JP7335920B2 - Drug release coating for medical devices - Google Patents

Description

Reference to Related Applications
[001] This application is a continuation-in-part of Application No. 12/121,986, filed May 16, 2008, which is a continuation-in-part of Application No. 11/942,452, 2007-11. filed on Jan. 19, which claims priority from US Provisional Application No. 60/860,084, filed on Nov. 20, 2006, US Provisional Application No. 60/880,742, filed on Jan. 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 present invention provide coated medical devices, particularly coated balloon catheters, and for rapidly delivering therapeutic agents to specific tissues or body cavities, for treating diseases, particularly stenoses and cavities. They relate to their use to reduce late lumen loss of body cavities. Aspects of the invention also included methods of making these medical devices, coatings applied to these medical devices, solutions for making these coatings, and arteries in particular using these coated medical devices. It relates to methods for treating body cavities such as the vascular system.

[003] It has become increasingly popular to treat a variety of medical conditions by introducing medical devices into the vascular system or other body cavities of human or animal patients, such as the esophagus, trachea, colon, bile ducts or ureters. It's here. For example, medical devices used to treat vascular disease include stents, catheters, balloon catheters, guidewires, cannulas, and the like. Although these medical devices appear effective at first, their benefit is often compromised by the development of complications such as late thrombosis or recurrence of disease such as stenosis (restenosis) after such procedures. .

[004] Restenosis, for example, involves a physiological response to vascular injury caused by angioplasty. Over time, de-endotheliazation and damage to smooth muscle cells result in thrombus deposition, leukocyte and macrophage infiltration, smooth muscle cell proliferation/migration, fibrogenesis and extracellular matrix deposition. Inflammation plays a pivotal role in linking initial vascular injury to the final outcome of neointimal proliferation and luminal injury. Leukocyte recruitment is limited to initial neutrophil infiltration in balloon-injured arteries, whereas initial neutrophil recruitment is followed by persistent macrophage accumulation in stented arteries. The widespread use of coronary stents is due to the development of more intense persistent inflammatory conditions due to chronic stimulation from implanted foreign bodies and, in the case of drug eluting stents (DES), to the biocompatibility of polymer coatings. Insufficient, it altered the vascular response to injury.

[005] Over the 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 a specific local site or organ within the body, it is advantageous to treat only those affected areas preferentially. This avoids high systemic drug levels that can produce adverse side effects, and concentrates therapeutic agents to the local area where they are needed. By treating only the diseased tissue, the total amount of drug used can be significantly reduced. Furthermore, local drug delivery enables the use of certain effective therapeutic agents that were previously thought to be too toxic or non-selective for systemic use.

[006] One 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 the blood vessel, the polymer degrades and the drug is slowly released. Sustained drug release over weeks to months has been reported as one of the major benefits of using DES. However, while sustained release may be advantageous when placing a foreign body such as a stent, it causes chronic irritation and inflammation, and inflammation and cell proliferation after acute injury if the foreign body is not implanted. It would be advantageous to rapidly deliver the drug to the vascular tissue during the procedure to prevent . Thus, a significant drawback of DES, or any other implantable medical device designed for sustained drug release, is the inability to rapidly release the drug into the blood vessel.

[007] Furthermore, although drug-eluting stents were initially shown to be an effective approach to reduce and prevent restenosis, their efficacy and safety have recently been questioned. Late thrombosis, a fatal complication of this procedure, has emerged as a major concern. Drug-eluting stents cause substantial impairment of arterial healing characterized by lack of complete reendothelialization and persistence of fibrin compared to bare metal stents (BMS), which leads to late DES thrombosis. has been interpreted as the root of Concerns have also been raised that polymer matrices embedding antiproliferative drugs on stents may exacerbate inflammation and thrombosis as the polymers used are not sufficiently biocompatible. These polymer systems are designed for long lasting drug delivery over days, months or years rather than over seconds or minutes. These polymer-drug coatings of 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 polymer systems as contemplated by embodiments of the present invention is not possible. Therefore, combining therapeutic agents and polymers in coatings for medical devices can have significant drawbacks.

[008] Another significant limitation of DES is that the water-insoluble drug is not uniformly distributed in the polymer matrix of the coating. Additionally, the drug and polymer are concentrated on the struts of the stent, but not in the spaces between the struts. This non-uniform drug distribution causes non-uniform drug release to the tissue vessel wall. This can lead to tissue damage and thrombosis in areas exposed to excess drug and hyperplasia and restenosis in undertreated areas. Thus, improving the solubility of the drug in the coating of the medical device by increasing the compatibility of the drug with the carrier, e.g., polymer matrix, in the coating, thereby eliminating drug crystal particles in the polymer matrix or other coating. There is a need to improve the uniformity of drug delivery to the target tissue by reducing or reducing its size to create uniform drug distribution in drug coatings on medical devices.

[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] Non-stented local delivery systems, such as balloon catheters, have also been effective in treating and preventing restenosis. The balloon is coated with an active agent such that when the vessel is dilated, the balloon is forced against the vessel wall to deliver the active agent. Therefore, when using balloon catheters, it is advantageous for the drug in the coating to be rapidly delivered and absorbed by the vascular tissue. Any coating components, such as lipids or polymers, or encapsulated particles that inhibit rapid release are of course disadvantageous for the intended use of balloon catheters, i.

[011] Hydrophilic drugs, such as heparin, have been reported to be delivered by balloon catheters coated with polymer hydrogels. However, polymer hydrogel coatings cannot effectively deliver water-insoluble drugs (eg, paclitaxel and rapamycin) because they are not miscible with hydrogel coatings. Furthermore, as the drug is released, the crosslinked polymer hydrogel remains on the balloon after the drug has been released. The iodine contrast agent iopromide has been used with paclitaxel to coat balloon catheters with some success in treating restenosis. Contrast agents have been reported to improve adherence of paclitaxel to the balloon surface. However, iodinated contrast agents have some well-known drawbacks. When used in diagnostic procedures, they may have a complication rate of 5-30%. These agents are associated with risks of bradycardia, ventricular arrhythmia, hypotension, heart block, sinus arrest, sinus tachycardia, and fibrillation. Iodinated contrast agents can also induce renal failure and, as a result, significant efforts are being made to remove these contrast agents from the vasculature after diagnostic procedures.

[012] Additionally, in 2006, the Food and Drug Administration (FDA) declared a severe risk factor known as Nephrogenic Systemic Fibrosis or Nephrogenic Fibrosing Dermopathy for contrast agents. A second public health advisory was issued for delayed adverse reactions. Due to the wide range of adverse events associated with intravascular delivery of contrast agents, there is a need for improved medical devices with coatings that do not inherently require additional administration of contrast agents to the patient 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 elimination. As they are large polar hydrophilic molecules, they are unable to cross membrane lipid bilayers and enter cells of the vascular system. Therefore, they are not optimally effective at carrying hydrophobic drugs such as paclitaxel into cells, with only 5-20% of paclitaxel reported to be taken up by vascular tissue after placement of these devices. Furthermore, the compatibility or miscibility of paclitaxel and iopromide is not good, and the integrity and uniformity of the coating is poor. Particles are easily flaking off and lost from the coating during handling. These drawbacks adversely affect the amount and uniformity of drug delivered to target tissues. Thus, improved coatings, i.e., coatings that not only avoid unnecessary contrast agent administration, but also maintain integrity during handling, deliver drug more effectively and uniformly, and facilitate its absorption by tissue. is required.

[014] Alternatively, coating balloon catheters with hydrophobic therapeutic agents mixed with oils or lipids or encapsulated in particles or polymers such as liposomes has been reported. All of these drug delivery formulations have significant drawbacks. Unlike hydrophilic contrast agents, oils and lipids are well miscible with water-insoluble drugs, such as paclitaxel or rapamycin, but the particle size of oils used to solubilize therapeutic agents is relatively unstable, measuring several hundred nanometers in diameter. It spans a wide particle size distribution from meters to several microns.

[015] Common micelles have a low loading capacity. Other drawbacks of oily liposome formulations are:
Drug absorption is dependent on the rate and extent of lipolysis. Lipolysis of oily triglycerides is difficult and depends on many factors, the triglyceride must be digested to release the drug in order to be absorbed by the affected tissue. Since liposomes and micelles cannot release hydrophobic drugs efficiently and therefore carry away the drug before it can be absorbed by the tissue, the amount of hydrophobic drug delivered to the tissue by these agents will be low. Thus, oils and lipids are ineffective in promoting rapid and efficient tissue drug uptake during very short device placement times, and no reports have shown these types of coatings to be effective. Since the drug is encapsulated in particles, micelles or liposomes, which requires significantly higher lipid concentrations than the drug, the drug to lipid ratio in these formulations is generally 0.2-0.3. 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 ranges from days to weeks or months. This property is undesirable in situations where drug release is in the seconds to minutes range. 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 out of the coating (reported ranges of months to years) and may be more difficult to penetrate rapidly into target tissues. . Microspheres made of polymeric materials such as polyester, when used to encapsulate water-insoluble drugs, cannot release the drug until the polymeric material degrades. Therefore, although these polymer microspheres are useful for sustained release of drugs over an extended period of time, they are unable to rapidly release drugs to facilitate tissue uptake.

[017] Combining drugs and medical devices is a complex technical field. It maintains adherence of the drug to the medical device until the device reaches the target site and then delivers the drug to the target tissue with desired release and absorption kinetics, along with the usual formulation challenges such as oral or injectable drugs. It also entails the challenge of Drug coatings on medical devices must also possess properties such that they do not break when the medical device, such as a balloon catheter or stent, is inflated and deflated. Additionally, the coating should not compromise functional performance such as balloon burst pressure and compliance or radial strength of a self-expanding or balloon-expandable stent. Coating thickness must also be kept to a minimum, as thick coatings increase the profile of the medical device and reduce its tracking and deliverability. These coatings generally contain few liquid chemical compounds commonly used to stabilize drugs. Therefore, formulations that work for pills or injections may not work at all for medical device coatings. If the drug is released too easily from the medical device, it may be lost in the middle of delivery before the device can be positioned at the target site, or there may be an explosive release of the drug from the medical device early in its inflation and it may enter the body cavity. It may be washed away before it comes into pressure contact with the target tissue of 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, in order to treat or prevent vascular and non-vascular diseases such as restenosis, a therapeutic agent, drug or bioactive substance is rapidly introduced into a localized tissue region during or after a medical procedure. There is still a need to develop highly specialized coatings that can be delivered directly. The medical device rapidly, effectively and efficiently releases the therapeutic agent at the desired target location, where the therapeutic agent rapidly permeates the target tissue to treat disease, such as reducing stenosis, restenosis and slowing of body lumens. Spontaneous lumen loss should be prevented.

[019] Furthermore, each therapeutic agent has different structures and properties, and therefore requires different formulations to achieve the desired coating properties and optimal therapeutic benefit. Therapeutic agents react differently with different drug carriers, and reactions between the drug and excipients can render the therapeutic agent inactive or produce potentially toxic degradation products. This is further complicated by the large surface area of drug-coated medical devices and the exposure to heat, moisture and oxidizing conditions during sterilization. These are of particular concern if the therapeutic agent is sensitive to moisture or susceptible to hydrolysis or oxidation. Paritaxel can be hydrolyzed and reacts with many compound functional groups. Rapamycin and its derivatives are readily hydrolyzed and oxidized. It is therefore an object of certain embodiments of the present invention to provide coatings for medical devices that contain additives and therapeutic agents that do not participate in the degradation of therapeutic agents, such as rapamycin and its derivatives, or prevent the sterilization and use of medical devices. The object is to provide a coating that protects the therapeutic agent from oxidation and hydrolysis upon pre-storage while still allowing delivery and penetration of therapeutic doses of the drug into the target tissue. Aspects of the present invention relate to compositions and manufacturing methods for making and processing coated medical devices that minimize oxidative and/or hydrolytic degradation of therapeutic agents such as rapamycin and its derivatives. Coatings of embodiments of the present invention comprise a therapeutic agent and at least one additive, wherein the additive is based on the unique properties of each therapeutic agent to minimize degradation of the therapeutic agent in the coating layer. to provide a safe and effective drug-coated medical device.

[020] The inventors have found that the outer surface of a medical device, particularly a balloon catheter or stent,
For example, we have found that coating with a layer containing a therapeutic agent and an additive having both hydrophilic and drug-affinity moieties is useful in solving the problems associated with coatings discussed above. Drug affinity moieties are hydrophobic moieties and/or have affinity for therapeutic agents through hydrogen bonding and/or van der Waals interactions. Surprisingly, the inventors have found that at least one additive comprising an affinity moiety and a drug affinity moiety according to aspects of the present invention, in combination with a therapeutic agent, can be used in medical devices without oils and lipids. We have found that effective drug delivery coatings are formed on top, thereby avoiding the lipid degradation dependence and other drawbacks of typical oil-based coating formulations. Additionally, additives according to aspects of the present invention facilitate rapid drug elution and excellent drug penetration into diseased tissue. Thus, coatings according to aspects of the present invention enhance the rate and/or extent of absorption of hydrophobic therapeutic agents in diseased tissue of the vascular system and other body cavities. In aspects of the present invention, the coated medical device delivers therapeutic agent to tissue during a very short deployment period of less than 2 minutes, reducing body lumen narrowing and delayed lumen loss.

[021] In one aspect, the present invention is a medical device for delivering therapeutic agents to tissue, comprising:
It relates to a medical device including a layer covering the outer surface of the medical device. The medical devices include 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, atherectomy devices, debulking catheters, stents, filters, stent grafts, covered stents, patches, wires, and One of the valves is included. Additionally, the tissue includes one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct.

[022] In one embodiment of the 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, wherein the drug affinity The moiety is at least one of a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding, and a moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein the additive is water soluble. and 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 embodiment of the medical device, the coating layer overlying the medical device comprises a therapeutic agent,
Antioxidants and additives, wherein the additive comprises a hydrophilic moiety and a drug affinity moiety, wherein the drug affinity moiety comprises a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding. , and at least one of the moieties that have an affinity for the therapeutic agent through van der Waals interactions, wherein the additive is water soluble, wherein the additive is 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, chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are selected from: amino alcohols, hydroxyl carboxylic acids, esters, amides, ethers. acid anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan, 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 derivatives, niacinamide, N-methylacetamide, N,N-dimethylacetamide, sulfacetamide sodium, versetamide, lauric acid diethanolamide, lauric myristate diethanolamide, N,N-bis(2 -hydroxyethyl stearamide), 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, butyryltrihexyl citrate, trimethyl citrate, acetic acid and anhydride, benzoic acid and anhydride, Diethylenetriaminepentaacetic acid dianhydride, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic acid and anhydride, diglycolic anhydride, glutaric anhydride, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, aspartic acid, nicotine acids, 2-pyrrolidone-5-carboxylic acid, aleuritic acid, shellolic acid, combinations of aminoalcohols and organic acids, and substituted molecules thereof.

[024] In one embodiment of the medical device, the coating layer overlying the medical device comprises a therapeutic agent,
Antioxidants and additives, wherein the additive comprises a hydrophilic moiety and a drug affinity moiety, wherein the drug affinity moiety comprises a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding. , and at least one of the moieties that have an affinity for the therapeutic agent through van der Waals interactions, wherein the additive is water soluble, wherein the additive is a surfactant and a chemical compound wherein 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: oligomeric or polymeric proanthocyanidins, polyphenols, polyphosphates, polyazomethines, high sulfate agar oligomers, chitooligosaccharides, poly Functional oligomeric thioethers including sterically hindered phenols, hindered amines, p-phenylenediamine, trimethyldihydroquinolones, and alkylated diphenylamines, hindered phenols, t -butyl, arylamines, phosphites, hydroxylamines, benzofuranones, p-phenylenediamine, diphenylamine, N,N' disubstituted p-phenylenediamines, butylated hydroxytoluene ("BHT"), butylated hydroxy Anisole (“BHA”), L-Ascorbate (Vitamin C), Vitamin E, Herbal Rosemary, Sage Extract, Glutathione, Resveratrol, Ethoxyquin, Rosmanol, Isorosmanol, Rosmaridiphenol ), propyl gallate, gallic acid, caffeic acid, p-coumeric acid, p-hydroxybenzoic acid, astaxanthin, ferulic acid, dehydrozingerone, chlorogenic acid, ellagic acid ( ellagic acid), propylparaben, sinapinic acid, daidzin, glycitin, genistin, 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 embodiment of the medical device, the coating layer overlying the outer surface of the medical device comprises a therapeutic agent, an antioxidant and an additive, the additive 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 Stearate, PEG-15 12-Hydroxystearate (Solutol 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, Soluplus, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft Copolymer, 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 Myristate, Polyglyceryl -6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, 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-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, Tetradecyl Sulfate Sodium, sodium myristyl sulfate, sodium octyl sulfate, medium chain-branched or unbranched alkyl sulfates, docusate sodium, sodium dioctylsulfosuccinate, sodium laurylsulfoacetate, sodium alkylbenzenesulfonate, sodium dodecylbenzenesulfonate, octoxynol , monoxinol, tyloxapol, 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 anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, pyrrolidonecarboxylic acid sodium acid, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; cycothiamine), dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamins K5, vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, fibrinogens, lipases, benzalkonium chloride, benzethonium chloride, docecyltrimethylammonium bromide, sodium docecylsulfates, dialkylmethylbenzylammonium chloride, and dialkyl esters of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and salts thereof, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic lactone, Lactone gulonic acid, lactone mannonic acid, lactone ribonate, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapic acid (sinapic acid), vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, gallic acid Acid catechin, tiletamine, ketamine, propofol, lactic acids, 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, soluble povidone, soluble polyvinylpyrrolidone with molecular weight less than 4000, Kollidon 12 PF, Kollidon 17 PF, urea, biuret, acetamide, lactic acid amide, amino acid amides, acetaminophen, uric acid, polyurea , urethane, urea derivatives, niacinamide, N-methylacetamide, N,N-dimethylacetamide, sulfacetamide sodium, vercetamide, lauric acid diethanolamide, lauric myristate diethanolamide, N,N-bis(2-hydroxy ethyl stearamide), cocamide MEA, cocamide DEA, arginine, and derivatives and combinations thereof.

[027] In one embodiment, the coating layer overlying 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, wherein the drug The affinity moiety is at least one of a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding, and a moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein one One of the above additives is a liquid additive.

[028] In one embodiment, the coating layer overlying the outer surface of the medical device comprises a therapeutic agent and at least one additive, the at least one additive comprising a first additive and a second additive, wherein , each additive comprises a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion comprises a hydrophobic portion, a portion that has affinity for the therapeutic agent through hydrogen bonding, and a therapeutic agent through van der Waals interactions. wherein the first additive has a greater affinity than the second additive.

[029] In one embodiment, the coating layer overlying the outer surface of the medical device comprises a therapeutic agent and at least one additive, the at least one additive comprising a first additive and a second additive, wherein , each additive comprises a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion comprises a hydrophobic portion, a portion that has affinity for the therapeutic agent through hydrogen bonding, and a therapeutic agent through van der Waals interaction. At least one of the moieties having affinity for the drug, wherein the HLB value of the first additive is higher than that of the second additive.

[030] In one embodiment, the coating layer overlying 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 comprises a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion includes a hydrophobic portion, a portion that has affinity for the therapeutic agent through hydrogen bonding, and a therapeutic agent through van der Waals interactions. wherein the Log P of the first additive is lower than that of the second additive.

[031] In one embodiment, the coating layer overlying 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 compound having at least one ester group. Contains chemical compounds. 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 with 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, butyryltrihexyl citrate, and trimethyl citrate.

[032] In one embodiment, the coating layer overlying the outer surface of the medical device comprises a therapeutic agent and at least one additive, the at least one additive comprising at least one chemical compound having at least one amide group. include. In certain embodiments, chemical compounds with at least one amide group are important to coating formulations. Urea is an example of a chemical compound with at least one amide group. Other examples of chemical compounds with at least one amide group include biuret, acetamide, lactamide, amino acid amides, acetaminophen, uric acid, polyurea, urethane, urea derivatives, niacinamide, N-methylacetamide, N,N - dimethylacetamide, sulfacetamide sodium, versetamide, lauric acid diethanolamide, lauric myristate diethanolamide, N,N-bis(2-hydroxyethyl stearamide), cocamide MEA, cocamide DEA, arginine, and others Included are organic acid amides, as well as derivatives thereof. Certain chemical compounds with at least one amide group also contain one or more hydroxyl, amino, carbonyl, acid or ester moieties.

