(19) &   

(11) EP 2 500 046 A2

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 19.09.2012 Bulletin 2012/38 A61L 29/16 (2006.01) A61L 31/16 (2006.01)

(21) Application number: 11176688.7

(22) Date of filing: 16.05.2008

(84) Designated Contracting States: (72) Inventor: Wang, Lixiao AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Medina, MN Minnesota 55356 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR (74) Representative: HOFFMANN EITLE Designated Extension States: Patent- und Rechtsanwälte AL BA MK RS Arabellastrasse 4 81925 München (DE) (30) Priority: 19.10.2007 US 981380 P 19.10.2007 US 981384 P Remarks: 19.11.2007 US 942452 •This application was filed on 05-08-2011 as a divisional application to the application mentioned (62) Document number(s) of the earlier application(s) in under INID code 62. accordance with Art. 76 EPC: •Claims filed after the date of receipt of the divisional 08767783.7 / 2 073 860 application (Rule 68(4) EPC).

(71) Applicant: Lutonix, Inc. Maple Grove, MN 55369 (US)

(54) Drug releasing coatings for medical devices

(57) The invention relates to a medical device for de- bonding, and a part that has an affinity to the therapeutic livering a therapeutic agent to a tissue. The medical de- agent by van der Waals interactions. In embodiments, vice has a layer overlying the exterior surface of the med- the additive is water- soluble. In further embodiments, the ical device. additive is at least one of a surfactant and a chemical The layer contains a therapeutic agent and an addi- compound, and the chemical compound has a molecular tive. In certain embodiments, the additive has a hy- weight of from 80 to 750 or has more than four hydroxyl drophilic part and a drug affinity part, wherein the drug groups. affinity part is at least one of a hydrophobic part, a part that has an affinity to the therapeutic agent by hydrogen EP 2 500 046 A2

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 500 046 A2 2

Description infiltration, while in stented arteries, early neutrophil re- cruitment is followed by prolonged macrophage accumu- CROSS REFERENCE TO RELATED APPLICATIONS lation. The widespread use of coronary stents has altered the vascular response to injury by causing a more intense [0001] This application is a continuation-in- part of Ap- 5 and prolonged inflammatory state, due to chronic irrita- plication No. 11/942,452, filed November 19, 2007, which tion from the implanted foreign body, and in the case of claims the benefit of priority of U.S. Provisional Applica- drug eluting stents (DES), from insufficient biocompati- tion No. 60/860,084, filed on November 20, 2006, U.S. bility of the polymer coating. Provisional Application No. 60/880,742, filed January 17, [0005] Over the past several years, numerous local 2007, U.S. Provisional Application No. 60/897,427, filed 10 drug delivery systems have been developed for the treat- on January 25, 2007, U.S. Provisional Application No. ment and/or the prevention of restenosis after balloon 60/903,529 filed on February 26, 2007, U.S. Provisional angioplasty or stenting. Examples include local drug de- Application No. 60/904,473 filed March 2, 2007, U.S. Pro- livery catheters, delivery balloon catheters, and polymer- visional Application No. 60/926,850 filed April 30, 2007, ic drug coated stents: Given that many diseases affect a U.S. Provisional Application No. 60/981,380 filed Octo- 15 specific local site or organ within the body, it is advanta- ber 19, 2007, and U.S. Provisional Application No. geous to preferentially treat only the affected area. This 60/981.384 filed October 19, 2007, the disclosures of all avoids high systemic drug levels, which may result in of which are incorporated by reference herein. adverse side effects, and concentrates therapeutic agents tin the local area where they are needed. By treat- FIELD OF THE INVENTION 20 ing just the diseased tissue, the total quantity of drug used may be significantly reduced. Moreover, local drug [0002] Embodiments of the present invention relate to delivery may allow for the use of certain effective thera- coated medical devices, and particularly to coated bal- peutic agents, which have previously been considered loon catheters, and their use for rapidly delivering a ther- too toxic or non-specific to use systemically. apeutic agent to particular tissue or body lumen, for treat- 25 [0006] One example of a local delivery system is a drug ment of disease and particularly for reducing stenosis eluting stent (DES). The stent is coated with a polymer and late lumen loss of a body lumen. Embodiments of into which drug is impregnated.When the stent is inserted the present invention also relate to methods of manufac- into a blood vessel, the polymer degrades and the drug turing these medical devices, the coatings provided on is slowly released. The slow release of the drug, which these medical devices, the solutions for making those 30 takes place over a period of weeks to months, has been coatings, and methods for treating a body lumen such reported as one of the main advantages of using DES. as the vasculature, including particularly arterial vascu- However, while slow release may be advantageous in lature, for example, using these coated medical devices. the case where a foreign body, such as a stent, is de- ployed, which is a source of chronic irritation and inflam- BACKGROUND OF THE INVENTION 35 mation, if a foreign body is not implanted it is instead advantageous to rapidly deliver drug to the vascular tis- [0003] It has become increasingly common to treat a sue at the time of treatment to inhibit inflammation and variety of medical conditions by introducing a medical cellular proliferation following acute injury. Thus, a con- device into the vascular system or other lumen within a siderable disadvantage of a DES, or any other implanted human or veterinary patient such as the esophagus, tra- 40 medical device designed for sustained release of a drug, chea, colon, biliary tract, or urinary tract. For example, is that the drug is incapable of being rapidly released into medical devices used for the treatment of vascular dis- the vessel. ease induce stents, catheters, balloon catheters, guide [0007] Additionally, while drug-eluting stents were in- wires, cannulas and the like. While these medical devices itially shown to be an effective technique for reducing and initially appear successful, the benefits are often com- 45 preventing restenosis, recently their efficacy and safety promised by the occurrence of complications, such as have been questioned. A life- threatening complication of late thrombosis, or recurrence of disease, such as sten- the technology, late thrombosis, has emerged as a major osis (restenosis), after such treatment. concern. Drug eluting stents cause substantial impair- [0004] Restenosis, for example, involves a physiolog- ment of arterial healing, characterized by a lack of com- ical response to the vascular injury caused by angi-50 plete re-endothelization and a persistence of fibrin when oplasty. Over time, de-endotheliaziation and injury to compared to bare metal stents (BMS), which is under- smooth muscle cells results in thrombus deposition, leu- stood to be the underlying cause of late DES thrombosis. kocyte and macrophage infiltration, smooth muscle cell Concerns have also beenraised that the polymeric matrix proliferation/migration, fibrosis and extracellular matrix on the stent in which the anti-proliferative drug is embed- deposition. Inflammation plays a pivotal role linking early 55 ded might exacerbate inflammation and thrombosis, vascular injury to the eventual consequence of neointimal since the polymers used are not sufficiently biocompat- growth and lumen compromise. In balloon-injured arter- ible. These polymeric systems are designed to facilitate ies, leukocyte recruitment is confined to early neutrophil long-term sustained release of drug over a period of days,

2 3 EP 2 500 046 A2 4 months, or years, not over a period of seconds or min- agents are associated with the risk of bradycardia, ven- utes. These polymeric drug coatings of medical devices tricular arrthymia, hypotension, heart block, sinus arrest, do not release the polymer, which remains on the device sinus tachycardia, and fibrillation. Iodine contrast agents even after drug is released. Even if biodegradable poly- may also induce renal failure, and as a result there are mers are used, polymer and drug are not released at the 5 significant efforts to remove these contrast agents from same time. Rapid release of drug, an intent of embodi- the vascular system after diagnostic procedures. ments of the present invention, from these polymeric sys- [0012] In addition, the Food and Drug Administration temsis not possible. Thus, combining atherapeutic agent (FDA) issued a second public health advisory in 2006 with a polymer in a medical device coating may have about a serious late adverse reaction to contrast agents significant disadvantages. 10 known as Nephrogenic Systemic Fibrosis or Nephrogen- [0008] Another important limitation of the DES is that ic Fibrosing Dermopathy. Given the breadth of adverse the water insoluble drugs are not evenly distributed in events associated with intravascular delivery of contrast the polymeric matrix of the coating. Furthermore, drug agents, improved medical devices are needed with coat- and polymer are concentrated on the struts of the stent, ings that do not inherently dose a patient with additional but not in gaps between the struts. The non- uniform dis- 15 contrast agent in order to deliver a desired therapeutic tribution of drug causes non-uniform drug release to the agent. tissue of the vessel walls. This may cause tissue damage [0013] Iodinated X-ray contrast agents are large hy- and thrombosis in areas exposed to excess drug and drophilic spherical molecules. They are characterized by hyperplasia and restenosis areas that are undertreated. an extracellular distribution and rapid glomerular filtration Thus, there is a need to improve the uniformity of drug 20 and renal excretion. They are unable to cross membrane delivery to target tissues by improving drug solubility in lipid bilayers to enter cells of the vasculature because coatings of medical devices by increasing the drug’s they are large, polar, hydrophilic molecules. They are compatibility with carriers in the coatings, such as a pol- therefore not optimally effective at carrying hydrophobic ymeric matrix, thereby eliminating or reducing the size drugs such as paclitaxel into cells, and the percent of of drug crystal particles in the polymeric matrix or other 25 paclitaxel reported to be taken up by vascular tissue after coating to create a uniform drug distribution in the drug deployment of these devices is only 5-20%. In addition, coating on the medical device. the compatability or miscibility of paclitaxel andiopromide [0009] Yet another important limitation of the DES is is not good, and the integrity and uniformity of the coating that only a limited amount of an active agent can be load- is poor. Particles from the coating easily flake off and are ed into the relatively small surface area of the stent. 30 lost during handling. These deficiencies adversely affect [0010] Non-stent based local delivery systems, such the amount and uniformity of drug delivered to target tis- as balloon catheters, have also been effective in the treat- sue. Improved coatings are therefore needed, coatings ment and prevention of restenosis. The balloon is coated that not only avoid unnecessary doses of contrast, but with an active agent, and when the blood vessel is dilated, that also maintain integrity during handling and more ef- the balloon is pressed against the vessel wall to deliver 35 fectively and uniformly deliver drug and facilitate its ab- the active agent. Thus, when balloon catheters are used, sorption by tissue. it is advantageous for the drug in the coating to be rapidly [0014] Alternatively, balloon catheters are reported to released and absorbed by blood vessel tissues. Any have been coated with hydrophobic therapeutic agents component of the coating that inhibits rapid release, such that have been mixed with oils or lipids or encapsulated as a lipid or polymer or an encapsulating particle, is nec- 40 in particles such as liposomes or polymers. All of these essarily disadvantageous to the intended use of the bal- drug delivery formulations have significant disadvantag- loon catheter, which is inflated for a very brief period of es. Unlike hydrophilic contrast agents, oils and lipids mix time and then removed from the body. well with water-insoluble drugs such as paclitaxel or ra- [0011] Hydrophilic drugs, such as heparin, have been pamycin, but the particle sizes of oils used for solubilizing reported to be deliverable by polymeric hydrogel coated 45 the therapeutic agents are relatively unstable, ranging in balloon catheters. However, a polymeric hydrogel coat- a broad particle size distribution from several hundred ing can not effectively deliver water insoluble drugs (such nanometers to several microns in diameter. as paclitaxel and rapamycin), because they can not mix [0015] Loading capacity of conventional micelles is with the hydrogel coating. Furthermore, as drug is re- low. Another disadvantage of oil-based liposome formu- leased, the cross-linked polymeric hydrogel remains on 50 lations is the dependence of drug absorption on the rate the balloon after drug is released. The iodine contrast and extent of lipolysis. Lipolysis of oil-based triglycerides agent iopromide has been used with paclitaxel to coat is difficult and dependent upon many factors, and triglyc- balloon catheters and has some success in treatment of erides must be digested and drug released in order to be restenosis. It was reported that contrast agent improves absorbedby diseased tissue. The amount of hydrophobic adhesion of paclitaxel to the balloon surface. However, 55 drug delivered to tissues by these agents will be low, iodinated contrast agents suffer from several well known because liposomes and micelles cannot efficiently re- disadvantages. When used for diagnostic procedures, lease hydrophobic drug, which they carry away before it they may have complication rates of 5-30%. These can be absorbed by tissues. Oils and lipids are therefore

3 5 EP 2 500 046 A2 6 not effective at rapidly and efficiently facilitating tissue liver therapeutic agents, drugs, or bioactive materials di- uptake of drug during a very brief device deployment rectly into a localized tissue area during or following a time, and no report has shown these types of coatings medical procedure, so as to treat or prevent vascular and to be effective. The ratio of drug to lipid in these formu- nonvascular diseases such as restenosis. The device lations is typically 0.2-0.3, because the drugs are encap- 5 should quickly release the therapeutic agent in an effec- sulated in the particles, miscelles, or liposomes, which tive and efficient manner at the desired target location, requires a significantly higher concentration of lipid than where the therapeutic agent should rapidly permeate the drug. These technologies involve forming the drug/lipid target tissue to treat disease, for example, to relieve ste- particles first and then coating medical devices with the nosis and prevent restenosis and late lumen loss of a prepared particles. There are several reports showing 10 body lumen. that drug release from these oil/ lipid formulations occurs in the range of days to weeks or months. This property SUMMARY OF THE INVENTION is not desirable for situations where drug release takes place in the range of seconds to minutes. Thus, the tech- [0019] The present inventor has found that coating the nology for oil/lipid formulation needs to be improved sig- 15 exterior surface of a medical device, and particularly of nificantly in order to be useful in such situations. a balloon catheter or a stent, for example, with a layer [0016] Drug that is encapsulated in polymeric particles comprising a therapeutic agent and an additive that has may take even longer to diffuse from the coating (the both a hydrophilic part and a drug affinity part is useful reported range is months to years) and will have further in solving the problems associated with the coatings dis- difficulty permeating target tissues rapidly. Microspheres 20 cussed above. The drug affinity part is a hydrophobic formed with polymeric materials, such as polyesters, part and/or has an affinity to the therapeutic agent by when used to encapsulate water insoluble drugs, are un- hydrogen bonding and/or van der Waals interactions. able to release the drug until the polymeric material is Surprisingly, the present inventor has found that the at degraded. Thus, these polymeric microspheres are use- least one additive according to embodiments of the ful for sustained release of drug over a long period of25 present invention, which comprises a hydrophilic partand time, but cannot rapidly release drug and facilitate tissue a drug affinity part, in combination with a therapeutic uptake. agent, forms an effective drug delivery coating on a med- [0017] Combining drugs and medical devices is a com- ical device without the use of oils and lipids, thereby plicated area of technology. It involves the usual formu- avoiding the lipolysis dependence and other disadvan- lation challenges, such as those of oral or injectable phar- 30 tages of conventional oil-based coating formulations. maceuticals, together with the added challenge of main- Moreover, the additives according to embodiments of the taining drug adherence to the medical device until it present invention facilitaterapid drug elution and superior reaches the target site and subsequently delivering the permeation of drug into tissues at a disease site. Thus, drug to the target tissues with the desired release and coatings according to embodiments of the present inven- absorption kinetics. Drug coatings of medical devices 35 tion provide an enhanced rate and/or extent of absorption must also have properties such that they do not crack of the hydrophobic therapeutic agent in diseased tissues upon expansion and contraction of the device, for exam- of the vasculature or other body lumen. In embodiments ple, of a balloon catheter or a stent. Furthermore, coat- of the present invention, the coated device delivers ther- ings must not impair functional performance such as apeutic agent to tissue during a very brief deployment burst pressure and compliance of balloons or the radial 40 time of less than 2 minutes and reduces stenosis and strength of self- or balloon- expanded stents. The coating late lumen loss of a body lumen. thickness must also be kept to a minimum, since a thick [0020] In one embodiment, the present invention re- coating would increase the medical device’s profile and lates to a medical device for delivering a therapeutic lead to poor trackability and deliverability. These coatings agent to a tissue, the device comprising a layer overlying generally contain almost no liquid chemicals, which typ- 45 an exterior surface of the medical device, The device ically are often used to stabilize drugs. Thus, formulations includes one of a balloon catheter, a perfusion balloon that are effective with pills or injectables might not work catheter, an infusion catheter such as distal perforated at all with coatings of medical device. If the drug releases drug infusion tube, a perforated balloon, spaced double from the device too easily, it may be lost during device balloon, porous balloon, and weeping balloon, a cutting delivery before it can be deployed at the target site, or it 50 balloon catheter, a scoring balloon catheter, a laser cath- may burst off the device during the initial phase of inflation eter, an atherectomy device, a debulking catheter, a and wash away before being pressed into contact with stent, a filter, a stent graft, a covered stent, a patch, a target tissue of a body lumen wall. If the drug adheres wire, and a valve. Further, the tissue includes tissue of too strongly, the device may be withdrawn before the one of coronary vasculature, peripheral vasculature, cer- drug can be released and absorbed by tissues at the55 ebral vasculature, esophagus, airways, sinus, trachea, target tissues. colon, biliary tract, urinary tract, prostate, and brain pas- [0018] Thus, there is still a need to develop highly spe- sages. cialized coatings for medical devices that can rapidly de- [0021] In one embodiment of the medical device, the

4 7 EP 2 500 046 A2 8 coating layer overlying the surface of a medical device 1000-5,000, more preferably less than 750-1,000, or comprises a therapeutic agent and an additive, wherein most preferably less than 750. Molecular weight of the the additive comprises a hydrophilic part and a drug af- additive is preferred to be less than that of the drug to be finity part, wherein the drug affinity part is at least one of delivered. Small molecules can diffuse quickly, and they a hydrophobic part, a part that has an affinity to the ther- 5 easily release from the surface of the delivery balloon, apeutic agent by hydrogen bonding, and a part that has carrying drug with them. They quickly diffuse away from an affinity to the therapeutic agent by van derWaals in- drug when the drug binds tissue. The molecular weight teractions, wherein the additive is water- soluble, wherein of the additives cannot be too low, however; additives the additive is at least one of a surfactant and a chemical with molecular weight less than 80 are not desirebale compound, and wherein the chemical compound has a 10 because they evaporate easily and are not stable com- molecular weight of from 80 to 750. ponents of the coating. In another embodiment, the ad- [0022] In one embodiment, the coating layer overlying ditive is a combination of a surfactant and a chemical the exterior surface of the medical device comprises a compound with one or more hydroxyl, amino, carbonyl, therapeutic agent and an additive, wherein the additive carboxyl, acid, amide, or ester groups. In another em- comprises a hydrophilic part and a drug affinity part,15 bodiment, the additive is a combination of an amino al- wherein the drug affinity part is at least one of a hydro- cohol and an organic acid; the combination is advanta- phobic part, a part that has an affinity to the therapeutic geous because it prevents instability that might otherwise agent by hydrogen bonding, and a part that has an affinity arise due to reactivity of acids or amines with drugs such to the therapeutic agent by van der Waals interactions, as paclitaxel. In another embodiment, the additive is hy- wherein the additive is at least one of a surfactant and a 20 droxyl ketone, hydroxyl lactone, hydroxyl acid, hydroxyl chemical compound, and wherein the chemical com- ester, or hydroxyl amide. In another embodiment, the ad- pound has more than four hydroxyl groups. In one em- ditive is gluconolactone or ribonic acid lactose thereof. bodiment, the chemical compound having more than four In yet another embodiment, the additive is chosen from hydroxyl groups has a melting point of 120°C or less, and meglumine/lactic acid, meglumine/gentisic acid, meglu- the chemical compound is an alcohol or an ester. 25 mine/acetic acid, lactobionic acid, Tween 20/sorbitol, [0023] In one embodiment, the layer overlying the ex- Tween 20/lactobionic acid, Tween 20/sugar or sugar de- terior surface of the medical device consists essentially rivatives and N-octanoyl N-methylglucamine. In another of the therapeutic agent and the additive. In one embod- embodiment, the additive is a vitamin or derivative there- iment, the layer overlying the exterior surface of the med- of. In another embodiment, the additive is an amino acid ical device does not include an iodine covalent bonded 30 or derivative thereof. In another embodiment, the additive contrast agent. In one embodiment, the chemical com- is a protein or derivative thereof. In another embodiment, pound has one or more hydroxyl, amino, carbonyl, car- the additive is an albumin. In another embodiment, the boxyl, acid, amide or ester groups. In one embodiment, additive is soluble in an aqueous solvent and is soluble the chemical compound is chosen from amino alcohols, in an organic solvent. In another embodiment, the addi- hydroxyl carboxylic acid, ester, anhydrides, hydroxyl ke- 35 tive is an organic acid or an anhydride thereof. In yet tone, hydroxyl lactone, hydroxyl ester, sugar phosphate, another embodiment, the additive is chosen from sorb- sugarsulfate, ethyl oxide,ethyl glycols, amino acids, pep- itan oleate and sorbitan fatty esters. tides, proteins, sorbitan, glycerol, polyalcohol, phos- [0026] In another embodiment, the coating layer over- phates, sulfates, organic acids, esters, salts, vitamins, lying the surface of a medical device comprises a thera- combinationsof aminoalcohol and organic acid, andtheir 40 peutic agent and an additive, wherein the additive is wa- substituted molecules. In another embodiment, the sur- ter-soluble, and wherein the additive is a chemical com- factant is chosen from ionic, nonionic, aliphatic, and ar- pound that has a molecular weight of from 80 to 750. omatic surfactants, PEG fatty esters, PEG omega-3 fatty [0027] In one embodiment, the layer overlying the ex- esters, ether, and alcohols, glycerol fatty esters, sorbitan terior surface of the medical device does not include oil, fatty esters, PEG glyceryl fatty esters, PEG sorbitan fatty 45 a lipid, or a polymer. In another embodiment, the layer esters, sugar fatty esters, PEG sugar esters and deriva- overlying the exterior surface of the medical device does tives thereof. not include oil. In another embodiment, the layer overly- [0024] In another embodiment, the coating layer over- ing the exterior surface of the medical device does not lying the surface of a medical device comprises a thera- include a polymer. In another embodiment, the layer peutic agent and an additive, wherein the additive is a 50 overlying the exterior surface of the medical device does surfactant. not include a purely hydrophobic additive. In one embod- [0025] In another embodiment, the additive is a chem- iment, the additive is not a therapeutic agent. In another ical compound having one or more hydroxyl, amino, car- embodiment, the additive is not salicylic acid or salts bonyl, carboxyl, acid, amide, ester groups. In another thereof. embodiment, the additive is a hydrophilic chemical com- 55 [0028] In another embodiment, the coating layer over- pound with one or more hydroxyl, amino, carbonyl, car- lying the surface of a medical device comprises a thera- boxyl, acid, amide, or ester groups with a molecular peutic agent and an additive, wherein the additive com- weight of less than 5,000-10,000, preferably less than prises a hydrophilic part and a drug affinity part, wherein

