The floating time in the arteries of pigs was 1 minute. Drugs, additives and top coatings were released. The catheter was then pulled out. Residual drug on the balloon catheter was analyzed by HPLC. The residual drug content of the control balloon catheter was 53% of the total loaded drug. The residual drug content of the top-coated balloon catheter was 88%. Topcoat reduced drug loss in blood vessels under conditions that mimic the movement of the device to the site of intervention. Formulation 18 was first coated on the balloon, then propylparaben as a top coating to cover the first coating layer, and the same animal testing as in Example 15 was performed. The drug content of the 3.5 mm balloon catheter was 3.39 μg / mm ² . After the operation, the residual drug content on the balloon was 64.5 μg, or 8.6% of the total loaded drug. The drug content in the tissue was 28.42 μg, or 4% of the total drug loaded.

[0398] Example 17
Six PTCA balloon components (3.5 and 3.0 mm in diameter and 20 mm in length) were loaded with the formulation 18 obtained in Example 1. A sufficient amount of drug (3 μg / mm ² ) was obtained on the surface of the balloon. The balloon was dried.

[0400] The formulation for the top coating layer was then prepared. The formulation of the top coating layer is paclitaxel and one additive selected from Tween 20, Tween 80, polypropylene glycol-425 (PPG-425) and polypropyl glycol-1000 (PPG-1000) in acetone. there were. Only formulation 18 was loaded on the balloon surface of the control catheter. The other balloon surface formulation 18 coating layer was coated with 25-50 mg of top coating formulation in acetone (approximately 50% by weight of paclitaxel). The coated balloon was dried for in vitro drug release testing.

[0401] A release experiment was designed to determine the amount of drug lost during balloon inflatation. Each coated balloon was inflated to 12 atm in 1% BSA solution at 37 ° C. for 2 minutes. Drugs, additives and top coatings were released. Residual drug on the balloon catheter was analyzed by HPLC. The residual drug content of the control balloon catheter was 34% of the total loaded drug. The residual drug content of balloon catheters containing a top coating layer containing Tween 20, Tween 80, polypropylene glycol-425 (PPG-425) or polypropyl glycol-1000 (PPG-1000) was 47%, 56% and 71%, respectively. And 81%. Therefore, the top coating layer reduced drug loss during swelling of balloon components in in vitro tests.

1. 1. A medical device for delivering a therapeutic agent to a tissue, comprising a layer covering the outer surface of the medical device, the layer containing a therapeutic agent, an antioxidant and an additive, wherein the additive is a hydrophilic moiety and A drug-affinity moiety is included, wherein the drug-affinity moiety is of a hydrophobic moiety, a moiety having an affinity for a therapeutic agent by hydrogen bonding, and a moiety having an affinity for a therapeutic agent due to van der Waals interaction. At least one, in which case the additive is water soluble, in which case the additive is at least one of a surfactant and a chemical compound, in which case the chemical compound is one or more hydroxyls, aminos. , A medical device having a carbonyl, carboxyl, acid, amide or ester group.

2. A medical device for delivering a therapeutic agent to a tissue, comprising a layer covering the outer surface of the medical device, the layer containing the therapeutic agent and one or more additives, where each additive is a hydrophilic moiety. And drug-affinitive moieties, where the drug-affinitive moiety is of the hydrophobic moiety, the moiety that has an affinity for the therapeutic agent due to hydrogen bonds, and the moiety that has an affinity for the therapeutic agent due to van der Waals interactions. A medical device, wherein one of one or more kinds of additives is a liquid additive.

3. 3. A medical device for delivering a therapeutic agent to a tissue, comprising a layer covering the outer surface of the medical device, the layer containing the therapeutic agent and at least one additive, wherein the at least one additive. Contains a first additive and a second additive, where each additive comprises a hydrophilic moiety and a drug-friendly moiety, where the drug-affinitive moiety is a hydrophobic moiety to the therapeutic agent by hydrogen bonding. A medical device that has an affinity and at least one portion that has an affinity for a therapeutic agent due to van der Waals interaction, wherein the first additive is more compatible than the second additive. ..

4. A medical device for delivering a therapeutic agent to a tissue, comprising a layer covering the outer surface of the medical device, the layer containing the therapeutic agent and at least one additive, wherein the at least one additive. Contains a first additive and a second additive, where each additive contains a hydrophilic moiety and a drug-friendly moiety, where the drug-affinitive moiety is a hydrophobic moiety, by hydrogen binding to the therapeutic agent. The HLB value of the first additive is higher than that of the second additive, at least one of the parts having affinity and the part having affinity for the therapeutic agent by van der Waals force interaction. , Medical equipment.