[033] One chemical compound with at least one amide group is soluble, low molecular weight povidone. Some examples of povidones include Kollidon 12 PF, Kollidon 17 PF, Kollidon 17, Kollidon 25, and Kollidon 30. Kollidon products include soluble and insoluble grades of polyvinylpyrrolidone of various molecular weights and particle sizes, vinylpyrrolidone/vinylacetate copolymers, and blends of polyvinylacetate and polyvinylpyrrolidone. The related products have the names Povidone, Crospovidone and Copovidone. Low molecular weight soluble povidones and copovidones are important additives in embodiments of the invention: eg Kollidon 12 PF, Kollidon 17 PF, and Kollidon 17. Solid povidone can maintain the integrity of the coating on the medical device. Low molecular weight povidone can be absorbed or permeated into the diseased tissue. Preferred molecular weight ranges for povidone are less than 54,000, less than 11,000, less than 7,000, and less than 4,000. Povidones can solubilize water-insoluble therapeutic agents. Povidones and copovidones are particularly useful in embodiments of the present invention because of their properties (solid, low molecular weight, and tissue absorption/permeability). Povidones can be used in combination with other additives in embodiments of the invention. In one embodiment, povidone and a nonionic surfactant (e.g., PEG-15 12-hydroxystearate (Solutol HS 15), Tween 20, Tween 80, Cremophor RH40, Cremophor EL and ELP) are combined with paclitaxel or rapamycin or their The analogs can be formulated as coatings for medical devices such as balloon catheters.

[034] In one embodiment, the coating 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, wherein the drug affinity moiety comprises: at least one of a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding, and a moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein the additive is a surfactant and at least one of the chemical compounds, wherein the chemical compound has more than four hydroxyl groups; In one embodiment, chemical compounds with more than 4 hydroxyl groups have a melting point of 120° C. or less, and the chemical compounds are alcohols or esters.

[035] In one embodiment, the layer covering the outer surface of the medical device consists essentially of the therapeutic agent and the 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 aspect, the chemical compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one aspect, the chemical compounds are amino alcohols, hydroxyl carboxylic acids, esters, anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan , glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohols and organic acids, and substituted molecules thereof. In other embodiments, the surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, esters of PEG omega-3 fatty acids, ethers, 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, and derivatives thereof.

[036] In other embodiments, the coating layer overlying the medical device comprises a therapeutic agent and an additive, wherein the additive is 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 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 with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxyl carboxylic acids, esters, amides, ethers, anhydrides, hydroxyl ketones. , hydroxyl lactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, It is selected from combinations of aminoalcohols and organic acids, and substituted molecules thereof.

[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 from 5,000 to less than 10,000, preferably from 1000 to less than 5,000; More preferably 750 to less than 1,000, or most preferably less than 750 hydrophilic chemical compounds. The molecular weight of the additive is preferably lower than that of the drug to be delivered. Small molecules can diffuse rapidly and they are easily released from the surface of the delivery balloon, carrying the drug with them. They rapidly diffuse away from the drug once 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 undesirable because they tend to evaporate and are not stable coating components. Additives may have a molecular weight of less than 80, less than 50, and less than 20, provided that the additive has a low molecular weight but is not volatile (e.g., a paste or solid) and does not evaporate or react easily. In other embodiments, the additive is a combination of a surfactant and a chemical compound with 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 is advantageous because it prevents In other embodiments, the additive is a hydroxyl ketone, hydroxyl lactone, hydroxyl acid, hydroxyl ester, or hydroxylamide. In other embodiments, the additive is gluconolactone or its ribonate lactone. In still other embodiments, 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 derivative thereof. In other embodiments, the additive is an amino acid or 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 aqueous solvents and soluble in organic solvents. In other embodiments, the additive is an organic acid or its anhydride. In still other embodiments, the additive is selected from sorbitan oleate and sorbitan fatty acid esters.

[039] In other embodiments, 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 of from 20 to 750. It is a chemical compound.

[040] In one embodiment, the layer covering the outer surface of the medical device does not contain oils, lipids, or polymers. In other embodiments, the layer covering the outer surface of the medical device does not contain oil. In other embodiments, 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 purely hydrophobic additives. In one aspect, the additive is not a therapeutic agent. In other embodiments, the additive is not salicylic acid or its salts.

[041] In other embodiments, 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, wherein the drug affinity moiety is , a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding, and a moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein the additive is: selected from: p-isononylphenoxy polyglycidol, PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, Tween 20, Tween 40, Tween 60, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate , Polyglyceryl oleate, Polyglyceryl myristate, Polyglyceryl palmitate, Polyglyceryl-6 laurate, Polyglyceryl-6 oleate, Polyglyceryl-6
Myristate, Polyglyceryl-6 Palmitate, Polyglyceryl-10 Laurate, Polyglyceryl-10 Oleate, Polyglyceryl-10 Myristate, Polyglyceryl-10 Palmitate PEG Sorbitan Monolaurate, PEG Sorbitan Monolaurate, PEG Sorbitan Monooleate, PEG Sorbitan Stearate , PEG oleyl ether, PEG lauryl ether, octoxynol, monoxinol, tyloxapol, 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 anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidonecarboxylate, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid; cetothiamine; cicotiamine, dexpanthenol, niacinamide, Nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamins U; albumin, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, fibrinogens, lipases, benzalkonium chloride, benzethonium chloride, docecil trimethylammonium bromide, sodium doceyl sulfates, dialkylmethylbenzylammonium chloride, and dialkyl esters of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, Meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, ribonic acid lactone, lactobionic acid, glucosamine , glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapinic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclo dextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid, any organic acid and Salts of organic amines, polyglycidol, glycerols, 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 and derivatives and combinations thereof.

[042] In one embodiment, the therapeutic agent is paclitaxel and its analogues, rapamycin and its analogues, beta-lapachone and its analogues, vital vitamin D and its analogues, and mixtures of these therapeutic agents. is one of In other embodiments, the therapeutic agent is in combination with a second therapeutic agent, wherein the therapeutic agent is one of paclitaxel, rapamycin, and analogs thereof, and the second therapeutic agent is beta-lapachone, One of vitamin D and their analogues.

[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 the layer. In another aspect, the medical device further includes a top layer overlying the surface of the layer to reduce drug loss as it travels through the body to tissue. In another embodiment, the top layer overlying the layer overlying the medical device comprises an additive that is less hydrophilic than the additive in the layer overlying the medical device, wherein the additive in the top layer is selected from: p-isononylphenoxy polyglycidol, PEG laurate, Tween 20, Tween 40, Tween 60, 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 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, Polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, octoxynol, monoxinol, tyloxapol, sucrose monopalmitate, monolaurin 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, glutamic acid, and methionine; acetic anhydride, benzoic anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidonecarboxylate, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic anhydride, diglycol anhydride acid, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; sicotiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, Menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2 - macroglobulins, fibronectins, vitronectins, fibrinogens, lipases, benzalkonium chloride, benzethonium chloride, docecyltrimethylammonium bromide, sodium docecyl sulfates, dialkylmethylbenzylammonium chloride and dialkyl esters of sodium sulfosuccinate, L - ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapinic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, Gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, 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.

[044] In another embodiment, the medical device further comprises a dimethylsulfoxide solvent layer, wherein the dimethylsulfoxide solvent layer covers the surface of said layer.
[045] In one embodiment of the medical device, the medical device can release the therapeutic agent and additive in about 0.1-2 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 aspect, the therapeutic agent is not water soluble.

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

[047] In other embodiments of the medical device, the layer overlying the medical device comprises a therapeutic agent and at least two additives, wherein each additive comprises a hydrophilic moiety and a drug affinity moiety, Wherein the drug affinity moiety is at least one of a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding, and a moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein , 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 with water. be. In another aspect of this aspect, the medical device further includes a top layer overlying the outer surface of the medical device to reduce loss during movement through the body to the target tissue.

[048] In other embodiments 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 moiety and a drug affinity moiety, wherein the drug affinity The moiety is at least one of a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding, and a moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein the additive is a therapeutic agent. It reduces the crystal size and particle number of the drug, where the additive is water soluble and the therapeutic drug is not.

[049] In other embodiments of the medical device, the layer overlying 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 The moiety is at least one of a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding, and a moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein the additive is an acid , esters, ethers, or alcohols, where the aliphatic chain can be inserted directly into the lipid membrane structure of tissues, where the therapeutic agent is not water soluble.

[050] In other embodiments 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 moiety and a drug affinity moiety, wherein the additive comprises It is capable of penetrating into and rearranging the lipid membrane structure of the tissue without the therapeutic agent being water soluble, entrapped in micelles, or entrapped in polymer particles.

[051] In other embodiments of the medical device, the layer overlying the medical device comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug affinity moiety, wherein the additive comprises With aliphatic chains of acids, esters, ethers or alcohols, the aliphatic chains can be inserted directly into the lipid membrane structure of the tissue, whereupon the additives can interact with each other through hydrogen bonding and/or van der Waals interactions. It has one or more functional groups that have affinity for the drug (functional groups include hydroxyl, ester, amide, carboxylic acid, primary, secondary and tertiary amine, carbonyl, anhydride, oxide, and aminoalcohols), wherein the therapeutic agent is not water-soluble, entrapped in micelles, or entrapped in polymer particles, wherein the layer contains no polymer, the layer contains iodine Contains no covalently bound contrast agents.

[052] In yet another aspect, the invention relates to a stent coating for delivering a therapeutic agent to tissue, the stent coating comprising a layer overlying the surface of the stent. In one aspect of this embodiment, the layer overlying the stent comprises a therapeutic agent, an additive, and a polymer matrix, wherein the therapeutic agent is dispersed as particles in the polymer matrix but is not encapsulated; As such, the additive comprises a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion comprises a hydrophobic portion, a portion that has affinity for the therapeutic agent through hydrogen bonding, and a therapeutic agent through van der Waals interactions. At least one of the moieties that has an affinity for the drug. In one aspect of this embodiment, 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 uniformity of distribution in the polymer matrix, and the additive improves the uniformity of distribution in the polymer matrix. Promotes rapid release of drug from

[053] In yet another aspect, the invention relates to medical device coatings made from certain mixtures for delivering drugs to tissues. In one aspect of this embodiment, the coating is made from a mixture comprising an organic phase containing drug particles dispersed therein and an aqueous phase containing a water-soluble additive. In one aspect of this embodiment, the water-soluble additives are selected from polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidinone, polypeptides, water-soluble surfactants, water-soluble vitamins, and proteins. In another aspect of this embodiment, preparation of the mixture comprises homogenization under high shear conditions and optionally 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 portion and a drug affinity portion, wherein the drug affinity portion comprises a hydrophobic portion, a hydrogen bonding and at least one of the moiety having affinity for the therapeutic agent through van der Waals interactions, wherein 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 20-750.

[055] In other embodiments 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 comprises a hydrophobic moieties, moieties that have affinity for therapeutic agents through hydrogen bonding, and moieties that have affinity for therapeutic agents through van der Waals interactions, wherein the additive is a surfactant and a chemical compound wherein the chemical compound has more than four hydroxyl groups. In one aspect of this embodiment, the chemical compound with more than 4 hydroxyl groups has a melting point of 120°C or less and the chemical compound is an alcohol or an ester.

[056] In one embodiment of the balloon catheter, the coating layer covering the outer surface of the medical device consists essentially of the therapeutic agent and the additive. In other embodiments, 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, esters of PEG omega-3 fatty acids, ethers, and alcohols, glycerol fatty acids 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 aspect, the chemical compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxyl carboxylic acids, esters and anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, Sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids , and substituted molecules thereof.

[058] In one embodiment of the balloon catheter, the coating layer covering the outer surface of the balloon does not contain purely hydrophobic additives. In another embodiment, the coating layer overlying 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 its salts. In other embodiments, the coating layer covering the surface of the balloon does not contain oils, lipids, or polymers. In yet another embodiment, the coating layer overlying the surface of the balloon does not contain oil. In another aspect of this embodiment, the coating layer does not contain a polymer.

[059] In one embodiment of the balloon catheter, the additives in the coating layer containing therapeutic agents and additives are selected from: p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween 60, 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 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, octoxynol, monoxinol, tyloxapol, 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 anhydride, ascorbic acid, 2-pyrrolidone-5 - carboxylic acids, sodium pyrrolidonecarboxylate, ethylenediaminetetraacetic acid dianhydride, maleic anhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; sicotiamine, dexpanthenol , niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamins K6, and vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, fibrinogens, lipases, benzalkonium chloride, chloride Benzethonium, docecyltrimethylammonium bromide, sodium docecyl sulfates, dialkylmethylbenzylammonium chloride, and dialkyl esters of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanol Amine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, glucoctanoic lactone, gulonic acid lactone, mannonic acid lactone, ribonic acid lactone, Lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapinic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol , xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid, any salts of organic acids and organic amines, 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.

[060] In one embodiment, the therapeutic agent is one of paclitaxel and its analogues, rapamycin and its analogues, beta-lapachone and its analogues, vital vitamin D and its analogues, and mixtures of these therapeutic agents. is. In other embodiments, the therapeutic agent is in combination with a second therapeutic agent, wherein the therapeutic agent is one of paclitaxel, rapamycin, and analogs thereof, and the second therapeutic agent is beta-lapachone, One of vitamin D and their analogues. In one aspect, 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 facilitates penetration and absorption of the therapeutic agent into the vascular tissue. In other embodiments, the therapeutic agent is not water soluble. In other embodiments, the excipient has a water and ethanol solubility of at least 1 mg/ml and the therapeutic agent is not water soluble.

[062] In one embodiment of the balloon catheter, the catheter further comprises an adhesive layer between the outer surface of the balloon and the coating layer. In another embodiment, the catheter further includes a top layer overlying the coating layer, which reduces loss of the therapeutic agent as it travels through the body to the blood vessel. The top layer comprises additives selected from additives according to aspects of the invention described herein. The top layer will gradually dissolve as it travels through the body to the body cavity at the target site for therapeutic intervention. This top layer will reduce drug loss during movement and increase drug availability to tissue when medical devices of embodiments of the present invention are brought into pressure contact with luminal tissue. In one embodiment, the additives in the top layer are less hydrophilic than the additives in the coating layer. In another embodiment, the catheter further comprises a dimethylsulfoxide solvent layer, wherein the dimethylsulfoxide solvent layer covers the surface of the coating layer.

[063] In one embodiment, the balloon catheter can release the therapeutic agent and additive in about 0.1-2 minutes to deliver the therapeutic agent to the blood vessel.
[064] In one embodiment of the 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 still other embodiments, the present invention relates to balloon catheters for delivering therapeutic agents to blood vessels. In one aspect of this aspect, the catheter includes an elongate member having a lumen and a distal end, an inflatable balloon connected to the distal end of the elongate member and in fluid communication with the lumen, and It includes a coating layer covering the outer surface of the balloon. In one aspect of this embodiment, the coating layer overlying the surface of the balloon comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion comprises a hydrophobic at least one of a functional moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding, and a moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein 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 from 20 to 750, wherein the catheter can be injected with the therapeutic agent and the additive 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 embodiment, the layer does not contain an iodinated contrast agent.

[066] In one embodiment, the balloon catheter further comprises a dimethylsulfoxide solvent layer overlying the coating layer, wherein the dimethylsulfoxide solvent layer enhances the ability of the therapeutic agent to penetrate into the blood vessel. In another embodiment, the balloon catheter further comprises an adhesive layer between the outer surface of the balloon and the coating layer. In still other embodiments, the catheter further includes a top layer overlying the coating layer, which maintains the integrity of the coating as it travels within the vessel to the target site for therapeutic intervention.

[067] In one embodiment, the concentration of therapeutic agent in the coating layer is from 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, esters of PEG omega-3 fatty acids, ethers, 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, and derivatives thereof. In one aspect, the chemical compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxyl carboxylic acids, esters and anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters. , sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, amino alcohols and organic acids combinations, as well as substituted molecules thereof. In one embodiment, the chemical compound has more than 4 hydroxyl groups, has a melting point of 120° C. or less, and the chemical compound is an alcohol or an ester.

[068] In one embodiment of the balloon catheter, the additive is selected from:
p-isononylphenoxy polyglycidol, 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 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, 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, Octoxynol, Monoxynol, Tyloxapol, 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 anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidonecarboxylate, ethylenediaminetetraacetic acid dianhydride, maleic anhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride , acetiamine, benfotiamine, pantothenic acid; cetotiamine; sicotiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, Menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectin , vitronectins, fibrinogens, lipases, benzalkonium chloride, benzethonium chloride, docecyltrimethylammonium bromide, sodium doceyl sulfates, dialkylmethylbenzylammonium chloride, and dialkyl esters of sodium sulfosuccinate, L-ascorbic acid and salts of, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyllactone, gluconolactone, glucoheptonolactone, Glucooctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid , lactitol, sinapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid, salts of any organic acids and organic amines, 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.

[069] In still other embodiments, the present invention relates to pharmaceutical compositions comprising a therapeutic agent and an excipient, wherein the excipient comprises a hydrophilic moiety and a drug affinity moiety, wherein the drug affinity The moiety is at least one of a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding, and a moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein 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 20-750. In one aspect of this embodiment, the pharmaceutical composition does not contain an iodine covalently bound imaging agent or polymer, wherein 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 with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxyl carboxylic acids, esters and anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters. , sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, amino alcohols and organic acids combinations, as well as substituted molecules thereof. In one embodiment, the chemical compound has more than 4 hydroxyl groups, has a melting point of 120° C. or less, and the chemical compound is an alcohol or an ester. In one embodiment, the surfactants are ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, esters of PEG omega-3 fatty acids, 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 excipient is selected from: p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG Glyceryl Stearate, Polyglyceryl Laurate, Tween 20, Tween 40, Tween 60, Polyglyceryl Oleate, Polyglyceryl Myristate, Polyglyceryl Palmitate, Polyglyceryl-6 Laurate, Polyglyceryl-6 Oleate, Polyglyceryl-6 Myristate, Polyglyceryl-6 Palmitate , Polyglyceryl-10 Laurate, Polyglyceryl-10 Oleate, Polyglyceryl-10 Myristate, Polyglyceryl-10 Palmitate PEG Sorbitan Monolaurate, PEG Sorbitan Monolaurate, PEG Sorbitan Monooleate, PEG Sorbitan Stearate, PEG Oleyl Ether, PEG Laura yl ether, octoxynol, monoxinol, tyloxapol, 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, glutamic acid, and methionine; acetic anhydride, benzoic anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidonecarboxylate, ethylenediamine tetra Acetic acid dianhydride, maleic anhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; cicotiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphorus Acid, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulins , caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, fibrinogens, lipases, benzalkonium chloride, benzethonium chloride, doceyltrimethylammonium bromide, sodium docecysulfate , dialkylmethylbenzylammonium chloride, and dialkyl esters of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols , glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoin acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl )-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, 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 glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, and derivatives and combinations thereof.

[072] In yet another embodiment, the present invention is a method for treating an afflicted body cavity or cavity after a surgical or interventional procedure, wherein a pharmaceutical composition is delivered to the surgical site by catheter injection or nebulization. wherein 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 is at least one of a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding, and a moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein 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 aspect, 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, esters of PEG omega-3 fatty acids, ethers, and alcohols, glycerol fatty acids 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 with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxyl carboxylic acids, esters and anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, Sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids , and substituted molecules thereof.

[074] In still other embodiments, the present invention provides ovarian, thoracic, lung, esophageal, head and neck, bladder,
Pharmaceutical compositions for treating cancers, including cancers of the prostate, brain, liver, colon, and lymphomas, wherein the composition comprises a therapeutic agent and an additive, wherein the additive is hydrophilic moieties and drug affinity moieties, wherein drug affinity moieties are hydrophobic moieties, moieties that have affinity for therapeutic agents through hydrogen bonding, and moieties that have affinity for therapeutic agents through van der Waals interactions. at least one of which the therapeutic agent is not encapsulated in micelles or encapsulated in polymer particles and wherein the composition does not contain an iodine covalently bound contrast agent. In one aspect of this embodiment, the therapeutic agent is selected from paclitaxel and its analogues and rapamycin and its analogues.

[075] In yet another aspect, the present 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 comprises a hydrophobic moiety, at least one of the moiety that has affinity for the therapeutic agent through hydrogen bonding and the moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein 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 20-750. In other embodiments, the solution for coating the medical device does not contain covalent iodine-bonded 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 with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxyl carboxylic acids, esters and anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, Sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids , and substituted molecules thereof. In one embodiment, the surfactants include ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, esters of PEG omega-3 fatty acids, ethers, 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, and derivatives thereof. In one embodiment, the therapeutic agent is paclitaxel or rapamycin or an analogue thereof.

[077] In other embodiments, the additives in the coating solution are selected from: p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, Tween 20, tween 60, Tween 80, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 Palmitate, Polyglyceryl-10 Laurate, Polyglyceryl-10 Oleate, Polyglyceryl-10 Myristate, Polyglyceryl-10 Palmitate PEG Sorbitan Monolaurate, PEG Sorbitan Monolaurate, PEG Sorbitan Monooleate, PEG Sorbitan Stearate, PEG Oleyl Ether, PEG Lauryl ether, octoxynol, monoxinol, tyloxapol, 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 anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidonecarboxylate, ethylenediamine Tetraacetic acid dianhydride, maleic anhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; cicotiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal phosphoric acid, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulin caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, fibrinogens, lipases, benzalkonium chloride, benzethonium chloride, doceyltrimethylammonium bromide, docecylsulfate Sodiums, dialkylmethylbenzylammonium chloride, and dialkyl esters of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, Benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxy propyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, 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 derivatives and combinations thereof.