5 9 EP 2 500 046 A2 10 the drug affinity part is at least one of a hydrophobic part, late, tiletamine, ketamine, propofol, lactic acids, acetic a part that has an affinity to the therapeutic agent by acid, salts of any organic acid and organic amine, poly- hydrogen bonding, and a part that has an affinity to the glycidol, glycerols, multiglycerols, galactitol, di(ethylene therapeutic agent by van der Waals interactions, and glycol), tri(ethylene glycol), tetra(ethylene glycol), penta wherein the additive is chosen from p-isononylphenoxy- 5 (ethylene glycol), poly(ethylene glycol) oligomers, di (pro- polyglycidol, PEG laurate, PEG oleate, PEG stearate, pylene glycol), tri(propylene glycol), tetra(propylene gly- PEG glyceryl laurate, Tween 20, Tween 40, Tween 60, col, and penta(propylene glycol), poly(propylene glycol) PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl oligomers, and derivatives and combinations thereof. laurate, plyglyceryl oleate, polyglyceryl myristate, polyg- [0029] In one embodiment, the therapeutic agent is lyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 10 one of paclitaxel and analogues thereof, rapamycin and oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmi- analogues thereof, beta-lapachone and analogues tate, polyglyceryl-10 laurate, plyglyceryl-10 oleate, poly- thereof, biological vitamin D and analogues thereof, and glyceryl-10 myristate, polyglyceryl-10 palmitate PEG a mixture of these therapeutic agents. In another embod- sorbitan monolaurate, PEG sorbitan monolaurate, PEG iment, the therapeutic agent is in combination with a sec- sorbitan monooleate, PEG sorbitan stearate, PEG oleyl 15 ond therapeutic agent, wherein the therapeutic agent is ether, PEG laurayl ether, octoxynol, monoxynol, tyloxa- one of paclitaxel, rapamycin, and analogues thereof, and pol, sucrose monopalmitate, sucrose monolaurate, de- wherein the second therapeutic agent is one of beta-la- canoyl-N-methylglucamide, n-decyl - β-D-glucopyrano- pachone, biological active vitamin D, and their ana- side, n-decyl - β -D-maltopyranoside, n-dodecyl - β -D- logues. glucopyranoside, n-dodecyl - β -D-maltoside, heptanoyl- 20 [0030] In one embodiment, the medical device com- N-methylglucamide, n-heptyl- β -D-glucopyranoside, n- prising a layer overlying an exterior surface of the medical heptyl - β -D-thioglucoside, n-hexyl - β -D-glucopyrano- device further comprises an adherent layer between the side, nonanoyl-N-methylglucamide, n-noyl - β -D-glucop- exterior surface of the medical device and the layer. In yranoside, octanoyl-N-methylglucamide, n-octyl- β-D- another embodiment, the device further comprises a top glucopyranoside, octyl - β -D-thioglucopyranoside; cys- 25 layer overlying the surface of the layer to reduce loss of tine, tyrosine, tryptophan, leucine, isoleucine, phenyla- drug during transit through a body to the tissue. In another lanine, asparagine, aspartic acid, glutamic acid, and me- embodiment, the top layer overlying the surface of the thionine; acetic anhydride, benzoic anhydride, ascorbic layer overlying the exterior surface of the medical device acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrro- comprises an additive that is less hydrophilic than the lidone carboxylate, ethylenediaminetetraacetic dianhy- 30 additive in the layer overlying the exterior surface of the dride, maleic and anhydride, succinic anhydride, digly- medical device, and wherein the additive of the top layer colic anhydride, glutaric anhydride, acetiamine, benfo- is chosen from p- isononylphenoxypolyglycidol, PEG lau- tiamine, pantothenic acid ; cetotiamine; cycothiamine, rate, Tween 20, Tween 40, Tween 60, PEG oleate, PEG dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5- stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG phosphate, nicotinamide ascorbate, riboflavin, riboflavin 35 glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate, phosphate, thiamine, folic acid, menadiol diphosphate, polyglyceryl myristate, polyglyceryl palmitate, polyglyc- menadione sodium bisulfite, menadoxime, vitamin B12, eryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myr- vitamin K5, vitamin K6, vitamin K6, and vitamin U; albu- istate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, min, immunoglobulins, caseins, hemoglobins, lys- plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyg- ozymes, immunoglobins, a-2-macroglobulin, 40 fi-lyceryl-10 palmitate PEG sorbitan monolaurate, PEG bronectins, vitronectins, firbinogens, lipases, benzalko- sorbitan monolaurate, PEG sorbitan monooleate, PEG nium chloride, benzethonium chloride, docecyl trimethyl sorbitan stearate, PEG oleyl ether, PEG laurayl ether, ammonium bromide, sodium docecylsulfates, dialkyl octoxynol, monoxynol, tyloxapol, sucrose monopalmi- methylbenzyl ammonium chloride, and dialkylesters of tate, sucrose monolaurate, decanoyl-N-methylgluca- sodium sulfonsuccinic acid, L-ascorbic acid and its salt, 45 mide, n-decyl - β -D- glucopyranoside, n- decyl - β -D-malt- D-glucoascorbic acid and its salt, tromethamine, trieth- opyranoside, n-dodecyl - β -D-glucopyranoside, n-do- anolamine, diethanolamine, meglumine, glucamine, decyl - β -D-maltoside, heptanoyl-N-methylglucamide, n- amine alcohols, glucoheptonic acid, glucomic acid, hy- heptyl- β-D-glucopyranoside, n-heptyl - β -D-thiogluco- droxyl ketone, hydroxyl lactone, gluconolactone, gluco- side, n-hexyl - β -D-glucopyranoside, nonanoyl-N-meth- heptonolactone, glucooctanoic lactone, gulonic acid lac- 50 ylglucamide, n-noyl - β -D-glucopyranoside, octanoyl-N- tone, mannoic lactone, ribonic acid lactone, lactobionic methylglucamide, n-octyl- β -D-glucopyranoside, octyl - acid, glucosamine, glutamic acid, benzyl alcohol, benzo- β -D-thioglucopyranoside; cystine, tyrosine, tryptophan, ic acid, hydroxybenzoic acid, propyl 4- hydroxybenzoate, leucine, isoleucine, phenylalanine, asparagine, aspartic lysine acetate salt, gentisic acid, lactobionic acid, lactitol, acid, glutamic acid, and methionine; acetic anhydride, sinapic acid, vanillic acid, vanillin, methyl paraben, propyl 55 benzoic anhydride, ascorbic acid, 2-pyrrolidone-5-car- paraben, sorbitol, xylitol, cyclodextrin, (2-hydroxypro- boxylic acid, sodium pyrrolidone carboxylate, ethylene- pyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic ac- diaminetetraacetic dianhydride, maleic and anhydride, id, lysine acetate, gentisic acid, catechin, catechin, gal- succinic anhydride, diglycolic anhydride, glutaric anhy-

6 11 EP 2 500 046 A2 12 dride, acetiamine, benfotiamine, pantothenic acid ; ceto- device comprises a therapeutic agent and at least two tiamine; cycothiamine, dexpanthenol, niacinamide, nic- additives, wherein each of the additives comprises a hy- otinic acid, pyridoxal 5-phosphate, nicotinamide ascor- drophilic part and a drug affinity part, wherein the drug bate, riboflavin, riboflavin phosphate, thiamine, folic acid, affinity part is at least one of a hydrophobic part, a part menadiol diphosphate, menadione sodium bisulfite, me- 5 that has an affinity to the therapeutic agent by hydrogen nadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin bonding, and a part that has an affinity to the therapeutic K6, and vitamin U; albumin, immunoglobulins, caseins, agent by van der Waals interactions, and wherein each hemoglobins, lysozymes, immunoglobins, a-2-mac- additive is soluble in polar organic solvent and is soluble roglobulin, fibronectins, vitronectins, firbinogens, lipas- in water. In one aspect of this embodiment, the polar es, benzalkonium chloride, benzethonium chloride,10 organic solvent is chosen from methanol, ethanol, iso- docecyl trimethyl ammonium bromide, sodium docecyl- propanol, acetone, dimethylformide, tetrahydrofuran, sulfates, dialkyl methylbenzyl ammonium chloride, and methylethyl ketone, dimethylsulfoxide, acetonitrile, ethyl dialkylesters of sodium sulfonsuccinic acid, L-ascorbic acetate, and chloroform and mixtures of these polar or- acid and its salt, glucoascorbic D- acid and its salt, ganic solvents with water. In another aspect of this em- tromethamine, triethanolamine, diethanolamine, meglu- 15 bodiment, the device further comprises a top layer over- mine, glucamine, amine alcohols, glucoheptonic acid, lying the surface of the layer overlying the exterior surface glucomic acid, hydroxyl ketone, hydroxyl lactone, glu- of the medical device to reduce loss of drug during transit conolactone, glucoheptonolactone, glucooctanoic lac- through a body to the target tissue. tone, gulonic acid lactone, mannoic lactone, ribonic acid [0035] In another embodiment of the medical device, lactone, lactobionic acid, glucosamine, glutamic acid, 20 the layer overlying the exterior surface of the medical benzyl alcohol, benzoic acid, hydroxybenzoic acid, pro- device comprises a therapeutic agent and an additive, pyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid, wherein the additive comprises a hydrophilic part and a lactobionic acid, lactitol, sinapic acid, vanillic acid, vanil- drug affinity part, wherein the drug affinity part is at least lin, methyl paraben, propyl paraben, sorbitol, xylitol, cy- one of a hydrophobic part, a part that has an affinity to clodextrin, (2-hydroxypropyl)-cyclodextrin, acetami-25 the therapeutic agent by hydrogen bonding, and a part nophen, ibuprofen, retinoic acid, lysine acetate, gentisic that has an affinity to the therapeutic agent by van der acid, catechin, catechin gallate, tiletamine, ketamine, Walls interactions, wherein the additive reduces crystal propofol, lactic acids, acetic acid, salts of any organic size and number of particles of the therapeutic agent, acid and organic amine, polyglycidol, glycerol, multiglyc- and wherein the additive is water-soluble and the thera- erols, galactitol, di(ethylene glycol), tri(ethylene glycol), 30 peutic agent is not water-soluble. tetra(ethylene glycol), penta(ethylene glycol), poly(ethyl- [0036] In another embodiment of the medical device, ene glycol) oligomers, di (propylene glycol), tri(propylene the layer overlying the exterior surface of the medical glycol), tetra(propylene glycol, and penta(propylene gly- device comprises a therapeutic agent and an additive, col), poly(propylene glycol) oligomers, a block copolymer wherein the additive comprises a hydrophilic part and a of polyethylene glycol and polypropylene glycol, and de- 35 drug affinity part, wherein the drug affinity part is at least rivatives and combinations thereof. one of a hydrophobic part, a part that has an affinity to [0031] In another embodiment, the medical device fur- the therapeutic agent by hydrogen bonding, and a part ther comprises a dimethylsulfoxide solvent layer, where- that has an affinity to the therapeutic agent by van der in the dimethylsulfoxide solvent layer is overlying the sur- Waals interactions, wherein the additive has a fatty chain face of the layer. 40 of an acid, ester, ether, or alcohol, wherein the fatty chain [0032] In one embodiment of the medical device, the can directly insert into lipid membrane structures of the device is capable of releasing the therapeutic agent and tissue, and wherein the therapeutic agent is not water- the additive and delivering therapeutic agent to the tissue soluble. in about 0.1 to 2 minutes. In one embodiment, the con- [0037] in another embodiment of the medical device, centration of the therapeutic agent in the layer is from 1 45 the layer overlying the exterior surface of the medical to 20 Pg/mm2. In one embodiment, the concentration of device comprises a therapeutic agent and an additive, the therapeutic agent in the layer is from 2 to 10 Pg/mm2. wherein the additive comprises a hydrophilic part and a In one embodiment, the therapeutic agent is not water- hydrophobic part, wherein the additive can penetrate into soluble. and rearrange lipid membrane structures of the tissue, [0033] In one embodiment, the additive enhances re- 50 and wherein the therapeutic agent is not water-soluble lease of the therapeutic agent off the balloon. In another and is not enclosed in micelles or encapsulated in poly- embodiment, the additive enhances penetration and ab- mer particles. sorption of the therapeutic agent in tissue. In another [0038] In another embodiment of the medical device, embodiment, the additive has a water and ethanol solu- the layer overlying the exterior surface of the medical bility of at least 1 mg/ml and the therapeutic agent is not 55 device comprises a therapeutic agent and an additive, water-soluble. wherein the additive comprises a hydrophilic part and a [0034] In another embodiment of the medical device, drug affinity part, wherein the additive has a fatty chain the layer overlying the exterior surface of the medical of an acid, ester, ether, or alcohol, wherein the fatty chain

7 13 EP 2 500 046 A2 14 directly inserts into lipid membrane structures of tissue, pound has a molecular weight of from 80 to 750. wherein the additive has one or more functional groups [0042] In another embodiment of the balloon catheter, which have affinity to the drug by hydrogen bonding the coating layer comprises a therapeutic agent and an and/or van der Waals interactions (the functional groups additive, wherein the additive comprises a hydrophilic include hydroxyl, ester, amide, carboxylic acid, primary, 5 part and a drug affinity part, wherein the drug affinity part second, and tertiary amine, carbonyl, anhydrides, ox- is at least one of a hydrophobic part, a part that has an ides, and amino alcohols), wherein the therapeutic agent affinity to the therapeutic agent by hydrogen bonding, is not water-soluble and is not enclosed in micelles or and a part that has an affinity to the therapeutic agent by encapsulated in polymer particles, and wherein the layer van der Waals interactions, wherein the additive is at does not include a polymer, and the layer does not in- 10 least one of a surfactant and a chemical compound, and clude an iodine covalent bonded contrast agent. wherein the chemical compound has more than four hy- [0039] In yet another embodiment, the present inven- droxyl groups. In one aspect of this embodiment, the tion relates to a stent coating for delivering a therapeutic chemical compound having more than four hydroxyl agent to a tissue, the stent coating comprising a layer groups has a melting point of 120°C or less, and the overlying a surface of the stent. In one aspect of this15 chemical compound is an alcohol or an ester. embodiment, the layer overlying the surface of the stent [0043] In one embodiment of the balloon catheter, the comprises a therapeutic agent, an additive, and a poly- coating layer overlying an exterior surface of the exterior mer matrix, wherein the therapeutic agent is dispersed, surface of the medical device consists essentially of the but not encapsulated, as particles in the polymer matrix, therapeutic agent and the additive. In another embodi- wherein the additive comprises a hydrophilic part and a 20 ment, the layer overlying the exterior surface of the med- drug affinity part, wherein the drug affinity is at least one ical device does not include an iodine covalent bonded of a hydrophobic part, a part that has an affinity to the contrast agent. therapeutic agent by hydrogen bonding, and a part that [0044] In one embodiment, the surfactant is chosen has an affinity to the therapeutic agent by van der Waals from ionic, nonionic, aliphatic, and aromatic surfactants, interactions. In one aspect of this embodiment, the ad- 25 PEG fatty esters, PEG omega-3 fatty esters, ether, and ditive improves the compatibility of the therapeutic agent alcohols, glycerol fatty esters, sorbitan fatty esters, PEG and the polymer matrix, the additive reduces the particle glyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty sizes and improves uniformity of distribution of the ther- esters, PEG sugar esters and derivatives thereof. In one apeutic agent in the polymer matrix, and the additive en- embodiment, the chemical compound has one or more hances rapid release of drug from the polymer matrix. 30 hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester [0040] In yet another embodiment, the present inven- groups. In one embodiment, the chemical compound tion relates to a medical device coating for delivering a having one or more hydroxyl, amino, carbonyl, carboxyl, drug to a tissue that is prepared from a mixture. In one acid, amide or ester groups is chosen from amino alco- aspect of this embodiment, the coating is prepared from hols, hydroxyl carboxylic acid, ester, and anhydrides, hy- a mixture comprising an organic phase containing drug 35 droxyl ketone, hydroxyl lactone, hydroxyl ester, sugar particles dispersed therein and an aqueous phase con- phosphate, sugar sulfate, ethyl oxide, ethyl glycols, ami- taining a water- soluble additive. In one aspect of this em- no acids, peptides, proteins, sorbitan, glycerol, polyalco- bodiment, the water-soluble additive is chosen from pol- hol, phosphates, sulfates, organic acids, esters, salts, yethylene glycol, polyvinyl alcohol, polyvinylpyrrolidi- vitamins, combinations of amino alcohol and organic ac- none, polypeptides, water-soluble surfactants, water- 40 id, and their substituted molecules. soluble vitamins, and proteins. In another aspect of this [0045] In one embodiment of the balloon catheter, the embodiment, the preparation of the mixture includes ho- coating layer overlying the exterior surface of the balloon mogenization under high shear conditions and optionally does not include a purely hydrophobic additive. In anoth- under pressure. er embodiment, the coating layer overlying the surface [0041] In another embodiment, the present invention 45 of the balloon does not contain an iodinated contrast relates to a balloon catheter for delivering a therapeutic agent. In another embodiment, the additive is not a ther- agent to a blood vessel, the catheter comprising a coating apeutic agent. In another embodiment, the the additive layer overlying an exterior surface of a balloon. In one is not salicylic acid or salts thereof. In another embodi- embodiment of the balloon catheter, the coating layer ment, the coating layer overlying the surface of the bal- comprises a therapeutic agent and an additive, wherein 50 loon does not include oil, a lipid, or a polymer. In yet the additive comprises a hydrophilic part and a drug af- another embodiment, the coating layer overlying the sur- finity part, wherein the drug affinity part is at least one of face of the balloon does not include oil. In another aspect a hydrophobic part, a part that has an affinity to the ther- of this embodiment, the coating layer does not include a apeutic agent by hydrogen bonding, and a part that has polymer. an affinity to the therapeutic agent by van der Waals in- 55 [0046] In one embodiment of the balloon catheter, the teractions, wherein the additive is water-soluble, and additive in the coating layer comprising the therapeutic wherein the additive is at least one of a surfactant and a agent and the additive is chosen from p- isononylphenox- chemical compound, and wherein the chemical com- ypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween

8 15 EP 2 500 046 A2 16

60, PEG oleate, PEG stearate, PEG glyceryl laurate, col, and penta(propylene glycol), poly(propylene glycol) PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl oligomers, a block copolymer of polyethylene glycol and laurate, plyglyceryl oleate, polyglyceryl myristate, polyg- polypropylene glycol, and derivatives and combinations lyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 thereof. oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmi- 5 [0047] In one embodiment, the therapeutic agent is tate, polyglyceryl-10 laurate, plyglyceryl-10 oleate, poly- one of paclitaxel and analogues thereof, rapamycin and glyceryl-10 myristate, polyglyceryl-10 palmitate PEG analogues thereof, beta-lapachone and analogues sorbitan monolaurate, PEG sorbitan monolaurate, PEG thereof, biological vitamin D and analogues thereof, and sorbitan monooleate, PEG sorbitan stearate, PEG oleyl a mixture of these therapeutic agents. In another embod- ether, PEG laurayl ether, octoxynol, monoxynol, tyloxa- 10 iment, the therapeutic agent is in combination with a sec- pol, sucrose monopalmitate, sucrose monolaurate, de- ond therapeutic agent, wherein the therapeutic agent is canoyl-N-methylglucamide, n-decyl - β -D-glucopyrano- one of paclitaxel, rapamycin, and analogues thereof, and side, n-decyl - β -D-maltopyranoside, n-dodecyl - β -D- wherein the second therapeutic agent is one of beta-la- glucopyranoside, n-dodecyl - β -D-maltoside, heptanoyl- pachone, biological active vitamin D, and their ana- N-methylglucamide, n-heptyl- β -D-glucopyranoside, n- 15 logues. In one embodiment, the therapeutic agent is not heptyl - β -D-thioglucoside, n-hexyl - β -D-glucopyrano- water soluble. side, nonanoyl-N-methylglucamide, n-noyl - β -D-glucop- [0048] In one embodiment, the additive is soluble in yranoside, octanoyl-N-methylglucamide, n-octyl- β -D- an organic solvent and in water. In another embodiment, glucopyranoside, octyl - β -D-thioglucopyranoside; cys- the additive enhances penetration and absorption of the tine, tyrosine, tryptophan, leucine, isoleucine, phenyla- 20 therapeutic agent in tissue of the blood vessel. In another lanine, asparagine, aspartic acid, glutamic acid, and me- embodiment, the therapeutic agent is not water- soluble. thionine; acetic anhydride, benzoic anhydride, ascorbic In another embodiment, the additive has water and eth- acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrro- anol solubility of at least 1 mg/ml, and the therapeutic lidone carboxylate, ethylenediaminetetraacetic dianhy- agent is not water-soluble. dride, maleic and anhydride, succinic anhydride, digly- 25 [0049] In one embodiment of the balloon catheter, the colic anhydride, glutaric anhydride, acetiamine, benfo- catheter further comprises an adherent layer between tiamine, pantothenic acid; cetotiamine; cycothiamine, the exterior surface of the balloon and the coating layer. dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5- In another embodiment, the catheter further comprises phosphate, nicotinamide ascorbate, riboflavin, riboflavin a top layer overlying the coating layer, wherein the top phosphate, thiamine, folic acid, menadiol diphosphate, 30 layer reduces loss of the therapeutic agent during transit menadione sodium bisulfite, menadoxime, vitamin B12, through a body to the blood vessel. The top layer com- vitamin K5, vitamin K6, vitamin K6, and vitamin U; albu- prises an additive selected from those additives, accord- min, immunoglobulins, caseins, hemoglobins, lys- ing to embodiments of the invention described herein. ozymes, immunoglobins, a-2-macroglobulin, fi-The top layer will be slowly dissolved during transit bronectins, vitronectins, firbinogens, lipases, benzalko- 35 through a body to the body lumen to the target site for nium chloride, benzethonium chloride, docecyl trimethyl therapeutic intervention. This top layer will reduce drug ammonium bromide, sodium docecylsulfates, dialkyl loss during transit and increase the drug available to the methylbenzyl ammonium chloride, and dialkylesters of tissue when the medical device of embodiments of the sodium sulfonsuccinic acid, L-ascorbic acid and its salt, present invention is pressed into contact with luminal tis- D-glucoascorbic acid and its salt, tromethamine, trieth- 40 sue. In one embodiment, the additive in the top layer is anolamine, diethanolamine, meglumine, glucamine, less hydrophilic than the additive in the coating layer. In amine alcohols, glucoheptonic acid, glucomic acid, hy- another embodiment, the catheter further comprises a droxyl ketone, hydroxyl lactone, gluconolactone, gluco- dimethylsulfoxide solvent layer, wherein the dimethylsul- heptonolactone, glucooctanoic lactone, gulonic acid lac- foxide solvent layer is overlying the surface of the coating tone, mannoic lactone, ribonic acid lactone, lactobionic 45 layer. acid, glucosamine, glutamic acid, benzyl alcohol, benzo- [0050] In one embodiment, the balloon catheter is ca- ic acid, hydroxybenzoic acid, propyl 4- hydroxybenzoate, pable of releasing the therapeutic agent and the additive lysine acetate salt, gentisic acid, lactobionic acid, lactitol, and delivering the therapeutic agent to the blood vessel sinapic acid, vanillic acid, vanillin, methyl paraben, propyl in about 0.1 to 2 minutes. paraben, sorbitol, xylitol, cyclodextrin, (2-hydroxypro- 50 [0051] In one embodiment of the balloon catheter, the pyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic ac- concentration of the therapeutic agent in the coating layer id, lysine acetate, gentisic acid, catechin, catechin gal- is from 1 to 20 Pg/mm2. In another embodiment, the con- late, tiletamine, ketamine, propofol, lactic acids, acetic centration of the therapeutic agent in the coating layer is acid, salts of any organic acid and organic amine, poly- from 2 to 10 Pg/mm2. glycidol, glycerol, multiglycerols, galactitol, di(ethylene 55 [0052] In yet a further embodiment, the present inven- glycol), tri(ethylene glycol), tetra(ethylene glycol), penta tion relates to a balloon catheter for delivering a thera- (ethylene glycol), poly(ethylene glycol) oligomers, di (pro- peutic agent to a blood vessel. In one aspect of this em- pylene glycol), tri(propylene glycol), tetra(propylene gly- bodiment, the catheter comprises an elongate member

9 17 EP 2 500 046 A2 18 having a lumen and a distal end, an expandable balloon laurate, PEG glyceryl oleate, PEG glyceryl stearate, pol- attached to the distal end of the elongate member and yglyceryl laurate, plyglyceryl oleate, polyglyceryl myr- in fluid communication with the lumen, and a coating layer istate, polyglyceryl palmitate, polyglyceryl-6 laurate, ply- overlying an exterior surface of the balloon. In one aspect glyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl- of this embodiment, the coating layer overlying the sur- 5 6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10 face of the balloon comprises a therapeutic agent and oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmi- an additive, wherein the additive comprises a hydrophilic tate PEG sorbitan monolaurate, PEG sorbitan, monolau- part and a drug affinity part, wherein the drug affinity part rate, PEG sorbitan monooleate, PEG sorbitan, stearate, is at least one of a hydrophobic part, a part that has an PEG oleyl ether, PEG laurayl ether, Tween 20, Tween affinity to the therapeutic agent by hydrogen bonding, 10 40, Tween 60, octoxynol, monoxynol, tyloxapol, sucrose and a part that has an affinity to the therapeutic agent by monopalmitate, sucrose monolaurate, decanoyl-N- van der Waals interactions, wherein the additive is water- methylglucamide, n-decyl - β -D-glucopyranoside, n-de- soluble, wherein the additive is at least one of a surfactant cyl - β -D-maltopyranoside, n-dodecyl - β -D-glucopyra- and a chemical compound, and wherein the chemical noside, n-dodecyl -β -D-maltoside, heptanoyl-N-methyl- compound has a molecular weight of from 80 to 750, and 15 glucamide, n-heptyl- β -D-glucopyranoside, n-heptyl - β wherein the catheter is capable of releasing the thera- -D-thioglucoside, n-hexyl - β -D-glucopyranoside, nona- peutic agent and the additive and delivering the thera- noyl-N-methylglucamide, n-noyl - β -D-glucopyranoside, peutic agent to tissue of the blood vessel in less than octanoyl-N-methylglucamide, n-octyl- β -D-glucopyran- about 2 minutes. In one aspect of this embodiment, the oside, octyl - β -D-thioglucopyranoside; cystine, tyrosine, layer does not contain an iodinated contrast agent. 20 tryptophan, leucine, isoleucine, phenylalanine, asparag- [0053] In one embodiment, the balloon catheter further ine, aspartic acid, glutamic acid, and methionine; acetic comprises a dimethylsulfoxide solvent layer overlying the anhydride, benzoic anhydride, ascorbic acid, pyrro- 2- coating layer, wherein the dimethylsulfoxide layer en- lidone-5-carboxylic acid, sodium pyrrolidone carboxy- hances the ability of the therapeutic agent to penetrate late, ethylenediaminetetraacetic dianhydride, maleic and into the blood vessel. In another embodiment, the balloon 25 anhydride, succinic anhydride, diglycolic anhydride, glu- catheter further comprises an adherent layer between taric anhydride, acetiamine, benfotiamine, pantothenic the exterior surface of the balloon and the coasting layer. acid; cetotiamine; cycothiamine, dexpanthenol, niacina- In yet another embodiment, the balloon catheter further mide, nicotinic acid, pyridoxal 5- phosphate, nicotinamide comprises a top layer overlying the coating layer, wherein ascorbate, riboflavin, riboflavinphosphate, thiamine, folic the top layer maintains integrity of the coating layer during 30 acid,menadiol diphosphate, menadione sodium bisulfite, transit through a blood vessel to the target site for ther- menadoxime, vitamin B12, vitamin K5, vitamin K6, vita- apeutic intervention. min K6, and vitamin U; albumin, immunoglobulins, ca- [0054] In one embodiment, the concentration of the seins, hemoglobins, lysozymes, immunoglobins, 2- a- therapeutic agent in the coating layer is from 2.5 to 6 macroglobulin, fibronectins, vitronectins, firbinogens, li- Pg/mm2. In one embodiment, the surfactant is chosen 35 pases, benzalkonium chloride, benzethonium chloride, from ionic, nonionic, aliphatic, and aromatic surfactants, docecyl trimethyl ammonium bromide, sodium docecyl- PEG fatty esters, PEG omega-3 fatty esters, ether, and sulfates, dialkyl methylbenzyl ammonium chloride, and alcohols, glycerol fatty esters, sorbitan fatty esters, PEG dialkylesters of sodium sulfonsuccinic acid, L-ascorbic glyceryl fatty esters, PEG sorbitan, fatty esters, sugar acid and its salt, glucoascorbic D- acid and its salt, fatty esters, PEG sugar esters and derivatives thereof. 40 tromethamine, triethanolamine, diethanolamine, meglu- In one embodiment, the chemical compound has one or mine, glucamine, amine alcohols, glucoheptonic acid, more hydroxyl, amino, carbonyl, carboxyl, acid, amide or glucomic acid, hydroxyl ketone, hydroxyl lactone, glu- ester groups. In one embodiment, the chemical com- conolactone, glucoheptonolactone, glucooctanoic lac- pound having one or more hydroxyl, amino, carbonyl, tone, gulonic acid lactone, mannoic lactone, ribonic acid carboxyl, acid, amide or ester groups is chosen from ami- 45 lactone, lactobionic acid, glucosamine, glutamic acid, no alcohols, hydroxyl carboxylic acid, ester, and anhy- benzyl alcohol, benzoic acid, hydroxybenzoic acid, pro- drides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester, pyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, lactobionic acid, lactitol, sinapic acid, vanillic acid, vanil- amino acids, peptides, proteins, sorbitan, glycerol, poly- lin, methyl paraben, propyl paraben, sorbitol, xylitol, cy- alcohol, phosphates, sulfates, organic acids, esters,50 clodextrin, (2-hydroxypropyl)-cyclodextrin, acetami- salts, vitamins, combinations of amino alcohol and or- nophen, ibuprofen, retinoic acid, lysine acetate, gentisic ganic acid, and their substituted molecules, In one em- acid, catechin, catechin gallate, tiletamine, ketamine, bodiment, the chemical compound has more than four propofol, lactic acids, acetic acid, salts of any organic hydroxyl groups and has a melting point of 120°C or less, acid and organic amine, polyglycidol, glycerol, multiglyc- and the chemical compound is an alcohol or an ester. 55 erols, galactitol, di(ethylene glycol), tri(ethylene glycol), [0055] In one embodiment of the balloon catheter, the tetra(ethylene glycol), penta(ethylene glycol), poly(ethyl- additive is chosen from p-isononylphenoxypolyglycidol, ene glycol) oligomers, di (propylene glycol), tri(propylene PEG laurate, PEG oleate, PEG stearate, PEG glyceryl glycol), tetra(propylene glycol, and penta(propylene gly-