5. A medical device for delivering a therapeutic agent to a tissue, comprising a layer covering the outer surface of the medical device, the layer containing the therapeutic agent and at least one additive, the at least one additive being the first. It contains an additive and a second additive, where each additive contains a hydrophilic moiety and a drug-friendly moiety, where the drug-affinitive moiety provides a hydrophobic moiety, an affinity for the therapeutic agent by hydrogen bonding. A medical device that has a portion and at least one portion that has an affinity for a therapeutic agent due to van der Waals interaction, wherein the Log P value of the first additive is lower than that of the second additive. ..

6. Antioxidants are oligomeric or polymeric proanthocyanidins, polyphenols, polyphosphates, polyazomethine, high sulfate agar oligomers, chito-oligosaccharides, polyfunctional oligomers thioethers, and sterically impaired phenols, hindered amines, etc. Those containing p-phenylenediamine, trimethyldihydroquinolones, and alkylated diphenylamines, hindered phenols, t-butyl, arylamines, phosphites, hydroxylamines, benzofuranones, p-phenylenediamine, diphenylamine, N, N'di-substituted p-phenylenediamines, butylated hydroxytoluene (“BHT”), butylated hydroxyanisole (“BHA”), L-ascorbate (vitamin C), vitamin E, herb rosemary, sage extract , Glutathion, resverator, ethoxyquin, rosmanol, isolosmanol, rosmaridiphenol, propyl gallate, gallic acid, coffee acid, p-cumeric acid, p-hydroxybenzoic acid, astaxanthin, ferulic acid, dehydrozingerone, chlorogenic acid, Elagic acid, propylparaben, synapic acid, daidin, glycitin, genistin, daizein, glycitein, genistein, isoflavones, tert-butylhydroquinone, di (stearyl) pentaerythritol diphosphite, tris (2,4-di-tert-butyl) Phenyl) phosphite, dilauryl thiodipropionate, bis (2,4-di-tert-butylphenyl) pentaerythritol diphosphite, octadecyl-3,5, di-tert-butyl-4-hydroxycinnamate, tetrakis- Methylene-3- (3', 5'-di-tert-butyl-4-hydroxyphenyl) propionate methane 2,5-di-tert-butylhydroquinone, ionol, pyrogallol, retinol, octadecyl-3- (3,5-) Di-tert-butyl-4-hydroxyphenyl) propionate, glutathione, lipoic acid, melatonin, tocopherols, tocotrienols, thiols, beta-carotene, retinoic acid, cryptoxanthin, 2,6-di-tert-butylphenol, carnivorous The medical device according to 1, which is at least one of propyl acid acid, catechin, catechin caricate, quercetin, and derivatives thereof.

7. Chemical compounds include aminoalcohols, hydroxylcarboxylic acids, esters, amides, ethers, acid anhydrides, hydroxylketones, hydroxyllactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides. , Protein, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids, and their substituted molecules. Medical equipment.

8. Surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, PEG omega-3 fatty acid esters, ethers, amides, and alcohols, glycerol fatty acid esters, sorbitan. The medical device according to 1, which is selected from fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters, sugar fatty acid esters, PEG sugar esters, and derivatives thereof.

9. The medical device according to 1, wherein the chemical compound has a molecular weight of 20 to 750.

Chemical compounds having 10.1 or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxylcarboxylic acids, esters, amides, ethers, acid anhydrides, hydroxylketones, hydroxyls. Lactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organic acids, esters, salts, vitamins, soluble povidone. , Soluble polyvinylpyrrolidone with a molecular weight of less than 4000, Kollidon 12 PF, Kollidon 17 PF, urea, biuret, acetamide, lactic acid amide, amino acid amide, acetaminophen, uric acid, polyurea, urethane, urea derivative, niacinamide, N-methylacetamide, N, N-Dimethylacetamide, Sulfacetamide Sodium, Versetamide, Lauric Acid Diethanolamide, Lauric Acid Myristic Acid Diethanolamide, N, N-Bis (2-Hydroxyethyl Stealamide), Cocamide MEA, Cocamide DEA, Arginine, Bis (2-ethylhexyl) phthalate, di-n-hexyl phthalate, diethyl phthalate, bis (2-ethylhexyl) adipate, dimethyl adipate, dioctyl adipate, dibutyl sebacate, dibutyl maleate, triethyl citrate, Acetyltriethyl citrate, trioctyl citrate, trihexyl citrate, butyryl trihexyl citrate, trimethyl citrate, acetic acid and anhydride, benzoic acid and anhydride, diethylenetriamine pentaacetate dianhydride, ethylenediaminetetraacetate dianhydride, maleic acid and anhydride. Things, succinic acid and anhydride, diglycolic acid anhydride, glutaric anhydride, ascorbic acid, citric acid, tartrate acid, lactic acid, oxalic acid aspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, alloyylic acid, sherophosphate, The medical device according to 1, which is selected from the combination of aminoalcohol and organic acid, as well as their substituted molecules.