[078] In yet another aspect, the present invention is a medical device for delivering a therapeutic agent to a tissue, comprising a first layer applied to an exterior surface of the medical device and a second layer overlying the first layer. Regarding medical devices. 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 is , hydrophobic moieties, moieties that have affinity for therapeutic agents through hydrogen bonding, and moieties that have affinity for therapeutic agents through van der Waals interactions. In one aspect of this embodiment, the first layer further comprises an additive, wherein the additive is water soluble and this layer does not contain an iodinated contrast agent. In another aspect of this embodiment, the second layer further comprises a therapeutic agent. In yet another aspect of this embodiment, 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 comprising a therapeutic agent and a top layer comprising an additive. In one aspect of this aspect, the top layer may overlie 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, hydrogen bonding to the therapeutic agent. at least one of the moiety having affinity and the moiety having affinity for the therapeutic agent through a van der Waals interaction, wherein the additive is water soluble, wherein the additive is a surfactant and a chemical compound, wherein the chemical compound has a molecular weight of from 20 to 750. In one aspect of this embodiment, the first layer does not contain an iodine covalently bound contrast agent. In another aspect of this embodiment, 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 embodiment, the method comprises: (a) preparing a coating solution comprising an organic solvent, a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug affinity moiety; As such, the drug affinity moiety is at least one of a hydrophobic moiety, a moiety having affinity for a therapeutic agent through hydrogen bonding, and a moiety having affinity for a therapeutic agent through van der Waals interactions, and wherein 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 from 80 to 750; (b) this applying the coating solution to the medical device; and (c) drying the coating solution to form a coating layer. In one aspect of this embodiment, the coating layer does not contain an iodine covalently bound contrast agent. In one aspect of this embodiment, the coating solution is applied by dipping a portion of the outer surface of the medical device into the coating solution. In another aspect of this embodiment, 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 embodiment, steps (b) and (c) are repeated until the therapeutically effective amount of the therapeutic agent in the coating layer is deposited on the surface of the medical device. In another aspect of this embodiment, the total thickness of the coating layer is from about 0.1 to 200 microns. In yet another aspect of this embodiment, the method further comprises applying a dimethylsulfoxide solvent to the dried coating layer obtained in step (c).

[081] In yet another aspect, the present invention relates to a method of making a drug-coated balloon catheter. In one aspect of this embodiment, the method comprises: (a) preparing a coating solution comprising an organic solvent, a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and a drug affinity moiety; As such, the drug affinity moiety is at least one of a hydrophobic moiety, a moiety having affinity for a therapeutic agent through hydrogen bonding, and a moiety having affinity for a therapeutic agent through van der Waals interactions, and wherein the additive is at least one of a surfactant and a chemical compound, wherein the chemical compound has a molecular weight of from 20 to 750; and (b) applying the coating solution to an inflated balloon catheter. and (c) deflate and collapse the balloon catheter to dry the coating solution and increase the uniformity of the drug coating.

[082] In yet another aspect, the present invention relates to a method of treating a blood vessel. In one aspect of this aspect, the method includes inserting a medical device comprising a coating layer into a blood vessel, wherein the coating layer comprises a therapeutic agent and an additive, wherein the additive comprises a hydrophilic moiety and Including drug affinity moieties, wherein the drug affinity moieties are hydrophobic moieties, moieties that have affinity for therapeutic agents through hydrogen bonding, and moieties that have affinity for therapeutic agents through van der Waals interactions. at least one, wherein 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 from 20 to 750 and release the therapeutic agent and additive in less than 2 minutes to deliver the therapeutic agent into the tissue of the blood vessel. In one aspect of this embodiment, 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 total occlusion or stenosis of a body passage. In one aspect of this aspect, the method comprises removing plaque from a body vessel and inserting a medical device comprising a coating layer into the body vessel, wherein the coating layer comprises a therapeutic agent and an additive, wherein , the additive comprises a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion comprises a hydrophobic portion, a portion that has affinity for the therapeutic agent through hydrogen bonding, and a portion that has affinity for the therapeutic agent through van der Waals interactions. at least one of the affinity moieties, wherein the additive is at least one of a surfactant and a chemical compound, wherein the chemical compound has a molecular weight of from 80 to 750; It then releases the therapeutic agent and additive in less than 2 minutes 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 bodily tissue comprising contacting a medical device comprising a coating layer with the bodily tissue, wherein the coating layer comprises a therapeutic agent and an additive. agents, wherein the additive comprises a hydrophilic moiety and a drug affinity moiety, wherein the drug affinity moiety comprises a hydrophobic moiety, a moiety with hydrogen bonding affinity for the therapeutic agent, and a van der Waals at least one of the moieties having an affinity for the therapeutic agent by interaction, wherein the additive is water-soluble, wherein the additive is at least one of a surfactant and a chemical compound; Yes, where the chemical compound has a molecular weight of 20 to 750 and releases the therapeutic agent and excipient in less than 2 minutes to deliver the therapeutic agent into the tissue of the blood vessel. In one aspect of this embodiment, the coating layer does not contain an iodine covalently bound contrast agent. In one aspect of this embodiment, the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. included.

[085] In yet another aspect, the invention relates to a method of making a balloon catheter.
In one aspect of this embodiment, the method prepares a solution comprising an organic solvent, a therapeutic agent and an excipient, wherein the excipient comprises a hydrophilic moiety and a drug affinity moiety, wherein the drug affinity moiety is at least one of a hydrophobic moiety, a moiety that has affinity for the therapeutic agent through hydrogen bonding, and a moiety that has affinity for the therapeutic agent through van der Waals interactions, wherein 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 from 20 to 750, the solution is applied to the balloon catheter, and the solvent including evaporating the In one embodiment, the coating layer does not contain an iodinated contrast agent.

[086] In yet another aspect, the present invention relates to a medical device comprising a layer covering an exterior surface of the medical device, the layer comprising a therapeutic agent and an additive, wherein the additive is a PEG fatty acid ester, a PEG fatty acid Ether, and one of PEG fatty alcohols. In one aspect of this embodiment, the additive is 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 dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. In another aspect of this embodiment, the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. includes one. In yet another aspect of this embodiment, the medical device includes balloon catheters, perfusion balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, 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 an exterior surface of the medical device, the layer comprising a therapeutic agent and an additive, wherein the additive is glycerol and polyglycerol fatty acid esters. and PEG glycerol fatty acid ester. In one aspect of this embodiment, the additive is polyglyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl linoleate, polyglyceryl-10 laurate, Polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10
Myristate, Polyglyceryl-10 Palmitate, Polyglyceryl-10 Linoleate, Polyglyceryl-6 Stearate, Polyglyceryl-6 Laurate, Polyglyceryl-6 Myristate, Polyglyceryl-6 Palmitate, and Polyglyceryl-6 Linoleate, Polyglyceryl Polyricinoleate, PEG-20 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 embodiment, the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. includes one. In yet another aspect of this embodiment, the medical device includes balloon catheters, perfusion balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, debulking catheters, stents, filters, stent grafts, coatings. One of a stent, patch, wire, and valve is included.

[088] In yet another aspect, the invention relates to a medical device comprising a layer covering an exterior surface of the medical device, the layer comprising a therapeutic agent and an additive, wherein the additive is sorbitan fatty acid ester and PEG sorbitan one of the esters. In one aspect of this embodiment, the additive is sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitan. monooleate, and PEG-20 sorbitan monostearate. In another aspect of this embodiment, the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. includes one. In yet another aspect of this embodiment, the medical device includes balloon catheters, perfusion balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, debulking catheters, stents, filters, stent grafts, coatings. One of a stent, patch, wire, and valve is included.

[089] In yet another aspect, the present invention relates to a medical device comprising a layer covering an exterior surface of the medical device, the layer comprising a therapeutic agent and an additive, wherein the additive is a chemical compound comprising a phenolic moiety. is. In one aspect of this embodiment, the additive is selected from p-isononylphenoxypolyglycidol, octoxynol, monoxynol, tyloxapol, octoxynol-9, and monoxynol-9. In another aspect of this embodiment, the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. includes one. In yet another aspect of this embodiment, the medical device includes balloon catheters, perfusion balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[090] In yet another aspect, the present invention relates to a medical device comprising a layer covering an exterior surface of the medical device, the layer comprising a therapeutic agent and an additive, wherein the additive is 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, 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, D-glucoascorbic acid and its salts, tromethamine, glucamine, glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl selected from lactones, gluconolactones, glucoheptonolactones, glucoctanoic acid lactones, gulonic acid lactones, mannonic acid lactones, ribonic acid lactones, lactobionic acid and glucosamine. In another aspect of this embodiment, the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. includes one. In yet another aspect of this embodiment, the medical device includes balloon catheters, perfusion balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, debulking catheters, stents, filters, stent grafts, coatings. One of a stent, patch, wire, and valve is included.

[091] In yet another aspect, the invention relates to a medical device comprising a layer covering an exterior surface of the medical device, the layer comprising a therapeutic agent and an additive, wherein the additive is an ionic surfactant. be. In one aspect of this embodiment, the additive is benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, doceyltrimethylammonium bromide, sodium doceyl sulfates, dialkylmethylbenzylammonium chloride, edrophosphonium chloride, domiphen bromide, selected from dialkyl esters of sodium sulfosuccinate, dioctyl sodium sulfosuccinate, sodium cholate, and sodium taurocholate; In another aspect of this embodiment, the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. includes one. In yet another aspect of this embodiment, the medical device includes balloon catheters, perfusion balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, debulking catheters, stents, filters, stent grafts, coatings. Includes one of stents, patches, wires, and valves.

[092] In yet another aspect, the present invention relates to a medical device comprising a layer covering an exterior surface of the medical device, the layer comprising a therapeutic agent and an additive, wherein the additive is a vitamin or vitamin derivative. . In one aspect of this embodiment, the additive is acetiamine, benfotiamine, pantothenic acid, cetotiamine, sicotiamine, dexpanthenol, niacinamide, nicotinic acid and its salts, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, phosphorus acid riboflavin, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, 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, fursultiamine, methylolriboflavin, octotiamine, prosultiamine, riboflavin, vinthimol, dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, disulfate selected from menadiol, menadiol, vitamin K1, vitamin K1 oxide, vitamin K2, and vitamin K--S(II); In another aspect of this embodiment, the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. includes one. In yet another aspect of this embodiment, the medical device includes balloon catheters, perfusion balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, debulking catheters, stents, filters, stent grafts, coatings. One of a stent, patch, wire, and valve is included.

[093] In yet another aspect, the invention relates to a medical device comprising a layer covering an exterior surface of the medical device, the layer comprising a therapeutic agent and an additive, wherein the additive is an amino acid, amino acid salt, or It is an amino acid derivative. In one aspect of this embodiment, the additive is alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, proline, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine. , and derivatives thereof. In another aspect of this embodiment, the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. includes one. In yet another aspect of this embodiment, the medical device includes balloon catheters, perfusion balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, debulking catheters, stents, filters, stent grafts, coatings. One of a stent, patch, wire, and valve is included.

[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 an exterior surface of the medical device, the layer comprising a therapeutic agent and an additive. , where the additive is a peptide, oligopeptide or protein. In one aspect of this embodiment, the additives are from albumins, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, fibrinogens, and lipases. selected. In another aspect of this embodiment, the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. includes one. In yet another aspect of this embodiment, the medical device includes balloon catheters, perfusion balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, debulking catheters, stents, filters, stent grafts, coatings. One of a stent, patch, wire, and valve is included.

[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 an exterior surface of the medical device, the layer comprising a therapeutic agent and an additive. , where additives include combinations or mixtures of both surfactants and chemical compounds, wherein the chemical compounds have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In one aspect of this embodiment, the surfactants include ionic, nonionic, aliphatic and aromatic surfactants, PEG fatty acid esters, esters of PEG omega-3 fatty acids, ethers, and alcohols, glycerol fatty acids 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, chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups have molecular weights from 20 to 750. In another aspect of this embodiment, the chemical compounds are amino alcohols, hydroxyl carboxylic acids, esters and anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, sorbitan. , glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohols and organic acids, and substituted molecules thereof. In another aspect of this embodiment, chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are selected from: acetic acid and anhydride, benzoic acid and anhydride, Diethylenetriaminepentaacetic acid dianhydride, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic acid and anhydride, diglycolic acid and anhydride, glutaric acid and anhydride, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid Asparagine acid, nicotinic acid, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, gluconic acid, hydroxyl ketone, hydroxyl Lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, 4-hydroxybenzoic acid Propyl, lysine acetate, gentisic acid, lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphates, glucopyranose phosphate, sugar sulfates, sinapinic acid, vanillic acid, vanillin, methylparaben, propylparaben, xylitol, 2-ethoxyethanol , cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid, any of the above salts of organic acids and amines, 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 embodiment, the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. includes one. In yet another aspect of this embodiment, the medical device includes balloon catheters, perfusion balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, debulking catheters, stents, filters, stent grafts, coatings. One of a stent, patch, wire, and valve is included.

[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, wherein , a chemical compound having 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, esters of PEG omega-3 fatty acids, 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, chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups have molecular weights from 20 to 750. In one embodiment, chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxyl carboxylic acids, esters and anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, Sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, amino acids It is selected from combinations of alcohols and organic acids, and substituted molecules thereof. In one embodiment, chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are selected from: L-ascorbic acid and salts thereof, D-glucoascorbic acid and salts thereof, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic lactone, gulonic lactone, mannonic acid lactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid, Vanillin, methylparaben, propylparaben, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid, ribonate lactone, meglumine/lactic acid, meglumine/genticin acid, meglumine/acetic acid, sorbitol, xylitol, 2-ethoxyethanol, sugars, galactose, glucose, mannose, xylose, sucrose, lactose, maltose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, any organic acid and Salts of organic amines, 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.

[097] In other embodiments, the present invention provides paclitaxel or rapamycin or derivatives thereof, and chemical compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups for administration to a mammal. wherein the chemical compound with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups has a molecular weight of from 20 to 750. In one aspect, the chemical compound with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups is hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic lactone, gulonic lactone , mannonic acid lactones, ribonic acid lactones, sugar phosphates, sugar sulfates, catechins, catechin gallates, and combinations of amino alcohols and organic acids. In one aspect of this embodiment, the amino alcohol is selected from tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, glucosamine, lysine, and derivatives thereof; the organic acid is 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 aminoalcohol and an organic acid for administration to a mammal, wherein Amino alcohols are selected from tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, glucosamine, lysine, and derivatives thereof; organic acids are glucoheptonic acid, glucomic acid, glutamic acid, benzoic acid, hydroxybenzoic acid, gentisic acid, lactobionic acid, 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, the medical device comprising a layer covering an exterior surface of the medical device, the layer comprising the therapeutic agent and an additive. , wherein the additive is selected from hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic lactone, gulonic lactone, mannonic lactone, ribonic 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 an exterior surface of the medical device, the layer comprising a therapeutic agent and an additive. , where the therapeutic agent is paclitaxel and its analogues or rapamycin and its analogues, and the excipient is sorbitol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol oligomers, polypropylene glycol oligomers, 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, wherein the drug to excipient weight ratio is from 0.5 to 3, wherein the therapeutic agent and excipient are released simultaneously.

[0101] Many embodiments of the present invention are particularly useful in treating vascular disease and reducing stenosis and delayed lumen loss, or are useful in making devices for that purpose.
[0102] It is intended that the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of the invention as claimed.

[0103] Figure 1 is a perspective view of an exemplary embodiment of a balloon catheter according to the present invention. [0104] Figures 2A-2C are cross-sectional views of the distal portion of different embodiments of the balloon catheter of Figure 1 taken along line AA, showing examples of coating layers.

[0105] Aspects of the present invention relate to medical devices, particularly balloon catheters and stents, with rapid release coatings, and methods for making such coated devices. Therapeutic agents according to aspects of the present invention do not require delayed or extended release, but preferably release the therapeutic agents and additives in a very short period of time upon contact with tissue to provide therapeutic effect. It is an object of the present invention to facilitate rapid and effective uptake by the target tissue while the device is temporarily positioned at the target site.

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

[0107] In one aspect, the present invention provides a medical device for delivering therapeutic agents to tissue. The medical device includes a layer applied to the outer surface of a medical device such as, for example, a balloon catheter or stent. This layer contains therapeutic agents and additives. For example, as shown in the embodiment depicted in FIG. 2A, balloon 12 is coated with layer 20 containing therapeutic agents and additives. In some embodiments, this layer consists essentially of therapeutic agent and additive, ie, this layer contains essentially only therapeutic agent and additive, and does not contain any significant other material components. In some embodiments, the medical device may include an adhesive layer. For example, balloon 12 is coated with adhesive layer 22, as shown in the embodiment depicted in FIG. 2B. A layer 24 containing therapeutic agents and additives covers this adhesive layer. The adhesive layer, a separate layer underlying 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 drug and excipients have different adhesions to the medical device, the adhesive layer can prevent differential loss of the components as they migrate to the target site for therapeutic intervention. can be maintained. Additionally, the adhesive layer can function to facilitate rapid release of the coating layer components away from the surface of the medical device upon contact with tissue at the target site. In other aspects, 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, e.g., during movement of the balloon 12 to the site of therapeutic intervention, or at the moment of initial inflation of the balloon 12. less drug layer loss prior to application.

[0108] In one embodiment, the concentration density of the at least one therapeutic agent applied to the surface of the medical device is from about 1 to 20 μg/ ^mm2 , or more preferably from about 2 to 6 μg/ ^mm2 . The weight ratio of therapeutic agent to additive is from about 0.5 to 100, such as from about 0.1 to 5, from 0.5 to 3, more such as from about 0.8 to 1.2. If the ratio (weight) of therapeutic agent to excipient is too low, the drug may be released prematurely; May not be absorbed by tissues.

[0109] In other embodiments, the layer comprises a therapeutic agent and an excipient, wherein the therapeutic agent is paclitaxel and its analogs or rapamycin and its analogs, and the excipients are sorbitol, diethylene glycol, triethylene glycol, tetra selected from ethylene glycol, xylitol, 2-ethoxyethanol, sugars, galactose, glucose, mannose, xylose, sucrose, lactose, maltose, Tween 20, Tween 40, Tween 60, and derivatives thereof, wherein therapy against additives The drug weight ratio is from 0.5 to 3. A ratio (by weight) of therapeutic agent to additive of less than 0.5 may result in premature release of the drug, while a ratio of greater than 3 will allow the drug to be released rapidly enough upon placement at the target site. may not elute or be absorbed into tissues. In other embodiments, a layer may contain a therapeutic agent and more than one additive. For example, one type of additive can act to improve adhesion to the balloon of other additive(s) that are superior in promoting drug release or tissue drug uptake.

[0110] Current drug-containing stent coatings include a drug and a polymer carrier. The drug is dispersed in the polymer matrix, sometimes as particles. For durable polymers, the drug is released over an extended period of time. The durable polymer remains permanently in the body with the stent. For biodegradable polymers such as PLLA, the drug is released in 1-3 months and then the polymer degrades in approximately one year or more. The drug is released as pure drug. Pure drug particles increase the risk of tissue toxicity. However, the additives of embodiments of the present invention will mitigate this risk when used as a stent coating in combination with a polymeric carrier. In embodiments of the present invention, the drug and additive in the polymer-based stent coating are different, but together are simultaneously released to the tissue. This will reduce the risk of drug toxicity to tissues.

[0111] In other embodiments, as a coating for a medical device such as a stent or balloon, the layer may comprise at least one therapeutic agent, at least one additive, and at least one polymeric carrier. The additive used in combination with the polymeric carrier in the stent coating may be at least one additive according to aspects of the invention discussed herein. Additives in the layer improve the compatibility of the drug with the polymeric 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 outcomes by more uniformly delivering drug to target tissues.

[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 additive(s). The second layer contains 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 therapeutic agent in the second layer is lower than the content of therapeutic agent in the first layer. In one embodiment, the second layer overlies the first layer. In this manner, the second layer reduces drug loss during placement of a medical device into a body vessel, such as as a balloon catheter travels through tortuous anatomy to a tissue site within the vascular system. can be prevented.

[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 additive(s). The second layer contains 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 overlays the first layer. This modality is useful, for example, for therapeutic agents that adhere too tightly to the balloon surface to elute rapidly from the balloon when inflated at the target site. In this manner, the first layer facilitates rapid release of the bulk of the drug in the second layer away from the surface of the medical device while the medical device is inflated at the target site of therapeutic intervention. perform the function of

[0114] In other embodiments, two or more therapeutic agents are used in combination in the drug-additive layer.
[0115] In still other embodiments, a medical device that includes a two-layer coating may include an adhesive layer. This adhesive layer does not contain a therapeutic agent. For example, the balloon 12 is coated with an adhesive layer 22, as shown in the embodiment depicted in FIG. 2C. Overlying the adhesive layer 22 is a first layer 26 containing a therapeutic agent and optionally an additive(s). Overlying the first layer 26 is an additive second layer 28 containing an additive and optionally a therapeutic agent. The adhesive layer enhances 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 drug and additive(s) in the first layer have different adhesive strengths to the medical device, the adhesive layer prevents differential loss of the components as they migrate to the target site for therapeutic intervention. The drug-to-excipient ratio and the excipient-to-excipient ratio can be maintained. Additionally, the adhesive layer can function to facilitate rapid elution of the coating layer from the surface of the medical device upon contact with tissue at the target site. In one embodiment, the first layer, second layer and adhesive layer each contain an additive.