10 19 EP 2 500 046 A2 20 col), poly(propylene glycol) oligomers, a block copolymer heptyl - β -D-thioglucoside, n-hexyl - β -D-glucopyrano- of polyethylene glycol and polypropylene glycol, and de- side, nonanoyl-N-methylglucamide, n-noyl - β -D-glucop- rivatives and combinations thereof. yranoside, octanoyl-N-methylglucamide, n-octyl- β -D- [0056] In yet a further embodiment, the present inven- glucopyranoside, octyl - β -D-thioglucopyranoside; cys- tion relates to a pharmaceutical composition comprising 5 tine, tyrosine, tryptophan, leucine, isoleucine, phenyla- a therapeutic agent and an additive, wherein the additive lanine, asparagine, aspartic acid, glutamic acid, and me- comprises a hydrophilic part and a drug affinity part, thionine; acetic anhydride, benzoic anhydride, ascorbic wherein the drug affinity part is at least one of a hydro- acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrro- phobic part, a part that has an affinity to the therapeutic lidone carboxylate, ethylenediaminetetraacetic dianhy- agent by hydrogen bonding, and a part that has an affinity 10 dride, maleic and anhydride, succinic anhydride, digly- to the therapeutic agent by van der Waals interactions, colic anhydride, glutaric anhydride, acetiamine, benfo- wherein the additive is water-soluble, wherein the addi- tiamine, pantothenic acid; cetotiamine; cycothiamine, tive is at least one of a surfactant and a chemical com- dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5- pound, and wherein the chemical compound has a mo- phosphate, nicotinamide ascorbate, riboflavin, riboflavin lecular weight of from 80 to 750. In one aspect of this 15 phosphate, thiamine, folic acid, menadiol diphosphate, embodiment, the pharmaceutical composition does not menadione sodium bisulfite, menadoxime, vitamin B12, include an iodine covalent bonded contrast agent or a vitamin K5, vitamin K6, vitamin K6, and vitamin U; albu- polymer, and wherein the therapeutic agent is not encap- min, immunoglobulins, caseins, hemoglobins, lys- sulated in miscelles or particles. ozymes, immunoglobins, macroglobulin, a-2- fi- [0057] In one embodiment, the chemical compound 20 bronectins, vitronectins, firbinogens, lipases, benzalko- has one or more hydroxyl, amino, carbonyl, carboxyl, ac- nium chloride, benzethonium chloride, docecyl trimethyl id, amide or ester groups. In one embodiment, the chem- ammonium bromide, sodium docecylsulfates, dialkyl ical compound having one or more hydroxyl, amino, car- methylbenzyl ammonium chloride, and dialkylesters of bonyl, carboxyl, acid, amide or ester groups is chosen sodium sulfonsuccinic acid, L-ascorbic acid and its salt, from amino alcohols, hydroxyl carboxylic acid, ester, and 25 D-glucoascorbic acid and its salt, tromethamine, trieth- anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl anolamine, diethanolamine, meglumine, glucamine, ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl amine alcohols, glucoheptonic acid, glucomic acid, hy- glycols, amino acids, peptides, proteins, sorbitan, glyc- droxyl ketone, hydroxyl lactone, gluconolactone, gluco- erol, polyalcohol, phosphates, sulfates, organic acids, heptonolactone, glucooctanoic lactone, gulonic acid lac- esters, salts, vitamins, combinations of amino alcohol 30 tone, mannoic lactone, ribonic acid lactone, lactobionic and organic acid, and their substituted molecules. In one acid, glucosamine, glutamic acid, benzyl alcohol, benzo- embodiment, the chemical compound has more than four ic acid, hydroxybenzoic acid, propyl 4- hydroxybenzoate, hydroxyl groups and has a melting point of 120°C or less, lysine acetate salt, gentisic acid, lactobionic acid, lactitol, and the chemical compound is an alcohol or an ester. In sinapic acid, vanillic acid, vanillin, methyl paraben, propyl one embodiment, the surfactant is chosen from ionic, no- 35 paraben, sorbitol, xylitol, cyclodextrin, (2-hydroxypro- nionic, aliphatic, and aromatic surfactants, PEG fatty es- pyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic ac- ters, PEG omega- 3 fatty esters, ether, and alcohols, glyc- id, lysine acetate, gentisic acid, catechin, catechin gal- erol fatty esters, sorbitan fatty esters, PEG glyceryl fatty late, tiletamine, ketamine, propofol, lactic acids, acetic esters, PEG sorbitan fatty esters, sugar fatty esters, PEG acid, salts of any organic acid and organic amine, poly- sugar esters and derivatives thereof. 40 glycidol, glycerol, multiglycerols, galactitol, di(ethylene [0058] In one embodiment of the pharmaceutical com- glycol), tri(ethylene glycol), tetra(ethylene glycol), penta position, the additive is chosen from p-isononylphenox- (ethylene glycol), poly(ethylene glycol) oligomers, di (pro- ypolyglycidol, PEG laurate, PEG oleate, PEG stearate, pylene glycol), tri(propylene glycol), tetra(propylene gly- PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl col, and penta(propylene glycol), poly(propylene glycol) stearate, polyglyceryl laurate, Tween 20, Tween 40,45 oligomers, a block copolymer of polyethylene glycol and Tween 60, plyglyceryl oleate, polyglyceryl myristate, pol- polypropylene glycol, and derivatives and combinations yglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 thereof. oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmi- [0059] In yet a further embodiment, the present inven- tate, polyglyceryl-10 iaurate, plyglyceryl-10 oleate, poly- tion relates to a method for treating a diseased body lu- glyceryl-10 myristate, polyglyceryl-10 palmitate PEG 50 men or cavity after a surgical or interventional procedure sorbitan monolaurate, PEG sorbitan monolaurate, PEG comprising delivering a pharmaceutical composition at a sorbitan monooleate, PEG sorbitan stearate, PEG oleyl surgical site by injection or spraying with a catheter, ether, PEG laurayl ether, octoxynol, monoxynol, tyloxa- wherein the composition comprises a therapeutic agent pol, sucrose monopalmitate, sucrose monolaurate, de- and an additive, wherein the additive comprises a hy- canoyl-N-methylglucamide, n-decyl - β -D-glucopyrano- 55 drophilic part and a drug affinity part, wherein the drug side, n-decyl - β -D-maltopyranoside, n-dodecyl - β -D- affinity part is at least one of a hydrophobic part, a part glucopyranoside, n-dodecyl - β -D-maltoside, heptanoyl- that has an affinity to the therapeutic agent by hydrogen N-methylglucamide, n-heptyl- β -D-glucopyranoside, n- bonding, and a part that has an affinity to the therapeutic

11 21 EP 2 500 046 A2 22 agent by van der Waals interactions, wherein the additive agent, an oil, a lipid, or a polymer. is at least one of a surfactant and a chemical compound, [0063] In one embodiment, the chemical compound and wherein the chemical compound has a molecular has one or more hydroxyl, amino, carbonyl, carboxyl, ac- weight of from 80 to 750. In one embodiment, the chem- id, amide or ester groups. In one embodiment, the chem- ical compound has one or more hydroxyl, amino, carbo- 5 ical compound having one or more hydroxyl, amino, car- nyl, carboxyl, acid, amide or ester groups. In one embod- bonyl, carboxyl, acid, amide or ester groups is chosen iment, the the additive is water- soluble, and wherein the from amino alcohols, hydroxyl carboxylic acid, ester, and composition does not include an iodine covalent bonded anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl contrast agent. ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl [0060] In one embodiment, the surfactant is chosen 10 glycols, amino acids, peptides, proteins, sorbitan, glyc- from ionic, nonionic, aliphatic, and aromatic surfactants, erol, polyalcohol, phosphates, sulfates, organic acids, PEG fatty esters, PEG omega-3 fatty esters, ether, and esters, salts, vitamins, combinations of amino alcohol alcohols, glycerol fatty esters, sorbitan fatty esters, PEG and organic acid, and their substituted molecules. In one glyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty embodiment, the surfactant is chosen from ionic, noni- esters, PEG sugar esters and derivatives thereof. In one 15 onic, aliphatic, and aromatic surfactants, PEG fatty es- embodiment, the chemical compound having one or ters, PEG omega- 3 fatty esters, ether, and alcohols, glyc- more hydroxyl, amino, carbonyl, carboxyl, acid, amide or erol fatty esters, sorbitan, fatty esters, PEG glyceryl fatty ester groups is chosen from amino alcohols, hydroxyl esters, PEG sorbitan fatty esters, sugar fatty esters, PEG carboxylic acid, ester, and anhydrides, hydroxyl ketone, sugar esters and derivatives thereof. In one embodiment, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugar 20 the therapeutic agent is paclitaxel or rapamycin or analog sulfate, ethyl oxide, ethyl glycols, amino acids, peptides, or derivative thereof. proteins,sorbitan, glycerol, polyalcohol, phosphates,sul- [0064] In another embodiment, the additive in the coat- fates, organic acids, esters, salts, vitamins, combinations ing solution is chosen from wherein the additive is chosen of amino alcohol and organic acid, and their substituted from p-isononylphenoxypolyglycidol, PEG laurate, PEG molecules. 25 oleate, PEG stearate, PEG glyceryl laurate, Tween 20, [0061] In yet a further embodiment, the present inven- tween 60, Tween 80, PEG glyceryl oleate, PEG glyceryl tion relates to a pharmaceutical composition for treating stearate, polyglyceryl laurate, plyglyceryl oleate, polyg- a cancer including cancers of the ovary, breast, lung, lyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 esophagus, head and neck region, bladder, prostate, laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate, brain, liver, colon and lymphomas, wherein the compo- 30 polyglyceryl-6 palmitate, polyglyceryl- 10 laurate, plyglyc- sition comprises a therapeutic agent and an additive, eryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl- 10 wherein the additive comprises a hydrophilic part and a palmitate PEG sorbitan monolaurate, PEG sorbitan, drug affinity part, wherein the drug affinity part is at least monolaurate, PEG sorbitan monooleate, PEG sorbitan one of a hydrophobic part, a part that has an affinity to stearate, PEG oleyl ether, PEG laurayl ether, octoxynol, the therapeutic agent by hydrogen bonding, and a part 35 monoxynol, tyloxapol, sucrose monopalmitate, sucrose that has an affinity to the therapeutic agent by van der monolaurate, decanoyl-N-methylglucamide, n-decyl - β Waals interactions, wherein the therapeutic agent is not -D-glucopyranoside, n-decyl - β -D-maltopyranoside, n- enclosed in micelles or encapsulated in polymer parti- dodecyl - β -D-glucopyranoside, n-dodecyl - β -D-malto- cles, and wherein the composition does not include an side, heptanoyl-N-methylglucamide, n-heptyl- β -D-glu- iodine covalent bonded contrast agent. In one aspect of 40 copyranoside, n-heptyl - β -D-thioglucoside, n-hexyl - β this embodiment, the therapeutic agent is chosen from -D-glucopyranoside, nonanoyl-N-methylglucamide, n- paclitaxel and analogues thereof and rapamycin and an- noyl - β -D-glucopyranoside, octanoyl-N-methylgluca- alogues thereof. mide, n-octyl- β-D-glucopyranoside, octyl - β -D-thioglu- [0062] In yet a further embodiment, the present inven- copyranoside; cystine, tyrosine, tryptophan, leucine, iso- tion relates to a solution for coating a medical device. In 45 leucine, phenylalanine, asparagine, aspartic acid, one aspect of this embodiment, the solution comprises glutamic acid, and methionine; acetic anhydride, benzoic an organic solvent, a therapeutic agent, and an additive, anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic ac- wherein the additive comprises a hydrophilic part and a id, sodium pyrrolidone carboxylate, ethylenediamine- drug affinity part, wherein the drug affinity part is at least tetraacetic dianhydride, maleic and anhydride, succinic one of a hydrophobic part, a part that has an affinity to 50 anhydride, diglycolic anhydride, glutaric anhydride, ace- the therapeutic agent by hydrogen bonding, and a part tiamine, benfotiamine, pantothenic acid; cetotiamine; cy- that has an affinity to the therapeutic agent by van der cothiamine, dexpanthenol, niacinamide, nicotinic acid, Waals interactions, wherein the additive is water- soluble, pyridoxal 5-phosphate, nicotinamide ascorbate, ribofla- wherein the additive is at least one of a surfactant and a vin, riboflavin phosphate, thiamine, folic acid, menadiol chemical compound, and wherein the chemical com-55 diphosphate, menadione sodium bisulfite, menadoxime, pound has a molecular weight of from 80 to 750. In an- vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vi- other embodiment, the solution for coating a medical de- tamin U; albumin, immunoglobulins, caseins, hemoglob- vice does not include an iodine covalent bonded contrast ins, lysozymes, immunoglobins, a-2-macroglobulin, fi-

12 23 EP 2 500 046 A2 24 bronectins, vitronectins, firbinogens, lipases, benzalko- has an affinity to the therapeutic agent by van der Waals nium chloride, benzethonium chloride, docecyl trimethyl interactions, wherein the additive is water-soluble, ammonium bromide, sodium docecylsulfates, dialkyl wherein the additive is at least one of a surfactant and a methylbenzyl ammonium chloride, and dialkylesters of chemical compound, and wherein the chemical com- sodium sulfonsuccinic acid, L-ascorbic acid and its salt, 5 pound has a molecular weight of from 80 to 750. In one D-glucoascorbic acid and its salt, tromethamine, trieth- aspect of this embodiment, the first layer does not include anolamine, diethanolamine, meglumine, glucamine, an iodine covalent bonded contrast agent. In another as- amine alcohols, glucoheptonic acid, glucomic acid, hy- pect of this embodiment, the top layer further comprises droxyl ketone, hydroxyl lactone, gluconolactone, gluco- a therapeutic agent. heptonolactone, glucooctanoic lactone, gulonic acid lac- 10 [0067] In a further embodiment, the present invention tone, mannoic lactone, ribonic acid lactone, lactobionic relates to a method for preparing a medical device. In acid, glucosamine, glutamic acid, benzyl alcohol, benzo- one aspect of this embodiment, the method comprises ic acid, hydroxybenzoic acid, propyl 4- hydroxybenzoate, (a) preparing a coating solution comprising an organic lysine acetate salt, gentisic acid, lactobionic acid, lactitol, solvent, a therapeutic agent, and an additive, wherein sinapic acid, vanillic acid, vanillin, methyl paraben, propyl 15 the additive comprises a hydrophilic part and a drug af- paraben, sorbitol, xylitol, cyclodextrin, (2-hydroxypro- finity part, wherein the drug affinity part is at least one of pyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic ac- a hydrophobic part, a part that has an affinity to the ther- id, lysine acetate, gentisic acid, catechin, catechin gal- apeutic agent by hydrogen bonding, and a part that has late, tiletamine, ketamine, propofol, lactic acids, acetic an affinity to the therapeutic agent by van der Waals in- acid, salts of any organic acid and organic amine, poly- 20 teractions, wherein the additive is water- soluble, wherein glycidol, glycerol, multiglycerols, galactitol, di(ethylene theadditive is at least one of a surfactant and a chemical glycol), tri(ethylene glycol), tetra(ethylene glycol), penta compound, and wherein the chemical compound has a (ethylene glycol), poly(ethylene glycol) oligomers, di (pro- molecular weight of from 80 to 750, (b) applying the coat- pylene glycol), tri(propylene glycol), tetra(propylene gly- ing solution to a medical device, and (c) drying the coating col, and penta(propylene glycol), poly(propylene glycol) 25 solution, forming a coating layer. In one aspect of this oligomers, a block copolymer of polyethylene glycol and embodiment, the coating layer does not include an iodine polypropylene glycol, and derivatives and combinations covalent bonded contrast agent. In one aspect of this thereof. embodiment, the coating solution is applied by dipping a [0065] In yet a further embodiment, the present inven- portion of the exterior surface of the medical device in tion relates to a medical device for delivering a therapeu- 30 the coating solution. In another aspect of this embodi- tic agent to a tissue, the device comprising a first layer ment, the coating solution is applied by spraying a portion applied to an exterior surface of the medical device, and of the exterior surface of the medical device with a coating a second layer overlying the first layer. In one aspect of solution. In another aspect of this embodiment, steps (b) this embodiment, the first layer comprises a therapeutic and (c) are repeated until a therapeutically effective agent, and the second layer comprises an additive,35 amount of the therapeutic agent in the coating layer is wherein the additive comprises a hydrophilic part and a depositedon the surface of the medical device. In another drug affinity part, wherein the drug affinity part is at least aspect of this embodiment, the total thickness of the coat- one of a hydrophobic part, a part that has an affinity to ing layer is from about 0,1 to 200 microns. In yet another the therapeutic agent by hydrogen bonding, and a part aspect of this embodiment, the method further comprises that has an affinity to the therapeutic agent by van der 40 applying a dimethylsulfoxide solvent to the dried coating Waals interactions. In one aspect of this embodiment, layer obtained in step (c). the first layer further comprises an additive, wherein the [0068] In a further embodiment, the present invention additive is water-soluble, and the layer does not include relates to a method for preparing a drug coated balloon an iodinated contrast agent. In another aspect of this em- catheter. In one aspect of this embodiment, the method bodiment, the second layer further comprises a thera- 45 comprises, (a) preparing a coating solution comprising peutic agent. In yet a further aspect of this embodiment, an organic solvent, a therapeutic agent, and an additive, the first layer further comprises an additive and the sec- wherein the additive comprises a hydrophilic part and a ond layer further comprises a therapeutic agent. drug affinity part, wherein the drug affinity is at least one [0066] in a further embodiment, the present invention of a hydrophobic part, a part that has an affinity to the relates to a two layer coating comprising a first layer com- 50 therapeutic agent by hydrogen bonding, and a part that prising a therapeutic agent, and a top layer comprising has an affinity to the therapeutic agent by van der Waals an additive. In one aspect of this embodiment, the top interactions, wherein the additive is at least one of a sur- layer may be overlying the first layer. In one aspect of factant and a chemical compound, and wherein the this embodiment, the additive in both the first layer and chemical compound has a molecular weight of from 80 in the top layer comprises a hydrophilic part and a drug 55 to 750, (b) applying the coating solution to an inflated affinity part, wherein the drug affinity part is at least one balloon catheter, and (c) deflating and folding the balloon of a hydrophobic part, a part that has an affinity to the catheter and drying the coating solution to increase uni- therapeutic agent by hydrogen bonding, and a part that formity of drug coating.

13 25 EP 2 500 046 A2 26

[0069] in a further embodiment, the present invention biliary tract, urinary tract, prostate, and brain passages. relates to a method for treating a blood vessel. In one [0072] In yet a further embodiment, the present inven- aspect of this embodiment, the method comprises insert- tion relates to a process of producing a balloon catheter. ing a medical device comprising a coating layer into the In one aspect of this embodiment, the process comprises blood vessel, wherein the coating layer comprises a ther- 5 preparing a solution comprising an organic solvent, a apeutic agent and an additive, wherein the additive com- therapeutic agents, and an additive, wherein the additive prises a hydrophilic part and a drug affinity part, wherein comprises a hydrophilic part and a drug affinity part, the drug affinity is at least one of a hydrophobic part, a wherein the drug affinity is at least one of a hydrophobic part that has an affinity to the therapeutic agent by hy- part, a part that has an affinity to the therapeutic agent drogen bonding, and a part that has an affinity to the10 by hydrogen bonding, and a part that has an affinity to therapeutic agent by van der Waals interactions, wherein the therapeutic agent by van der Waals interactions, the additive is water-soluble, wherein the additive is at wherein the additive is water-soluble, wherein the addi- least one of a surfactant and a chemical compound, and tive is at least one of a surfactant and a chemical com- wherein the chemical compound has a molecular weight pound, and wherein the chemical compound has a mo- of from 80 to 750, and releasing the therapeutic agent 15 lecular weight of from 80 to 750, applying the solution to and the additive and delivering the therapeutic agent into the balloon catheter, and evaporating the solvent. In one the tissue of the blood vessel in 2 minutes or less. In one embodiment, the solution does not contain an iodinated aspect of this embodiment, the coating layer does not contrast agent. include an iodine covalent bonded contrast agent. [0073] in yet a further embodiment, the present inven- [0070] In a further embodiment, the present invention 20 tion relates to a medical device comprising a layer over- relates to a method for treating a total occlusion or nar- lying an exterior surface of the medical device, the layer rowing of body passages. In one aspect of this embodi- comprising a therapeutic agent and an additive, wherein ment, the method comprises removing plaques from the the additive is one of PEG fatty ester, PEG fatty ether, body passage, inserting a medical device comprising a and PEG fatty alcohols. In one aspect of this embodi- coating layer into the body passage, wherein the coating 25 ment, the additive is chosen from wherein the additive is layer comprises a therapeutic agent and an additive, chosen from PEG-8 laurate, PEG-8 oleate, PEG-8 stea- wherein the additive comprises a hydrophilic part and a rate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, drug affinity part, wherein the drug affinity part is at least PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG- one of a hydrophobic part, a part that has an affinity to 20 laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20 the therapeutic agent by hydrogen bonding, and a part 30 dioleate, PEG-20 distearate, PEG- 32 dilaurate and PEG- that has an affinity to the therapeutic agent by van der 32 dioleate. In another aspect of this embodiment, the Waals interactions, wherein the additive is at least one tissue includes tissue of one of coronary vasculature, pe- of a surfactant and a chemical compound, and wherein ripheral vasculature, cerebral vasculature, esophagus, the chemical compound has a molecular weight of from airways, sinus, trachea, colon, biliary tract, urinary tract, 80 to 750, and releasing the therapeutic agent and the 35 prostate, and brain passages. In yet another aspect of additive and delivering the therapeutic agent into the tis- this embodiment, the device includes one of a balloon sue of the body passage in 2 minutes or less. catheter, a perfusion balloon catheter, an infusion cath- [0071] In a further embodiment, the present invention eter, a cutting balloon catheter, a scoring balloon cathe- relates to a method for treating tissue of a body compris- ter, a laser catheter, an atherectomy device, a debulking ing bringing a medical device comprising a coating layer 40 catheter, a stent, a filter, a stent graft, a covered stent, a into contact with tissue of the body, wherein the coating patch, a wire, and a valve. layer comprises a therapeutic agent and an additive, [0074] In yet a further embodiment, the present inven- wherein the additive comprises a hydrophilic part and a tion relates to a medical device comprising a layer over- drug affinity part, wherein the drug affinity part is at least lying an exterior surface of the medical device, the layer one of a hydrophobic part, a part that has an affinity to 45 comprising a therapeutic agent and an additive, wherein the therapeutic agent by hydrogen bonding, and a part the additive is one of glycerol and polyglycerol fatty esters that has an affinity to the therapeutic agent by van der and PEG glycerol fatty esters. In one aspect of this em- Waals interactions, wherein the additive is water- soluble, bodiment, the additive is chosen from polyglyceryl oleate, wherein the additive is at least one of a surfactant and a polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyg- chemical compound, and wherein the chemical com-50 lyceryl stearate, polyglyceryl laurate, polyglyceryl myr- pound has a molecular weight of from 80 to 750, and istate, polyglyceryl palmitate, polyglyceryl linoleate, pol- releasing the therapeutic agent and the additive and de- yglyceryl-10 laurate, polyglyceryl-10 oleate, polyglycer- livering the therapeutic agent into the tissue in 2 minutes yl-10 mono, dioleate, polyglyceryl-10 stearate, polyglyc- or less. In one embodiment, the coating layer does not eryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl- include an iodine covalent contrast agent. In one aspect 55 10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 of this embodiment, the tissue includes tissue of one of stearate, polyglyceryl-6 laurate, polyglyceryl- 6 myristate, coronary vasculature, peripheral vasculature, cerebral polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate, vasculature, esophagus, airways, sinus, trachea, colon, polyglyceryl polyricinoleates, PEG-20 glyceryl laurate,