11. A medical device for delivering a therapeutic agent to a tissue, which comprises a layer covering the outer surface of the medical device, the layer containing a therapeutic agent, an antioxidant and an additive, wherein the additive is p-isononyl. Phenoxypolyglycidol, PEG laurate, Tween 20, Tween 21, Tween 40, Tween 60, Tween 61, Tween 80, Tween 81, Tween 85, PEG oleate, PEG steerate, PEG-15 12-hydroxystearate (Soltol HS 15). ), Cremophor EL and ELP, Cremophor RH40, polyester-PEG block copolymer, PLLA-PEG, PEG-PLLA-PEG, PEG-PPG, PEG-PPG-PEG, polyethylene glycol graft copolymer, Soluprus, polyvinylcaprolactam-polyvinyl acetate- Polyethylene glycol graft copolymer, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl millistate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 milli State, Polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 millistate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG Oleyl Ether, PEG Lauryl Ether, Laneth-5, Laneth-10, Laneth-15, Laneth-20, Laneth-25, Laneth-40), Laureth-5, laureth-10, Laureth-15, laureth-20, Laureth-25, laureth-40, Oleth-2, Oleth-5, Oleth-10, Oleth-12, Oleth-16, Oleth-20, and Oleth-25, Steareth-2, Steareth-7, Steareth-8, Steareth -10, Steareth-16, Steareth-20, Stear eth-25, Steareth-80, Ceteth-5, Ceteth-10, Ceteth-15, Ceteth-20, Ceteth-25, Ceteth-30, Ceteth-40, PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl Ether (Brij 30), sodium lauryl sulfate, sodium dodecyl sulfate, sodium lauryl ether sulfate, sodium cetostearyl sulfate, sodium cetearyl sulfate, sodium tetradecyl sulfate, sulfated castor oil, sodium cholesteryl sulfate, sodium tetradecyl sulfate, sodium myristyl sulfate, octyl sulfate. Sodium, medium chain-branched or non-branched alkyl sulphates, sodium doxate, sodium dioctyl sulfosuccinate, sodium lauryl sulfosuccinate, sodium alkylbenzene sulfonate, sodium dodecylbenzene sulfonate, octoxinol, monoxinol, tyroxapole, monopalmitic acid Sulfose, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β- D-Maltside, Heptanoyl-N-Methyl Glucamide, n-Heptyl-β-D-Glucopyranoside, n-Heptyl-β-D-Thioglucoside, n-Hexyl-β-D-Glucopyranoside, Nonanoyl-N-Methyl Glucamide , N-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, Asparagine, asparagic acid, glutamate, and methionine; acetic acid anhydride, benzoic acid anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate, dianehydride ethylenediaminetetraacetate, maleic acid and anhydride, succinic anhydride, Diglycolic acid anhydride, glutaric anhydride, acetylamine, benfotiamine, pantothenic acid; setothiamine; sicothamine, dexpantenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate, ascorbic acid nicotine amide, riboflavin, riboflavin phosphate, thiamine , Folic acid, Menadiol diphosphate, sodium benzosulfate, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysoteams, immunoglobins, a-2 -Macroglobulin, fibronectins, bitronectins, fibrinogens, lipases, benzalconium chloride, benzethonium chloride, doceciltrimethylammonium bromide, sodium docecilsulfate, dialkylmethylbenzylammonium chloride, and dialkylesters of sodium sulfosuccinate, L. -Ascorbic acid and its salts, D-Glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumin, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, Glucoheptonolactone, glucooctanoic acid lactone, glonic acid lactone, mannonic acid lactone, ribbon acid lactone, lactobionic acid, glucosamine, glutamate, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, Genticinic acid, lactobionic acid, lactitol, cinnapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl) -cyclodextrin, acetaminophen, ibprofen, retinoic acid, lysine acetate, Genticinic acid, catechin, catechin gallate, tyretamine, ketamine, propofol, lactic acid, acetic acid and anhydride, benzoic acid and anhydride, diethylenetriamine pentaacetate dianhydride, ethylenediaminetetraacetate dianhydride, maleic acid and anhydride, succinic acid and Anhydride, diglycolic acid anhydride, glutaric anhydride, citric acid, tartaric acid, oxalic acid asparagic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, alloyylic acid, shelophosphate, bisphthalate (2-ethylhexyl), phthalate. Di-n-hexyl acid, diethyl phthalate, bis (2-ethylhexyl) adipate, dimethyl adipate, dioctyl adipate, dibutyl sebacate, dibutyl maleate, triethyl citrate, acetyltriethyl citrate, trioctyl citrate, Trihexyl citrate, butyryl trihexyl citrate, trimethyl citrate, salts of any organic acid and organic amine, polyglycidol, glycerol, multiglycerols, galactitol, di (ethylene glycol), tri (ethylene glycol), tetra (Ethethylene glycol), penta (ethylene glycol), poly (ethylene glycol) oligomers, di (propylene glycol), tri (propylene glycol), tetra (propylene glycol), and penta (propylene glycol), poly (propylene glycol) oligomers, Block copolymer of polyethylene glycol and polypropylene glycol, soluble povidone, soluble polyvinylpyrrolidone with a molecular weight of less than 4000, Kollidon 12 PF, Kollidon 17 PF, urea, biuret, acetamide, lactic acid amide, amino acid amide, acetaminophen, uric acid, polyurea, urethane, Urea Derivatives, Niacinamide, N-Methylacetamide, N, N-Dimethylacetamide, Sulfacetamide Sodium, Versetamide, Laurate Diethanolamide, Laurate Myristic Acid Diethanolamide, N, N-Bis (2-Hydroxyethyl Steal A medical device selected from amide), cocamide MEA, cocamide DEA, arginine, and derivatives and combinations thereof.