[0116] Treatment with dimethylsulfoxide (DMSO) or other solvents is advantageous in some cases, as DMSO can further enhance the penetration and absorption of drugs into tissues. DMSO displaces water from the lipid head groups and protein domains of the membrane lipid bilayer of target cells, indirectly loosening lipid structures to facilitate drug absorption and penetration.

[0117] In still other embodiments, the present invention treats diseased body lumens or cavities following surgical or interventional procedures (PTCA, PTA, stent placement, resection of diseased tissue such as cancer, and reduction or treatment of strictures). wherein the pharmaceutical 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 is a hydrophobic moiety and/or has affinity for the therapeutic agent through hydrogen bonding and/or van der Waals interactions, where the therapeutic agent is not entrapped in micelles or entrapped in polymer particles. not

[0118] Other embodiments, namely complications or disease recurrence ( For example, cancer or restenosis), the pharmaceutical composition is applied locally at or near the site of intervention by a coated medical device (e.g., 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 into cavities formed by surgical removal of cancerous tissue to reduce the risk of recurrence. As another example, methods of delivering pharmaceutical compositions include placing medical devices (eg, guide catheters or drug infusion catheters) in the blood to prevent restenosis after vascular interventions such as PTCA, PTA, stent placement. injecting a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutic agent and an excipient, wherein the excipient comprises a hydrophilic portion and a drug affinity portion, wherein the drug The affinity moiety is a hydrophobic moiety and/or has affinity for the therapeutic agent through hydrogen bonding and/or van der Waals interactions, where the therapeutic agent is not encapsulated in micelles or polymer particles. not enclosed in

[0119] Many embodiments of the present invention are particularly useful for treating vascular disease, reducing stenosis and delayed lumen loss, or making a device for that purpose or treating the disease. Useful for methods.

[0120] Additives
[0121] The additive of embodiments of the present invention has two parts. One part is the hydrophobic part and the other part is the drug affinity part. Drug affinity moieties are hydrophobic moieties and/or have affinity for therapeutic agents through hydrogen bonding and/or van der Waals interactions. The drug affinity portion of the additive can bind lipophilic drugs such as rapamycin or paclitaxel. Hydrophilic moieties facilitate diffusion and enhance tissue penetration of the drug. It may be used by preventing the aggregation of hydrophobic drug molecules with each other or onto medical devices, by increasing the solubility of the drug within the interstitial space, and/or by allowing the drug to pass through the polar head groups of the cell membrane of the target tissue. By facilitating access to the lipid bilayer through the lipid bilayer, it can facilitate rapid migration of the drug away from the medical device when placed at the target site. The additive of embodiments of the present invention has two parts that work together to facilitate rapid release of the drug from the surface of the medical device when deployed and uptake into the target tissue (for which the drug has a high affinity). On the one hand, it prevents premature release of the drug from the medical device prior to its placement at the target site.

[0122] In embodiments of the present invention, the therapeutic agent is rapidly released and immediately absorbed after contacting the tissue with the medical device. For example, certain embodiments of the medical devices of the present invention include drug-coated balloon catheters, which apply a lipophilic antiproliferative drug (eg, paclitaxel or rapamycin) to short-term direct pressure contact during balloon angioplasty. delivers high drug concentrations to the vascular tissue by Lipophilic drugs are preferentially retained in the target tissue at the site of delivery where they prevent hyperplasia and restenosis and allow endothelialization. In these embodiments, the coating formulations of the present invention not only facilitate the rapid release of drug from the balloon surface upon deployment and the migration of the drug into the target tissue, but also penetrate tortuous arterial structures. prevents the drug from diffusing out of the medical device before reaching the target tissue during its migration through the balloon, and prevents the drug from diffusing from the medical device before the drug coating comes into direct pressure contact with the surface of the vessel wall early in balloon inflation. Prevent explosive release.

[0123] Additives according to certain embodiments have a drug affinity portion and a hydrophilic portion. Drug affinity moieties are hydrophobic moieties and/or have affinity for therapeutic agents through hydrogen bonding and/or van der Waals interactions. Drug affinity moieties include aliphatic and aromatic hydrocarbon-based compounds such as benzene, toluene, and alkanes, among others. These moieties are not water soluble. They can bind both hydrophobic drugs and cell membrane lipids with which they share structural similarities. They have no covalently bound iodine. The drug affinity moiety can include functional groups that can form hydrogen bonds with the drug and itself. Hydrophilic moieties include, among others, hydroxyl groups, amine groups, amide groups, carbonyl groups, carboxylic acids and anhydrides, ethyl oxide, ethyl glycol, polyethylene glycol, ascorbic acid, amino acids, amino alcohols, glucose, sucrose, sorbitan, glycerol, Polyalcohols, phosphates, sulfates, organic salts, and substituted molecules thereof can be included. For example, one or more hydroxyl, carboxyl, acid, amide or amine groups may be advantageous; they can readily displace water molecules hydrogen bonding to polar head groups of cell membranes and surface proteins. , can serve to remove this barrier between hydrophobic drugs and cell membrane lipids. These moieties are soluble in water and polar solvents. These additives are not oils, lipids or polymers. The therapeutic agent is not encapsulated in micelles or liposomes, or encapsulated in polymer particles. The additive of embodiments of the present invention has both a component that binds the drug and a component that, when deployed, facilitates the rapid release of the drug from the medical device and into the target tissue.

[0124] The additives of embodiments of this 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 include amino alcohols, hydroxyl carboxylic acids and anhydrides, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sugars, glucose. , sucrose, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, and substituted molecules thereof.

[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 contains a polar or hydrophilic portion and a non-polar hydrophobic (lipophilic) portion.

[0126] An empirical parameter commonly used in medicinal chemistry to characterize the relative hydrophilicity and hydrophobicity of pharmaceutical compounds is the partition coefficient, P, of two immiscible solvents (usually octanol and water). is the ratio of the concentrations of non-ionized compounds in the two phases of a mixture of , thus ([solute] octanol/[solute] water). Compounds with higher log P are more hydrophobic, while compounds with lower log P are more hydrophilic. Lipinski's law suggests that pharmaceutical compounds with log P<5 are generally more membrane permeable. For purposes of certain embodiments of the present invention, excipients preferably have a log P lower than the log P of the drug in which they are formulated (as an example, paclitaxel has a log P of 7.4). The larger the log P difference between the drug and excipient, 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 facilitates release of the drug in an aqueous environment from the surface of the device to which the drug would otherwise be tightly attached. , which facilitates drug delivery to the tissue during short-term placement at the intervention site. 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. While the octanol-water partition coefficient P, or log P, is useful as a measure of relative hydrophilicity and hydrophobicity, it is useful in determining suitable additives for use in embodiments of the present invention. It's only a rough indicator.

[0127] The coatings of embodiments of the present invention comprise a therapeutic agent and at least one additive, wherein the additive is combined with the therapeutic agent in the coating layer based on the unique properties of each therapeutic agent to produce a therapeutic agent. To provide a drug-coated medical device that minimizes degradation and is safe and effective. The additives of aspects of the invention do not chemically react with the functional groups of the therapeutically active agent. Each therapeutically active agent has its own chemical structure and properties, reacts differently with different drug carrier excipients, and drug-excipient reactions render the therapeutic agent inactive or produce potentially toxic degradation products. may generate The additive is chosen so that it does not have functional groups that chemically react with functional groups on the therapeutically active agent. Otherwise, such a reaction between drug and excipient would render the therapeutic agent inactive or produce potentially toxic degradation products. To minimize degradation of the therapeutic agent and to ensure that drug-coated medical devices are safe and effective, it is important to match the therapeutic agent with the excipient(s) of choice. Paclitaxel reacts with many functional groups such as acids, water, oxygen, and amines. Rapamycin and its derivatives can be easily hydrolyzed or oxidized. The large surface area of coated medical devices makes optimization of active agent stability in the coating all the more important. Drug-coated medical devices are exposed to high heat, moisture, and oxidizing conditions during sterilization, and they are often stored for long periods of time prior to use. The excipients of embodiments of the present invention are carefully selected to minimize degradation of the therapeutic when exposed to harsh conditions and when stored for long periods of time. Certain drugs, such as rapamycin and its derivatives, are sensitive to oxygen and moisture and are susceptible to oxidation and hydrolysis. The inventors have discovered that antioxidants are additives that protect drugs such as rapamycin from oxidation and hydrolysis. An aspect of the present invention is a coating for a medical device comprising an additive and an active agent, wherein the additive does not participate in the degradation of the active agent or--such as additives that are antioxidants--degrades the active agent. Provides a coating that protects against

[0128] Aspects of the present invention also include methods for making coated medical devices that minimize oxidative and/or hydrolytic degradation of sensitive therapeutic agents such as rapamycin and its derivatives (preparation of coating composition). and methods for processing). Processing, packaging, and storage of coated medical devices are particularly important to drug stability, and in embodiments of the present invention, reducing oxygen and moisture during packaging reduces oxidation and hydrolysis of therapeutic agents over time during long-term storage. is further suppressed. Methods of certain embodiments provide processing and packaging of coated medical devices to minimize degradation of therapeutic agents.

[0129] Suitable excipients that can be used in embodiments of the present invention include, without limitation, organic and inorganic pharmaceutical excipients, natural products and their derivatives (e.g., sugars, vitamins, amino acids, peptides, proteins, and fatty 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 exhaustive. Numerous other additives can be used for the purposes of this invention.

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

[0132] An empirical parameter commonly used 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 oils, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions. Have. Using HLB values as a rough guide, hydrophilic surfactants are generally compounds with HLB values greater than about 10, and generally anionic, cationic, or zwitterionic compounds for which HLB values are not applicable. Conceivable. Similarly, a hydrophobic surfactant is a compound with an HLB value of less than about ten. In certain aspects of the invention, higher HLB values are preferred because high hydrophilicity can facilitate the release of hydrophobic drugs from the surface of medical devices. In one embodiment, the HLB of the surfactant is greater than about 10. In other embodiments, the HLB of the additive is greater than about 14. Alternatively, surfactants with lower HLB when used in topcoats over drug layers containing highly hydrophilic additives, for example, to inhibit drug loss prior to placement of the medical device at the target site. agents may be preferred. The HLB value of the surfactant additive in certain embodiments is in the range of 0.0-40.

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

[0134] PEG-fatty acids and PEG-fatty acid mono- and diesters
[0135] Although polyethylene glycol (PEG) itself does not function as a surfactant, various PEG-fatty acid esters have useful surfactant properties. Among the PEG-fatty acid monoesters, esters of lauric, oleic, and stearic, myristoleic, palmitoleic, linoleic, linolenic, eicosapentaenoic, erucic, ricinoleic, and docosahexaenoic acids are of the present invention. Most useful for embodiments. 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, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate. PEG-15 12-hydroxystearate (Solutol HS 15) is a nonionic surfactant used in injectable solutions. Solutol HS 15 is a preferred additive in certain embodiments of the present invention because it is a white paste at room temperature and becomes liquid at about 30° C. above room temperature but below body temperature. HLB values range from 4-20.

[0136] This additive (eg, Solutol HS 15) is in a paste, solid or crystalline state at room temperature and becomes liquid at body temperature. Certain additives that are liquid at room temperature can make it difficult to create evenly coated medical devices. Certain liquid additives may interfere with solvent evaporation or may not remain in place on the surface of the medical device during the device coating process at room temperature, such as the balloon portion of a balloon catheter. In certain embodiments of the present invention, pasty and solid additives are preferred because they can remain localized as a uniform coating on the medical device, allowing it to dry at room temperature. . In one aspect, when the solid coating on the medical device is exposed to a higher physiological temperature of about 37° C. when placed within the human body, it becomes liquid. In these embodiments, the liquid coating is very easily released from the surface of the medical device and readily migrates into the diseased tissue. Additives with temperature-induced state changes under physiological conditions are of critical importance in certain aspects of the invention, particularly in drug-coated balloon catheters. In certain embodiments, both solid and liquid additives are used in combination in the drug coatings of the present invention. This combination improves the integrity of the medical device coating. In certain embodiments of the invention, at least one solid additive is used in the drug coating.

[0137] Polyethylene glycol fatty acid diesters are also suitable for use as surfactants in compositions of embodiments of the present invention. Most preferred hydrophilic surfactants include PEG-20
Included are dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. HLB values range from 5-15.

[0138] Generally, mixtures of surfactants are also useful in embodiments of this invention, including mixtures of two or more commercially available surfactants, and mixtures of surfactants and other additive(s). Includes mixtures. Some PEG-fatty acid esters are commercially available as mixtures of mono- 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
[0142] Numerous surfactants with varying degrees of hydrophobicity or hydrophilicity can be produced by reaction of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils. Most commonly, the oils used are castor or hydrogenated castor oils, or edible vegetable oils such as corn, olive, arachis, palm kernel, apricot kernel or almond oil (almond oil). Preferred alcohols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol and pentaerythritol. Preferred hydrophilic surfactants among these alcohol-oil transesterified surfactants are PEG-35 castor oil, polyethylene glycol-glycerol ricinoleate (Incrocas-35, and Cremophor EL and ELP), 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 Glycerides (Crovol M70), PEG-60 Tonsil 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 caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capric glycerides (Softigen 767). Preferred hydrophobic surfactants of 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 almond oil (Labrafil. RTM. M 1966 CS), PEG-6 apricot kernel oil (Labrafil. RTM. M 1944 CS), PEG-6 olive oil (Labrafil. RTM. M 1980 CS), PEG-6 peanut oil (Labrafil. 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 Triolein (Labrafil. RTM .b M 2735 CS), PEG-8 Corn Oil (Labrafil. RTM. WL 2609 BS), PEG-20 Corn Glycerides (Crovol M40), and PEG-20 Tonsil Glycerides (Crovol A40).

[0143] Fatty acid polyglyceryl
Polyglyceryl esters of fatty acids are also suitable surfactants for use in embodiments of the present invention. Among fatty acid polyglyceryl esters, preferred hydrophobic surfactants include polyglyceryl oleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO), polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate, polyglyceryl myristate, polyglyceryl Palmitate, and polyglyceryl linoleate. Preferred hydrophilic surfactants include polyglyceryl-10 laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn 1-O), and polyglyceryl-10 mono, dioleate (Caprol.RTM. PEG 860), polyglyceryl -10 stearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and polyglyceryl -6 Contains linoleate. Polyglyceryl polyricinoleates (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 embodiments of the present invention. Within this surfactant class, preferred hydrophobic surfactants include propylene glycol monolaurate (Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propylene glycol monooleate (Myverol P-O6), propylene glycol dioleate. 200), and propylene glycol dioctanoate (Captex.RTM. 800).

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

[0148] Polyethylene glycol sorbitan fatty acid ester
[0149] A wide variety of PEG-sorbitan fatty acid esters are available and suitable for use as surfactants in embodiments of the present invention. Among PEG-sorbitan fatty acid esters, preferred surfactants include PEG-20 sorbitan monolaurate (Tween-20), PEG-4 sorbitan monolaurate (Tween-21), 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). Laurate esters are preferred because they have shorter lipid chains compared to oleate esters and enhance drug absorption.

[0150] Polyethylene glycol alkyl ether
[0151] Ethers of polyethylene glycol and alkyl alcohols are suitable surfactants for use in embodiments of the present invention. Preferred ethers include Laneths (Laneth-5, Laneth-10, Laneth-15, Laneth-20, Laneth-25, and Laneth-40), laureths (Laureth-5, laureth-10, Laureth-15, laureth -20, Laureth-25, and Laureth-40), Oleths (Oleth-2, Oleth-5, Oleth-10, Oleth-12, Oleth-16, Oleth-20, and Oleth-25), Steareths (Steareth -2, Steareth-7, Steareth-8, Steareth-10, Steareth-16, Steareth-20, Steareth-25, and Steareth-80), Ceteth (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 suitable surfactants for use in embodiments of the present invention. Preferred surfactants of 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-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, and octyl-β-D-thio Contains glucopyranosides.

[0154] Polyethylene glycol alkylphenol
[0155] Several PEG-alkylphenol surfactants, such as PEG-10-100 nonylphenol and PEG-15-100 octylphenol ether, Tyloxapol, octoxynol, nonoxynol, are available and are surfactant 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, comprising hydrophilic POE and hydrophobic POP moieties in well-defined ratios and locations, provides a wide variety of surfactants suitable for use in embodiments of the present invention. do. These surfactants are available under various trade names, including the Synperonic PE series (ICI); Pluronic. RTM. series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The common name for these polymers is "poloxamer" (CAS 9003-11-6). These polymers have the formula:
[0158] _HO ( _C2H4O ) _a ( _C3H6O ) _b (C2H4O) _aH : where "a" and " _b " are polyoxyethylene units and polyoxyethylene units _{, respectively} . Represents the number of propylene units.

[0159] Preferred hydrophilic surfactants of 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, comprising hydrophilic polyethylene glycol (PEG) moieties and hydrophobic polyester moieties in well-defined ratios and locations, makes them suitable for a wide variety of interfacial surfaces for use in embodiments of the present invention. Provide an active agent. Polyesters in these block polymers include: poly(L-lactide) (PLLA), poly(DL-lactide) (PDLLA), poly(D-lactide) (PDLA), polycaprolactone ( PCL), polyesteramide (PEA), polyhydroxyalkanoates, polyhydroxybutyrate (PHB), polyhydroxybutyrate-co-hydroxyvalerates (PHBV), polyhydroxybutyrate-co-hydroxyhexanoate ( PHBHx), polyamino acids, polyglycolide or polyglycolic acid (PGA), polyglycolide and its copolymers (poly(lactic-co-glycolic acid) with lactic acid, poly(glycolide-co-caprolactone) with ε-caprolactone, and poly(glycolide-co-trimethylene carbonate) with trimethylene carbonate), and copolyesters thereof. 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 multi-block copolymers. Hydrophilic blocks may also 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 polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. This copolymer is a solubilizer with an amphiphilic chemical structure and can solubilize poorly soluble drugs such as paclitaxel, rapamycin and their derivatives in aqueous media. The molecular weight of this copolymer is between 90,000 and 14,000.
It is in the range of 0 g/mol.

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

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

[0167] Sorbitan monopalmitate, an amphipathic derivative of vitamin C, which has vitamin C activity, can serve two important functions in the solubilization system. First, it possesses effective polar groups that can modulate the microenvironment. These polar groups are the same groups that form organic vitamin C itself (ascorbic acid), which is one of the most water-soluble organic solid compounds available: ascorbic acid can be up to about 30 wt/wt% in water. Soluble (e.g. very close to the solubility of sodium chloride). Second, as the pH increases, some of the ascorbyl palmitate is converted to a more soluble salt, such as sodium ascorbyl palmitate.

[0168] Ionic Surfactants
[0169] Ionic surfactants, including cationic, anionic and zwitterionic surfactants, are suitable hydrophilic surfactants for use in embodiments of the present invention.

[0170] Anionic surfactants are those that carry a negative charge on the hydrophilic portion. A major class of anionic surfactants used as additives in embodiments of the present invention are those containing carboxylate, sulfate and sulfonate ions. Preferred cations for use in embodiments 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 myristoyl sarcosinate. Anionic surfactants with sulfate groups include sodium lauryl sulfate, sodium dodecyl sulfate, mono-, di-, and triethanolamine lauryl 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, other medium-chain-branched or unbranched alkyl sulfates, and ammonium lauryl sulfate. Anionic surfactants with sulfonate groups include docusate sodium, sodium dioctylsulfosuccinate, sodium laurylsulfoacetate, sodium alkylbenzenesulfonate, sodium dodecylbenzenesulfonate, sodium diisobutylsulfosuccinate, sodium diamylsulfosuccinate, sulfosuccinate. acid di(2-ethylhexyl), and bis(1-methylamyl)sodium sulfosuccinate.

[0171] The most common cationic surfactants used in embodiments of the present invention are quaternary ammonium compounds having the general formulas R ₁ , R ₂ , R ₃ , R ₄ N ^{+ X-} , and the formula X 1 ^- in which is usually a chlorine or bromide ion and R represents an alkyl group containing C8-18 atoms. These types of surfactants are of pharmaceutical importance because of their bactericidal properties. The primary cationic surfactants used in the preparation of pharmaceuticals and medical devices in the present invention are quaternary ammonium salts. These surfactants include cetrimide, cetrimonium bromide, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, hexadecyltrimethylammonium chloride, stearalkonium chloride, lauralconium chloride, tetradecylammonium chloride, myristylpicoli 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 therapeutic agents.