14 27 EP 2 500 046 A2 28

PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG- cyl - β -D-maltopyranoside, n-dodecyl - β -D-glucopyra- 20 glyceryl oleate, and PEG- 30 glyceryl oleate. In anoth- noside, n-dodecyl - β -D-maltoside, heptanoyl-N-meth- er aspect of this embodiment, the tissue includes tissue ylglucamide, n-heptyl- β -D-glucopyranoside, n-heptyl - of one of coronary vasculature, peripheral vasculature, β -D-thioglucoside, n-hexyl - β -D-glucopyranoside, no- cerebral vasculature, esophagus, airways, sinus, tra- 5 nanoyl-N-methylglucamide, n-noyl - β -D-glucopyrano- chea, colon, biliary tract, urinary tract, prostate, and brain side, octanoyl-N-methylglucamide, n-octyl- β -D-glucop- passages. In yet another aspect of this embodiment, the yranoside, octyl -β -D-thioglucopyranoside, D-glu- device includes one of a balloon catheter, a perfusion coascorbic acid and its salt, tromethamine, glucamine, balloon catheter, an infusion catheter, a cutting balloon glucoheptonic acid, glucomic acid, hydroxyl ketone, hy- catheter, a scoring balloon catheter, a laser catheter, an 10 droxyl lactone, gluconolactone, glucoheptonolactone, atherectomy device, a debulking catheter, a stent, a filter, glucooctanoic lactone, gulonic acid lactone, mannoic lac- a stent graft, a covered stent, a patch, a wire, and a valve. tone, ribonic acid lactone, lactobionic acid, and glu- [0075] In yet a further embodiment, the present inven- cosamine. In another aspect of this embodiment, the tis- tion relates to a medical device comprising a layer over- sue includes tissue of one of coronary vasculature, pe- lying an exterior surface of the medical device, the layer 15 ripheral vasculature, cerebral vasculature, esophagus, comprising a therapeutic agent and an additive, wherein airways, sinus, trachea, colon, biliary tract, urinary tract, the additive is one of sorbitan fatty esters, and PEG sorb- prostate, and brain passages. In yet another aspect of itan esters. In one aspect of this embodiment, the additive this embodiment, the device includes one of a balloon is chosen from sorbitan monolaurate, sorbitan mon- catheter, a perfusion balloon catheter, an infusion cath- opalmitate, sorbitan monooleate, sorbitan monostear- 20 eter, a cutting balloon catheter, a scoring balloon cathe- ate, PEG-20 sorbitan, monolaurate, PEG-20 sorbitan ter, a laser catheter, an atherectomy device, a debulking monopalmitate, PEG-20 sorbitan, monooleate, and catheter, a stent, a filter, a stent graft, a covered stent, a PEG-20 sorbitan monostearate. In another aspect of this patch, a wire, and a valve. embodiment, the tissueincludes tissueof oneof coronary [0078] In yet a further embodiment, the present inven- vasculature, peripheral vasculature, cerebral vascula- 25 tion relates to a medical device comprising a layer over- ture, esophagus, airways, sinus, trachea, colon, biliary lying an exterior surface of the medical device, the layer tract, urinary tract, prostate, and brain passages. In yet comprising a therapeutic agent and an additive, wherein another aspect of this embodiment, the device includes the additive is an ionic surfactant. In one aspect of this one of a balloon catheter, a perfusion balloon catheter, embodiment, the additive is chosen from benzalkonium an infusion catheter, a cutting balloon catheter, a scoring 30 chloride, benzethonium chloride, cetylpyridinium chlo- balloon catheter, a laser catheter, an atherectomy de- ride, docecyl trimethyl ammonium bromide, sodium vice, a debulking catheter, a stent, a filter, a stent graft, docecylsulfates, dialkyl methylbenzyl ammonium chlo- a covered stent, a patch, a wire, and a valve. ride, edrophonium chloride, domiphen bromide, di- [0076] In yet a further embodiment, the present inven- alkylesters of sodium sulfonsuccinic acid, sodium dioctyl tion relates to a medical device comprising a layer over- 35 sulfosuccinate, sodium cholate, and sodium taurochola- lying an exterior surface of the medical device, the layer te. In another aspect of this embodiment, the tissue in- comprising a therapeutic agent and an additive, wherein cludes tissue of one of coronary vasculature, peripheral the additive is a chemical compound containing a phenol vasculature, cerebral vasculature, esophagus, airways, moiety. In one aspect of this embodiment, the additive is sinus, trachea, colon, biliary tract, urinary tract, prostate, chosen from p-isononylphenoxypolyglycidol, octoxynol, 40 and brain passages. In yet another aspect of this embod- monoxynol, tyloxapol, octoxynol-9, and monoxynol- 9. In iment, the device includes one of a balloon catheter, a another aspect of this embodiment, the tissue includes perfusion balloon catheter, infusion catheter, a cutting tissue of one of coronary vasculature, peripheral vascu- balloon catheter, a scoring balloon catheter, a laser cath- lature, cerebral vasculature, esophagus, airways, sinus, eter, an atherectomy device, a debulking catheter, a trachea, colon, biliary tract, urinary tract, prostate, and 45 stent, a filter, a stent graft, a covered stent, a patch, a brain passages. In yet another aspect of this embodi- wire, and a valve. ment, the device includes one of a balloon catheter, a [0079] In yet a further embodiment, the present inven- perfusion balloon catheter, an infusion catheter, a cutting tion relates to a medical device comprising a layer over- balloon catheter, a scoring balloon catheter, a laser cath- lying an exterior surface of the medical device, the layer eter, an atherectomy device, a debulking catheter, a50 comprising a therapeutic agent and an additive, wherein stent, a filter, a stent graft, a covered stent, a patch, a the additive is a vitamin or vitamin derivative. In one as- wire, and a valve. pect of this embodiment, the additive is chosen from ace- [0077] In yet a further embodiment, the present inven- tiamine, benfotiamine, pantothenic acid, cetotiamine, cy- tion relates to a medical device comprising a layer over- cothiamine, dexpanthenol, niacinamide, nicotinic acid lying an exterior surface of the medical device, the layer 55 and its salts, pyridoxal 5- phosphate, nicotinamide ascor- comprising a therapeutic agent and an additive, the ad- bate, riboflavin, riboflavin phosphate, thiamine, folic acid, ditive is chosen from sucrose monolaurate, decanoyl- N- menadiol diphosphate, menadione sodium bisulfite, me- methylglucamide, n-decyl - β -D-glucopyranoside, n-de- nadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin

15 29 EP 2 500 046 A2 30

K6, vitamin U, ergosterol, 1-alpha-hydroxycholecal- cif- stent, a filter, a stent graft, a covered sent, a patch, a erol, vitamin D2, vitamin D3, alpha-carotene, beta- caro- wire, and a valve. tene, gamma-carotene, vitamin A, fursultiamine, methy- [0082] In yet a further embodiment, the present inven- lolriboflavin, octotiamine, prosultiamine, riboflavine, vin- tion relates to a medical device for delivering a therapeu- tiamol, dihydrovitamin K1, menadiol diacetate, menadiol 5 tic agent to a tissue, the device comprising a layer over- dibutyrate, menadiol disulfate, menadiol, vitamin K1, vi- lying an exterior surface of the medical device, the layer tamin K1 oxide, vitamins K2, and vitamin K-S(II). In an- comprising a therapeutic agent and an additive, wherein other aspect of this embodiment, the tissue includes tis- the additive includes a combination or mixture of both a sue of one of coronary vasculature, peripheral vascula- surfactant and a chemical compound, wherein the chem- ture, cerebral vasculature, esophagus, airways, sinus, 10 ical compound has one or more hydroxyl, amino, carbo- trachea, colon, biliary tract, urinary tract, prostate, and nyl, carboxyl, acid, amide or ester groups. In one aspect brain passages. In yet another aspect of this embodi- of this embodiment, the surfactant is chosen from ionic, ment, the device includes one of a balloon catheter, a nonionic, aliphatic, and aromatic surfactants, PEG fatty perfusion balloon catheter, infusion catheter, a cutting esters, PEG omega-3 fatty esters, ether, and alcohols, balloon catheter, a scoring balloon catheter, a laser cath- 15 glycerol fatty esters, sorbitan fatty esters, PEG glyceryl eter, an atherectomy device, a debulking catheter, a fatty esters, PEG sorbitan fatty esters, sugar fatty esters, stent, a filter, a stent graft, a covered stent, a patch, a PEG sugar esters and derivatives thereof. In another as- wire, and a valve. pect of this embodiment, the chemical compound having [0080] In yet a further embodiment, the present inven- one or more hydroxyl, amino, carbonyl, carboxyl, acid, tion relates to a medical device comprising a layer over- 20 amide or ester groups has a molecular weight of from 80 lying an exterior surface of the medical device, the layer to 750. In another aspect of this embodiment, the chem- comprising a therapeutic agent and an additive, wherein ical compound is chosen from amino alcohols, hydroxyl the additive is an amino acid, an amino acid salt, or an carboxylic acid, ester, and anhydrides, hydroxyl ketone, amino acid derivative. In one aspect of this embodiment, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugar the additive is chosen from alanine, arginine, asparagine, 25 sulfate, ethyl oxide, ethyl glycols, amino acids, sorbitan, aspartic acid, cysteine, glutamic acid, glutamine, glycine, glycerol, polyalcohol, phosphates, sulfates, organic ac- histidine, proline, isoleucine, leucine, lysine, methionine, ids,esters, salts, vitamins, combinations of amino alcohol phenylalanine, serine, threonine, tryptophan, tyrosine, and organic acid, and their substituted molecules. In an- valine, and derivatives thereof. In another aspect of this other aspect of this embodiment, the chemical compound embodiment, the tissues, includes tissue of one of coro- 30 having one or more hydroxyl, amino, carbonyl, carboxyl, nary vasculature, peripheral vasculature, cerebral vas- acid, amide or ester groups is chosen from acetic acid culature, esophagus, airways, sinus, trachea, colon, bil- and anhydride, benzoic acid and anhydride, diethylene- iary tract, urinary tract, prostate, and brain passages. In triaminepentaacetic acid dianhydride, ethylenediamine- yet another aspect of this embodiment, the device in- tetraacetic dianhydride, maleic acid and anhydride, suc- cludesone of a balloon catheter, aperfusion balloon cath- 35 cinic acid and anhydride, diglycolic acid and anhydride, eter, infusion catheter, a cutting balloon catheter, a scor- glutaric acid and anhydride, ascorbic acid, citric acid, tar- ing balloon catheter, a laser catheter, an atherectomy taric acid, lactic acid, oxalic acid aspartic acid, nicotinic device, a debulking catheter, a stent, a filter, a stent graft, acid, L-ascorbic acid and its salt, D-glucoascorbic acid a covered stent, a patch, a wire, and a valve. and its salt, tromethamine, triethanolamine, dieth- [0081] In yet a further embodiment, the present inven- 40 anolamine, meglumine, glucamine, amine alcohols, glu- tion relates to a medical device for delivering a therapeu- coheptonic acid, glucomic acid, hydroxyl ketone, hy- tic agent to a tissue, the device comprising a layer over- droxyl lactone, gluconolactone, glucoheptonolactone, lying an exterior surface of the medical device, the layer glucooctanoic lactone, gulonic acid lactone, mannoic lac- comprising a therapeutic agent and an additive, wherein tone, ribonic acid lactone, lactobionic acid, glucosamine, the additive is a peptide, oligopeptide, or protein. In one 45 glutamic acid, benzyl alcohol, benzoic acid, hydroxyben- aspect of this embodiment, the additive is chosen from zoic acid, propyl 4- hydroxybenzoate, lysine acetate salt, albumins, immunoglobulins, caseins, hemoglobins, lys- gentisic acid, lactobionic acid, lactitol, sorbitol, glucitol, ozymes, immunoglobins, a-2-macroglobulin, fi-sugar phosphates, glucopyranose phosphate, sugar sul- bronectins, vitronectins, firbinogens, and lipases. In an- phates, sinapic acid, vanillic acid, vanillin, methyl pa- other aspect of this embodiment, the tissue includes tis- 50 raben, propyl paraben, xylitol, 2-ethoxyethanol, cyclo- sue of one of coronary vasculature, peripheral vascula- dextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ture, cerebral vasculature, esophagus, airways, sinus, ibuprofen, retinoic acid, lysine acetate, gentisic acid, cat- trachea, colon, biliary tract, urinary tract, prostate, and echin, catechin gallate, tiletamine, ketamine, propofol, brain passages. In yet another aspect of this embodi- lactic acids, acetic acid, salts of any organic acid and ment, the device includes one of a balloon catheter, a 55 amine described above, polyglycidol, glycerol, multiglyc- perfusion balloon catheter, infusion catheter, a cutting erols, galactitol, di(ethylene glycol), tri(ethylene glycol), balloon catheter, a scoring balloon catheter, a laser cath- tetra(ethylene glycol), penta(ethylene glycol), poly(ethyl- eter, an atherectomy device, a debulking catheter, a ene glycol) oligomers, di (propylene glycol), tri(propylene

16 31 EP 2 500 046 A2 32 glycol), tetra(propylene glycol, and penta(propylene gly- glucose, mannose, xylose, sucrose, lactose, maltose, cy- col), poly(propylene glycol) oligomers, a block copolymer clodextrin, (2-hydroxypropyl)-cyclodextrin, salts of any of polyethylene glycol and polypropylene glycol, and de- organic acid and organic amine, polyglycidol, glycerol, rivatives and combinations thereof. In another aspect of multiglycerols, galactitol, di (ethylene glycol), tri(ethylene this embodiment, the tissue includes tissue of one of cor- 5 glycol), tetra(ethylene glycol), penta (ethylene glycol), po- onary vasculature, peripheral vasculature, cerebral vas- ly(ethylene glycol) oligomers, di(propylene glycol), tri culature, esophagus, airways, sinus, trachea, colon, bil- (propylene glycol), tetra (propylene glycol, andpenta (pro- iary tract, urinary tract, prostate, and brain passages. In pylene glycol), poly(propylene glycol) oligomers, a block yet another aspect of this embodiment, the device in- copolymer of polyethylene glycol and polypropylene gly- cludesone of a balloon catheter, aperfusion balloon cath- 10 col, and derivatives and combinations thereof. eter, infusion catheter, a cutting balloon catheter, a scor- [0084] In another embodiment, the present invention ing balloon catheter, a laser catheter, an atherectomy relates to a pharmaceutical formulation for administration device, a debulking catheter, a stent, a filter, a stent graft, to a mammal comprising paclitaxel or rapamycin or de- a covered stent, a patch, a wire, and a valve. rivatives thereof, and a chemical compound with one or [0083] In another embodiment, the present invention 15 more hydroxyl, amino, carbonyl, carboxyl, acid, amide or relates to a pharmaceutical formulation for administration ester groups, wherein the chemical compound with one to a mammal comprising paclitaxel or rapamycin or de- or more hydroxyl, amino, carbonyl, carboxyl, acid, amide rivatives thereof; and a combination of both a surfactant or ester groups has a molecular weight of from 80 to 750. and a chemical compound, wherein the chemical com- In one embodiment, the chemical compound with one or pound has one or more hydroxyl, amino, carbonyl, car- 20 more hydroxyl, amino, carbonyl, carboxyl, acid, amide, boxyl, acid, amide or ester groups. In one embodiment, or ester groups is chosen from hydroxyl ketone, hydroxyl the surfactant is chosen from ionic, nonionic, aliphatic, lactone, gluconolactone, glucoheptonolactone, glu- and aromatic surfactants, PEG fatty esters, PEG omega- cooctanoic lactone, gulonic acid lactone, mannoic lac- 3 fatty esters, ether, and alcohols, glycerol fatty esters, tone, ribonic acid lactone, sugar phosphate, sugar sul- sorbitan fatty esters, PEG glyceryl fatty esters, PEG sorb- 25 fate, catechin, catechin gallate, and combinations of ami- itan, fatty esters, sugar fatty esters, PEG sugar esters no alcohol and organic acid. In one aspect of this em- and derivativesthereof. In oneembodiment, the chemical bodiment, the amino alcohol is chosen from trometh- compound having one or more hydroxyl, amino, carbo- amine, triethanolamine, diethanolamine, meglumine, nyl, carboxyl, acid, amide or ester groups has a molecular glucamine, glucosamine, lysine, and derivatives thereof; weight of from 80 to 750. In one embodiment, the chem- 30 and the organic acid is chosen from glucoheptonic acid, ical compound having one or more hydroxyl, amino, car- glucomic acid, glutamic acid, benzoic acid, hydroxyben- bonyl, carboxyl, acid, amide, or ester groups is chosen zoic acid, gentisic acid, lactobionic acid, vanillic acid, lac- from amino alcohols, hydroxyl carboxylic acid, ester, and tic acids, acetic acid, and derivatives thereof. anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl [0085] In yet another embodiment, the present inven- ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl 35 tion relates to a pharmaceutical formulation for adminis- glycols, amino acids, peptides, proteins, sugars, glucose, tration to a mammal comprising: paclitaxel or rapamycin sucrose, sorbitan, glycerol, polyalcohol, phosphates, sul- or derivatives thereof; and a combination of amino alco- fates, organic acids, esters, salts, vitamins, combinations hol and organic acid, wherein the amino alcohol is chosen of amino alcohol and organic acid, and their substituted from tromethamine, triethanolamine, diethanolamine, molecules. In one embodiment, the chemical compound 40 meglumine, glucamine, glucosamine, lysine, and deriv- having one or more hydroxyl, amino, carbonyl, carboxyl, atives thereof; and the organic acid is chosen from glu- acid, amide or ester groups is chosen from L-ascorbic coheptonic acid, glucomic acid, glutamic acid, benzoic acid and its salt, glucoascorbic D- acid and its salt, acid, hydroxybenzoic acid, gentisic acid, lactobionic acid, tromethamine, triethanolamine, diethanolamine, meglu- vanillic acid, lactic acids, acetic acid, and derivatives mine, glucamine, amine alcohols, glucoheptonic acid, 45 thereof. glucomic acid, hydroxyl ketone, hydroxyl lactone, glu- [0086] In yet another embodiment, the present inven- conolactone, glucoheptonolactone, glucooctanoic lac- tion relates to a medical device for delivering a therapeu- tone, gulonic acid lactone, mannoic lactone, ribonic acid tic agent to a tissue, the device comprising a layer over- lactone, lactobionic acid, glucosamine, glutamic acid, lying an exterior surface of the medical device, the layer benzyl alcohol, benzoic acid, hydroxybenzoic acid, pro- 50 comprising a therapeutic agent and an additive, wherein pyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid, the additive is chosen from hydroxyl ketone, hydroxyl lac- lactobionic acid, lactitol, sinapic acid, vanillic acid, vanil- tone, gluconolactone, glucoheptonolactone, glucoocta- lin, methyl paraben, propyl paraben, acetaminophen, noic lactone, gulonic acid lactone, mannoic lactone, ri- ibuprofen, retinoic acid, lysine acetate, gentisic acid, cat- bonic acid lactone and lactobionic acid. echin, catechin gallate, tiletamine, ketamine, propofol, 55 [0087] in yet another embodiment, the present inven- lactic acids, acetic acid, ribonic acid lactone, meglumine/ tion relates to a medical device for delivering a therapeu- lactic acid, meglumine/gentisic acid, meglumine/acetic tic agent to a tissue, the device comprising a layer over- acid, sorbitol, xylitol, 2- ethoxyethanol, sugars, galactose, lying an exterior surface of the medical device, the layer

17 33 EP 2 500 046 A2 34 comprising a therapeutic agent and an additive, wherein inflation media (e.g., air, saline, or contrast media). Flex- the therapeutic agent is paclitaxel and analogues thereof ible member 14 may be a tube made of suitable biocom- or rapamycin and analogues thereof, and the additive is patible material and having one or more lumens therein. chosen from sorbitol, diethylene glycol, triethylene glycol, At least one of the lumens is configured to receive infla- tetraethylene glycol, polyethylene glycol oligomers, poly- 5 tion media and pass such media to balloon 12 for its propylene glycol oligomers, block copolymer oligomers expansion. The balloon catheter may be a rapid ex- of polyethylene glycol and polypropylene glycol, xylitol, change or over-the-wire catheter and made of any suit- 2-ethoxyethanol, sugars, galactose, glucose, mannose, able biocompatible material. xylose, sucrose, lactose, maltose, Tween 20, Tween 40, [0094] In one embodiment, the present invention pro- Tween 60, and their derivatives, wherein the ratio by10 vides a medical device for delivering a therapeutic agent weight of drug to additive is from 0.5 to 3, wherein the to a tissue. The device includes a layer applied to an therapeutic agent and the additive are simultaneously exterior surface of the medical device, such as a balloon released. catheter or stent, for example. The layer includes a ther- [0088] Many embodiments of the present invention are apeutic agent and an additive. For example, as shown particularly useful for treating vascular disease and for 15 in the embodiment depicted in Fig. 2A, the balloon 12 is reducing stenosis and late luminal loss, or are useful in coated with a layer 20 that includes a therapeutic agent the manufacture of devices for that purpose. and an additive. In some embodiments, the layer consists [0089] It is understood that both the foregoing general essentially of a therapeutic agent and an additive, i.e., description and the following detailed description are ex- the layer includes only the therapeutic agent and the ad- emplary and explanatory only and are not restrictive of 20 ditive, without any other materially significant compo- the present invention as claimed. nents. In some embodiments, the device may optionally include an adherent layer. For example, as shown in the BRIEF DESCRIPTION OF THE DRAWINGS embodiment depicted in Fig. 2B, the balloon 12 is coated with an adherent layer 22. A layer 24 that includes a ther- [0090] Figure 1 is a perspective view of an exemplary 25 apeutic agent and an additive is overlying the adherent embodiment of a balloon catheter according to the layer. The adherent layer, which is a separate layer un- present invention. derlying the drug coating layer, improves the adherence [0091] Figures 2A-2C are cross-sectional views of dif- of the drug coating layer to the exterior surface of the ferent embodiments of the distal portion of the balloon medical device and protects coating integrity. For exam- catheter of Fig. 1, taken along line A-A, showing exem- 30 ple, if drug and additive differ in their adherence to the plary coating layers. medical device, the adherent layer may prevent differen- tial loss of components and maintain drug- to-additive ra- DETAILED DESCRIPTION OF EXEMPLARY EMBOD- tio in the coating during transit to a target site for thera- IMENTS peutic intervention. Furthermore, the adherent layer may 35 function to facilitate rapid release of coating layer com- [0092] Embodiments of the present invention relate to ponents off the device surface upon contact with tissues medical devices, including particularly balloon catheters at the target site. In other embodiments, the device may and stents, having a rapid drug-releasing coating and include a top layer. The top layer may reduce loss of the methods for preparing such coated devices. The thera- drug layer before it is brought into contact with target peutic agent according to embodiments of the present 40 tissues, for example during transit of the balloon 12 to invention does not require a delayed or long term release the site of therapeutic intervention or during the first mo- and instead preferably the therapeutic agent and the ad- ments of inflation of balloon 12 before coating layer 20 ditive are released in a very short time period to provide is pressed into direct contact with target tissue. a therapeutic effect upon contact with tissue. An object [0095] In one embodiment, the concentration density of embodiments of the present invention is to facilitate 45 ofthe at least one therapeutic agent applied to the surface rapid and efficient uptake of drug by target tissue during of the medical device is from about 1 to 20 Pg/mm2, or transitory device deployment at a target site. more preferably from about 2 to 6 Pg/mm2. The ratio by [0093] As shown in Fig. 1, in one embodiment, the weight of therapeutic agent to the additive is from about medicaldevice is a balloon catheter. The balloon catheter 0.5 to 100, for example, from about 0.1 to 5, from 0.5 to may be any suitable catheter for the desired use, includ- 50 3, and further for example, from about 0.8 to 1.2. If the ing conventional balloon catheters known to one of ordi- ratio (by weight) of the therapeutic agent to the additive nary skill in the art. For example, balloon catheter 10 may is too low, then drug may release prematurely, and if the include an expandable, inflatable balloon 12 at a distal ratio is too high, then drug may not elute quickly enough end of the catheter 10, a handle assembly 16 at a prox- or be absorbed by tissue when deployed at the target site. imalend of the catheter10, and an elongate flexible mem- 55 [0096] In another embodiment, the layer comprises a ber 14 extending between the proximal and distal ends. therapeutic agent and an additive, wherein the therapeu- Handle assembly 16 may connect to and/or receive one tic agent is paclitaxel and analogues thereof or rapamycin or more suitable medical devices, such as a source of and analogues thereof, and the additive is chosen from