12. 1. The tissue comprises one of the coronary, peripheral, cerebral, esophageal, airway, sinuses, trachea, colon, bile duct, ureter, prostate and cerebral tract. Medical equipment.

13. Medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherosctomy tools, devalking catheters, stents, filters, stent grafts, coated stents, patches, wires, and valves. The medical device according to 1, including one of them.

14. 1. Therapeutic agent is one of paclitaxel and its analogs, rapamycin and its analogs, beta-rapacon and its analogs, biovitamin D and its analogs, and mixtures of these therapeutic agents. Medical equipment.

15. The medical device according to 1, wherein the medical device further includes an uppermost layer covering the surface of a layer covering the outer surface of the medical device in order to reduce the loss of the drug as it travels through the body to the target tissue.

16. The medical device according to 1, wherein the medical device can release the therapeutic agent and the additive and deliver the therapeutic agent to the tissue in about 0.1 to 2 minutes.

17. The medical device according to 1, wherein the layer consists essentially of a therapeutic agent, an antioxidant and an additive.

18. The medical device according to 1, wherein the concentration of the therapeutic agent in the layer is from 1 to 20 μg / mm ^2.

10 Catheter 12 Balloon 14 Flexible member 16 Handle assembly 20 Coating layer 22 Adhesive layer 24 Layer containing therapeutic agents and additives 26 First layer 28 Second layer

Claims (8)

A sterilized balloon catheter for delivering a therapeutic agent to a tissue, wherein the sterilized balloon catheter comprises a coating layer covering the outer surface of the balloon.
The coating layer contains a therapeutic agent, an antioxidant, a first additive and a second additive.
The therapeutic agent is rapamycin, paclitaxel, or a combination thereof.
The first additive is PEG-20 sorbitan monooleate, PEG-20 sorbitan monolaurate, PEG-15 12-hydroxystearate, Oleth-10, Oleth-20, PEG-b-PLA, PEG-35 castor oil, And sorbitol selected from the group
The second additive was selected from the group consisting of sodium dioctyl sulfosuccinate, sodium dodecyl sulfate , and polyvinylpyrrolidone.
The antioxidant is at least one of butylated hydroxytoluene (“BHT”) or butylated hydroxyanisole (“BHA”).
Balloon catheter. The balloon catheter according to claim 1, wherein the therapeutic agent is rapamycin. The balloon catheter according to claim 1, wherein the first additive is PEG-20 sorbitan monolaurate. The balloon catheter according to claim 1, wherein the first additive is sorbitol. The balloon catheter according to claim 1, wherein the second additive is sodium dioctyl sulfosuccinate. The balloon catheter according to claim 1, wherein the second additive is polyvinylpyrrolidone. The balloon catheter according to claim 1, wherein the concentration of the therapeutic agent in the coating layer is from 1 μg / mm ² to 20 μg / mm ^2. 1. The tissue comprises one of the coronary, peripheral, cerebral, esophageal, respiratory, sinus, trachea, colon, bile duct, ureter, prostate and cerebral tract. The described balloon catheter.

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