[0172] Zwitterionic or amphoteric surfactants include dodecyl betaine, cocamidopropyl betaine, cocoampho clycinate, among others.
[0173] Preferred ionic surfactants include 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, other medium-chain-branched or unbranched alkyl sulfates, docusate sodium, sodium dioctylsulfosuccinate, sodium laurylsulfoacetate, sodium alkylbenzenesulfonate, sodium dodecylbenzenesulfonate, benzalkonium chloride , benzethonium chloride, cetylpyridinium chloride, doceyltrimethylammonium bromide, sodium doceyl sulfates, dialkylmethylbenzylammonium chloride, edrophonium chloride, domiphen bromide, dialkyl esters of sodium sulfosuccinate, sodium dioctylsulfosuccinate, sodium cholate, and taurochol Contains sodium phosphate. These quaternary ammonium salts are preferred additives. They are soluble 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 adhesion 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 very stable under heat. They survive ethylene oxide sterilization processes. They do not react with drugs such as paclitaxel or rapamycin in the sterilization process. Hydroxyl, ester, and amide groups are preferred as they are not expected to react with the drug, while amine and acid groups often do react with paclitaxel or rapamycin during disinfection. 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 during the medical device delivery process, while leaving it at the target site for a very short duration of 0.2-2 minutes. Facilitates rapid release and elution of paclitaxel upon administration. Drug absorption by target site tissues is unexpectedly high in experiments.

[0175] Chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties
[0176] Chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties include amino alcohols, hydroxyl carboxylic acids, esters and anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, Sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids , as well as substituted molecules thereof. Hydrophilic chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties with molecular weights from 5,000 to less than 10,000 are preferred for certain embodiments. In other embodiments, the molecular weight of the additive with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties is preferably from 1000 to less than 5,000, or more preferably from 750 to less than 1,000, or most preferably less than 750. In these embodiments, the molecular weight of the additive is preferably less than that of the drug to be delivered. Additionally, it is preferred that the additive have a molecular weight greater than 80, as molecules with a molecular weight of less than 80 are highly volatile and do not remain in the medical device coating. If the additive is volatile or liquid at room temperature, it is important that its molecular weight is greater than 80 so that the additive is not lost during solvent evaporation during the coating process. However, in certain embodiments where the additive is not volatile, such as solid additives alcohols, esters, amides, acids, amines, and their derivatives, the additive may readily evaporate from the coating. The additive may have a molecular weight of less than 80, less than 60, and less than 20. Solid additives may be crystalline, semi-crystalline, and amorphous. Small molecules can diffuse rapidly. They themselves can readily elute from the delivery balloon to facilitate drug release, and they can diffuse out of the drug once it binds to the tissues of the body cavity. In certain embodiments, more than four hydroxyl groups are preferred, for example for high molecular weight additives. Large molecules diffuse slowly. If the additive or chemical compound has a high molecular weight, e.g., a molecular weight greater than 800, greater than 1000, greater than 1200, greater than 1500, or greater than 2000, large molecules are less likely to elute from the surface of the medical device. It may be too slow 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 relatively large molecules to rapidly release drugs. The increased hydrophilicity aids the elution of the coating from the balloon, facilitates drug release, and enhances drug migration across the water barrier and polar head groups of the lipid bilayer to penetrate tissue; Or facilitate. Hydroxyl groups are preferred as hydrophilic moieties because they are not expected to react with water-insoluble drugs such as paclitaxel or rapamycin. In some embodiments, chemical compounds containing more than 4 hydroxyl groups have a melting point of 120° C. or less. In some embodiments, a chemical compound containing more than four hydroxyl groups has three adjacent hydroxyl groups, all of which are on one side of the molecule in configuration. For example, sorbitol and xylitol have three adjacent hydroxyl groups all on one side of the molecule in configuration, whereas galactitol does not. This difference affects the physical properties of the isomers, such as their melting temperatures. This configuration of three adjacent hydroxyl groups can enhance drug binding. This will improve the compatibility of the water-insoluble drug with the hydrophilic excipient and improve the uptake and absorption of the drug by tissues.

[0177] Chemical compounds with amide moieties are important to coating formulations in certain embodiments of the invention. Urea is an example of a chemical compound with an amide group. Others include biuret, acetamide, lactic acid amide, amino acid amide, acetaminophen, uric acid, polyurea, urethane, urea derivatives, niacinamide, N-methylacetamide, N,N-dimethylacetamide, sodium sulfacetamide, versetamide, Lauric acid diethanolamide, lauric myristate diethanolamide, N,N-bis(2-hydroxyethyl stearamide), cocamide MEA, cocamide DEA, arginine, and other organic acid amides, and derivatives thereof . Certain chemical compounds with amide groups also have one or more hydroxyl, amino, carbonyl, carboxyl, acid, or ester moieties.

[0178] One chemical compound with an amide group is soluble, low molecular weight povidone. Povidones include Kollidon 12 PF, Kollidon 17 PF, Kollidon 17, Kollidon 25, and Kollidon 30. Kollidon products consist of soluble and insoluble grades of polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate copolymers, and blends of polyvinylacetate and polyvinylpyrrolidone in various molecular weights and particle sizes. Family products are labeled Povidone, Crospovidone 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 very important. Solid povidone can maintain the integrity of the coating on the medical device. Low molecular weight povidone can be absorbed or permeated into the diseased tissue. Preferred molecular weight ranges for povidone are less than 54,000, less than 11,000, less than 7,000, less than 4,000. They are capable of solubilizing water-insoluble therapeutic agents. Povidone and copovidone are particularly useful in the present invention because of their solid, low molecular weight and tissue absorption/permeation properties. Povidone can be used in combination with other additives in the present invention. In one embodiment, povidone and a nonionic surfactant (e.g., PEG-15 12-hydroxystearate (Solutol HS 15), Tween 20, Tween 80, Cremophor RH40, Cremophor EL and ELP) are combined with paclitaxel or rapamycin or their The analogs can be formulated as coatings on medical devices such as balloon catheters.

[0179] Chemical compounds with ester moieties are of particular interest to the coating formulations of certain embodiments. 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, butyryltrihexyl citrate, and trimethyl citrate.

[0180] Certain of the chemical compounds described herein with one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties are extremely stable under heat. They survive the ethylene oxide sterilization process and do not react with the water-insoluble drugs paclitaxel or rapamycin during the sterilization process. In contrast, L-ascorbic acid and its salts and diethanolamine do not necessarily survive such sterilization processes and they react with paclitaxel. Therefore, alternative sterilization methods are preferred for L-ascorbic acid and diethanolamine. Hydroxyl, ester, and amide groups are preferred because they are not expected to react with therapeutic agents such as paclitaxel or rapamycin. Amine and acid groups sometimes do react with paclitaxel; for example, experiments have shown that benzoic acid, gentisic acid, diethanolamine, and ascorbic acid were not stable under the processes of ethylene oxide sterilization, heating, and aging and did react with paclitaxel. . When formulating the chemical compounds described herein 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, a topcoat layer may be advantageous. The chemical compounds herein cause the drug to elute rapidly from the balloon when placed at the target site. Surprisingly, when the coating contains these additives, experiments show that even though some drug is lost in transporting the medical device to the target site, drug absorption by tissues is reduced by, for example, ribonate lactone and For additive hydroxyl lactones such as gluconolactone, it is unexpectedly high at only 0.2-2 minutes after placement.

[0181] Antioxidants
[0182] Antioxidants are molecules that can slow or prevent the oxidation of other molecules. Oxidative reactions can generate free radicals, which can initiate chain reactions and cause degradation of sensitive therapeutics such as rapamycin and its derivatives. Antioxidants terminate these chain reactions by scavenging free radicals, which in turn inhibit oxidation of active agents by themselves being oxidized. Antioxidants are used in certain embodiments as additives to prevent or retard oxidation of therapeutic agents in medical device coatings. Antioxidants are a type of free radical scavenger. Antioxidants, alone or in combination with other additives, may be used in certain aspects of the invention to prevent degradation of the active therapeutic agent during sterilization or storage prior to use.

[0183] Some representative examples of antioxidants that can be used in the methods of the present invention include, without limitation, oligomeric or polymeric proanthocyanidins, polyphenols, polyphosphates, polyazomethines, high sulfate agar oligomers, chitosan polyfunctional oligomeric thioethers including, but not limited to, sterically hindered phenols, hindered amines such as p-phenylenediamine, trimethyldihydroquinolones, and alkylated diphenylamines. substituted phenolic compounds containing one or more bulky functional groups such as tert-butyl (hindered phenols), arylamines, phosphites, hydroxylamines, and benzofuranones. Aromatic amines such as p-phenylenediamine, diphenylamine, and N,N' disubstituted p-phenylenediamines can also be used as free radical scavengers. Other examples include, without limitation, butylated hydroxytoluene (“BHT”), butylated hydroxyanisole (“BHA”), L-ascorbate (vitamin C), vitamin E, herbs rosemary, sage extract, glutathione. , resveratrol, ethoxyquin, rosmanol, isorosmanol, rosmaridiphenol, propyl gallate, gallic acid, caffeic acid, p-coumeric acid, p-hydroxybenzoic acid, astaxanthin, ferulic acid, dehydrozingerone , chlorogenic acid, ellagic acid, propylparaben, sinapinic acid, daidzin, glycitin, genistin, daidzein, glycitein, genistein, 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. Some examples of hindered phenols include, without limitation, 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, 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, catechins, gallic acid. Catechins, and quercetin can be included. Preferred antioxidants are butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).

[0184] Fat-soluble vitamins and salts thereof
[0185] Vitamins A, D, E and K, in their various forms and in provitamin forms, are considered fat-soluble vitamins, in addition to many other vitamins and vitamin sources or related vitamins. are also lipophilic, have polar groups and relatively high octanol-water partition coefficients. Clearly, the general class of such compounds has a history of safe use and a high profit/loss ratio, making them useful as additives in embodiments of the present invention.

[0186] The following examples of fat-soluble vitamin derivatives and/or vitamin sources are also useful as additives: alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, tocopherol acetate, ergosterol, 1-alpha- Hydroxycholecalciferol, vitamin D2, vitamin D3, alpha-carotene, beta-carotene, gamma-carotene, vitamin A, fursultiamine, methylol riboflavin, octotiamine, prosultiamine, riboflavin, vinthimol, dihydrovitamin K1, 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 and although it is water soluble at physiological pH it can be formulated in the free acid form. Other derivatives of fat-soluble vitamins useful in aspects of the present invention are readily obtainable by well-known chemical reactions with hydrophilic molecules.

[0187] Water-Soluble Vitamins and Their Amphiphilic 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 multivalent ions into amphiphilic forms with relatively high octanol-water partition coefficients and polar groups. Again, such compounds may have low toxicity and high benefit-to-benefit ratio, making them useful as additives in embodiments of the present invention. These salts can also be useful as additives in embodiments of the invention. Examples of water-soluble vitamins and derivatives include, without limitation, acetiamine, benfotiamine, pantothenic acid, cetotiamine, sicotiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, Riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U. As also 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 include acids containing hydrophobic groups, such as fatty acids (particularly lauric acid, oleic acid, myristic acid, palmitic acid, stearic acid, or 2-ethylhexanoic acid). , poorly soluble amino acids, benzoic acid, salicylic acid, or simple acid-base reactions with acidic fat-soluble vitamins (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 prepared by reaction with reactants containing hydrophobic groups such as stearylamine or riboflavin to form compounds useful in aspects of the present invention. Coupling of palmitate chains to vitamin C yields ascorbyl palmitate.

[0190] Amino acids and their salts
[0191] Alanine, arginine, asparagines, 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 embodiments of the present invention.

[0192] Certain amino acids, in their zwitterionic form and/or in their salt forms with monovalent or polyvalent ions, have polar groups and relatively high octanol-water partition coefficients, Useful for aspects of the present invention. For the purposes of this disclosure, "low-solubility amino acid" shall mean an amino acid with 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] Dimers, sugar conjugates, and other derivatives of amino acids are also useful. Hydrophilic molecules can be attached to hydrophobic amino acids, or hydrophobic molecules to hydrophilic amino acids, by simple reactions well known in the art to produce still other additives useful in aspects of the present 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 readily coupled, and different amino acid sequences can be tested to maximize drug tissue penetration. .

[0197] Proteins are also useful as additives in embodiments of the invention. For example, serum albumin is a particularly preferred excipient because it is water-soluble and contains significant drug-binding hydrophobic moieties: paclitaxel is 89%-98% protein-bound after intravenous infusion in humans; Rapamycin is 92% bound to proteins, primarily (97%) to albumin. Furthermore, the solubility of paclitaxel in PBS is increased more than 20-fold by the addition of BSA. Albumin is naturally present in high concentrations in serum, making it extremely safe for intravascular use in humans.

[0198] Other useful proteins include, without limitation, other albumins, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, Fibrinogens, lipases, etc. are included.

[0199] Organic acids and their esters, amides and anhydrides
[0200] Examples are acetic acid and anhydride, benzoic acid and anhydride, diethylenetriaminepentaacetic acid dianhydride, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic acid and anhydride, diglycolic anhydride, glutaric anhydride, Ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, aspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, aloyritic acid, sherolic acid, and 2-pyrrolidone. Aloyritic acid and sherolic acid can form a resin called shellac. Paclitaxel, alloyritic acid, and sherolic acid together can be used as drug-releasing coatings for balloon catheters.

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

[0202] Other chemical compounds with one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties
[0203] Additives according to embodiments of the present invention include both cyclic and linear aliphatic and aromatic aminoalcohols, alcohols, amines, acids, amides and hydroxyl acids. Examples are: L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxyl Ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, 4- propyl hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphates, glucopyranose phosphate, sugar sulfates, sinapinic acid, vanillic acid, vanillin, methylparaben, propylparaben, xylitol, 2 - ethoxyethanol, sugars, galactose, glucose, ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose, fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, Lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid, salts of any of the above organic acids and amines, 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 glycols), 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, for example, the first additive comprises a surfactant and the second additive comprises one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or include chemical compounds with ester moieties.

[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. A formulation containing a mixture of two excipients and a water-insoluble drug is superior to a mixture containing either excipient alone in certain cases. Hydrophobic drugs bind extremely water-soluble small molecules weaker than do surfactants. They often phase separate from small water-soluble molecules, which can result in sub-optimal coating uniformity and integrity. Water-insoluble drugs have a higher Log P than both surfactants and water-soluble small molecules. However, the Log P of surfactants is generally higher than the Log P of chemical compounds with one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties. Surfactants have relatively high Log P (usually greater than 0) and water-soluble molecules have low Log P (usually less than 0). Certain surfactants, when used as additives in embodiments of the present invention, adhere so strongly to water-insoluble drugs and to the surface of medical devices that the drug cannot be rapidly released from the surface of the medical device at the target site. In contrast, certain water-soluble small molecules (chemical compounds with one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties) bind very weakly to medical devices, thus preventing them from reaching their target sites. Second, the drug is released, for example, into the serum as the coated balloon catheter travels to the site targeted for intervention. Surprisingly, by adjusting the concentration ratio of hydrophilic small molecules and surfactants in the formulation, the stability of the coating during migration, and the ability to swell and press against the tissue of the lumen wall at the target site of therapeutic intervention. The inventors have found that rapid drug release upon application is in some cases superior to formulations containing either additive alone. Additionally, 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 better adhesion to drugs and small molecules. The long-chain hydrophobic portion of the surfactant binds the drug tightly, while the hydrophilic portion of the surfactant binds water-soluble small molecules.

[0207] Surfactants in a mixture or combination include all surfactants described herein for use in embodiments of the invention. Surfactants 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-isononylphenoxy polyglycidol, 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 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, Polyglyceryl-10 myristate, 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, octoxynol, monoxinol, tyloxapol, 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 - Thioglucopyranosides, and their derivatives.

[0208] Chemical compounds having one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties in a mixture or combination include one or more of the compounds described herein for use in embodiments of the invention. All chemical compounds with hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties are included. A chemical compound with one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties in a mixture has at least one hydroxyl group in one aspect of the invention. In certain embodiments, more than four hydroxyl groups are preferred, for example for high molecular weight additives. In some embodiments, chemical compounds with more than 4 hydroxyl groups have a melting point of 120° C. or less. Large molecules diffuse slowly. If the additive or chemical compound has a high molecular weight, e.g., a molecular weight greater than 800, greater than 1000, greater than 1200, greater than 1500, or greater than 2000, large molecules are less likely to elute from the surface of the medical device. It may be too slow 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 relatively large molecules to rapidly release drugs. Increased hydrophilicity helps the coating elute away from the balloon, facilitating drug release and enhancing tissue penetration of the drug by translocating it across the water barrier and polar head groups of the lipid bilayer cause or facilitate Hydroxyl groups are preferred as hydrophilic moieties because they are not expected to react with water-insoluble drugs such as paclitaxel or rapamycin.

[0209] Chemical compounds with one or more hydroxyl, amine, carbonyl, carboxyl, acid, amide or ester moieties in the mixture are selected from: L-ascorbic acid and its salts, D-glucoascorbine. Acids and their salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic lactone, gulonic acid Lactones, mannonic acid lactones, ribonic acid lactones, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salts, gentisic acid, lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphates, glucopyranose phosphate, sugar sulfates, sinapinic acid, vanillic acid, vanillin, methylparaben, propylparaben, xylitol, 2-ethoxyethanol, sugars, galactose, glucose, ribose, mannose, xylose, sucrose, lactose, maltose , arabinose, lyxose, fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid, salts of organic acids and amines of any of the above, 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 their Derivatives and combinations.

[0210] A mixture or combination of a surfactant and a water-soluble small molecule provides 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 the quality, uniformity and integrity of the coating so that particles do not fall off the balloon during handling. Surfactants reduce drug loss during transport to target sites. Water soluble chemical compounds enhance drug release from the balloon and drug absorption into the tissue. Experiments have shown that this combination was surprisingly effective in blocking drug release upon migration and achieving high drug levels in tissues after very short durations of 0.2-2 minutes of placement. . Moreover, in animal studies, it effectively reduced arterial stenosis and delayed lumen loss.

[0211] Certain mixtures or combinations of surfactants and water-soluble small molecules are very stable under heat. They survive the ethylene oxide sterilization process and do not react with the water-insoluble drugs paclitaxel or rapamycin during the sterilization process. Hydroxyl, ester and amide groups are preferred as they are not believed to react with drugs such as paclitaxel or rapamycin. Amine and acid groups sometimes do react with paclitaxel under ethylene oxide sterilization, heating and aging and are not stable. When formulating the mixtures or combinations described herein with paclitaxel, a topcoat layer may be advantageous to protect the drug layer and prevent premature drug loss between devices.

[0212] Liquid Additive
[0213] Solid additives are often used in drug-coated medical devices. The iodine contrast agent iopromide has been used with paclitaxel to coat balloon catheters. These types of coatings do not contain liquid chemical compounds. The coating is an agglomeration of paclitaxel and iopromide solids on the surface of the balloon catheter. This coating does not adhere to medical devices and coating particles slough off during handling and interventional operations. Water-insoluble drugs such as paclitaxel, rapamycin, and their analogues are often solid chemical compounds. In embodiments of the present invention, liquid additives can be used in medical device coatings to improve the integrity of the coating. The use of liquid additives that can improve the compatibility of solid drugs and/or other solid additives is preferred. The use of liquid additives that can form solid coating solutions that are not agglomerates of two or more solid particles is preferred. The use of at least one liquid excipient is preferred when the other excipients and drug are solids.

[0214] The liquid additive used in embodiments of the present invention is not a solvent. Solvents such as ethanol, methanol, dimethylsulfoxide, and acetone will have evaporated after drying the coating. In other words, no solvent will remain in the coating after drying the coating. In contrast, liquid additives in embodiments of the present invention will remain in the coating after the coating 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 portion and a drug affinity portion, wherein the drug affinity portion includes a hydrophobic portion, a portion that has affinity for the therapeutic agent through hydrogen bonding, and a portion that has affinity for the therapeutic agent through van der Waals interactions. At least one of the moieties with affinity. Liquid additives are not oils.

[0215] Nonionic surfactants are often liquid additives. Examples of liquid additives include PEG-fatty acids and esters, PEG-oil transesterification products, polyglyceryl fatty acids and esters, propylene glycol fatty acid esters, PEG sorbitan fatty acid esters, and PEG alkyl ethers mentioned above. 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 2, 3 or 4 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 aspect, 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 different than the second additive. have a structure In another aspect, 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 less than that of the second additive. higher than anything In yet another aspect, the coating layer comprises at least one additive, the at least one additive comprising a first additive and a second additive, wherein the Log P value of the first additive is lower than that of the drug. For example, sorbitol (Log P −4.67) is more hydrophilic than Tween 20 (Log P approximately 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 surfactant, such as 2, 3 or 4 surfactants. In one aspect, the coating layer comprises at least one surfactant, the at least one surfactant comprising a first surfactant and a second surfactant, the first surfactant comprising the second surfactant. more hydrophilic than the agent. In another aspect, the coating layer comprises at least one surfactant, the at least one surfactant comprises a first surfactant and a second surfactant, the HLB value of the first surfactant being 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 docusate sodium (HLB 10). Tween 80 (HBL 15) is more hydrophilic than Creamophor EL (HBL 13).