18 35 EP 2 500 046 A2 36 sorbitol, diethylene glycol, triethylene glycol, tetraethyl- site of therapeutic intervention. ene glycol, xylitol, 2-ethoxyethanol, sugars, galactose, [0100] In other embodiments, two or more therapeutic glucose, mannose, xylose, sucrose, lactose, maltose, agents are used in combination in the drug- additive layer. Tween 20, Tween 40, Tween 60, and their derivatives, [0101] In a further embodiment, the device having a wherein the ratio by weight of the therapeutic agent to 5 two layer coating may optionally include an adherent lay- the additive is from 0.5 to 3. If the ratio of drug to additive er. The adherent layer does not contain a therapeutic is below 0.5, then drug may release prematurely, and if agent. For example, as shown in the embodiment depict- ratio is above 3, then drug may not elute quickly enough ed in Fig. 2C, the balloon 12 is coated with an adherent or be absorbed by tissue when deployed at the target layer 22. A first layer 26 that comprises a therapeutic site. In other embodiments, the layer may include a ther- 10 agent and optionally an additive or additives is overlying apeutic agent and more than one additive. For example, the adherent layer 22. A second layer 28 that comprises one additive may serve to improve balloon adhesion of an additive and optionally a therapeutic agent is overlying another additive or additives that are superior at promot- the first layer 26. The adherent layer improves the ad- ing drug release or tissue uptake of drug. herence of the first layer to the exterior surface of the [0097] In other embodiments, the layer may include at 15 medical device and protects the integrity of the first layer. least one therapeutic agent, at least one additive, and at For example, if drug and additive or additives in the first least one polymer carrier for coating of a medical device layer differ in their strength of adherence to the medical such as a stent or a balloon. The therapeutic agent is not device, the adherent layer may prevent differential loss encapsulated in polymer particles. The additive in the of components and maintain drug-to-additive and addi- layer improves compatibility of the drug and polymer car- 20 tive-to-additive ratio in the first and second layers during rier. It reduces the size or eliminates drug crystal particles transit to a target site for therapeutic intervention. Fur- in the polymer matrix of the coating. The uniform drug thermore, the adherent layer may function to facilitate distribution in the coating improves clinical outcomes by rapid elution of coating layer off the device surface upon more uniformly delivering drug to target tissues. contact with tissues at the target site. In one embodiment, [0098] In another embodiment, the device comprises 25 the first layer, the second layer, and the adherent layer two layers applied to an exterior surface of the medical each contain an additive. device, and particularly a balloon catheter, for example. [0102] Optionally, post-treatment with dimethylsulfox- The first layer comprises a therapeutic agent. The first ide (DMSO) or other solvent may be advantageous since layer may optionally comprise an additive or additives. DMSO may further enhance penetration and absorption The second layer comprises an additive or additives. The 30 of drug into tissue. DMSO displaces water from the lipid second layer may optionally include at least a therapeutic head groups and protein domains of the membrane lipid agent. When the first and second layers both contain a bilayer of target cells to indirectly loosen the lipid struc- therapeutic agent, the content of the therapeutic agent ture, accelerating drug absorption and penetration. in the second layer is lower than the content of the ther- [0103] In a further embodiment, the present invention apeutic agent in the first layer. In one embodiment, the 35 relates to a pharmaceutical composition for treating a second layer is overlying the first layer. In this arrange- diseased body lumen or cavities after surgical or inter- ment, the second layer can present drug loss during de- ventional procedures (PTCA, PTA, stent placement, ex- ployment of the medical device into body passageways, cision of diseased tissue such as cancer, and relieving for example, as a balloon catheter traverses the tortuous or treating stenosis), wherein the pharmaceutical com- anatomy to a tissue site in the vasculature. 40 position comprises a therapeutic agent and an additive, [0099] In another embodiment, the device comprises wherein the additive comprises a hydrophilic part and a two layers applied to an exterior surface of the medical drug affinity part, wherein the drug affinity part is a hy- device, and particularly a balloon catheter, for example. drophobic part and/or has an affinity to the therapeutic The first layer comprises a therapeutic agent. The first agent by hydrogen bonding and/or van der Waals inter- layer may optionally comprise an additive or additives. 45 actions, and wherein the therapeutic agent is not en- The second layer comprises an additive or additives. The closed in micelles or encapsulated in polymer particles. second layer may optionally include at least a therapeutic [0104] In another embodiment, a method of preventing agent. When the first and second layers both contain a complications or recurrence of disease (such as cancer therapeutic agent, the content of the therapeutic agent or restenosis) after a surgical or interventional procedure inthe first layer is lower than the content of the therapeutic 50 such as PTCA, PTA, stent deployment, stenosis or agent in the second layer. In one embodiment, the sec- plaque removal by debulking, atherectomy, or laser pro- ond layer is overlying the first layer. This arrangement is cedures, the pharmaceutical composition is locally deliv- useful, for example, in the case of a therapeutic agent ered at or near the site of intervention by means of a that adheres too tightly to the balloon surface to rapidly coated medical device (such as a drug-coated balloon), elute off the balloon when inflated at the target site. In 55 or by spray, by injection, or by deposition. For example, this arrangement, the first layer functions to facilitate rap- the pharmaceutical composition may be delivered by id release of the bulk of drug, which is in the second layer, spray, injection, balloon or other method of deposition, off the surface of the device while it is inflated at the target into cavities created by surgical removal of cancer tissue

19 37 EP 2 500 046 A2 38 in order to reduce the risk of recurrence. As another ex- during transit through tortuous arterial anatomy prior to ample, a method for delivering the pharmaceutical com- reaching the target site and from exploding off the device position comprises inserting a medical device (such as during the initial phase of balloon inflation, before the guide catheter or a drug infusion catheter) into the blood drug coating is pressed into direct contact with the sur- to inject the pharmaceutical composition after a vascular 5 face of the vessel wall. intervention such as PTCA, PTA, or stent placement to [0109] The additive according to certain embodiments prevent restenosis, wherein the pharmaceutical compo- has a drug affinity part and a hydrophilic part. The drug sition comprises a therapeutic agent and an additive, affinity part is a hydrophobic part and/or has an affinity wherein the additive comprises a hydrophilic part and a to the therapeutic agent by hydrogen bonding and/or van drug affinity part, wherein the drug affinity part is a hy- 10 der Waals interactions. The drug affinity part may include drophobic part and/or has an affinity to the therapeutic aliphatic and aromatic organic hydrocarbon compounds, agent by hydrogen bonding and/or Van der Waals inter- such as benzene, toluene, and alkanes, among others. actions, and wherein the therapeutic agent is not en- These parts are not water soluble. They may bind both closed in micelles or encapsulated in polymer particles. hydrophobic drug, with which they share structural sim- [0105] Many embodiments of the present invention are 15 ilarities, and lipids of cell membranes. They have no cov- particularly useful for treating vascular disease and for alently bonded iodine. The drug affinity part may include reducing stenosis and late luminal loss, or are useful in functional groupsthat can formhydrogen bonds with drug the manufacture of devices for that purpose or in methods and with itself. The hydrophilic part may include hydroxyl of treating that disease. groups, amine groups, amide groups, carbonyl groups, [0106] Additive 20 carboxylic acid and anhydrides, ethyl oxide, ethyl glycol, [0107] The additive of embodiments of the present in- polyethylene glycol, ascorbic acid, amino acid, amino al- vention has two parts. One part is hydrophilic and the cohol, glucose, sucrose, sorbitan, glycerol, polyalcohol, other part is a drug affinity part. The drug affinity part is phosphates, sulfates, organic salts and their substituted a hydrophobic part and/or has an affinity to the therapeu- molecules, among others. One or more hydroxyl, car- tic agent by hydrogen bonding and/or van der Waals in- 25 boxyl, acid, amide or amine groups, for example, may be teractions. The drug affinity part of the additive may bind advantageous since they easily displace water mole- the lipophilic drug, such as rapamycin or paclitaxel. The cules that are hydrogen- bound to polar head groups and hydrophilic portion accelerates diffusion and increases surface proteins of cell membranes and may function to permeation of the drug into tissue. It may facilitate rapid remove this barrier between hydrophobic drug and cell movement of drug off the medical device during deploy- 30 membrane lipid. These parts can dissolve in water and ment at the target site by preventing hydrophobic drug polar solvents. These additives are not oils, lipids, or pol- molecules from clumping to each other and to the device, ymers. The therapeutic agent is not enclosed in micelles increasing drug solubility in interstitial spaces, and/or ac- or liposomes or encapsulated in polymer particles. The celerating drug passage through polar head groups to additive of embodiments of the present invention has the lipid bilayer of cell membranes of target tissues. The 35 components to both bind drug and facilitate its rapid additives of embodiments of the present invention have movement off the medical device during deployment and two parts that function together to facilitate rapid release into target tissues. of drug off the device surface and uptake by target tissue [0110] The additives in embodiments of the present during deployment (by accelerating drug contact with tis- invention are surfactants and chemical compounds with sues for which drug has high affinity) while preventing 40 one or more hydroxyl, amino, carbonyl, carboxyl, acid, the premature release of drug from the device surface amide or ester moieties. The surfactants include ionic, prior to device deployment at the target site. nonionic, aliphatic, and aromatic surfactants. The chem- [0108] In embodiments of the present invention, the ical compounds with one or more hydroxyl, amino, car- therapeutic agent is rapidly released after the medical bonyl, carboxyl, acid, amide or ester moieties are chosen device is brought into contact with tissue and is readily 45 from amino alcohols, hydroxyl carboxylic acid and anhy- absorbed. For example, certain embodiments of devices drides, ethyl oxide, ethyl glycols, amino acids, peptides, of the present invention include drug coated balloon cath- proteins, sugars, glucose, sucrose, sorbitan, glycerol, eters that deliver a lipophilic anti-proliferative pharma- polyalcohol, phosphates, sulfates, organic acids, esters, ceutical (such as paclitaxel or rapamycin) to vascular tis- salts, vitamins, and their substituted molecules. sue through brief, direct pressure contact at high drug 50 [0111] As is well known in the art, the terms "hy- concentration during balloon angioplasty. The lipophilic drophilic" and "hydrophobic" are relative terms. To func- drug is preferentially retained in target tissue at the de- tion as an additive in exemplary embodiments of the livery site, where it inhibits hyperplasia and restenosis present invention, the compound includes polar or yet allows endothelialization. In these embodiments, charged hydrophilic moieties as well as non- polar hydro- coating formulations of the present invention not only fa- 55 phobic (lipophilic) moieties. cilitate rapid release of drug from the balloon surface and [0112] An empirical parameter commonly used in me- transfer of drug into target tissues during deployment, dicinal chemistry to characterize the relative hydrophilic- but also prevent drug from diffusing away from the device ity and hydrophobicity of pharmaceutical compounds is

20 39 EP 2 500 046 A2 40 the partition coefficient, P, the ratio of concentrations of tions. Using HLB values as a rough guide, hydrophilic unionized compound in the two phases of a mixture of surfactants are generally considered to be those com- two immiscible solvents, usually octanol and water, such pounds having an HLB value greater than about 10, as that P =([solute] octanol / [solute] water).Compounds with well as anionic, cationic, or zwitterionic compounds for higher log Ps are more hydrophobic, while compounds 5 which the HLB scale is not generally applicable. Similarly, with lower log Ps are more hydrophilic. Lipinski’s rule hydrophobic surfactants are compounds having an HLB suggests that pharmaceutical compounds having log P value less than about 10. in certain embodiments of the < 5 are typically more membrane permeable. For pur- present invention, a higher HLB value is preferred, since poses of certain embodiments of the present invention, increased hydrophilicity may facilitate release of hydro- it is preferable that the additive has log P less than log P 10 phobic drug from the surface of the device. In one em- of the drug to be formulated (as an example, log P of bodiment, the HLB of the surfactant additive is higher paclitaxel is 7.4). A greater log P difference between the than 10. In another embodiment, the additive HLB is high- drug and the additive can facilitate phase separation of er than 14. Alternatively, surfactants having lower HLB drug. For example, if log P of the additive is much lower may be preferred when used to prevent drug loss prior than log P of the drug, the additive may accelerate the 15 to device deployment at the target site, for example in a release of drug in an aqueous environment from the sur- top coat over a drug layer that has a very hydrophilic face of a device to which drug might otherwise tightly additive. adhere, thereby accelerating drug delivery to tissue dur- [0117] It should be understood that the HLB value of ing brief deployment at the site of intervention. In certain a surfactant is merely a rough guide generally used to embodiments of the present invention, log P of the addi- 20 enable formulation of industrial, pharmaceutical and cos- tive is negative. In other embodiments, log P of the ad- metic emulsions, for example. For many important sur- ditive is less than log P of the drug. While a compound’s factants, including several polyethoxylated surfactants, octanol-water partition coefficient P or log P is useful as it has been reported that HLB values can differ by as a measurement of relative hydrophilicity and hydropho- much as about 8 HLB units,depending upon the empirical bicity, it is merely a rough guide that may be useful in 25 method chosen to determine the HLB value (Schott, J, defining suitable additives for use in embodiments of the Pharm. Sciences, 79(1), 87-88 (1990)). Keeping these present invention. inherent difficulties in mind, and using HLB values as a [0113] Suitable additives that can be used in embodi- guide, surfactants may be identified that have suitable ments of the present invention include, without limitation, hydrophilicity or hydrophobicity for use in embodiments organic and inorganic pharmaceutical excipients, natural 30 of the present invention, as described herein. products and derivatives thereof (such as sugars, vita- [0118] PEG- Fatty Acids and PEG-Fatty Acid Mono mins, amino acids, peptides, proteins, and fatty acids), and Diesters low molecular weight oligomers, surfactants (anionic, [0119] Although polyethylene glycol (PEG) itself does cationic, non-ionic, and ionic), and mixtures thereof. The not function as a surfactant, a variety of PEG-fatty acid following detailed list of additives useful in the present 35 esters have useful surfactant properties. Among the invention is provided for exemplary purposes only and is PEG-fatty acid monoesters, esters of lauric acid, oleic not intended to be comprehensive. Many other additives acid, and stearic acid are most useful in embodiments of may be useful for purposes of the present invention. the present invention. Preferred hydrophilic surfactants [0114] Surfactants include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, [0115] The surfactant can be any surfactant suitable 40 PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-1 for use in pharmaceutical compositions. Such sur- 2 laurate, PEG-12 oleate, PEG-1 5 oleate, PEG-20 lau- factants can be anionic, cationic, zwitterionic or non-ion- rate and PEG- 20 oleate. The HLB values are in the range ic. Mixtures of surfactants are also within the scope of of 4-20. the invention, as are combinations of surfactant and other [0120] Polyethylene glycol fatty acid diesters are also additives. Surfactant often have one or more long aliphat- 45 suitable for use as surfactants in the compositions of em- ic chains such as fatty acids that may insert directly into bodiments of the present invention. Most preferred hy- lipid bilayers of cell membranes to form part of the lipid drophilic surfactants includes PEG- 20 dilaurate, PEG- 20 structure,while other components of the surfactants loos- dioleate, PEG-20 distearate, PEG- 32 dilaurate and PEG- en the lipid structure and enhance drug penetration and 32 dioleate. The HLB values are in the range of 5-15. absorption. The contrast agent iopromide does not have 50 [0121] In general, mixtures of surfactants are also use- these properties. ful in embodiments of the present invention, including [0116] An empirical parameter commonly used to mixtures of two or more commercial surfactants as well characterize the relative hydrophilicity and hydrophobic- as mixtures of surfactants with another additive or addi- ity of surfactants is the hydrophilic-lipophilic balance tives. Several PEG-fatty acid esters are marketed com- ("HLB" value). Surfactants with lower HLB values are 55 mercially as mixtures or mono- and diesters. more hydrophobic, and have greater solubility in oils, [0122] Polyethylene Glycol Glycerol Fatty Acid Esters while surfactants with higher HLB values are more hy- [0123] Preferred hydrophilic surfactants are PEG-20 drophilic, and have greater solubility in aqueous solu- glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyc-

21 41 EP 2 500 046 A2 42 eryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyc- rate (Lauroglycol FCC), propylene glycol ricinoleate (Pro- eryl oleate. pymuls), propylene glycol monooleate (Myverol P-06), [0124] Alcohol-Oil Transesterification Products propylene glycol dicaprylate/dicaprate (Captex.RTM. [0125] A large number of surfactants of different de- 200), and propylene glycol dioctanoate (Captex.RTM. grees of hydrophobicity or hydrophilicity can be prepared 5 800). by reaction of alcohols or polyalcohol with a variety of [0130] Sterol and Sterol Derivatives natural and/or hydrogenated oils. Most commonly, the [0131] Sterols and derivatives of sterols are suitable oils used are castor oil or hydrogenated castor oil, or an surfactants for use in embodiments of the present inven- edible vegetable oil such as corn oil, olive oil, peanut oil, tion. Preferred derivatives include the polyethylene glycol palm kernel oil, apricot kernel oil, or almond oil. Preferred 10 derivatives. A preferred surfactant in this class is PEG- alcohols include glycerol, propylene glycol, ethylene gly- 24 cholesterol ether (Solulan C-24). col, polyethylene glycol, sorbitol, and pentaerythritol. [0132] Polyethylene Glycol Sorbitan Fatty Acid Esters Among these alcohol-oil transesterified surfactants, pre- [0133] A variety of PEG-sorbitan fatty acid esters are ferred hydrophilic surfactants are PEG-35 castor oil available and are suitable for use as surfactants in em- (lncrocas-35), PEG-40 hydrogenated castor oil (Cremo- 15 bodiments of the present invention. Among the PEG- phor RH 40), PEG- 25 trioleate (TAGAT.RTM. TO), PEG- sorbitan fatty acid esters, preferred surfactants include 60 corn glycerides (Crovol M70), PEG-60 almond oil PEG-20 sorbitan monolaurate (Tween-20), PEG-20 (Crovol A70), PEG-40 palm kernel oil (Crovol PK70), sorbitan monopalmitate (Tween-40), PEG-20 sorbitan PEG-50 castor oil (Emalex C- 50), PEG-50 hydrogenated monostearate (Tween-60). Laurate esters are preferred castor oil (Emalex HC-50), PEG-8 caprylic /capric glyc- 20 because they have a short lipid chain compared with erides (Labrasol), and PEG-6 caprylic /capric glycerides oleate esters, increasing drug absorption. (Softigen 767). Preferred hydrophobic surfactants in this [0134] Polyethylene Glycol Alkyl Ethers class include PEG- 5 hydrogenated castor oil, PEG- 7 hy- [0135] Ethers of polyethylene glycol and alkyl alcohols drogenated castor oil, PEG-9 hydrogenated castor oil, are suitable surfactants for use in embodiments of the PEG-6 corn oil (Labrafil.RTM. M 2125 CS), PEG-6 al- 25 present invention. Preferred ethers include PEG-3 oleyl mond oil (Labrafil.RTM, M 1966 CS), PEG- 6 apricot ker- ether (Volpo 3) and PEG-4 lauryl ether (Brij 30). nel oil (Labrafil.RTM. M 1944 CS), PEG-6 olive oil (La- [0136] Sugar and Its Derivatives brafil.RTM. M 1980 CS), PEG- 6 peanut oil (Labrafil.RTM. [0137] Sugar derivatives are suitable surfactants for M 1969 CS), PEG-6 hydrogenated palm kernel oil (La- use in embodiments of the present invention. Preferred brafil.RTM. M 2130 BS), PEG-6 palm kernel oil (Labra- 30 surfactants in this class include sucrose monopalmitate, fil.RTM. M 2130 CS), PEG-6 triolein (Labrafil.RTM.b M sucrose monolaurate, decanoyl-N-methylglucamide, n- 2735 CS), PEG-8 corn oil (Labrafil.RTM. WL 2609 BS), decyl - β -D-glucopyranoside, n-decyl - β -D-maltopyra- PEG-20 corn glycerides (Crovol M40), and PEG-20 al- noside, n-dodecyl - β -D-glucopyranoside, n-dodecyl - β mond glycerides (Crovol A40). -D-maltoside, heptanoyl-N-methylglucamide, n-heptyl- β [0126] Polyglyceryl Fatty Acids 35 -D-glucopyranoside, n-heptyl - β -D-thioglucoside, n- [0127] Polyglycerol esters of fatty acids are also suit- hexyl - β -D-glucopyranoside, nonanoyl-N-methylgluca- able surfactants for use in embodiments of the present mide, n-noyl - β -D-glucopyranoside, octanoyl-N-meth- invention. Among the polyglyceryl fatty acid esters, pre- ylglucamide, n-octyl- β -D-glucopyranoside, and octyl - ferred hydrophobic surfactants include polyglyceryl β -D-thioglucopyranoside. oleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol 40 [0138] Polyethylene Glycol Alkyl Phenols DGDO), polyglyceryl-10 trioleate, polyglyceryl stearate, [0139] Several PEG-alkyl phenol surfactants are avail- polyglyceryl laurate, polyglyceryl myristate, polyglyceryl able, such as PEG-10-100 nonyl phenol and PEG- palmitate, and polyglyceryl linoleate. Preferred hy- 15-100 octyl phenol ether, Tyloxapol, octoxynol, nonox- drophilic surfactants include polyglyceryl- 10 laurate (Nik- ynol, and are suitable for use in embodiments of the kol Decaglyn L), 1- polyglyceryl-10 oleate (Nikkol45 present invention. Decaglyn 1-O), and polyglyceryl-10 mono, dioleate [0140] Polyoxyethylene-Polyoxypropylene (POE- (Caprol.RTM. PEG 860), polyglyceryl-10 stearate, poly- POP) Block Copolymers glyceryl-10 laurate, polyglyceryl-10 myristate, polyglyc- [0141] The POE-POP block copolymers are a unique eryl-10 palmitate, polyglyceryl- 10 linoleate, polyglyceryl- class of polymeric surfactants. The unique structure of 6 stearate, polyglyceryl-6 laurate, polyglyceryl-6 myr- 50 the surfactants, with hydrophilic POE and hydrophobic istate, polyglyceryl-6 palmitate, and polyglyceryl-6 li- POP moieties in well-defined ratios and positions, pro- noleate. Polyglyceryl polyricinoleates (Polymuls) are al- vides a wide variety of surfactants suitable for use in em- so preferred surfactants. bodiments of the present invention. These surfactants [0128] Propylene Glycol Fatty Acid Esters are available under various trade names, including Syn- [0129] Esters of propylene glycol and fatty acids are 55 peronic PE series (ICI); Pluronic.RTM. series (BASF), suitable surfactants for use in embodiments of the Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, present invention. In this surfactant class, preferred hy- and Plurodac. The generic term for these polymers is drophobic surfactants include propylene glycol monolau- "poloxamer" (CAS 9003-11-6). These polymers have the

22 43 EP 2 500 046 A2 44 formula: axel, experimentally it protects drug from premature re- [0142] HO (C2H4O)a(C3H6O)b(C2H4O)aH where "a" lease during the device delivery process while facilitating and "b" denote the number of polyoxyethylene and poly- rapid release and elution of paclitaxel during a very brief oxypropylene units, respectively. deployment time of 0.2 to 2 minutes at the target site. [0143] Preferred hydrophilic surfactants of this class 5 Drug absorption by tissues at the target site is unexpect- include Poloxamers 108, 188, 297, 238, 288, 338, and edly high experimentally. 407. Preferred hydrophobic surfactants in this class in- [0150] Chemical compounds with one or more hy- clude Poloxamers 124,182,183. 212, 339 , and 335. droxyl, amino, carbonyl, carboxyl, acid, amide or ester [0144] Sorbitan Fatty Acid Esters moieties [0145] Sorbitan esters of fatty acids are suitable sur- 10 [0151] The chemical compounds with one or more hy- factants for use in embodiments of the present invention. droxyl, amino, carbonyl, carboxyl, acid, amide or ester Among these esters, preferred hydrophobic surfactants moieties include amino alcohols, hydroxyl carboxylic ac- include sorbitan monolaurate (Arlacel 20), sorbitan mon- id, ester, and anhydrides, hydroxyl ketone, hydroxyl lac- opalmitate (Span-40), and sorbitan monooleate (Span- tone, hydroxyl ester, sugar phosphate, sugar sulfate, 80), sorbitan monostearate. 15 ethyloxide, ethyl glycols, amino acids, peptides, proteins, [0146] The sorbitan monopalmitate, an amphiphilic de- sorbitan, glycerol, polyalcohol, phosphates, sulfates, or- rivative of Vitamin C (which has Vitamin C activity), can ganic acids, esters, salts, vitamins, combinations of ami- serve two important functions in solubilization systems. no alcohols and organic acids, and their substituted mol- First, it possesses effective polar groups that can mod- ecules. Hydrophilic chemical compounds with one or ulate the microenvironment. These polar groups are the 20 more hydroxyl, amino, carbonyl, carboxyl, acid, amide or same groups that make vitamin C itself (ascorbic acid) ester moieties having a molecular weight less than one of the most water-soluble organic solid compounds 5,000-10,000 are preferred in certain embodiments. In available: ascorbic acid is soluble to about 30 wt/wt % in other embodiments, molecular weight of the additive with water (very close to the solubility of sodium chloride, for one or more hydroxyl, amino, carbonyl, carboxyl, acid, example). And second, when the pH increases so as to 25 amide, or ester moieties is preferably less than convert a fraction of the ascorbyl palmitate, to a more 1000-5,000, or more preferably less than 750-1,000, or soluble salt, such as sodium ascorbyl palmitate. most preferably less than 750. In these embodiments, [0147] Ionic Surfactants the molecular weight of the additive is preferred to be [0148] Ionic surfactants, including cationic, anionic less than that of the drug to be delivered. Further, the and zwitterionic surfactants, are suitable hydrophilic sur- 30 molecular weight of the additive is preferred to be higher factants for use in embodiments of the present invention. than 80 since molecules with molecular weight less than Preferred ionic surfactants include quaternary ammoni- 80 very easily evaporate and do not stay in the coating um salts, fatty acid salts and bile salts. Specifically, pre- of a medical device. Small molecules can diffuse quickly. ferred ionic surfactants include benzalkonium chloride, They can release themselves easily from the delivery benzethonium chloride, cetylpyridinium chloride, docecyl 35 balloon, accelerating release of drug, and they can dif- trimethyl ammonium bromide, sodium docecylsulfates, fuse away from drug when the drug binds tissue of the dialkyl methylbenzyl ammonium chloride, edrophonium body lumen. chloride, domiphen bromide, dialkylesters of sodium sul- [0152] In certain embodiments, more than four hy- fonsuccinic acid, sodium dioctyl sulfosuccinate, sodium droxyl groups are preferred, for example in the case of cholate, and sodium taurocholate. These quaternary am- 40 a high molecular weight additive. Large molecules diffuse monium salts are preferred additives. They can be dis- slowly. If the molecular weight of the additive or the chem- solved in both organic solvents (such as ethanol, ace- ical compound is high, for example if the molecular weight tone, and toluene) and water. This is especially useful is above 800, above 1000, above 1200, above 1500, or for medical device coatings because it simplifies the above 2000; large molecules may elute off of the surface preparation and coating process and has good adhesive 45 of the medical device too slowly to release drug under 2 properties. Water insoluble drugs are commonly dis- minutes. If these large molecules contain more than four solved in organic solvents. hydroxyl groups they have increased hydrophilic proper- [0149] Some of the surfactants described herein are ties, which is necessary for relatively large molecules to very stable under heating. They survive an ethylene ox- release drug quickly. The increased hydrophilicity helps ide sterilization process. They do not react with drugs 50 elute the coating off the balloon, accelerates release of such as paclitaxel or rapamycin under the sterilization drug, and improves or facilitates drug movement through process. The hydroxyl, ester, amide groups are preferred water barrier and polar head groups of lipid bilayers to because they are unlikely to react with drug, white amine penetrate tissues. The hydroxyl group is preferred as the and acid groups often do react with paclitaxel or rapamy- hydrophilic moiety because it is unlikely to react with wa- cin during sterilization. Furthermore, surfactant additives 55 ter insoluble drug, such as paclitaxel or rapamycin. In improve the integrity and quality of the coating layer, so some embodiments, the chemical compound having that particles do not fall off during handling. When the more than four hydroxyl, groups has a melting point of surfactants described herein are formulated with paclit- 120°C or less. In some embodiments, the chemical com-