[0219] Preferred excipients include: p-isononylphenoxy polyglycidol, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl -6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate Laurate, PEG sorbitan monooleate, PEG sorbitan stearate, octoxynol, monoxinol, tyloxapol, 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 (amino acids); cetotiamine; cicotiamine, dexpanthenol, niacinamide, nicotine Acids and their salts, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 , and vitamin U (vitamins); albumin, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, fibrinogens, lipases, benzalcochloride sodium, benzethonium chloride, docecyltrimethylammonium bromide, sodium doceyl sulfates, dialkylmethylbenzylammonium chloride, and dialkyl esters of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine , triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, ribbon Acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin, methylparaben, propyl Paraben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, 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 their derivatives and Combinations (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 surfaces of polyamide medical devices such as balloon catheters. As such, they can be used in the adhesive layer, top layer, and/or drug layer of embodiments of the present invention. Aromatic and aliphatic groups enhance the solubility of water-insoluble drugs in the coating solution, and alcohol and acid polar groups enhance tissue penetration of the drug.

[0220] Other preferred additives according to embodiments of the present invention include combinations or mixtures of aminoalcohols and organic acids or amide reaction products. Examples are lysine/glutamic acid, lysine acetate, lactobionic acid/meglumine, lactobionic acid/tromethanemine, lactobionic acid/diethanolamine, lactic acid/meglumine, lactic acid/tromethanemine, lactic acid/diethanolamine, gentisic acid/meglumine, gentisic acid/tromethanemine, gencitic acid/diethanolamine, vanillic acid/meglumine, vanillic acid/trometanemine, vanillic acid/diethanolamine, benzoic acid/meglumine, benzoic acid/trometanemine, benzoic acid/diethanolamine, acetic acid/meglumine, acetic acid/trometanemine, and acetic acid/diethanolamine.

[0221] Other preferred additives according to embodiments of the present invention include hydroxyl ketones, hydroxyl lactones, hydroxyl acids, hydroxyl esters, and hydroxylamides. Examples are gluconolactone, D-glucoheptono-1,4-lactone, glucoctanoic lactone, gulonic acid lactone, mannonic acid lactone, erythronic acid lactone, ribonic acid lactone, glucuronic acid, gluconic acid, gentisic acid, lactobionic acid, Lactic acid, acetaminophen, vanillic acid, sinapinic acid, hydroxybenzoic acid, methylparaben, propylparaben, and derivatives thereof.

[0222] Other preferred additives that can be used in embodiments of the present invention include riboflavin, riboflavin sodium phosphate, vitamin D3, folic acid (vitamin B9), vitamin 12, diethylenetriaminepentaacetic acid dianhydride, ethylenediaminetetraacetic acid dianhydride, malein acids and anhydrides, succinic anhydride, diglycolic anhydride, glutaric anhydride, L-ascorbic acid, thiamine, nicotinamide, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, cysteine, tyrosine, tryptophan, leucine, Included are isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine.

[0223] From a structural standpoint, 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 contain amine, alcohol, ester, amide, anhydride, carboxylic acid, and/or hydroxyl groups. They can form hydrogen bonds and/or van der Waals interactions with drugs. They are also useful in the top layer of coatings. For example, compounds containing one or more hydroxyl, carboxyl, or amine groups facilitate drug release from the medical device surface and readily exclude water contacting the polar headgroups of cell membranes and surface proteins, thereby rendering hydrophobic drugs It is particularly useful as an additive because it can remove this barrier to the permeability of They promote movement of hydrophobic drugs away from the balloon and into cell membranes and tissue lipid layers, where the drug has a very high affinity. They can also carry or facilitate movement of drugs away from the balloon and into a more aqueous environment, such as within the interstitial space of vascular tissue damaged by balloon angioplasty or stent dilatation. Additives such as polyglyceryl fatty acid esters, ascorbic acid esters of fatty acids, sugar esters of fatty acids, alcohols and ethers form fatty chains that can be integrated into the lipid structures of target tissue membranes and carry drugs into the lipid structures. Have. Some amino acids, vitamins and organic acids have aromatic C=N groups as well as amino, hydroxyl and carboxylic acid moieties in their structures. They contain structural moieties that can bind or complex hydrophobic drugs such as paclitaxel or rapamycin, and they prevent tissue penetration by removing the hydrophobic barrier between the hydrophobic drug and the lipid structures of cell membranes. It also has a structure that facilitates.

[0224] For example, isononylphenyl polyglycidol (Olin-10 G and Surfactant-10G), 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 portion. These hydroxyl groups have a very good affinity for the vessel wall and are able to exclude hydrogen-bonded water molecules. At the same time they possess 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 target cell's lipid membrane can further facilitate the penetration of hydrophobic drugs into the tissue.

[0225] As other examples, L-ascorbic acid, thiamine, maleic acids, niacinamide, and 2-pyrrolidone-5-carboxylic acid all have very high water and ethanol solubility, as well as low molecular weight and small size. . They also have structural components containing aromatic C═N, amino, hydroxyl, and carboxylic acid groups. These structures have very good compatibility with paclitaxel and rapamycin and can increase the solubility of these water-insoluble drugs in water and enhance their absorption into tissues. However, they often adhere poorly to medical device surfaces. 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 as they have anti-restenotic effects on their own and reduce thrombosis, especially when used in combination with paclitaxel.

[0226] In embodiments of the present invention, the additive is soluble in aqueous solvents and soluble in organic solvents. Examples of hydrophobic compounds that lack 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 genotoxic.

[0227] In one embodiment, the concentration density of the at least one therapeutic agent applied to the surface of the medical device is from about 1 to 20 μg/ ^mm2 , or more preferably from about 2 to 6 μg/ ^mm2 . In one aspect, the concentration of the 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 in embodiments of the invention is about 20 to 0.05, preferably about 10 to 0.5, or more preferably about 5 to 0.8.

[0228] The relative amounts of therapeutic agent and additive in the coating layer can vary depending on the likely environment of application. The optimum amount of additive is determined by, for example, the critical micelle concentration of the selected individual therapeutic agent and additive, the surface modifier if it forms micelles, the hydrophilic-lipophilic-balance (HLB) of the surfactant. , or on the octonol-water partition coefficient (P) of the additive, the melting point of the additive, the water solubility of the additive and/or therapeutic agent, the surface tension of the aqueous solution of the surface modifier, and the like.

[0229] In exemplary coating compositions of embodiments of the present invention, the additive is a carrier, a clear aqueous dispersion or emulsion or solution containing a hydrophobic therapeutic agent in an aqueous or organic solution when diluted with an aqueous solution. is present in such an amount as to form If the relative amount of surfactant is too high, the resulting dispersion will be visibly "turbid".

[0230] Optical clarity of an aqueous dispersion can be measured using standard quantitative methods for turbidity evaluation. One convenient way to measure turbidity is to measure the amount of light of a particular wavelength that is transmitted through the solution, for example with a UV-visible spectrophotometer. Using this method, optical clarity corresponds to high transmission since a more turbid solution will scatter more of the incident light, resulting in a lower transmission measurement.

[0231] Another method for measuring optical clarity and carrier diffusivity through an aqueous boundary layer is a quantitative measurement of the size of the particles that make up the dispersion. These measurements can be performed with commercially available particle size analyzers.

[0232] Other considerations will further inform the selection of the relative proportions of the various additives. These considerations include the biotolerability of the additive and the target dose of the hydrophobic therapeutic agent to be delivered.

[0233] Therapeutic Agents
[0234] The drug or bioactive agent that can be used in embodiments of the present invention can be any therapeutic agent or substance. Drugs may be in various physical states, such as molecular distributions, crystalline or clustered forms. Examples of drugs that are particularly useful in aspects of the present invention include substantially water-insoluble drugs that are lipophilic, such as paclitaxel, rapamycin, daunorubicin, doxorubicin, lapachone, vitamins D2 and D3, and analogues and derivatives thereof. These drugs are particularly suitable for use in coatings on balloon catheters used to treat vascular tissue.

[0235] Other drugs that can be used in aspects of this invention include, without limitation, glucocorticoids (e.g., dexamethasone, betamethasone), hirudin, angiopeptins, aspirin, growth factors, antisense drugs, anticancer drugs, Antiproliferative agents, oligonucleotides, and more generally antiplatelet agents, anticoagulants, cytostatics, antioxidants, antimetabolites, antichemotactic agents, and anti-inflammatory agents are included.

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

[0237] Antiplatelet agents can include drugs such as aspirin and dipyridamole. Aspirin is classified as an analgesic, antipyretic, anti-inflammatory and antiplatelet agent. Dipyridamole is a drug similar to aspirin in that it has antiplatelet properties. Dipyridamole is also classified as a coronary vasodilator. Anticoagulants for use in aspects of the present invention can include drugs such as heparin, protamine, hirudin and tick anticoagulant protein. Antioxidants can include probucol. Antiproliferative agents can include drugs such as amlodipine and doxazosin. Cytostatics and antimetabolites that can be used in aspects of the present invention include methotrexate, azathioprine, vincristine, vinblastine, 5-fluorouracil, adriamycin and mutamycin ( mutamycin) can be included. Antibiotics for use in aspects of the present invention include penicillins, cefoxitin, oxacillin, tobramycin and gentamicin. Suitable antioxidants for use in aspects of the invention include probucol. Additionally, genes or nucleic acids or portions thereof can be used as therapeutic agents in aspects of the present invention. Additionally, collagen synthesis inhibitors, such as tranilast, can be used as therapeutic agents in aspects of the present invention.

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

[0239] Drugs for use in embodiments of the present invention also include: everolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin. ), ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin
, atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, nimustine ), carmustine, lomustine, cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan, ifosfamide, trofosfamide, chlorambucil ( chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, temozolomide, thiotepa, daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, 5 '-fludarabine dihydrogen phosphate, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin (carboplatin), cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin aldesleukin, tretinoin,
Asparaginase, pegaspargase, anastrozole, exemestane, letrozole, formestane, aminoglutethimide, adriamycin, azithromycin, Spira spiramycin, cepharantin, smc growth inhibitor-2w, epothilone A and B, mitoxantrone, azathioprine, mycophenolatmofetil, c-myc-anti sense, b-myc-antisense, betulinic acid, camptothecin, lapachol, beta.-lapachone, podophyllotoxin, betulin, podophil podophyllic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b, lenograstim (r-HuG-CSF), filgrastim , macrogol, dacarbazine, basiliximab, daclizumab, selectins (cytokine antagonists), CETP inhibitors, cadherins, cytokinin inhibitors, COX-2 inhibitors, NFkB , angiopeptin, ciprofloxacin, camptothecin, fluroblastin, monoclonal antibodies that inhibit muscle cell proliferation, bFGF antagonists, probucol, prostaglandins , 1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one, scopoletin, colchicine, NO donors, such as pentaerythritol tetranitrate and syndnoeimines, S-nitroso derivatives, tamoxifen, staurosporine, beta-estradiol, a-estradiol, estriol, estrone, ethinylestradiol, fosfestrol , medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other teniposides indicated in cancer therapy, verapamil, tyrosine Kinase inhibitors (tyrphostines), cyclosporin A, 6-a-hydroxy-paclitaxel, baccatin, taxotere and other macrocyclic oligomers of carbon suboxide. ) (MCS) and its derivatives, mofebutazone, acemethacin, diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenam mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate ), oxaceprol, celecoxib, beta.-sitosterin, ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol , benzocaine, aescin, ellipticine, D-24851 (Calbiochem), colcemid, cytochalasin A to E, indanocine, nocodazole, S 100 protein , bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase-stimulating factor tissue inhibitors of metalproteinases-1 and -2, free nucleic acids, nucleic acids incorporated into viral mediators, DNA and RNA fragments, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotides, VEGF inhibitors, IGF-1, active agents of the antibiotic group such as cefadroxil, cefazolin (cefazolin), cefaclor, cefotaxim, tobramycin, gentamycin, penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazol, antithrombosis drugs such as argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulfated and N-reacetylated heparin, tissue plasminogen actin beta, GpIIb/IIIa platelet membrane receptor, factor Xa inhibitory antibody, heparin, hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase, warfarin, urokinase, blood vessels Dilators such as dipyramidole, trapidil, nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin, ACE inhibitors such as captopril, cilazapril, lisinopril , enalapril, losartan, thiol protease inhibitors, prostacyclin, vapiprost, interferon a, beta and y, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis modulators, For example p65 NF-kB or Bcl-xL antisense oligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, Boswell Boswellic acids and their derivatives, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone, mutamycin ( mutamycin, procainamide, retinoic acid, quinidine, disopyramide, flecainide, propafenone, sotalol, amidorone, natural and synthetic steroids such as bryophyllin A, inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances (NSAIDs) 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 ), antiprotozoal agents such as chloroquine, mefloquine, quinine, other natural terpenoids such as hippocaesculin, barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelic acid (4,7 -oxycycloanisomelic acid), baccharinoids 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, taxamirin (taxamairins) A and B, regenilol, triptolide, as well as other cymarins, apocymarin, aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburin chloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-beta-hydroxypregnadiene-3,20-dione, bilobol, ginkgol, ginkgolic acid , helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, glycoside 1a, podophyllotoxin, justicidin A and B, lareatin ( larreatin, malloterin, mallotochromanol, 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, methylsorbate methylsorbifolin, sphatheliachromen, stizophyllin, mansonine, strebloside, akagerine, dihydrousambarensine, hydroxyusambarine, stricno strychnopentamine, strychnophylline, usambarine, usambarensine, berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol , methoxylariciresinol, syringaresinol, umbelliferone, afromoson, acetylvismione B, desacetylvismione A, and bismion ( vismione) A and B.

[0240] Combinations of drugs may also be used in embodiments of the invention. Some combinations have additive effects because they have different mechanisms; eg, paclitaxel and rapamycin, paclitaxel and active vitamin D, paclitaxel and lapachone, rapamycin and active vitamin D, rapamycin and rapachone. Because of the additive effect, drug doses can also be reduced. These combinations can reduce complications from using high doses of drugs.

[0241] Adhesive layer
[0242] The adhesive layer, an optional layer underlying the drug coating layer, improves the adhesion of the drug coating layer to the outer surface of the medical device and protects the integrity of the coating. If the adhesion of the drug and excipient to the medical device is different, the adhesive layer provides a constant drug-to-excipient or drug-to-drug ratio in the drug layer and during therapeutic drug delivery at the target site of intervention. Differences in drug layer component loss (during migration) or elution (at the target site) can be prevented in order to maintain . Additionally, the adhesive layer may function to facilitate the release of coating layer components that might otherwise adhere too strongly to the medical device to be eluted during short-term contact with tissue at the target site. can. For example, if a particular drug binds tightly to the 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 noted above, the adhesive layer comprises a polymer or an additive or a mixture of both. Polymers useful in forming the adhesive layer are biocompatible and avoid irritation of body tissue. Some examples of polymers useful in forming the adhesive layer are biostable polymers such as polyurethanes, silicones, and polyesters. Other polymers useful in forming the adhesive layer include polymers that can be dissolved and polymerized on the medical device.

[0244] Some examples of polymers useful in the adhesive layer of embodiments of the present invention include the following: polyolefins, polyisobutylene, ethylene-α-olefin copolymers, acrylic acid polymers and copolymers, polyvinyl chloride. , polyvinyl methyl ether, polyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinyl acetate, ethylene-methyl methacrylate copolymer, acrylonitrile-styrene copolymer, ABS resin, nylon 12 and block copolymers thereof, poly Caprolactone, polyoxymethylenes, polyethers, epoxy resins, polyurethanes, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ether, carboxymethylcellulose, chitins, polylactic acid, Polyglycolic acid, polylactic acid-polyethylene oxide copolymers, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, and mixtures and block copolymers thereof.

[0245] Since medical devices are subject to mechanical manipulation, i.e., expansion and contraction, examples of polymers useful in the adhesive layer include elastomeric polymers such as silicones (e.g., polysiloxanes and substituted polysiloxanes), polyurethanes, types, 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 with these polymers when the device is subjected to force or stress.

[0246] The adhesive layer maintains the integrity and adhesion of the coating layer to the medical device and promotes both drug and excipient attachment during transfer and rapid elution when placed at the therapeutic intervention site. To that end, one or more of the additives mentioned above, or other ingredients may also be included.

[0247] top layer
[0248] To further protect the integrity of the drug layer, a top layer is optionally applied to aid in movement through tortuous anatomy to the target site or during initial expansion of the medical device. Drug loss can be prevented before the coating is in direct contact with the target tissue. The top layer can protect the drug layer while gradually releasing it into the body cavity. If the top layer is composed of a more hydrophobic high molecular weight additive, 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 are hydrophobic. They can be used in the top layer. On the other hand, the top layer should not erode too slowly or may actually slow the release of the drug when in place at the target site. Other additives useful in the top layer include additives 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 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 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate , PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, octoxynol, monoxinol, tyloxapol, 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 anhydride, ascorbic acid, 2-pyrrolidone- 5-carboxylic acid, sodium pyrrolidonecarboxylate, ethylenediaminetetraacetic acid dianhydride, maleic anhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; sicotiamine, dexpane tenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, fibrinogens, lipases, benzalkonium chloride, Benzethonium chloride, docecyltrimethylammonium bromide, sodium docecyl sulfates, dialkylmethylbenzylammonium chloride, and dialkyl esters of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, tri Ethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic lactone, gulonic acid lactone, mannonic acid lactone, ribonic acid lactone , lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin, methylparaben, propylparaben, Sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid, any Salts of Organic Acids and Organic Amines, 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.

[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) alkanes 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, Trascutol, and benzyl alcohol, (e) ethers (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. A preferred solvent in the top layer is acetone.

[0251] Organic solvents such as short chain alcohols, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide, and the like are preferred solvents that are particularly useful in embodiments of the invention; these organic solvents generally disintegrate colloidal aggregates. , because they together solubilize all the components in the coating solution.

[0252] The therapeutic agent and excipient(s) can be dispersed, solubilized, or otherwise mixed in a solvent. The weight percent of drug and excipients in the solvent may range from 0.1 to 80 weight percent, preferably from 2 to 20 weight percent.

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

[0254] In other embodiments, more than one solvent, more than one therapeutic agent, and/or more than one additive 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 the medical device, such as casting, spinning, spraying, dipping (immersing), inkjet printing, electrostatic methods, and combinations of these methods. The choice of application method depends primarily on the viscosity and surface tension of the solution. Dipping and spraying are preferred for embodiments of the present invention because they make it easier to control the uniformity of the thickness of the coating layer applied to the medical device and the concentration of the therapeutic agent. Regardless of whether the coating is applied by spraying or dipping or other methods or a combination of methods, each layer is usually coated with a medical coating to control the uniformity and concentration of therapeutic substances and additives applied to the medical device. The device is deposited in multiple application steps.

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

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

[0259] An application tool that can be used is a paint jar, such as Badger Model 150, connected to an airbrush, supplied with a source of pressurized air via a regulator (Norgren, 0-160 psi). When using such an application tool, air is supplied when the brush hose is connected to a source of compressed air downstream of the regulator. Adjust the pressure to about 15-25 psi and release the trigger to check the nozzle condition.

[0260] Prior to spraying, both ends of the relaxed balloon were secured to the fixture with two elastic retainers, ie, alligator clips, to allow the balloon to be deflated and folded, or inflated or partially inflated and folded. Adjust the distance between the clips so that they are kept in place. The rotor is then activated and the rotation speed is adjusted to the desired coating speed of about 40 rpm.

[0261] While rotating the balloon in a substantially horizontal plane, adjust the spray nozzle so that the distance from the nozzle to the balloon is about 1-4 inches. First, sweep 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 speed such that one spraying cycle is performed in about 3 balloon revolutions. , spraying the coating solution substantially horizontally. The balloon is repeatedly sprayed with the coating solution, followed by drying, until an effective amount of drug is deposited on the balloon.

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

[0263] It should be understood that this description of application equipment, fixtures, and spraying methods is exemplary only. Any other suitable spraying method or other technique may be used for coating medical devices, particularly balloons of balloon catheters, or stent delivery systems or stents.

[0264] After the medical device is sprayed with the coating solution, the coated balloon is dried, during which time the solvent in the coating solution evaporates. This results in a coating matrix containing the therapeutic agent on the balloon. An example drying method is to place 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. Times and temperatures may vary depending on individual additives and therapeutic agents.

[0265] Optimal Post-Processing
[0266] After the drug-additive containing layer is deposited on the medical device of certain embodiments of the present invention, dimethylsulfoxide (DMSO) or other solvent is dipped or sprayed or otherwise applied to the final surface of the coating. may DMSO readily dissolves drugs, readily penetrates membranes, and can enhance tissue absorption.

[0267] Medical devices according to embodiments of the present invention are particularly applicable to treat occlusions or blockages in any body vessel, including: the vascular system, including the coronary, peripheral and cerebral vasculature; , gastrointestinal tract including esophagus, stomach, small intestine and colon, pulmonary tract including trachea, bronchi, bronchioles, sinuses, bile ducts, ureters, prostatic ducts and brain ducts. They are particularly suitable for treating tissue of the vascular system, for example with balloon catheters or stents.

[0268] Yet another aspect of the invention relates to a method of treating a blood vessel. The method includes inserting a medical device including a coating into a blood vessel. The coating layer contains therapeutic agents and additives. In this aspect, the medical device can be constructed with at least one inflatable portion. Some examples of such devices include balloon catheters, perfusion balloon catheters, infusion catheters such as distal perforated drug infusion catheters, perforated balloons, spaced double balloons, perforated balloons, and sweep balloons, cutting balloon catheters, score Included are ring balloon catheters, self-expanding and balloon-expandable stents, guide catheters, guide wires, embolic protection devices, and various imaging devices.

[0269] As noted above, one example of a medical device that is particularly useful with the present invention is a coated balloon catheter. A balloon catheter generally has a long, thin, hollow tube with a small deflated balloon. In embodiments of the invention, the balloon is coated with a drug solution. The balloon is then manipulated through the cardiovascular system to reach blockages, occlusions, or other sites requiring therapeutic agents. Once in place, the balloon is inflated to contact the vessel wall and/or blockage or occlusion. It is an object of the present invention to rapidly deliver drugs to target tissues and facilitate absorption by the tissues. It would be advantageous to effectively deliver the drug to the tissue in the shortest possible time period while the medical device is positioned at the target site. For example, drug coating at a balloon inflation time of about 0.1-30 minutes, or preferably about 0.1-10 minutes, or more preferably about 0.2-2 minutes, or most preferably about 0.1-1 minutes. is brought into pressure contact with diseased vascular tissue to release the therapeutic agent into those tissues, eg, the vessel wall.

[0270] If a therapeutically effective amount of drug could be delivered according to embodiments of the present invention, eg, into the arterial wall, the need for stents could be eliminated in some cases, preventing the complications associated with fracture and thrombosis.

[0271] If stent deployment is still desired, a particularly preferred use for aspects of the invention is to clamp a stent, eg, a bare metal stent (BMS), onto a drug-coated balloon, eg, as described in aspects herein. be. Upon inflation of the balloon and placement of the stent at the diseased vessel site, an effective amount of drug is delivered into the arterial wall to prevent or lessen the severity of restenosis and other complications. Alternatively, the stent and balloon may be coated together, or the stent may be coated and then tacked onto the balloon.

[0272] Additionally, balloon catheters can be used alone or in combination with other methods for treating the vascular system, such as photodynamic therapy or atherectomy, to treat vascular tissue/diseases. Atherectomy is a procedure to remove plaque from an artery. Specifically, atherectomy removes plaque from 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 distal end of the catheter. A catheter is inserted into the body and advanced through the artery to the stenosis. After a portion of the plaque has been removed by atherectomy, balloon angioplasty using a coated balloon according to aspects of the present invention can be performed. Additionally, stent deployment can be performed subsequently or concurrently with inflation of the coated balloon as described above. Photodynamic therapy is a method that uses light or radiant energy to kill target cells within a patient. Photoactivated photosensitizers can be delivered to specific tissue regions according to aspects of the present invention. A targeted light or radiation source selectively activates the drug to generate a cytotoxic response and mediate an antiproliferative therapeutic effect.

[0273] In certain embodiments of drug-containing coatings and layers according to the present invention, the coatings or layers do not contain polymers, oils, or lipids. Furthermore, therapeutic agents are not encapsulated in polymeric particles, micelles, or liposomes. As noted above, such formulations have significant drawbacks, particularly in the setting of diseased tissue of the vascular system, which can inhibit the intended effective and rapid drug release and tissue penetration.

[0274] While various embodiments have been specifically illustrated and described herein, modifications and variations of the invention are encompassed by the foregoing teachings and within the scope of the claims that do not depart from the spirit and intended scope of the invention. It will be recognized that the rights are included.

[0275] Except for operating examples or unless otherwise indicated, all numerical values expressing amounts of ingredients in a layer, reaction conditions, etc. used in the specification and claims are in all instances It should be interpreted as modified by the term "about". Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending on the desired properties sought by the present disclosure.

[0276] Preparation
[0277] The medical devices and coating layers of embodiments of the present invention can be made in a variety of ways. For example, a coating solution can be prepared by dispersing, dissolving, spreading, or otherwise mixing all of the ingredients, such as therapeutic agents, excipients, and solvents, together at the same time. 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 the therapeutic agent to the solvent and then adding the additive. Alternatively, the additive may be added to the solvent first and then the therapeutic agent added later. Since the excipient will increase the drug solubility in the solvent, if the solvent used does not dissolve the drug sufficiently, it is preferable to add the excipient to the solvent first, then the drug.

[0278] Examples
[0279] The following examples include embodiments of medical devices and coating layers within the scope of the present invention. The following examples are considered to be illustrative of the invention, but they should not be construed as limitations on the invention.

[0280] Example A
[0281] Preparation of coating solution (if necessary, add a small amount of water not exceeding 10% by volume sufficient to dissolve all solutes):
[0282] Formulation 1.1: 30-90 mg rapamycin, 1-2% (wt% relative to rapamycin) butylated hydroxytoluene (BHT), 15-90 mg Tween
80, 30-90 mg of docusate sodium (dioctyl sodium sulfosuccinate) and 1-3 ml of ethanol were mixed.

[0283] Formulation 1.2: 30-90 mg rapamycin, 1-2% (wt% relative to rapamycin) butylated hydroxyanisole (BHA), 15-90 mg Tween 80, 30-90 mg docusate sodium (dioctyl sodium sulfosuccinate), and 1-3 ml of ethanol were mixed.

[0284] Formulation 1.3: Mix 30-90 mg rapamycin, no BHT or BHA, 15-90 mg Tween 80, 30-90 mg docusate sodium (dioctyl sodium sulfosuccinate), and 1-3 ml ethanol. did.

[0285] Formulation 1.4: 30-90 mg rapamycin, 1-2% (wt% relative to rapamycin) BHA or BHT, 15-90 mg Solutol HS 15, 5-30 mg sodium dodecyl sulfate, and 1-3 ml of ethanol was mixed.

[0286] Formulation 1.5: 30-90 mg rapamycin, 1-2% (wt % relative to rapamycin) BHA or BHT, 15-90 mg Oleth 20, 15-90 mg docusate sodium (dioctyl sodium sulfosuccinate) , and 1-3 ml of ethanol were mixed.

[0287] Formulation 1.6: 30-90 mg rapamycin, 1-2% (% by weight relative to rapamycin) BHA or BHT, 15-90 mg polyethylene glycol-b-poly(lactide) (PEG-b-PLA) , 30-120 mg of docusate sodium (dioctyl sodium sulfosuccinate), and 1-3 ml of ethanol were mixed.

[0288] Formulation 1.7: 30-90 mg rapamycin, 1-2% (% by weight relative to rapamycin) BHA or BHT, 15-90 mg Tween 81, 30-90 mg Oleth 20, and 1-3 ml ethanol. were mixed.

[0289] Formulation 1.8: 30-90 mg rapamycin, 1-2% (wt% relative to rapamycin) BHA or BHA, 45-225 mg polyethylene glycol-b-poly(lactide) (PEG-b-PLA) , and 1-3 ml of ethanol were mixed.

[0290] Formulation 1.9: 30-90 mg rapamycin, 1-2% (wt% relative to rapamycin) BHA or BHA, 30-180 mg docusate sodium (dioctyl sodium sulfosuccinate), and 1-3 ml ethanol were mixed.

[0291] Formulation 1.10: 30-90 mg rapamycin, 1-2% (wt% relative to rapamycin) BHA or BHA, 15-45 mg Oleth 10, 15-45 mg Oleth 20, and 1-3 ml ethanol. were mixed.

[0292] Formulation 1.11: 30-90 mg rapamycin, 1-2% (wt% relative to rapamycin) BHA or BHT, 15-90 mg Solutol HS 15, 15-90 mg docusate sodium (sodium dioctyl sulfosuccinate). ), and 1-3 ml of ethanol were mixed.

[0293] Formulation 1.12: 30-90 mg rapamycin, 1-2% (wt% relative to 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.

[0294] Formulation 1.13: 30-90 mg rapamycin, 1-2% (wt% relative to rapamycin) BHA or BHA, 3-135 mg Solutol HS 15, and 1-3 ml ethanol were mixed.

[0295] Formulation 1.14: 30-90 mg rapamycin, 1-2% (% by weight relative to rapamycin) BHA or BHT, 3-135 mg Solutol HS 15, 3-90 mg Tween 81, and 1-3 ml Ethanol was mixed.

[0296] Formulation 1.15: 30-90 mg rapamycin, 1-2% (wt% relative to rapamycin) BHA or BHT, 3-135 mg Solutol HS 15, 3-90 mg soluble polyvinylpyrrolidone (Povidone or Kollidon 12PF). ), and 1-3 ml of ethanol were mixed.

[0297] Formulation 1.16: 30-90 mg rapamycin, 1-2% (wt% relative to rapamycin) BHA or BHT, 3-90 mg soluble polyvinylpyrrolidone (povidone or Kollidon 12PF), and 1-3 ml ethanol. were mixed.

[0298] Formulation 1.17: 30-90 mg rapamycin, 1-2% (wt % relative to rapamycin) BHA or BHT, 3-90 mg Cremophor EL (PEG-35 castor oil or polyethylene glycol-glycerol ricinoleate), and 1-3 ml of ethanol were mixed.

[0299] Formulation 1.18: 30-90 mg rapamycin, 1-2% (% by weight relative to rapamycin) BHA or BHT, 3-135 mg Cremophor EL (PEG-35 castor oil or polyethylene glycol-glycerol ricinoleate), 3-90 mg of Tween 81 and 1-3 ml of ethanol were mixed.

[0300] Formulation 1.19: 30-90 mg rapamycin, 1-2% (wt% relative to 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 relative to rapamycin) BHA or BHT, 3-90 mg Solutol HS 15, 3-90 mg sorbitol, and 1-3 ml ethanol. were mixed.

[0302] Formulation 1.21: 30-90 mg rapamycin, 1-2% (wt% relative to 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.

[0303] Formulation 1.22: 30-90 mg rapamycin, 1-2% (% by weight relative to rapamycin) BHA or BHT, 3-90 mg Tween 20 (polysorbate 20), 3-90 mg Tween 81 (polysorbate 81 ), and 1-3 ml of ethanol were mixed.

[0304] Formulation 1.23: 30-90 mg rapamycin, 1-2% (wt% relative to rapamycin) BHA or BHT, 3-90 mg soluble polyvinylpyrrolidone (povidone or Kollidon 12 PF), 3-90 mg Tween 20 (polysorbate 20), 3-90 mg of Tween 81 (polysorbate 81), and 1-3 ml of ethanol were mixed.

[0305] Formulation 1.24: 30-90 mg rapamycin, 1-2% (wt% relative to 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.

[0306] Formulation 1.25: 30-90 mg rapamycin, 1-2% (wt% relative to 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-glycerol ricinoleate), 3-90 mg lecithin, and 1-3 ml ethanol were mixed.

[0307] Example B
[0308] Five PTCA balloon catheters (3 mm diameter and 20 mm length) were coated using the method described in US Patent Application Publication No. 2010-0055294-A1, which is incorporated herein in its entirety. did. These PTCA balloon catheters were inflated at 1-3 atmospheres. The inflated balloon was loaded with, sprayed with, or dipped into, the formulations of Example A (1.1-1.3). The balloons were then dried and reloaded, sprayed or soaked until a sufficient amount of drug (3 μg/mm ² ) was obtained on the balloon. The coated balloons were collapsed, then repackaged and sterilized for analytical testing. Recovered rapamycin content was as follows: Formulation 1.1 79% for BHT added, Formulation 1.2 BHA added 100%, Formulation 1.3 BHT or no BHA added from 14%. 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, folded balloons were then repackaged, sterilized for animal testing, and optionally vacuum dried.

[0311] Procedure : Coated PTCA balloon catheters were inserted into target sites (LAD, LCX and RCA) in the coronary vasculature of 25-45 lb pigs. The balloon was inflated to approximately 12 atmospheres. The overdilatation ratio (ratio of balloon diameter to vessel diameter) was about 1.15-1.40. The drug was delivered into the target tissue during the 30-60 second inflation period. The balloon catheter was then deflated and withdrawn from the animal's body. Target vessels were harvested 0.25-24 hours after this procedure. Drug content in the target tissue and residual drug remaining on the balloon were analyzed by tissue extraction and HPLC.

[0312] In some of these animal studies, stents were crimped to drug-coated balloon catheters prior to deployment. In long-term animal studies, angiography was performed before and after all interventions and 28-35 days after manipulation (described above). Lumen diameter was measured and delayed lumen loss was calculated. Late lumen loss is defined as the smallest lumen diameter measured after the follow-up period (usually weeks to months after interventions such as angioplasty and stent placement in this instance) and the smallest lumen measured immediately after the intervention. difference in diameter. Restenosis can be quantified by diameter stenosis, which is the difference between the mean luminal diameter after follow-up and immediately after manipulation divided by the mean luminal diameter immediately after manipulation. 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 deployed with an uncoated balloon. Coated balloon catheters were then inserted into target sites (LAD, LCX and RCA) in the coronary vasculature of 25-45 pound pigs. 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. Tissues harvested 15-30 minutes after the procedure had a drug content of 40.2 μg, or 7.6% of the total drug initially loaded into the balloon. The expansion ratio during operation is 1.2-1.4. Late lumen loss after 28-35 days was 0.76 (sd 0.22) mm.

[0314] An 18 mm stent was deployed from the uncoated balloon. Coated balloon catheters were then inserted into target sites (LAD, LCX and RCA) in the coronary vasculature of 25-45 pound pigs. 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, or 1% of the total drug loaded. Tissues harvested 15-30 min after manipulation had a drug content of 6.3 μg, or 1-3.0% of the total drug loaded. After 28-35 days, the late lumen loss was 0.76 (sd 0.28) mm.

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

[0316] 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 drug loaded. The drug content of tissue harvested 15-30 minutes after manipulation was 16 μg, or 8.9% of the total drug loaded. The drug content of tissue harvested 28 days after manipulation was 7.7 ng/mg tissue. After 28-35 days, the late 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 drug loaded. Tissues harvested 15-30 minutes after manipulation had a drug content of 51.8 μg, or 9.0% of the total drug loaded. The drug content of tissue harvested 28 days after manipulation was 6.15 ng/mg tissue. After 28-35 days, the late 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 drug loaded. Tissues harvested 15-30 minutes after manipulation had a drug content of 11.3 μg, or 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, or 13.0% of the total drug loaded. Tissues harvested 28 days after manipulation had a drug content of 0.7 ng/mg tissue. After 28-35 days, the late 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 drug loaded. The drug content of tissue harvested 28 days after manipulation 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 drug loaded. The drug content of tissue harvested 28 days after manipulation was 10.75 ng/mg tissue. After 28-35 days, the late 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 ethanol was mixed.

[0325] Formulation 2: 50-150 mg (0.05-0.16 mmole) of rapamycin, 2-6 ml of acetone (or ethanol), 50-200 mg of polyglyceryl-10 oleate, and 0.5 ml of 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 octoxynol-9, and 0.5 ml ethanol. did.

[0327] 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 were mixed.

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

[0329] 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) mixed.

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

[0331] Formulation 8: 50-150 mg (0.05-0.16 mmole) of rapamycin, 2-6 ml of acetone (or ethanol), and 50-200 mg of nicotinic acid (in 1 ml of 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.

[0334] 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 ethanol.

[0335] Formulation 12: 50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (or ethanol), 75 mg octoxynol-9
, 75 mg of thiamine hydrochloride (in 1 ml of water or ethanol), and 0.5 ml of ethanol were mixed.

[0336] 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.

[0337] 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 ethanol.

[0338] 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 of methylene chloride. This solution was added to 30 ml 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 of methylene chloride and 10-30 mg of p-isononylphenoxypolyglycidol. This solution was added to 30 ml 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.

[0341] Formulation 18: 50-100 mg (0.06-0.12 mmmole) 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.

[0342] Formulation 19: 35-70 mg (0.042-0.084 mmmole) 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 were mixed.

[0343] Formulation 20: 35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.4-1.0 ml acetone, 0.4-1.0 ml ethanol, 0.2-0.4 ml Water, 35-70 mg Tween 20, and 35-70 mg sorbitol were mixed.

[0344] Formulation 21: 40-80 mg (0.048-0.096 mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 ml ethanol, 40-80 mg meglumine, and 32 ˜64 mg of gemcitic acid (equimolar ratio with meglumine) was mixed.

[0345] 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, 35-70 mg of lactobionic acid, and 10-20 mg of diethanolamine (equimolar ratio with lactobionic acid) were mixed.

[0346] Formulation 23: 35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 ml ethanol, and 70-140 mg N-octanoyl N-methylglucamine was mixed.

[0347] 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 meglumine, and 18-36 mg lactic acid (equimolar ratio with meglumine) were mixed.

[0348] 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 gensitic acid, and 30-60 mg of diethanolamine (equimolar ratio with gensitic acid) were mixed.

[0349] Formulation 26: Comparative solution - 50 mg (0.06 mmole) paclitaxel, 1 ml ethanol, 0.2 ml acetone, and 0.042 ml Ultravist 370 were mixed.

[0350] Formulation 27: Comparative solution - 40 mg (0.048 mmole) of paclitaxel, 0.5 ml of ethanol, and 0.5 ml of acetone were mixed.
[0351] Formulation 28: 35-70 mg (0.042-0.084 mmmole) 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 collapsed with three wings under vacuum. Example 1 to the balloon folded under vacuum
formulation (1-17) was sprayed or dipped into it. The folded balloon was then dried, sprayed or dipped again until a sufficient amount of drug (3 μg/mm ² ) was obtained on the balloon, dried and sprayed or dipped again. The coated, 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 tri-wing folded under vacuum. Formulations (1-5) of Example 1 were sprayed or dipped into the folded balloon under vacuum. The folded balloon was then dried and re-sprayed or dipped with formulation (6-10), dried and re-sprayed or dipped until a sufficient amount of drug (3 μg/mm ² ) was obtained on the balloon. did. The coated, 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) anchored with bare metal coronary stents were sprayed or dipped with formulations (1-5) of Example 1. These stent delivery systems were then dried and the formulation (6-1
0), dried, and re-sprayed or dipped until a sufficient amount of drug (3 μg/mm ² ) was obtained on the balloon. The coated, folded stent delivery system was then sterilized for animal testing.

[0358] Example 5
[0359] Drug-coated and uncoated balloon catheters (as controls) were inserted into the coronary arteries of pigs. The balloon was overinflated (1:1.2), the inflated balloon was held within the vessel for 60 seconds to release the drug and additive, then deflated and withdrawn from the pig. Animals were angiographed after 3 days, 31 days, 3 months, 6 months, 9 months and 12 months. After 60 minutes, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months, the amount of drug in the arterial tissue of sacrificed animals was measured.

[0360] Example 6
[0361] Five coronary stents (3 mm diameter and 18 mm length) were spray or dip coated with the formulation of Example 1 (1-17). These stents were then dried, sprayed or dipped again until a sufficient amount of drug (3 μg/mm ² ) was obtained on the stents, and dried again. The coated stent was then clamped 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 controls) were inserted into porcine coronary arteries and then the balloons were overinflated (1:1.2). The stent was implanted, drug and additive released, the balloon deflated and withdrawn from the pig. Animals were then angiographed 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 sacrificed animals was measured.

[0364] Example 8
[0365] Five PTCA balloon catheters were sprayed or soaked with the formulation (1-17) of Example 1, dried, and again until a sufficient amount of drug (3 μg/mm ² ) was obtained on the balloons. It was sprayed or dipped and dried again. A bare metal coronary stent (3 mm diameter and 20 mm length) was clamped 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 or dipped with formulations (1-5) of Example 1, dried, and sprayed or dipped again with formulations (6-10). The balloons were then dried and sprayed or dipped again until a sufficient amount of drug (3 μg/mm ² ) was obtained on the balloon. A bare metal coronary stent (3 mm diameter and 20 mm length) was clamped to each coated balloon. These coated balloons with bare metal coronary stents were packaged and sterilized for animal testing.

[0368] Example 10
[0369] The drug-coated balloon expandable bare metal stents of Examples 8 and 9 and the plain balloon expandable bare metal stent (as a control) were inserted into porcine coronary arteries and the balloons were overexpanded (1:1 .2). The stent was implanted and the balloon was held inflated for 60 seconds to release the drug and additive, then the balloon was deflated and withdrawn from the pig. Animals were then angiographed 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 is measured in arterial tissue of sacrificed animals.

[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 anhydride, and 0.5 ml of ethanol were mixed and then the solution was Stir until obtained. Five PTCA balloon catheters were sprayed or dipped with this solution, dried, and sprayed or dipped again until a sufficient amount of drug (3 μg/mm ² ) was obtained on the balloons. The coated balloon was then treated under high pH (range pH 8-11.5) conditions to hydrolyze the anhydride. This can be confirmed by the IR method. At this point the hydrophilicity of the coating had increased. The coated balloons were then sterilized for animal testing.

[0372] Example 12
[0373] Drug-coated and uncoated balloon catheters (as controls) were inserted bronchoscopically into the pulmonary airways of pigs. The balloon was inflated and the inflated balloon was held in the lumen for 60 seconds to release the drug and additive. The balloon was deflated and withdrawn from the pig. After 3 days, 31 days, 3 months, 6 months, 9 months and 12 months, the animals were then examined bronchoscopically and tissue samples taken for pathophysiological examination and quantification of drug uptake.