23 45 EP 2 500 046 A2 46 pound having more than four hydroxyl groups has three pha-carotene, beta-carotene, gamma-carotene, vitamin adjacent hydroxyl groups that in stereo configuration are A, fursultiamine, methylolriboflavin, octotiamine, pro- all on one side of the molecule. For example, sorbitol and sultiamine, riboflavine, vintiamol, dihydrovitamin K1, me- xylitol have three adjacent hydroxyl groups that in ster- nadiol diacetate, menadiol dibutyrate, menadiol disul- eoconfiguration are all on one side of the molecule, while 5 fate, menadiol, vitamin K1, vitamin K1 oxide, vitamins galactitol does not. The difference impacts the physical K2, and vitamin K-S (II). Folic acid is also of this type, and properties of the isomers such as the melting tempera- although it is water- soluble at physiological pH, it can be ture. The stereoconfiguration of the three adjacent hy- formulated in the free acid form. Other derivatives of tat- droxyl groups may enhance drug binding. This will lead soluble vitamins useful in embodiments of the present to improved compatibility of the water insoluble drug and 10 invention may easily be obtained via well known chemical hydrophilic additive, and improved tissue uptake and ab- reactions with hydrophilic molecules. sorption of drug. [0157] water-soluble vitamins and Their Amphiphilic [0153] Some of the chemical compouds with one or Derivatives more hydroxyl, amine, carbonyl, carboxyl, or ester moi- [0158] Vitamins B, C, U, pantothenic acid, folic acid, eties described herein are very stable under heating.15 and some of themenadiorle- related vitamins/ provitamins They survive an ethylene oxide sterilization process and in many of their various forms are considered water- sol- do not react with the water insoluble drug paclitaxel or uble vitamins. These may also be conjugated or com- rapamycin during sterilization. L-ascorbic acid and its salt plexed with hydrophobic moieties or multivalent ions into and diethanolamine, on the other hand, do not necessar- amphiphilic forms having relatively high octanol-water ily survive such a sterilization process, and they react 20 partition coefficients and polar groups. Again, such com- with paclitaxel. A different sterilization method is there- pounds can be of low toxicity and high benefit to risk ratio, fore preferred for L-ascorbic acid and diethanolamine. making them useful as additives in embodiments of the Hydroxyl, ester, and amide groups are preferred because present invention. Salts of these can also be useful as they are unlikely to react with therapeutic agents such additives in the present invention. Examples of water- as paclitaxel or rapamycin. Sometimes, amine and acid 25 soluble vitamins and derivatives include, without limita- groups do react with paclitaxel, for example, experimen- tion, acetiamine, benfotiamine, pantothenic acid, ceto- tally, benzoic acid, gentisic acid, diethanolamine, and tiamine, cycothiamine, dexpanthenol, niacinamide, nic- ascorbic acid were not stable under ethylene oxide ster- otinic acid, pyridoxal 5-phosphate, nicotinamide ascor- ilization, heating, and aging process and reacted with bate, riboflavin, riboflavin phosphate, thiamine, folic acid, paclitaxel. When the chemical compounds described30 menadiol diphosphate, menadione sodium bisulfite, me- herein are formulated with paclitaxel, a top coat layer nadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin may be advantageous in order to prevent premature drug K6, and vitamin U. Also, as mentioned above, folic acid loss during the device delivery process before deploy- is, over a wide pH range including physiological pH, wa- ment at the target site, since hydrophilic small molecules ter-soluble, as a salt. sometimes release drug too easily. The chemical com- 35 [0159] Compounds in which an amino or other basic pounds herein rapidly elute drug off the balloon during group is present can easily be modified by simple acid- deployment at the target site. Surprisingly, even though base reaction with a hydrophobic group-containing acid some drug is lost during transit of the device to the target such as a fatty acid (especially lauric, oleic, myristic, pal- site when the coating contains these additives, experi- mitic, stearic, or 2- ethylhexanoic acid), low- solubility ami- mentally drug absorption by tissue is unexpectedly high 40 no acid, benzoic acid, salicylic acid, or an acidic fat-sol- after only 0.2-2 minutes of deployment, for example, with uble vitamin (such as riboflavin). Other compounds might the additive hydroxyl lactones such as ribonic acid lac- be obtained by reacting such an acid with another group tone and gluconolactone. on the vitamin such as a hydroxyl group to form a linkage [0154] Fat-soluble Vitamins and Salts Thereof such as an ester linkage, etc. Derivatives of a water- sol- [0155] Vitamins A, D, E and K in many of their various 45 uble vitamin containing an acidic group can be generated forms and provitamin forms are considered as fat- soluble in reactions with a hydrophobic group-containing reac- vitamins and in addition to these a number of other vita- tant such as stearylamine or riboflavine, for example, to mins and vitamin sources or close relatives are also fat- create a compound that is useful in embodiments of the soluble and have polar groups, and relatively high octa- present invention. The linkage of a palmitate chain to nol-water partition coefficients. Clearly, the general class 50 vitamin C yields ascorbyl palmitate. of such compounds has a history of safe use and high [0160] Amino Acids and Their Salts benefit to risk ratio, making them useful as additives in [0161] Alanine, arginine, asparagines, aspartic acid, embodiments of the present invention. cysteine, cystine, glutamic acid, glutamine, glycine, his- [0156] The following examples of fat-soluble vitamin tidine, proline, isoleucine, leucine, lysine, methionine, derivatives and/or sources are also useful as additives: 55 phenylalanine, serine, threonine, tryptophan, tyrosine, Alpha-tocopherol, beta-tocopherol, gamma-tocopherol, valine, and derivatives thereof are other useful additives delta-tocopherol, tocopherol acetate, ergosterol, al- 1- in embodiments of the invention. pha-hydroxycholecal- ciferol, vitamin D2, vitamin D3, al- [0162] Certain amino acids, in their zwitterionic form

24 47 EP 2 500 046 A2 48 and/or in a salt form with a monovalent or multivalent ion, into the vessel walls. have polar groups, relatively high octanol- water partition [0172] Other chemical compounds with one or more coefficients, and are useful in embodiments of the hydroxyl, amine, carbonyl, carboxyl, or ester moieties present invention. In the context of the present disclosure [0173] The additives according to embodiments in- we take "low-solubility amino acid"’ to mean an amino 5 clude amino alcohols, alcohols, amine, acids, amides acid which has a solubility in unbuffered water of less and hydroxyl acids in both cyclo and linear aliphatic and than about 4% (40 mg/ml). These includes Cystine, ty- aromatic groups. Examples are L-ascorbic acid and its rosine, tryptophan, leucine, isoleucine, phenylalanine, salt, D-glucoascorbic acid and its salt, tromethamine, tri- asparagine, aspartic acid, glutamic acid, and methio- ethanolamine, diethanolamine, meglumine, glucamine, nine;. 10 amine alcohols, glucoheptonic acid, glucomic acid, hy- [0163] Amino acid dimers, sugar- conjugates, and oth- droxyl ketone, hydroxyl lactone, gluconolactone, gluco- er derivatives are also useful. Through simple reactions heptonolactone, glucooctanoic lactone, gulonic acid lac- well known in the art hydrophilic molecules may be joined tone, mannoic lactone, ribonic acid lactone, lactobionic to hydrophobic amino acids, or hydrophobic molecules acid, glucosamine, glutamic acid, benzyl alcohol, benzo- to hydrophilic amino acids, to make additional additives 15 ic acid, hydroxybenzoic acid, propyl 4- hydroxybenzoate, useful in embodiments of the present invention. lysine acetate salt, gentisic acid, lactobionic acid, lactitol, [0164] Catecholamines, such as dopamine, levodopa, sorbitol, glucitol, sugar phosphates, glucopyranose carbidopa, and DOPA, are also useful as additives. phosphate, sugar sulphates, sinapic acid, vanillic acid, [0165] Oligopeptides, Peptides and Proteins vanillin, methyl paraben, propyl paraben, xylitol, 2-ethox- [0166] Oligopeptides and peptides are useful as addi- 20 yethanol, sugars, galactose, glucose, ribose, mannose, tives, since hydrophobic and hydrophilic amino acids xylose, sucrose, lactose, maltose, arabinose, lyxose, may be easily coupled and various sequences of amino fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acids may be tested to maximally facilitate permeation acetaminophen, ibuprofen, retinoic acid, lysine acetate, of tissue by drug. gentisic acid, catechin, catechin gallate, tiletamine, ket- [0167] Proteins are also useful as additives in embod- 25 amine, propofol, lactic acids, acetic acid, salts of any or- iments of the present invention. Serum albumin, for ex- ganic acid and amine described above, polyglycidol, ample, is a particularly preferred additive since it is water- glycerol, multiglycerols, galactitol, di(ethylene glycol), tri soluble and contains significant hydrophobic parts to bind (ethylene glycol), tetra(ethylene glycol), penta(ethylene drug: paclitaxel is 89% to 98% protein-bound after human glycol),poly (ethyleneglycol) oligomers, di(propylene gly- intravenous infusion, and rapamycin is 92% protein30 col), tri(propylene glycol), tetra(propylene glycol, and bound, primarily (97%) to albumin. Furthermore, paclit- penta(propylene glycol), poly(propylene glycol) oligom- axel solubility in PBS increases over 20- fold with the ad- ers, a block copolymer of polyethylene glycol and poly- dition of BSA. Albumin is naturally present at high con- propylene glycol, and derivatives and combinations centrations in serum and is thus very safe for human thereof. intravascular use. 35 [0174] Combinations of additives are also useful for [0168] Other useful proteins include, without limitation, purposes of the present invention. other albumins, immunoglobulins, caseins, hemoglob- [0175] One embodiment comprises the combination ins, lysozymes, immunoglobins, a-2-macroglobulin, fi- or mixture of two additives, for example, a first additive bronectins, vitronectins, firbinogens, lipases, and the comprising a surfactant and a second additive compris- like. 40 ing a chemical compound with one or more hydroxyl, [0169] Organic Acids and Their Esters and Anhy- amine, carbonyl, carboxyl, or ester moieties. drides [0176] The combination or mixture of the surfactant [0170] Examples are acetic acid and anhydride, ben- and the small water- soluble molecule (the chemical com- zoic acid and anhydride, diethylenetriaminepentaacetic pounds with one or more hydroxyl, amine, carbonyl, car- acid dianhydride, ethylenediaminetetraacetic dianhy-45 boxyl, or ester moieties) has advantages. Formulation dride, maleic acid and anhydride, succinic acid and an- comprising mixtures of the two additives with water-in- hydride, diglycolic anhydride, glutaric anhydride, ascor- soluble drug are in certain cases superior to mixtures bic acid, citric acid, tartaric acid, lactic acid, oxalic acid including either additive alone, The hydrophobic drugs aspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic bind extremely water-soluble small molecules more acid, and 2-pyrrolidone. 50 poorly than they do surfactants. They are often phase [0171] These esters and anhydrides are soluble in or- separated from the small water- soluble molecules, which ganic solvents such as ethanol, acetone, methylethylke- can lead to suboptimal coating uniformity and integrity. tone, ethylacetate. The water insoluble drugs can be dis- The water-insoluble drug has Log P higher than both that solved in organic solvent with these esters and anhy- of the surfactant and that of small water-soluble mole- drides, then coated easily on to the medical device, then 55 cules. However, Log P of the surfactant is typically higher hydrolyzed under high pH conditions. The hydrolyzed an- than Log P of the chemical compounds with one or more hydrides or esters are acids or alcohols, which are water hydroxyl, gamine, carbonyl, carboxyl, or ester moieties. soluble and can effectively carry the drugs off the device The surfactant has a relatively high Log P (usually above

25 49 EP 2 500 046 A2 50

0) and the water soluble molecules have low Log P (usu- mixture or the combination include all of the chemical ally below 0). Some surfactants, when used as additives compounds with one or more hydroxyl, amine, carbonyl, in embodiments of the present invention, adhere so carboxyl, or ester moieties described herein for use in strongly to the water-insoluble drug and the surface of embodiments of the invention. The chemical compound the medical device that drug is not able to rapidly release 5 with one or more hydroxyl, amine, carbonyl, carboxyl, or from the surface of the medical device at the target site. ester moieties in the mixture has at least one hydroxyl On the other hand, some of the water- soluble small mol- group in one of the embodiments in the inventions. In ecules (with one or more hydroxyl, amine, carbonyl, car- certain embodiments, more than four hydroxyl groups boxyl, or ester moieties) adhere so poorly to the medical are preferred, for example in the case of a high molecular device that they release drug before it reaches the target 10 weight additive. In some embodiments, the chemical site, for example, into serum during the transit of a coated compound having more than four hydroxyl groups has a balloon catheter to the site targeted for intervention. Su- melting point of 120°C or less. Large molecules diffuse prisingly, by adjusting the ratio of the concentrations of slowly. If the molecular weight of the additive or the chem- the small hydrophilic molecule and the surfactant in the ical compound is high, for example if the molecular weight formulation, the inventor has found that the coating sta- 15 is above 800, above 1000, above 1200, above 1500, or bility during transit and rapid drug release when inflated above 2000; large molecules may elute off of the surface and pressed against tissues of the lumen wall at the target of the medical device too slowly to release drug under 2 site of therapeutic intervention in certain cases is superior minutes. If these large molecules contain more than four to a formulation comprising either additive alone. Fur- hydroxyl groups they have increased hydrophilic proper- thermore, the miscibility and compatibility of the water- 20 ties, which is necessary for relatively large molecules to insoluble drug and the highly water- soluble molecules is release drug quickly. The increased hydrophilicity helps improved by the presence of the surfactant. The sur- elute the coating off the balloon, accelerates release of factant also improves coating uniformity and integrity by drug, and improves or facilitates drug movement through its good adhesion to the drug and the small molecules. water barrier and polar head groups of lipid bilayers to The long chain hydrophobic part of the surfactant binds 25 penetrate tissues. The hydroxyl group is preferred as the drug tightly while the hydrophilic part of the surfactant hydrophilic moiety because it is unlikely to react with wa- binds the water-soluble, small molecules. ter insoluble drug, such as paclitaxel or rapamycin. [0177] The surfactants in the mixture or the combina- [0179] The chemical compound with one or more hy- tion include all of the surfactants described herein for use droxyl, amine, carbonyl, carboxyl, or ester moieties in the in embodiments of the invention. The surfactant in the 30 mixture is chosen from L-ascorbic acid and its salt, D- mixture may be chosen from PEG fatty esters, PEG ome- glucoascorbic acid and its salt, tromethamine, trieth- ga-3 fatty esters and alcohols, glycerol fatty esters, sorb- anolamine, diethanolamine, meglumine, glucamine, itan fatty esters, PEG glyceryl fatty esters, PEG sorbitan amine alcohols, glucoheptonic acid, glucomic acid, hy- fatty esters, sugar fatty esters, PEG sugar esters, Tween droxyl ketone, hydroxyl lactone, gluconolactone, gluco- 20, Tween 40, Tween 60, p-isononylphenoxypolyglyci- 35 heptonolactone, glucooctanoic lactone, gulonic acid lac- dol, PEG laurate, PEG oleate, PEG stearate, PEG glyc- tone, mannoic lactone, ribonic acid lactone, lactobionic eryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, acid, glucosamine, glutamic acid, benzyl alcohol, benzo- polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myr- ic acid, hydroxybenzoic acid, propyl 4- hydroxybenzoate, istate, polyglyceryl palmitate, polyglyceryl-6 iaurate, ply- lysine acetate salt, gentisic acid, lactobionic acid, lactitol, glyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl- 40 sorbitol, glucitol, sugar phosphates, glucopyranose 6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10 phosphate, sugar sulphates, sinapic acid, vanillic acid, oleate, polyglyceryl-10 myristate, polyglyceryl-10 vanillin, methyl paraben, propyl paraben, xylitol, 2-ethox- palmitate , PEG sorbitan monolaurate, PEG sorbitan yethanol, sugars, galactose, glucose, ribose, mannose, monolaurate, PEG sorbitan monooleate, PEG sorbitan xylose, sucrose, lactose, maltose, arabinose, lyxose, stearate, PEG oleyl ether, PEG laurayl ether, Tween 20, 45 fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, Tween 40, Tween 60, Tween 80, octoxynol, monoxynol, acetaminophen, ibuprofen, retinoic acid, lysine acetate, tyloxapol, sucrose monopalmitate, sucrose monolau- gentisic acid, catechin, catechin gallate, tiletamine, ket- rate, decanoyl-N-methylglucamide, n-decyl - β -D-glu- amine, propofol, lactic acids, acetic acid, salts of any or- copyranoside,n- decyl- β -D- maltopyranoside,n-dodecy! ganic acid and amine, described above, polyglycidol, - β -D-glucopyranoside, n-dodecyl - β -D-maltoside, hep- 50 glycerol, multiglycerols, galactitol, di(ethylene glycol), tri tanoyl-N-methylglucamide, n-heptyl- β -D-glucopyrano- (ethylene glycol), tetra(ethylene glycol), penta(ethylene side, n-heptyl - β -D-thioglucoside, n-hexyl - β -D-glucop- glycol),poly (ethyleneglycol) oligomers, di(propylene gly- yranoside, nonanoyl-N-methylglucamide, n-noyl - β -D- col), tri(propylene glycol), tetra(propylene glycol, and glucopyranoside, octanoyl-N-methylglucamide, n-octyl- penta(propylene glycol), poly(propylene glycol) oligom- β -D-glucopyranoside, octyl - β -D-thioglucopyranoside 55 ers, a block copolymer of polyethylene glycol and poly- and their derivatives. propylene glycol, and derivatives and combinations [0178] The chemical compound with one or more hy- thereof. droxyl, amine, carbonyl, carboxyl, or ester moieties in the [0180] Mixtures or combinations of a surfactant and a

26 51 EP 2 500 046 A2 52 water-soluble small molecule confer the advantages of ronectins, firbinogens, lipases, benzalkonium chloride, both additives. The water insoluble drug often has a poor benzethonium chloride, docecyl trimethyl ammonium compatibility with highly water-soluble chemical com- bromide, sodium docecylsulfates, dialkyl methylbenzyl pounds, and the surfactant improves compatibility. The ammonium chloride, and dialkylesters of sodium sulfon- surfactant also improves the coating quality, uniformity, 5 succinic acid, L-ascorbic acid and its salt, D- glucoascor- and integrity, and particles do not fall off the balloon dur- bic acid and its salt, tromethamine, triethanolamine, di- ing handling. The surfactant reduces drug loss during ethanolamine, meglumine, glucamine, amine alcohols, transit to a target site. The water-soluble chemical com- glucoheptonic acid, glucomic acid, hydroxyl ketone, hy- pound improves the release of drug off the balloon and droxyl lactone, gluconolactone, glucoheptonolactone, absorption of the drug in the tissue. Experimentally, the 10 glucooctanoic lactone, gulonic acid lactone, mannoic lac- combination was surprisingly effective at preventing drug tone, ribonic acid lactone, lactobionic acid, , glu- release during transit and achieving high drug levels in cosamine, glutamic acid, benzyl alcohol, benzoic acid, tissue after very brief 0.2-2 minute deployment. Further- hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine more, in animal studies it effectively reduced arterial ste- acetate salt, gentisic acid, lactobionic acid, lactitol, sinap- nosis and late lumen loss. 15 ic acid, vanillic acid, vanillin, methyl paraben, propyl pa- [0181] Some of the mixtures or combinations of sur- raben, sorbitol, xylitol, cyclodextrin, hydroxypro- (2- factants and water-soluble small molecules are very sta- pyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic ac- ble under heating. They survived an ethylene oxide ster- id, lysine acetate, gentisic acid, catechin, catechin gal- ilization process and do not react with the water insoluble late, tiletamine, ketamine, propofol, lactic acids, acetic drug paclitaxel or rapamycin during sterilization. The hy- 20 acid, salts of any organic acid and organic amine, poly- droxyl, ester, amide groups are preferred because they glycidol, glycerol, multiglycerols, galactitol, di(ethylene are unlikely to react with therapeutic agents such as pa- glycol), tri(ethylene glycol), tetra(ethylene glycol), penta clitaxel or rapamycin. Sometimes amine and acid groups (ethylene glycol), poly (ethylene glycol) oligomers, di (pro- do react with paclitaxel and are not stable under ethylene pylene glycol), tri(propylene glycol), tetra(propylene gly- oxide sterilization, heating, and aging. When the mixtures 25 col, and penta(propylene glycol), poly(propylene glycol) or combinations described herein are formulated with pa- oligomers, a block copolymer of polyethylene glycol and clitaxel, a top coat layer may be advantageous in order polypropylene glycol, and derivatives and combinations to protect the drug layer and from premature drug loss thereof.(chemical compounds with one or more hydroxyl, during the device. amino, carbonyl, carboxyl, or ester moieties). Some of [0182] Preferred additives include p-isononylphenox- 30 these additives are both water-soluble and organic sol- ypolyglycidol, PEG glyceryl oleate, PEG glyceryl stear- vent-soluble. They have good adhesive properties and ate, polyglyceryl laurate, plyglyceryl oleate, polyglyceryl adhere to the surface of polyamide medical devices, such myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, as balloon catheters. They may therefore be used in the plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyc- adherent layer, top layer, and/or in the drug layer of em- eryl-6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10 35 bodiments of the present invention. The aromatic and oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmi- aliphatic groups increase the solubility of water insoluble tate, PEG sorbitan monolaurate, PEG sorbitan monolau- drugs in the coating solution, and the polar groups of rate, PEG sorbitan monooleate, PEG sorbitan stearate, alcohols and acids accelerate drug permeation of tissue. octoxynol, monoxynol, tyloxapol, sucrose monopalmi- [0183] Other preferred additives according to embod- tate, sucrose monolaurate, decanoyl-N-methylgluca- 40 iments of the invention include the combination or mixture mide, n-decyl - β-D-glucopyranoside, n-decyl - β -D-malt- or amide reaction products of an amino alcohol and an opyranoside, n-dodecyl -β -D-glucopyranoside, n-do- organic acid. Examples are lysine/glutamic acid, lysine decyl - β -D-maltoside, heptanoyl-N-methylglucamide, n- acetate, lactobionic acid/meglumine, lactobionic acid/ heptyl- P -D-glucopyranoside, n-heptyl - β -D-thiogluco- tromethanemine, lactobionic acid/diethanolamine, lactic side, n-hexyl - β -D-glucopyranoside, nonanoyl-N-meth- 45 acid/meglumine, lactic acid/tromethanemine, lactic acid/ ylglucamide, n-noyl- β -D-glucopyranoside, octanoyl-N- diethanolamine, gentisic acid/meglumine, gentisic acid/ methylglucamide, n-octyl- β -D-glucopyranoside, octyl - tromethanemine, gensitic acid/diethanolamine, vanillic β -D-thioglucopyranoside; cystine, tyrosine, tryptophan, acid/meglumine, vanillic acid/tromethanemine, vanillic leucine, isoleucine, phenylalanine, asparagine, aspartic acid/diethanolamine, benzoic acid/meglumine, benzoic acid, glutamic acid, and methionine (amino acids); ceto- 50 acid/tromethanemine, benzoic acid/diethanolamine, tiamine; cycothiamine, dexpanthenol, niacinamide, nic- acetic acid/meglumine, acetic acid/ tromethanemine, and otinic acid and its salt, pyridoxal 5-phosphate, nicotina- acetic acid/diethanolamine. mide ascorbate, riboflavin, riboflavin phosphate, thia- [0184] Other preferred additives according to embod- mine, folic acid, menadiol diphosphate, menadione so- iments of the invention include hydroxyl ketone, hydroxyl dium bisulfite, menadoxime, vitamin B12, vitamin K5, vi- 55 lactone, hydroxyl acid, hydroxyl ester, and hydroxyl tamin K6, vitamin K6, and vitamin U (vitamins); albumin, amide. Examples are gluconolactone, D-glucoheptono- immunoglobulins, caseins, hemoglobins, lysozymes, im- 1,4-lactone, glucooctanoic lactone, gulonic acid lactone, munoglobins, a-2-macroglobulin, fibronectins, vit- mannoic lactone, erythronic acid lactone, ribonic acid lac-

27 53 EP 2 500 046 A2 54 tone, glucuronic acid, gluconic acid, gentisic acid, lacto- bound water molecules. At the same time, they have long bionic acid, lactic acid, acetaminophen, vanillic acid, si- chains of fatty acid, alcohol, ether and ester that can both napic acid, hydroxybenzoic acid, methyl paraben, propyl complex with hydrophobic drugand integrateinto the lipid paraben, and derivatives thereof. structure of the cell membranes to form the part of the [0185] Other preferred additives that may be useful in 5 lipid structure. This deformation or loosening of the lipid embodiments of the present invention include riboflavin, membrane of target cells may further accelerate perme- riboflavin-phosphate sodium, Vitamin D3, folic acid (vi- ation of hydrophobic drug into tissue. tamin B9), vitamin 12, diethylenetriaminepentaacetic ac- [0188] For another example, L-ascorbic acid, thia- id dianhydride, ethylenediaminetetraacetic dianhydride, mine, maleic acids, niacinamide, and 2-pyrrolidone-5- maleic acid and anhydride, succinic acid and anhydride, 10 carboxylic acid all have a very high water and ethanol diglycolic anhydride, glutaric anhydride, L- ascorbic acid, solubility and a low molecular weight and small size. They thiamine, nicotinamide, nicotinic acid, 2-pyrrolidone-5- also have structural components including aromatic carboxylic acid, cystine, tyrosine, tryptophan, leucine, C=N, amino, hydroxyl, and carboxylic groups. These isoleucine, phenylalanine, asparagine, aspartic acid, structures have very good compatibility with paclitaxel glutamic acid, and methionine. 15 and rapamycin and can increase the solubility of these [0186] From a structural point of view, these additives water-insoluble drugs in water and enhance their absorp- sharestructural similarities and arecompatible with water tion into tissues. However, they often have poor adhesion insoluble drugs (such as paclitaxel and rapamycin). They to the surface of medical devices. They are therefore often contain double bonds such as C=C, C=N, C=O in preferably used in combination with other additives in the aromatic or aliphatic structures. These additives also20 drug layer and top layer where they are useful to enhance contain amine, alcohol, ester, amide, anhydride, carbox- drug absorption. Vitamin D2 and D3 are especially useful ylic acid, and/or hydroxyl groups. They may form hydro- because they themselves have anti-restenotic effects gen bonds and/or van der Waals interactions with drug. and reduce thrombosis, especially when used in combi- They are also useful in the top layer in the coating. Com- nation with paclitaxel. pounds containing one or more hydroxyl, carboxyl, or 25 [0189] In embodiments of the present invention, the amine, groups, for example, are especially useful as ad- additive is soluble in aqueous solvents and is soluble in ditives since they facilitate drug release from the device organic solvents. Extremely hydrophobic compounds surface and easily displace water next to the polar head that lack sufficient hydrophilic parts and are insoluble in groups and surface proteins of cell membranes and may aqueous solvent, such as the dye Sudan Red, are not thereby remove this barrier to hydrophobic drug perme- 30 useful as additives in these embodiments. Sudan red is ability, They accelerate movement of a hydrophobic drug also genotoxic. off the balloon to the lipid layer of cell membranes and [0190] In one embodiment, the concentration density tissues for which it has very high affinity. They may also ofthe at least one therapeutic agent applied to the surface carry or accelerate the movement of drug off the balloon of the medical device is from about 1 to 20 pg/mm2, or into more aqueous environments such as the interstitial 35 more preferably from about 2 to 6 Pg/mm2. In one em- space, for example, of vascular tissues that have been bodiment, the concentration of the at least one additive injured by balloon angioplasty or stent expansion. Addi- applied to the surface of the medical device is from about tives such as polyglyceryl fatty esters, ascorbic ester of 1 to 20 Pg/mm2. The ratio of additives to drug by weight fattyacids, sugar esters, alcohols and ethers of fatty acids in the coating layer in embodiments of the present inven- have fatty chains that can integrate into the lipid structure 40 tion is about 20 to 0.05, preferably about 10 to 0.5, or of target tissue membranes, carrying drug to lipid struc- more preferably about 5 to 0.8. tures. Some of the amino acids, vitamins and organic [0191] The relative amount of the therapeutic agent acids have aromatic C=N groups as well as amino, hy- and the additive in the coating layer may vary depending droxyl, and carboxylic components to their structure. on applicable circumstances. The optimal amount of the They have structural parts that can bind or complex with 45 additive can depend upon, for example, the particular hydrophobic drug, such as paclitaxel or rapamycin, and therapeutic agent and additive selected, the critical mi- they also have structural parts that facilitate tissue pen- celle concentration of the surface modifier if it forms mi- etration by removing barriers between hydrophobic drug celles, the hydrophilic-lipophilic-balance (HLB) of a sur- and lipid structure of cell membranes. factant or an additive’s octonol- water partition coefficient [0187] For example, isononylphenylpolyglycidol (Olin- 50 (P), the melting point of the additive, the water solubility 10 G and Surfactant-10G), PEG glyceryl monooleate, of the additive and/or therapeutic agent, the surface ten- sorbitan monolaurate (Arlacel 20), sorbitan monopalmi- sion of water solutions of the surface modifier, etc. tate (Span-40), sorbitan monooleate (Span- 80), sorbitan [0192] The additives are present in exemplary coating monostearate, polyglyceryl-10 oleate, polyglyceryl-10 compositions of embodiments of the present invention in laurate, polyglyceryl-10 palmitate, and polyglyceryl-10 55 amounts such that upon dilution with an aqueous solu- stearate all have more than four hydroxyl groups in their tion, the carrier forms a clear, aqueous dispersion or hydrophilic part. These hydroxyl groups have very good emulsion or solution, containing the hydrophobic thera- affinity for the vessel wall and can displace hydrogen- peutic agent in aqueous and organic solution. When the

28 55 EP 2 500 046 A2 56 relative amount of surfactant is too great, the resulting include probucol. Anti-proliferative agents can includes dispersion is visibly "cloudy". drugs such as amlodipine and doxazosin. Anti-mitotic [0193] The optical clarity of the aqueous dispersion agents and anti-metabolite agents that can be used in can be measured using standard quantitative techniques embodiments of the present invention includes drugs for turbidity assessment. One convenient procedure to 5 such as methotrexate, azathioprine, vincristine, vinblas- measure turbidity is to measure the amount of light of a tine, 5-fluorouracil, adriamycin, and mutamycin. Antibi- given wavelength transmitted by the solution, using, for otic agents for use in embodiments of the present inven- example, an UV-visible spectrophotometer. Using this tion include penicillin, cefoxitin, oxacillin, tobramycin, and measure, optical clarity corresponds to high transmit- gentamicin. Suitable antioxidants for use in embodi- tance, since cloudier solutions will scatter more of the 10 ments of the present invention include probucol. Addi- incident radiation, resulting in lower transmittance meas- tionally, genes or nucleic acids, or portions thereof can urements. be used as the therapeutic agent in embodiments of the [0194] Another method of determining optical clarity present invention. Furthermore, collagen-synthesis in- and carrier diffusivity through the aqueous boundary lay- hibitors, such as tranilast, can be used as a therapeutic er is to quantitatively measure the size of the particles of 15 agent in embodiments of the present invention. which the dispersion is composed. These measurements [0201] Photosensitizing agents for photodynamic or can be performed on commercially available particle size radiation therapy, including various porphyrin com- analyzer. pounds such as porfimer, for example, are also useful [0195] Other considerations will further inform the as drugs in embodiments of the present invention. choice of specific proportions of different additives.20 [0202] Drugs for use in embodiments of the present These considerations include the degree of bioaccepta- invention also include everolimus, somatostatin, tac- bility of the additives and the desired dosage of hydro- rolimus, roxithromycin, dunaimycin, ascomycin, bafilo- phobic therapeutic agent to be provided. mycin, erythromycin, midecamycin, josamycin, concan- [0196] Therapeutic Agent amycin, clarithromycin, troleandomycin, folimycin, ceriv- [0197] The drugs or biologically active materials, which 25 astatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, can be used in embodiments of the present invention, atorvastatin, pravastatin, pitavastatin, vinblastine, vinc- can be any therapeutic agent or substance. The drugs ristine, vindesine, vinorelbine, etoposide, teniposide, can be of various physical states, e.g., molecular distri- nimustine, carmustine, lomustine, cyclophosphamide, 4- bution, crystal forms or cluster forms. Examples of drugs hydroxycyclophosphamide, estramustine, melphalan, that are especially useful in embodiments of the present 30 ifosfamide, trofosfamide, chlorambucil, bendamustine, invention are lipophilic substantially water insoluble dacarbazine, busulfan, procarbazine, treosulfan, temo- drugs, such as paclitaxel, rapamycin, daunorubicin, dox- zolomide, thiotepa, daunorubicin, doxorubicin, aclaru- orubicin, lapachone, vitamin D2 and D3 and analogues bicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mi- and derivatives thereof. These drugs are especially suit- tomycin, dactinomycin, methotrexate, fludarabine, able for use in a coating on a balloon catheter used to 35 fludarabine-5’-dihydrogenphosphate, cladribine, mer- treat tissue of the vasculature. captopurine, thioguanine, cytarabine, fluorouracil, gem- [0198] Other drugs that may be useful in embodiments citabine, capecitabine, docetaxel, carboplatin, cisplatin, of the present invention include, without limitation, glu- oxaliplatin, amsacrine, irinotecan, topotecan, hydroxy- cocorticoids (e.g., dexamethasone, betamethasone), carbamide, miltefosine, pentostatin, aldesleukin, tretin- hirudin, angiopeptin, aspirin, growth factors, antisense 40 oin, asparaginase, pegaspargase, anastrozole, exemes- agents, anti-cancer agents, anti-proliferative agents, ol- tane, letrozole, formestane, aminoglutethimide, adriamy- igonucleotides, and, more generally, anti- platelet agents, cin, azithromycin, spiramycin, cepharantin, smc prolifer- anti-coagulant agents, anti-mitotic agents, antioxidants, ationinhibitor- 2w, epothilone Aand B,mitoxantrone, aza- anti-metabolite agents, anti-chemotactic, and anti-in- thioprine, mycophenolatmofetil, myc- c- antisense, b- flammatory agents. 45 myc-antisense, betulinic acid, camptothecin, lapachol, [0199] Also useful in embodiments of the present in- beta.-lapachone, podophyllotoxin, betulin, podophyllic vention are polynucleotides, antisense, RNAi, or siRNA, acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), for example, that inhibit inflammation and/or smooth peginterferon a-2b, lenograstim (r-HuG-CSF), filgrastim, muscle cell or fibroblast proliferation. macrogol, dacarbazine, basiliximab, daclizumab, selec- [0200] Anti-platelet agents can include drugs such as 50 tin (cytokine antagonist), CETP inhibitor, cadherines, cy- aspirin and dipyridamole. Aspirin is classified as an an- tokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin, algesic, antipyretic, anti-inflammatory and anti-platelet ciprafloxacin, camptothecin, fluroblastin, monoclonal an- drug. Dipyridamole is a drug similar to aspirin in that it tibodies, which inhibit the muscle cell proliferation, bFGF has anti-platelet characteristics. Dipyridamole is also antagonists, probucol, prostaglandins, 1,11-dimethoxy- classified as a coronary vasodilator. Anti-coagulant55 canthin-6-one, hydroxy- 1- 11-methoxycanthin-6-one, agents for use in embodiments of the present Invention scopoletin, colchicine, NO donors such as pentaerythritol can include drugs such as heparin, protamine, hirudin tetranitrate and syndnoeimines, nitrosoderivatives, S- and tick anticoagulant protein. Antioxidant agents can tamoxifen, staurosporine, beta- estradiol, a-estradiol, es-

29 57 EP 2 500 046 A2 58 triol, estrone, ethinylestradiol, fosfestrol, medroxypro- agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, gesterone, estradiol cypionates, estradiol benzoates, tra- 4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 nilast, kamebakaurin and other terpenoids, which are ap- and B7, tubeimoside, bruceanol A, B and C, bruceanti- plied in the therapy of cancer, verapamil, tyrosine kinase noside C, yadanziosides N and P, isodeoxyelephantopin, inhibitors (tyrphostines), cyclosporine A, 6-a-hydroxy- 5 tomenphantopin A and B, coronarin A, B, C and D, ursolic paclitaxel, baccatin, taxotere and other macrocyclic oli- acid, hyptatic acid A, zeorin, iso- iridogermanal, mayten- gomers of carbon suboxide (MCS) and derivatives there- foliol, effusantin A, excisanin A and B, longikaurin B, scul- of, mofebutazone, acemetacin, diclofenac, lonazolac, poneatin C, kamebaunin, leukamenin A and B, 13,18- dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ke- dehydro-6-a-senecioyloxychaparrin, taxamairin A and B, toprofen, mefenamic acid, piroxicam, meloxicam, chlo- 10 regenilol, triptolide, moreover cymarin, apocymarin, aris- roquine phosphate, penicillamine, hydroxychloroquine, tolochic acid, anopterin, hydroxyanopterin, anemonin, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, protoanemonin, berberine, cheliburin chloride, cictoxin, beta. -sitosterin, ademetionine, myrtecaine, polidocanol, sinococuline, bombrestatin A and B, cudraisoflavone A, nonivamide, levomenthol, benzocaine, aescin, ellipti- curcumin, dihydronitidine, nitidine chloride, 12-beta-hy- cine, D-24851 (Calbiochem), colcemid, cytochalasin A- 15 droxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic E, indanocine, nocodazole, S 100 protein, bacitracin, vit- acid, helenalin, indicine, indicine-N-oxide, lasiocarpine, ronectin receptor antagonists, azelastine, guanidyl cy- inotodiol, glycoside 1a, podophyllotoxin, justicidin A and clase stimulator tissue inhibitor of metal proteinase-1 and B, larreatin, malloterin, mallotochromanol, isobutyrylmal- -2, free nucleic acids, nucleic acids incorporated into vi- lotochromanol, maquiroside A, marchantin A, maytan- rus transmitters, DNA and RNA fragments, plasminogen 20 sine, lycoridicin, margetine, pancratistatin, liriodenine, activator inhibitor-1, plasminogen activator inhibitor-2, bisparthenolidine, oxoushinsunine, aristolactam- All, bis- antisense oligonucleotides, VEGF inhibitors, IGF-1, ac- parthenolidine, periplocoside A, ghalakinoside, ursolic tive agents from the group of antibiotics such as cefadrox- acid, deoxypsorospermin, psychorubin, ricin A, sangui- il, cefazolin, cefaclor, cefotaxim, tobramycin, gentamy- narine, manwu wheat acid, methylsorbifolin, sphathelia- cin, penicillins such as dicloxacillin, oxaciliin, sulfona- 25 chromen, stizophyllin, mansonine, strebloside, akage- mides, metronidazol, antithrombotics such as arga- rine, dihydrousambarensine, hydroxyusambarine, troban, aspirin, abciximab, synthetic antithrombin, biva- strychnopentamine, strychnophylline, usambarine, us- lirudin, coumadin, enoxaparin, desulphated and N- ambarensine, berberine, liriodenine, oxoushinsunine, reacetylated heparin, tissue plasminogen activator, GpI- daphnoretin, lariciresinol, methoxylariciresinol, syrin- Ib/IIIa platelet membrane receptor, factor Xa inhibitor an- 30 garesinol, umbelliferon, afromoson, acetylvismione B, tibody, heparin, hirudin, r-hirudin, PPACK, protamin, desacetylvismione A, and vismione A and B. prourokinase, streptokinase, warfarin, urokinase, va- [0203] A combination of drugs can also be used in em- sodilators such as dipyramidole, trapidil, nitroprussides, bodiments of the present invention. Some of the combi- PDGF antagonists such as triazolopyrimidine and nations have additive effects because they have a differ- seramin, ACE inhibitors such as captopril, cilazapril, lisi- 35 ent mechanism, such as paclitaxel and rapamycin, pacl- nopril, enalapril, losartan, thiol protease inhibitors, pros- itaxel and active vitamin D, paclitaxel and lapachone, ra- tacyclin, vapiprost, interferon a, .beta and y, histamine pamycin and active vitamin D, rapamycin and lapachone. antagonists, serotonin blockers, apoptosis inhibitors, ap- Because of the additive effects, the dose of the drug can optosis regulators such as p65 NF- kB or Bcl- xL antisense be reduced as well. These combinations may reduce oligonucleotides, halofuginone, nifedipine, tranilast, mol- 40 complications from using a high dose of the drug. sidomine, tea polyphenols, epicatechin gallate, epigallo- [0204] Adherent Layer catechin gallate, Boswellic acids and derivatives thereof, [0205] The adherent layer, which is an optional layer leflunomide, anakinra, etanercept, sulfasalazine, etopo- underlying the drug coating layer, improves the adher- side, dicloxacillin, tetracycline, triamcinolone, mutamy- ence of the drug coating layer to the exterior surface of cin, procainamide, retinoic acid, quinidine, disopyramide, 45 the medical device and protects coating integrity. If drug flecainide, propafenone, sotalol, amidorone, natural and and additive differ in their adherence to the medical de- synthetically obtained steroids such as bryophyllin A, in- vice, the adherent layer may prevent differential loss (dur- otodiol, maquiroside A, ghalakinoside, mansonine, stre- ing transit) or elution (at the target site) of drug layer com- bloside, hydrocortisone, betamethasone, dexametha- ponents in order to maintain consistent drug-to-additive sone, non-steroidal substances (NSAIDS) such as feno- 50 or drug-to-drug ratio in the drug layer and therapeutic profen, ibuprofen, indomethacin, naproxen, phenylbuta- delivery at the target site of intervention. Furthermore, zone and other antiviral agents such as acyclovir, gan- the adherent layer may function to facilitate release of ciclovir and zidovudine, antimycotics such as clotrima- coating layer components which otherwise might adhere zole, flucytosine, griseofulvin, ketoconazole, micona- too strongly to the device for elution during brief contact zole, nystatin, terbinafine, antiprozoal agents such as 55 with tissues at the target site. For example, in the case chloroquine, mefloquine, quinine, moreover natural ter- where a particular drug binds the medical device tightly, penoids such as hippocaesculin, barringtogenol-C21 more hydrophilic components are incorporated into the -angelate, 14-dehydroagrostistachin, agroskerin, adherent layer in order to decrease affinity of the drug to

30 59 EP 2 500 046 A2 60 the device surface. weight additives include polyethylene oxide, polyethyl- [0206] As described above, the adherent layer com- ene glycol, and polyvinyl pyrrolidone. Hydrophobic drug prises a polymer or an additive or mixtures of both. The itself can act as a top layer component. For example, polymers that are useful for forming the adherent layer paclitaxel or rapamycin are hydrophobic. They can be are ones that are biocompatible and avoid irritation of 5 used in the top layer. On the other hand, the top layer body tissue. Some examples of polymers that are useful cannot erode too slowly or it might actually slow the re- for forming the adherent layer are polymers that are bi- lease of drug during deployment at the target site. Other ostable, such as polyurethanes, silicones, and polyes- additives useful in the top coat include additives that ters. Other polymers that are useful for forming the ad- strongly interact with drug or with the coating layer, such herent layer include polymers that can be dissolved and 10 as p-isononylphenoxypolyglycidol, PEG laurate, Tween polymerized on the medical device. 20, Tween 40, Tween 60, PEG oleate, PEG stearate, [0207] Some examples of polymers that are useful in PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl the adherent layer of embodiments of the present inven- stearate, polyglyceryl laurate, plyglyceryl oleate, polyg- tion include polyolefins, polyisobutylene, ethylene- α-ole- lyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 fin copolymers, acrylic polymers and copolymers, poly- 15 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate, vinyl chloride, polyvinyl methyl ether, polyvinylidene flu- polyglyceryl-6 palmitate, polyglyceryl- 10 laurate, plyglyc- oride and polyvinylidene chloride, polyacrylonitrile, poly- eryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl- 10 vinyl ketones, polystyrene, polyvinyl acetate, ethylene- palmitate PEG sorbitan, monolaurate, PEG sorbitan methyl methacrylate copolymers, acrylonitrile-styrene monolaurate, PEG sorbitan monooleate, PEG sorbitan copolymers, ABS resins, Nylon 12 and its block copoly- 20 stearate, PEG oleyl ether, PEG laurayl ether, octoxynol, mers,polycaprolactone, polyoxymethylenes, polyethers, monoxynol, tyloxapol, sucrose monopalmitate, sucrose epoxy resins, polyurethanes, rayon- triacetate, cellulose, monolaurate, decanoyl-N-methylglucamide, n-decyl -β cellulose acetate, cellulose butyrate, cellophane, cellu- -D-glucopyranoside, n-decyl - β -D-maltopyranoside, n- lose nitrate, cellulose propionate, cellulose ethers, car- dodecyl - β -D-glucopyranoside, n-dodecyl - β-D-malto- boxymethyl cellulose, chitins, polylactic acid, polyglycolic 25 side, heptanoyl-N-methylglucamide, n-heptyl- β -D-glu- acid, polylactic acid- polyethylene oxide copolymers, pol- copyranoside, n-heptyl - β -D-thioglucoside, n-hexyl - β yethylene glycol, polypropylene glycol, polyvinyl alcohol, -D-glucopyranoside, nonanoyl-N-methylglucamide, n- and mixtures and block copolymers thereof. noyl - β -D-glucopyranoside, octanoyl-N-methylgluca- [0208] Since the medical device undergoes mechani- mide, n-octyl- β -D-glucopyranoside, octyl - β -D-thioglu- cal manipulation, i.e., expansion and contraction, exam- 30 copyranoside; cystine, tyrosine, tryptophan, leucine, iso- ples of polymers that are useful in the adherent layer leucine, phenylalanine, asparagine, aspartic acid, include elastomeric polymers, such as silicones (e.g., glutamic acid, and methionine; acetic anhydride, benzoic polysiloxanes and substituted polysiloxanes), poly- anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic ac- urethanes, thermoplastic elastomers, ethylene vinyl ac- id, sodium pyrrolidone carboxylate, ethylenediamine- etate copolymers, polyolefin elastomers, and EPDM rub- 35 tetraacetic dianhydride, maleic and anhydride, succinic bers. Due to the elastic nature of these polymers, when anhydride, diglycolic anhydride, glutaric anhydride, ace- these polymers are used, the coating better adheres to tiamine, benfotiamine, pantothenic acid; cetotiamine; cy- the surface of the medical device when the device is sub- cothiamine, dexpanthenol, niacinamide, nicotinic acid, jected to forces or stress. pyridoxal 5-phosphate, nicotinamide ascorbate, ribofla- [0209] The adherent layer may also comprise one or 40 vin, riboflavin phosphate, thiamine, folic acid, menadiol more of the additives previously described, or other com- diphosphate, menadione sodium bisulfite, menadoxime, ponents, in order to maintain the integrity and adherence vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vi- of the coating layer to the device and to facilitate both tamin U; albumin, immunoglobulins, caseins, hemoglob- adherence of drug and additive components during tran- ins, lysozymes, immunoglobins, a-2-macroglobulin, fi- sit and rapid elution during deployment at the site of ther- 45 bronectins, vitronectins, firbinogens, lipases, benzalko- apeutic intervention. nium chloride, benzethonium chloride, docecyl trimethyl [0210] Top Layer ammonium bromide, sodium docecylsulfates, dialkyl [0211] In order to further protect the integrity of the methylbenzyl ammonium chloride, and dialkylesters of drug layer, an optional top layer may be applied toprevent sodium sulfonsuccinic acid, L-ascorbic acid and its salt, loss of drug during transit through tortuous anatomy to 50 D-glucoascorbic acid and its salt, tromethamine, trieth- the target site or during the initial expansion of the device anolamine, diethanolamine, meglumine, glucamine, beforethe coating makes direct contactwith target tissue. amine alcohols, glucoheptonic acid, glucomic acid, hy- The top layer may release slowly in the body lumen while droxyl ketone, hydroxyl lactone, gluconolactone, gluco- protecting the drug layer. The top layer will erode more heptonolactone, glucooctanoic lactone, gulonic acid lac- slowly if it is comprised of more hydrophobic, high mo- 55 tone, mannoic lactone, ribonic acid lactone, lactobionic lecular weight additives. Surfactants are examples of acid, glucosamine, glutamic acid, benzyl alcohol, benzo- more hydrophobic structures with long fatty chains, such ic acid, hydroxybenzoic acid, propyl 4- hydroxybenzoate, asTween 20 and polyglyceryl oleate. High molecular lysine acetate salt, gentisic acid, lactobionic acid, lactitol,