[0374] Example 13
[0375] An uncoated stent delivery catheter was inserted into the porcine vessel lumen. The balloon was inflated, the stent deployed, and the deflated balloon withdrawn. Pharmaceutical formulations 1-15 (10-100 ml) of Example 1 were injected at the stent implantation site (approximately 5-15 mg drug per pig). The drug was then absorbed into the injured tissue. Animals were then examined and tissue samples taken for pathophysiological examination.

[0376] Example 14
[0377] Affected tissue (breast cancer or prostate or atheroma or stricture) was surgically removed from the human body. Pharmaceutical formulations 1-15 (10-100 ml) of Example 1 were injected into or over the surgical cavity created by this surgical intervention (approximately 5-20 mg of drug). Local drug delivery has included injection through long needles, guide catheters, guide 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 collapsed and then dried. The coated, folded balloons were then repackaged and sterilized for animal testing.

[0380] Coated PTCA balloon catheters were inserted into target sites (LAD, LCX and RCA) in the coronary vasculature of 25-45 pound pigs. The balloon was inflated to approximately 12 atmospheres. The overdilatation ratio (ratio of balloon diameter to vessel diameter) is about 1.15-1
. was 40. The drug was delivered into the target tissue during the 30-60 second swelling period. The balloon catheter was then deflated and withdrawn from the animal's body. Target vessels were harvested 0.25-24 hours after this procedure. Drug content in the target tissue and residual drug remaining on the balloon were analyzed by tissue extraction and HPLC.

[0381] In some of these animal studies, stents were clamped to drug-coated balloon catheters prior to deployment. In long-term animal studies, angiography was performed before and after all interventions and 28-35 days post-operation. Lumen diameter was measured and delayed lumen loss was calculated. Late lumen loss is defined as the minimum lumen diameter measured after the follow-up period (usually weeks to months after interventions such as angioplasty and stenting in this example) and the minimum internal diameter measured immediately after the intervention. difference in lumen diameter. Restenosis can be quantified by diameter stenosis, which is the difference between the mean luminal diameter after follow-up and immediately after manipulation divided by the mean luminal diameter immediately after manipulation. 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 the 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. Tissues harvested 15-30 minutes after the procedure had a drug content of 64.79 μg, or 9.2% of the total drug initially loaded into the balloon. When an 18 mm stent was deployed with a coated balloon, the residual drug on the balloon was 31.96 μg, ie 4.5% of the drug loaded, and the drug content in tissue harvested 15-30 minutes after the procedure was 96.96 μg. 49 μg, or 13.7% of the drug load. The expansion ratio in operation is 1.3. Late lumen loss after 28-35 days was 0.10 (sd 0.2) mm. Diameter constriction is 3.3%.

[0383] The drug content of Formulation 19 on the 3.5 mm balloon catheter was 3.08 μg/mm ² . After manipulation, the residual drug on the balloon was 80.58 μg, or 11.4% of the total drug loaded. Tissues harvested 15-30 minutes after manipulation had a drug content of 42.23 μg, or 6.0% of the total drug loaded. After 28-35 days, the late lumen loss was 0.30 (sd 0.23) mm. Diameter stenosis was 5.4%.

[0384] The drug content of Formulation 20 on a 3.5 mm balloon catheter was 3.61 μg/mm ² . After manipulation, the residual drug on the balloon was 174.24 μg, or 24.7% of the total drug loaded. Tissues harvested 15-30 minutes after manipulation had a drug content of 83.83 μg, or 11.9% of the total drug loaded. With the pre-tacked 18 mm stent in place, the residual drug on the balloon was 114.53 μg, or 16.1% of the total drug loaded, and the drug content in tissue harvested 15-30 minutes after the procedure was 147.53 μg. 95 μg or 18.1% of total drug loaded. The expansion ratio in the run was 1.3. Late lumen loss after 28-35 days was 0.10 (sd 0.1) mm. Diameter stenosis was 3.4%.

[0385] The drug content of Formulation 21 on the 3.5 mm balloon catheter was 4.71 μg/mm ² . After manipulation, the residual drug on the balloon was 44.39 μg, or 6.3% of the total drug loaded. The drug content of tissue harvested 15-30 minutes after manipulation was 77.87 μg, or 11.0% of total drug loaded. After 28-35 days, the late lumen loss was 0.23 (sd 0.44) mm. Diameter stenosis was 7.3%.

[0386] The drug content of Formulation 22 on the 3.5 mm balloon catheter was 3.85 μg/mm ² . After manipulation, the residual drug on the balloon was 24.59 μg, or 3.5% of the total drug loaded. The drug content of tissue harvested 15-30 minutes after manipulation was 37.97μ.
g, or 5.4% of total drug loaded. After 28-35 days, the late lumen loss was 0.33 (sd 0.14) mm. Diameter stenosis was 6.7%.

[0387] The drug content of Formulation 23 on a 3.5 mm balloon catheter was 3.75 μg/mm ² . After manipulation, the residual drug on the balloon was 0.82 μg, or 0.1% of the total drug loaded. The drug content of tissue harvested 60 minutes after manipulation was 45.23 μg, or 5.5% of total drug loaded. After 28-35 days, the late lumen loss was 0.49 (sd 0.26) mm. Diameter stenosis was 11.3%.

[0388] The drug content of Formulation 24 on a 3.5 mm balloon catheter was 3.35 μg/mm ² . After manipulation, the residual drug on the balloon was 62.07 μg, or 7.5% of the total drug loaded. The drug content of tissue harvested 60 minutes after manipulation was 40.55 μg, or 4.9% of total drug loaded. After 28-35 days, the late lumen loss was 0.47 (sd 0.33) mm. Diameter stenosis was 9.9%.

[0389] The drug content of Formulation 25 on a 3.5 mm balloon catheter was 3.41 μg/mm ² . After manipulation, the residual drug on the balloon was 50.0 μg, or 6.0% of the total drug loaded. The drug content of tissue harvested 60 minutes after manipulation was 26.72 μg, or 3.2% of total drug loaded. After 28-35 days, the late lumen loss was 0.36 (sd 0.41) mm. Diameter stenosis was 9.3%.

[0390] The drug content of Formulation 28 on a 3.5 mm balloon catheter was 3.10 μg/mm ² . After manipulation, the residual drug on the balloon was 1.9% of the total drug loaded. The drug content of tissue harvested 2 hours after manipulation was 34.17 μg, or 5.0% of total drug loaded. In tissues harvested 24 hours after manipulation, tissue drug content was 28.92 μg, or 4.2% of total drug loaded.

[0391] The drug content of the control formulation (uncoated balloon) on the 3.5 mm balloon catheter was 0.0 μg/mm ² . After manipulation, the residual drug on the balloon was 0% of the total drug loaded. Tissues harvested 15 minutes after manipulation contained 0 μg of drug. Tissue drug content was 0 μg in tissues harvested 24 hours after manipulation. After 28-35 days, the late lumen loss was 0.67 (sd 0.27) mm. Diameter constriction is 20.8%. In the second replicate, the expansion ratio was 1.3. Late lumen loss was 1.1 (sd 0.1) mm. 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 procedure, residual drug on the balloon was 13.52 μg, or 1.9% of total drug loaded. The tissue drug content was 28.32 μg, or 4.0% of the total drug loaded. When the balloon with the pre-tacked 18 mm stent was deployed, the residual drug on the balloon was 26.45 μg, or 3.7% of the total drug loaded. The tissue drug content was 113.79 μg, or 16.1% of the drug load. After 28-35 days, the late lumen loss was 0.27 (sd 0.15) mm. Diameter stenosis was 7.1%.

[0393] The drug content of Formulation 27 (no additives) on the 3.5 mm balloon catheter was 4.22 μg/mm ² . After manipulation, the residual drug on the balloon was 321.97 μg, or 45.6% of the total drug loaded. The tissue drug content was 12.83 μg, or 1.8% of the total drug loaded.

[0394] Surprisingly, after placement of balloons coated with Formulations 18-25 and 28 according to embodiments of the present invention, the concentration of drug absorbed by porcine coronary artery tissue was significantly higher than that delivered by balloons coated with Comparative Formulation 26. and higher than those coated with drug-only Formulation 27. Late lumen loss after 28-35 days of follow-up was less than 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 balloons were loaded with Formulations 18-25 and 28 of Example 1. A sufficient amount of drug (3 μg/mm ² ) was obtained on the balloon surface. The inflated balloon was dried. A topcoat was then applied to the drug-coated balloon. Top coating formulations in acetone or ethanol were selected from gentisic acid, methylparaben, acetic acid, Tween 20, vanillin and aspirin. The coated, folded balloons were dried, then repackaged and sterilized for animal testing.

[0397] A flotation experiment was designed to determine the amount of drug lost prior to inflation during insertion and movement of a balloon catheter to a target site. A control balloon catheter was coated with Formulation 18. A top-coated catheter was also made with a propylparaben top-coating. For top-coated catheters, balloon catheters were coated with Formulation 18, then dried and 25-50 mg of propylparaben (approximately 50% by weight of paclitaxel) in acetone was coated onto the Formulation 18 coating. Control and top-coated balloon catheters were inserted into porcine arteries. The floating time in the pig artery was 1 minute. Drugs, additives and top coatings were released. The catheter was then withdrawn. Residual drug on the balloon catheter was analyzed by HPLC. The residual drug content of the control balloon catheter was 53% of the total drug loaded. The residual drug content of the top-coated balloon catheter was 88%. The topcoat reduced intravascular drug loss in conditions mimicking device movement to the intervention site. The same animal testing as in Example 15 was performed with Formulation 18 first coated onto the balloon and propylparaben coated as a top coating over this first coating layer. The drug content of the 3.5 mm balloon catheter was 3.39 μg/mm ² . After manipulation, the residual drug content on the balloon was 64.5 μg, or 8.6% of the total drug loaded. The drug content in tissue was 28.42 μg, or 4% of total drug loaded.

[0398] Example 17
[0399] Six PTCA balloon components (3.5 and 3.0 mm diameter and 20 mm length) were loaded with Formulation 18 obtained in Example 1. A sufficient amount of drug (3 μg/mm ² ) was obtained on the balloon surface. The balloon was dried.

[0400] A 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. The balloon surface of the control catheter was loaded with Formulation 18 only. 25-50 mg of the top coating formulation (approximately 50% by weight of paclitaxel) in acetone was coated onto the Formulation 18 coating layer on the other balloon surface. The coated balloons were dried for in vitro drug release testing.

[0401] A release experiment was designed to determine the amount of drug lost upon balloon inflation. 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 drug loaded. Balloon catheters containing top coating layers containing Tween 20, Tween 80, polypropylene glycol-425 (PPG-425) or polypropyl glycol-1000 (PPG-1000) had residual drug content of 47%, 56%, and 71%, respectively. and 81%. Thus, the top coating layer reduced drug loss upon inflation of the balloon component in in vitro tests.

1. A medical device for delivering a therapeutic agent to a tissue comprising a layer covering an exterior surface of the medical device, the layer comprising a therapeutic agent, an antioxidant and an additive, wherein the additive comprises a hydrophilic moiety and Including drug affinity moieties, wherein the drug affinity moieties are hydrophobic moieties, moieties that have affinity for therapeutic agents through hydrogen bonding, and moieties that have affinity for therapeutic agents through van der Waals interactions. at least one, wherein the additive is water-soluble, wherein the additive is at least one of a surfactant and a chemical compound, wherein the chemical compound comprises one or more hydroxyl, amino , carbonyl, carboxyl, acid, amide or ester groups.

2. A medical device for delivering a therapeutic agent to a tissue comprising a layer overlying the medical device, the layer comprising a therapeutic agent and one or more additives, each additive comprising a hydrophilic moiety and drug affinity moieties, wherein the drug affinity moieties are hydrophobic moieties, moieties that have affinity for therapeutic agents through hydrogen bonding, and moieties that have affinity for therapeutic agents through van der Waals interactions. wherein one of the one or more additives is a liquid additive.

3. A medical device for delivering a therapeutic agent to a tissue, comprising a layer overlying the medical device, said layer comprising a therapeutic agent and at least one additive, wherein said at least one additive contains a first additive and a second additive, wherein each additive comprises a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion is a hydrophobic portion, hydrogen bonding to the therapeutic agent and at least one of a moiety having an affinity for a therapeutic agent through a van der Waals interaction, wherein the first additive has a greater affinity than the second additive. .

4. A medical device for delivering a therapeutic agent to a tissue, comprising a layer overlying the medical device, said layer comprising a therapeutic agent and at least one additive, wherein said at least one additive contains a first additive and a second additive, wherein each additive comprises a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion is a hydrophobic portion, hydrogen bonding to the therapeutic agent and at least one of a moiety having an affinity for the therapeutic agent through van der Waals interaction, wherein the HLB value of the first additive is higher than that of the second additive , medical tools.

5. A medical device for delivering a therapeutic agent to a tissue, comprising a layer overlying the medical device, the layer comprising a therapeutic agent and at least one additive, the at least one additive comprising a first An additive and a second additive, wherein each additive comprises a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion comprises a hydrophobic portion, hydrogen bonding to provide affinity for the therapeutic agent. and having an affinity for a therapeutic agent through a 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, polyazomethines, high sulfate agar oligomers, chitooligosaccharides, polyfunctional oligomeric thioethers, including sterically hindered phenols, hindered amines, including p-phenylenediamine, trimethyldihydroquinolones, and alkylated diphenylamines, hindered phenols, t-butyl, arylamines, phosphites, hydroxylamines, benzofuranones, p-phenylenediamine, diphenylamine, N,N' disubstituted p-phenylenediamines, butylated hydroxytoluene ("BHT"), butylated hydroxyanisole ("BHA"), L-ascorbate (vitamin C), vitamin E, herbs rosemary, sage extract , glutathione, resveratrol, ethoxyquin, rosmanol, isorosmanol, rosmaridiphenol, propyl gallate, gallic acid, caffeic acid, p-cumeric acid, p-hydroxybenzoic acid, astaxanthin, ferulic acid, dehydrozingerone, chlorogenic acid, Ellagic acid, propylparaben, sinapic acid, daidzin, glycitin, genistin, daidzein, 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, gallic 2. The medical device according to 1, which is at least one of propyl acid, catechin, catechin gallate, quercetin, and derivatives thereof.

7. Chemical compounds include amino alcohols, hydroxyl carboxylic acids, esters, amides, ethers, acid anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides , proteins, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohols and organic acids, and substituted molecules thereof, according to 1. medical tools.

8. Surfactants include 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 2. The medical device according to 1, 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. 2. The medical device according to 1, wherein the chemical compound has a molecular weight of 20 to 750.

10. Chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups are amino alcohols, hydroxyl carboxylic acids, esters, amides, ethers, anhydrides, hydroxyl ketones, hydroxyl Lactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, soluble povidone , soluble polyvinylpyrrolidone with molecular weight 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 myristate diethanolamide, N,N-bis(2-hydroxyethyl stearamide), 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, butyryltrihexyl citrate, trimethyl citrate, acetic acid and anhydride, benzoic acid and anhydride, diethylenetriaminepentaacetic acid dianhydride, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride diglycolic anhydride, glutaric anhydride, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, aspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, aloyritic acid, sherolic acid 2. The medical device according to 1, which is selected from combinations of aminoalcohols and organic acids, and substituted molecules thereof.

11. A medical device for delivering a therapeutic agent to a tissue, comprising a layer overlying the medical device, the layer comprising 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 Stearate, PEG-15 12-Hydroxystearate (Solutol 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, Soluplus, polyvinylcaprolactam-polyvinylacetate- Polyethylene Glycol Graft Copolymer, 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 Milli State, Polyglyceryl-6 Palmitate, Polyglyceryl-10 Laurate, Polyglyceryl-10 Oleate, Polyglyceryl-10 Myristate, 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-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, sodium octyl sulfate, medium chain-branched or unbranched alkyl sulfates, docusate sodium, sodium dioctyl sulfosuccinate, sodium lauryl sulfoacetate, sodium alkylbenzene sulfonate, sodium dodecylbenzene sulfonate, Octoxynol, monoxinol, tyloxapol, 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 anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidonecarboxylate, ethylenediaminetetraacetic acid dianhydride , maleic anhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; cicotiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate, ascorbine nicotinamide acid, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulins, caseins , hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, fibrinogens, lipases, benzalkonium chloride, benzethonium chloride, doceyltrimethylammonium bromide, sodium doceyl sulfate, dialkyl Methylbenzylammonium chloride and dialkyl ester of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid , glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxy Benzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapinic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclo Dextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid and anhydride, benzoic acid and anhydride, diethylenetriaminepentaacetic acid dianhydride, ethylenediamine Tetraacetic acid dianhydride, maleic acid and anhydride, succinic acid and anhydride, diglycolic anhydride, glutaric anhydride, citric acid, tartaric acid, oxalic acid, aspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, aroirithic acid , sherolic acid, 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, butyryltrihexyl citrate, trimethyl citrate, 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, soluble povidone, soluble polyvinylpyrrolidone with molecular weight 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, lauric acid diethanolamide, lauric myristate diethanolamide , N,N-bis(2-hydroxyethyl stearamide), cocamide MEA, cocamide DEA, arginine, and derivatives and combinations thereof.

12. 2. The method of claim 1, wherein the tissue comprises one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostatic duct and brain duct. medical tools.

13. Medical devices include balloon catheters, perfused balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, debulking catheters, stents, filters, stent grafts, covered stents, patches, wires, and valves. 1. The medical device according to 1, comprising one of:

14. 2. The therapeutic agent is one of paclitaxel and its analogues, rapamycin and its analogues, beta-lapachone and its analogues, vital vitamin D and its analogues, and mixtures of these therapeutic agents. medical tools.

15. 2. The medical device of Claim 1, further comprising a top layer overlying the layer covering the outer surface of the medical device to reduce drug loss as it travels through the body to the target tissue.

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

17. 2. The medical device according to 1, wherein the layer consists essentially of therapeutic agents, antioxidants and additives.

18. 2. The medical device according to 1, wherein the concentration of therapeutic agent within the layer is from 1 to 20 μg/mm ² .
Aspects of the invention also include the following.
Aspect 1 A balloon catheter for delivering a therapeutic agent to tissue, the balloon catheter comprising a coating layer covering the outer surface of the balloon,
the coating layer comprises 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,
A balloon catheter, wherein the second additive is selected from the group consisting of sodium dioctyl sulfosuccinate, sodium doceyl sulfate, and polyvinylpyrrolidone.
Aspect 2
The balloon catheter of aspect 1, wherein the antioxidant is at least one of butylated hydroxytoluene (“BHT”) or butylated hydroxyanisole (“BHA”).
Aspect 3
The balloon catheter of aspect 1, wherein said therapeutic agent is rapamycin.
Aspect 4
The balloon catheter of aspect 1, wherein the first additive is PEG-20 sorbitan monolaurate.
Aspect 5
The balloon catheter of aspect 1, wherein the first additive is sorbitol.
Aspect 6
A balloon catheter according to aspect 1, wherein the second additive is sodium dioctyl sulfosuccinate.
Aspect 7
A balloon catheter according to aspect 1, wherein the second additive is polyvinylpyrrolidone.
Aspect 8
A balloon catheter according to aspect 1, wherein the concentration of therapeutic agent in said coating layer is from 1 μg/mm ² to 20 μg/mm ² .
Aspect 9
Aspect 1. according to aspect 1, wherein the tissue comprises tissue of one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and brain duct. balloon catheter.
Aspect 10
The balloon catheter of aspect 1, wherein the balloon catheter is sterilized.

10 Catheter 12 Balloon 14 Flexible Member 16 Handle Assembly 20 Coating Layer 22 Adhesive Layer 24 Layer Containing Therapeutic Agent and Additives 26 First Layer 28 Second Layer

Claims (12)

1. A sterile balloon catheter for delivering a therapeutic agent to tissue, the sterile balloon catheter comprising a coating layer covering the outer surface of the balloon,
the coating layer comprises a therapeutic agent, an antioxidant, and a first additive;
the therapeutic agent is rapamycin, paclitaxel, or a combination thereof;
the first additive is a surfactant,
A balloon catheter, wherein the antioxidant is at least one of butylated hydroxytoluene (“BHT”) or butylated hydroxyanisole (“BHA”). 2. The balloon catheter of claim 1, wherein said therapeutic agent is rapamycin. 2. The balloon catheter of Claim 1, wherein the first additive is an anionic surfactant. 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; 2. The balloon catheter of claim 1, selected from the group consisting of sorbitol, sodium dioctylsulfosuccinate and sodium dodecylsulfate. 5. The balloon catheter of claim 4, wherein the first additive is PEG-20 sorbitan monolaurate. 5. The balloon catheter of Claim 4, wherein the first additive is sorbitol. 5. The balloon catheter of claim 4, wherein the first additive is sodium dioctyl sulfosuccinate. 5. The balloon catheter of claim 4, wherein the first additive is sodium dodecyl sulfate. 2. The balloon catheter of claim 1, further comprising a second additive that is polyvinylpyrrolidone. 2. The balloon catheter of claim 1, wherein the concentration of therapeutic agent in said coating layer is from 1 [mu]g/mm ^<2> to 20 [mu]g/mm ^<2> . 2. The tissue comprises tissue of one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, ureter, prostate and brain duct. Balloon catheter as described. 2. The balloon catheter of claim 1, wherein said coating layer is sterilized .

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