31 61 EP 2 500 046 A2 62 sinapic acid, vanillic acid, vanillin, methyl paraben, propyl [0217] In other embodiments, two or more solvents, paraben, sorbitol, xylitol, cyclodextrin, (2-hydroxypro- two or more therapeutic agents, and/or two or more ad- pyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic ac- ditives may be used in the coating solution. id, lysine acetate, gentisic acid, catechin, catechin gal- [0218] In other embodiments, a therapeutic agent, an late, tiletamine, ketamine, propofol, lactic acids, acetic 5 additive and a polymeric material may be used in the acid, salts of any organic acid and organic amine, poly- coating solution, for example in a stent coating. In the glycidol, glycerol, multiglycerols, galactitol, di(ethylene coating, the therapeutic agent is not encapsulated in pol- glycol), tri(ethylene glycol), tetra(ethylene glycol), penta ymer particles. (ethylene glycol), poly(ethylene glycol) oligomers, di (pro- [0219] Various techniques may be used for applying a pylene glycol), tri(propylene glycol), tetra(propylene gly- 10 coatingsolution to amedical device such ascasting, spin- col, and penta(propylene glycol), poly(propylene glycol) ning, spraying, dipping (immersing), ink jet printing, elec- oligomers, a block copolymer of polyethylene glycol and trostatic techniques, and combinations of these process- polypropylene glycol, and derivatives and combinations es. Choosing an application technique principally de- thereof. pends on the viscosity and surface tension of the solution. [0212] Solvents 15 In embodiments of the present invention, dipping and [0213] Solvents for preparing of the coating layer may spraying are preferred because it makes it easier to con- includes, as examples, any combination of one or more trol the uniformity of the thickness of the coating layer as of the following: (a) water, (b) alkanes such as hexane, well as the concentration of the therapeutic agent applied octane, cyclohexane, and heptane, (c) aromatic solvents to the medical device. Regardless of whether the coating such as benzene, toluene, and xylene, (d) alcohols such 20 is applied by spraying or by dipping or by another method as ethanol, propanol, and isopropanol, diethylamide, eth- or combination of methods, each layer is usually depos- ylene glycol monoethyl ether, Trascutol, and benzyl al- ited on the medical device in multiple application steps cohol (e) ethers such as dioxane, dimethyl ether and tet- in order to control the uniformity and the amount of ther- rahydrofuran, (f) esters/acetates such as ethyl acetate apeutic substance and additive applied to the medical and isobutyl acetate, (g) ketones such as acetone, ace- 25 device. tonitrile, diethyl ketone, and methyl ethyl ketone, and (h) [0220] Each applied layer is from about 0.1 microns to mixture of water and organic solvents such as water/ eth- 15 microns in thickness. The total number of layers ap- anol, water/acetone, water/methanol, water/tetrahydro- plied to the medical device is in a range of from about 2 furan, A preferred solvent in the top coating layer is ac- to 50. The total thickness of the coating is from about 2 etone. 30 to 200 microns. [0214] Organic solvents, such as short-chained alco- [0221] As discussed above, spraying and dipping are hol, dioxane, tetrahydrofuran, dimethylformamide, ace- particularly useful coating techniques for use in embod- tonitrile, dimethylsulfoxide, etc., are particularly useful iments of the present invention. In a spraying technique, and preferred solvents in embodiments of the present a coating solution or suspension of an embodiment of invention because these organic solvents generally dis- 35 the present invention is prepared and then transferred to rupt collodial aggregates and co-solubilize all the com- an application device for applying the coating solution or ponents in the coating solution. suspension to a balloon catheter. [0215] The therapeutic agent and additive or additives [0222] An application device that may be used is a may be dispersed in, solubilized, or otherwise mixed in paint jar attached to an air brush, such as a Badger Model the solvent. The weight percent of drug and additives in 40 150, supplied with a source of pressurized air through a the solvent may be in the range of 0.1-80% by weight, regulator (Norgren, 0-160 psi). When using such an ap- preferably 2-20% by weight. plication device, once the brush hose is attached to the [0216] Another embodiment of the invention relates to source of compressed air downstream of the regulator, a method for preparing a medical device, particularly, for the air is applied. The pressure is adjusted to approxi- example, a balloon catheter or a stent. First, a coating 45 mately 15-25 psi and the nozzle condition checked by solution or suspension comprising at least one solvent, depressing the trigger. at least one therapeutic agent, and at least one additive [0223] Prior to spraying, both ends of the relaxed bal- is prepared. In at least one embodiment, the coating so- loon are fastened to the fixture by two resilient retainers, lution or suspension includes only these three compo- i.e., alligator clips, and the distance between the clips is nents. The content of the therapeutic agent in the coating 50 adjusted so that the balloon remained in a deflated, fold- solution can be from 0.5-50% by weight based on the ed, or an inflated or partially inflated, unfolded condition. total weight of the solution. The content of the additive in The rotor is then energized and the spin speed adjusted the coating solution can be from 1-45% by weight, 1 to to the desired coating speed, about 40 rpm. 40% by weight, or from 1-15% by weight based on the [0224] With the balloon rotating in a substantially hor- total weight of the solution. The amount of solvent used 55 izontal plane, the spray nozzle is adjusted so that the dependson the coating processand viscosity.It will affect distance from the nozzle to the balloon is about 1-4 inch- the uniformity of the drug-additive coating but will be es. First, the coating solution is sprayed substantially hor- evaporated. izontally with the brush being directed along the balloon

32 63 EP 2 500 046 A2 64 from the distal end of the balloon to the proximal end and loon, porous balloon, and weeping balloon, cutting bal- then from the proximal end to the distal end in a sweeping loon catheters, scoring balloon catheters, self-expanded motion at a speed such that one spray cycle occurred in and balloon expanded-stents, guide catheters, guide about three balloon rotations. The balloon is repeatedly wires, embolic protection devices, and various imaging sprayed with the coating solution, followed by drying, until 5 devices. an effective amount of the drug is deposited on the bal- [0232] As mentioned above, one example of a medical loon. device that is particularly useful in the present invention [0225] In one embodiment of the present invention, the is a coated balloon catheter. A balloon catheter typically balloon is inflated or partially inflated, the coating solution has a long, narrow, hollow tube tabbed with a miniature, is applied to the inflated balloon, for example by spraying, 10 deflated balloon. In embodiments of the present inven- and then the balloon is deflated and folded before drying. tion, the balloon is coated with a drug solution. Then, the Drying may be performed under vacuum. balloon is maneuvered through the cardiovascular sys- [0226] It should be understood that this description of tem to the site of a blockage, occlusion, or other tissue an application device, fixture, and spraying technique is requiring a therapeutic agent. Once in the proper posi- exemplary only. Any other suitable spraying or other15 tion, the balloon is inflated and contacts the walls of the technique may be used for coating the medical device, blood vessel and/or a blockage or occlusion. It is an ob- particularly for coating the balloon of a balloon catheter ject of embodiments of the present invention to rapidly or stent delivery system or stent. deliver drug to and facilitate absorption by target tissue. [0227] After the medical device is sprayed with the It is advantageous to efficiently deliver drug to tissue in coating solution, the coated balloon is subjected to a dry- 20 as brief a period of time as possible while the device is ing in which the solvent in the coating solution is evapo- deployed at the target site. The therapeutic agent is re- rated. This produces a coating matrix on the balloon con- leased into such tissue, for example the vessel walls, in taining the therapeutic agent. One example of a drying about 0.1 to 30 minutes, for example, or preferably about technique is placing a coated balloon into an oven at 0.1 to 10 minutes, or more preferably about 0.2 to 2 min- approximately 20°C or higher for approximately 24 hours. 25 utes, or most preferably, about 0.1 to 1 minutes, of bal- Any other suitable method of drying the coating solution loon inflation time pressing the drug coating into contact may be used. The time and temperature may vary with with diseased vascular tissue. particular additives and therapeutic agents. [0233] Given that a therapeutically effective amount of [0228] Optional Post Treatment the drug can be delivered by embodiments of the present [0229] After depositing the drug-additive containing 30 invention into, for example, the arterial wall, in some cas- layer on the device of certain embodiments of the present es the need for a stent may be eliminated, obviating the invention, dimethyl sulfoxide (DMSO) or other solvent complications of fracture and thrombosis associated may be applied, by dip or spray or other method, to the therewith. finished surface of the coating. DMSO readily dissolves [0234] Should placement of a stent still be desired, a drugs and easily penetrates membranes and may en- 35 particularly preferred use for embodiments of the present hance tissue absorption. invention is to crimp a stent, such as a bare metal stent [0230] It is contemplated that the medical devices of (BMS), for example, over the drug coated balloon de- embodiments of the present invention have applicability scribed in embodiments herein. When the balloon is in- for treating blockages and occlusions of any body pas- flated to deploy the stent at the site of diseased vascu- sageways, including, among others, the vasculature, in- 40 lature, an effective amount of drug is delivered into the cluding coronary, peripheral, and cerebral vasculature, arterial wall to prevent or decrease the severity of reste- the gastrointestinal tract, including the esophagus, stom- nosis or other complications. Alternatively, the stent and ach, small intestine, and colon, the pulmonary airways, balloon may be coated together, or the stent may be coat- including the trachea, bronchi, bronchioles, the sinus, the ed and then crimped on a balloon. biliary tract, the urinary tract, prostate and brain passag- 45 [0235] Further, the balloon catheter may be used to es. They are especially suited for treating tissue of the treat vascular tissue/ disease alone or in combination with vasculature with, for example, a balloon catheter or a other methods for treating the vasculature, for example, stent. photodynamic therapy or atherectomy. Atherectomy is a [0231] Yet another embodiment of the present inven- procedure to remove plaque from arteries. Specifically, tion relates to a method of treating a blood vessel. The 50 atherectomy removes plaque from peripheral and coro- method includes inserting a medical device comprising nary arteries. The medical device used for peripheral or a coating into a blood vessel. The coating layer comprises coronary atherectomy may be a laser catheter or a ro- a therapeutic agent and an additive. In this embodiment, tablator or a direct atherectomy device on the end of a the medical device can be configured as having at least catheter. The catheter is inserted into the body and ad- an expandable portion. Some examples of such devices 55 vanced through an artery to the area of narrowing. After include balloon catheters, perfusion balloon catheters, the atherectomy has removed some of the plaque, bal- an infusion catheter such as distal perforated drug infu- loon angioplasty using the coated balloon of embodi- sion catheters, a perforated balloon, spaced double bal- ments of the present invention may be performed, in ad-

33 65 EP 2 500 046 A2 66 dition, stenting may be performed thereafter, or simulta- present invention. neous with expansion of the coated balloon as described [0243] Example 1. above. Photodynamic therapy is a procedure where light [0244] Preparation of coating solutions: or irradiated energy is used to kill target cells in a patient. [0245] Formulation 1-50-150 mg (0.06-0.18 mmole) A light-activated photosensitizing drug may be delivered 5 paclitaxel, 2-6 ml acetone (or ethanol), 25-100 mg ascor- to specific areas of tissue by embodiments of the present byl palmitate, 25-100 mg L-ascorbic acid and 0.5 ml eth- invention. A targeted light or radiation source selectively anol were mixed. activates the drug to produce a cytotoxic response and [0246] Formulation 2-50-150 mg (0.05-0.16 mmole) mediate a therapeutic anti-proliferative effect. rapamycin, 2-6 ml acetone (or ethanol), 50-200 mg pol- [0236] In some of the embodiments of drug- containing 10 yglyceryl-10 oleate and 0.5 ml ethanol were wemixed. coatings and layers according to the present invention, [0247] Formulation 3-50-150 mg (0.06-0.18 mmole) the coating or layer does not include polymers, oils, or paclitaxel, 2-6 ml acetone (or ethanol), 50-200 mg octox- lipids. And, furthermore, the therapeutic agent is not en- ynol-9 and 0.5 ml ethanol were mixed. capsulated in polymer particles, micelles, or liposomes. [0248] Formulation 4-50-150 mg (0,05-0.16 mmole) As described above, such formulations have significant 15 rapamycin, 2-6 ml acetone (or ethanol), 50-200 mg p- disadvantages and can inhibit the intended efficient, rap- isononylphenoxypolyglycidol and 0.5 ml ethanol were id release and tissue penetration of the agent, especially mixed. in the environment of diseased tissue of the vasculature. [0249] Formulation 5-50-150 mg (0.06-0.18 mmole) [0237] Although various embodiments are specifically paclitaxel, 2-6 ml acetone (or ethanol), 50-200 mg Ty- illustrated and described herein, it will be appreciated 20 loxapol and 0.5 ml methanol were mixed. that modifications and variations of the present invention [0250] Formulation 6-50-150 mg (0.05-0.16 mmole) are covered by the above teachings and are within the rapamycin in 2-6 ml acetone (or ethanol), 50-150 mg L- purview of the appended claims without departing from ascorbic acid in 1 ml water or ethanol, both, then were the spirit and intended scope of the invention. mixed. [0238] Other than the operating examples, or where 25 [0251] Formulation 7-50-150 mg (0.06-0.18 mmole) otherwise indicated, all numbers expressing quantities paclitaxel, 2-6 ml acetone (or ethanol), 50-150 mg niac- of components in a layer, reaction conditions, and so inamide in 1 ml water or ethanol, were mixed. forth used in the specification and claims are to be un- [0252] Formulation 8--50-150 mg (0.05-0.16 mmole) derstood as being modified in all instances by the term rapamycin, 2-6 ml acetone (or ethanol), 50-200 mg nic- "about." Accordingly, unless otherwise indicated to the 30 otinic acid in 1 ml water or ethanol, were mixed. contrary, the numerical parameters set forth in this spec- [0253] Formulation 9-50-150 mg (0.06-0.18 mmole) ification and attached claims are approximations that paclitaxel, 2-6 ml ethanol (or acetone), 150 mg thiamine may vary depending upon the desired properties sought hydrochloride in 1 ml water, and 0.5 ml were mixed. to be obtained by the present disclosure, [0254] Formulation 10-50-150 mg (0.05-0.16 mmole) [0239] Preparation 35 rapamycin, 2-6 ml acetone or ethanol, 150 mg 2-pyrro- [0240] The medical device and the coating layers of lidone-5-carboxylic acid in 1 ml water or ethanol, awere embodiments of the present invention can be made ac- mixed. cording to various methods. For example, the coating [0255] Formulation 11-50-150 mg (0.06-0.18 mmole) solution can be prepared by dispersing, dissolving, dif- paclitaxel, 2-6 ml acetone (or ethanol), 75 mg p-isonon- fusing, or otherwise mixing all the ingredients, such as a 40 ylphenoxypolyglycidol, 75 mg niacinamide in 1 ml water therapeutic agent, an additive, and a solvents, simulta- or ethanol, and 0.5 ml ethanol were mixed. neously together. Also, the coating solution can be pre- [0256] Formulation 12-50-150 mg (0.05-0.16 mmole) pared by sequentially adding each component based on rapamycin, 2-6 ml acetone (or ethanol), 75 mg Octoxy- solubility or any other parameters. For example, the coat- nol-9, 75 mg thiamine hydrochloride in 1 ml water or eth- ing solution can be prepared by first adding the thera- 45 anol, and 0.5 ml ethanol were mixed. peutic agent to the solvent and then adding the additive. [0257] Formulation 13-50-150 mg (0.06-0.18 mmole) Alternatively, the additive can be added to the solvent paclitaxel, 2-6 ml acetone (or ethanol), 75 mg p-isonon- first and then the therapeutic agent can be later added. ylphenoxypolyglycidol, 75 mg 2- pyrrolidone-5-carboxylic If the solvent used does not sufficiently dissolve the drug, acid in 1 ml water or ethanol , and 0.5 ml ethanol were it is preferable to first add the additive to the solvent, then 50 mixed. the drug, since the additive will increase drug solubility [0258] Formulation 14-50-150 mg (0.06-0.18 mmole) in the solvent. paclitaxel, 2-6 ml acetone (or ethanol), 75 mg p-isonon- [0241] EXAMPLES ylphenoxypolyglycidol, 75 mg nicotinic acid in 1 ml water [0242] The following examples include embodiments or ethanol , and 0.5 ml methanol were mixed. of medical devices and coating layers within the scope 55 [0259] Formulation 15 50-150 mg (0.06-0.18 mmole) of the present invention. While the following examples paclitaxel, 2-6ml acetone (or ethanol), 75 mg p-isonon- are considered to embody the present invention, the ex- ylphenoxypolyglycidol, 75 mg L- ascorbic acid in 1 ml wa- amples should not be interpreted as limitations upon the ter or ethanol, and 0.5 ml ethanol were mixed.

34 67 EP 2 500 046 A2 68

[0260] Formulation 16 50-150 mg (0.06-0.18 mmole) anol, 35-70 mg Triton X-100, and 35-70 mg N- heptanoyl paclitaxel was dissolved in 5-10 ml ethylene chloride. The N-methylglucamine were mixed. solution was added to 30 ml of human serum albumin [0273] Example 2 solution (5%w/v). The solution was then homogenized [0274] 5 PTCA balloon catheters (3 mm in diameter for 5 minutes at low speed to form an emulsion. The emul- 5 and 20 mm in length) were folded with three wings under sion was then sonicated at 40 kHz at 50-90% power at vacuum. The folded balloon under vacuum was sprayed 0 to 5°C for 1 to 5 min. or dipped in a formulation (1-17) in example 1. The folded [0261] Formulation 17-50-150 mg (0.05-0.16 mmole) balloon was then dried, sprayed or dipped again, dried rapamycin was dissolved in 5-10 ml methylene chloride again, and sprayed or dipped again until sufficient and 10-30 mg p-isononylphenoxypolyglycidol. The solu- 10 amount of drug on the balloon (3 microgram per square tion was added to 30 ml of human serum albumin solution mm) was obtained. The coated folded balloon was then (5%w/v). The solution was then homogenized for 5 min- rewrapped and sterilized for animal testing. utes at low speed to form an emulsion, The emulsion was [0275] Example 3 then sonicated at 40 kHz at 50-90% power at 0 to 5 °C [0276] 5 PTCA balloon catheters (3 mm in diameter for 1 to 5 min. 15 and 20 mm in length) was folded with three wings under [0262] Formulation 18-50-100 mg (0.06-0.12 vacuum. The folded balloon under vacuum was sprayed mmmole) paclitaxel, 1-1.6 ml acetone, 1-1.6 ml ethanol, or dipped in a formulation (1-5) in example 1. The folded 0.4-1.0 ml water, and 50-200 mg gluconolactone were balloon was then dried, sprayed or dipped again in a for- mixed. mulation (6-10), dried, and sprayed or dipped again until [0263] Formulation 19-35-70 mg (0.042-0.08420 sufficient amount of drug on the balloon (3 microgram mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 ml eth- per square mm) was obtained. The coated folded balloon anol, 35-70 mg Tween 20, and 35-70 mg N-octanoyl N- was then rewrapped and sterilized for animal testing. methylglucamine were mixed. [0277] Example 4 [0264] Formulation 20-35-70 mg (0.042-0.084 [0278] 5 PTCA balloon catheters crimped with bare mmmole) paclitaxel, 0.4-1.0 ml acetone, 0.4-1.0 ml eth- 25 metal coronary stent (3 mm in diameter and 20 mm in anol, 0.2-0.4 ml water, 35-70 mg Tween 20, and 35-70 length) were sprayed or dipped in a formulation (1-5) in mg sorbitol were mixed. example 1. The stent delivery system was then dried, [0265] Formulation 21-40-80 mg (0.048-0.096 sprayed or dipped again in a formulation (6-10), dried mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 ml eth- and sprayed or dipped again until sufficient amount of anol, 40-80 mg meglumine, and 32-64 mg gensitic acid 30 drug on the stent and balloon (3 microgram per square (equal molar ratio with meglumine) were mixed. mm) is obtained. The coated folded stent delivery system [0266] Formulation 22-35-70 mg (0.042-0.084 was then sterilized for animal testing. mmmole) paclitaxel, 0.4-0.8 ml acetone, 0.4-0.8 ml eth- [0279] Example 5 anol, D.25-0.60 ml water, 35-70 mg lactobionic acid, and [0280] Drug coated balloon catheters and uncoated 10-20 mg diethanolamine (equal molar ratio with lacto- 35 balloon catheters (as control) were inserted into coronary bionic acid) were mixed. arteries in pigs. The balloon was over dilated (1: 1.2), and [0267] Formulation 23-35-70 mg (0,042-0.084 the inflated balloon was held in the vessel for 60 seconds mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 ml eth- to release drug and additive, then deflated and withdraw anol, and 70-140 mg N-octanoyl N-methylglucamine from the pig. The animals were angiographed after 3 were mixed. 40 days, 31 days, 3 months, 6 months, 9 months and 12 [0268] Formulation 24-35-70 mg (0.042-0.084 months. The amount of drug in the artery tissues of the mmmole) paclitaxel, 0.4-0.8 ml acetone, 0.4-0.8 ml eth- sacrificed animal was measured after 60 minutes, 3 days, anol, 0.2-0.4 ml water, 35-70 mg meglumine, and 18-36 31 days, 3 months, 6 months, 9 months and 12 months. mg lactic acid (equal molar ratio with meglumine) were [0281] Example 6 mixed. 45 [0282] 5 coronary stents (3 mm in diameter and 18 mm [0269] Formulation 25-50-100 mg (0.06-0.12 mmole) in length) were spray or dip coated with the formulation paclitaxel, 0.8-1.6 ml acetone, 0.8-1.6 ml ethanol, 0.4-1.0 (1-17) in example 1. The stents were then dried, sprayed ml water, 50-100 mg gensitic acid, and 30-60 mg dieth- or dipped again, and dried again until a sufficient amount anolamine (equal molar ratio with gensitic acid) were of drug on the stent (3 microgram per square mm) is mixed. 50 obtained. The coated stent was then crimped on PTCA [0270] Formulation 26-Comparison solution-50 mg balloon catheters (3 mm in diameters and 20 mm in (0.06 mole)paclitaxel, 1ml ethanol, 0.2ml acetone, 0.042 length). The coated stents with balloon catheters were ml Ultravist 370 were mixed. then sterilized for animal testing. [0271] Formulation 27-Comparison solution-40 mg [0283] Example 7 (0.048 mmole) paclitaxel, 0.5 ml ethanol, 0.5 ml acetone 55 [0284] The drug coated stent and uncoated stent (as were mixed. control) were inserted into coronary arteries in pigs, then [0272] Formulation 28-35-70 mg (0.042-0.084 the balloon was over dilated (1:1.2). The stent was im- mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 ml eth- planted and drug and additive released, and the balloon

35 69 EP 2 500 046 A2 70 was deflated and withdrawn from the pig. The animals was dilated, and the inflated balloon was held expanded were then angiographed after 5, 30, 60 minutes, 3 days, in the lumen for 60 seconds to release drug and additive. 31 days, 3 months, 6 months, 9 months and 12 months. The balloon was deflated and withdrawn from the pig. The amount of drug in the artery tissues of the sacrificed The animals were then examined bronchoscopically and animal was measured 60 minutes, 1 day, 3 days, 31 days, 5 tissues samples were taken for pathology and quantifi- 3 months, 6 months, 9 months and 12 months. cation of drug uptake after 3 days, 31 days, 3 months, 6 [0285] Example 8 months, 9 months and 12 months. [0286] 5 PTCA balloon catheters were sprayed or [0295] Example 13 dipped in the formulation (1-17) in example 1, dried, and [0296] The uncoated stent delivery catheters were in- sprayed or dipped and dried again until sufficient amount 10 serted into the vascular lumen in pigs. The balloon was of drug on balloon is obtained (3 microgram per square dilated, the stent was deployed and the deflated balloon mm) was obtained. A bare metal coronary stent (3 mm was the withdrawn. The pharmaceutical formulation 1-15 in diameter and 20 mm in length) was crimped on each of example 1 (10 - 100 ml) was injected (about 5-15 mg coated balloon. The coated balloons with crimped bare drug per pig) at the site of stent implantation. The drug metal stents were then wrapped and sterilized for animal 15 was then absorbed by injuried tissue. The animals were test. then examined and tissues samples were taken for pa- [0287] Example 9 thology. [0288] 5 PTCA balloon catheters were sprayed or [0297] Example 14 dipped in a formulation (1-5) in example 1, dried, and [0298] The diseased tissue (breast cancer or prostate sprayed or dipped again in a formulation (6-10). Balloons 20 or atheroma or stenosis) was removed surgically from a were then dried and sprayed or dipped again until suffi- human body. The pharmaceutical formulation 1-15 of ex- cient amount of drug on the balloon (3 microgram per ample 1 (10-100 ml) was then injected into or onto the square mm) was obtained. A bare metal coronary stent surgical cavities created by the surgical intervention (3 mm in diameter and 20 mm in length) was crimped on (about 5 - 20 mg drug). The local drug delivery included each coated balloon. The coated balloons with crimped 25 injection by long needle, guide catheters, introducer bare metal stents were then wrapped and sterilized for shealth, drug infusion tube and other drug delivery cath- animal test. eters. The drug was then absorbed by tissue at the target [0289] Example 10 site. [0290] The drug coated baboon-expandable bare met- [0299] Example 15 al stent of Examples 8 and 9 and plain balloon-expand- 30 [0300] 6 PTCA balloon catheters (3.5 and 3.0 mm in able bare metal stent (as control) were inserted into cor- diameter and 20 mm in length) were inflated at 1-3 atm. onary arteries in pigs, and the balloon is over dilated (1: The inflated balloon was loaded with a formulation 18-28 1.2). Sent is implanted, and the balloon was held inflated in example 1. A sufficient amount of drug on the balloon for 60 seconds to release drug and additive, and the bal- (3 microgram per square mm) was obtained. The inflated loon was deflated and withdraw from the pig. The animals 35 balloon was folded, and then dried. The coated folded were then angiographed after 5, 30, 60 minutes, 3 days, balloon was then rewrapped and sterilized for animal 31 days, 3 months, 6 months, 9 months and 12 months. testing. The amount of drug in the artery tissues of the sacrificed [0301] The coated PTCA balloon catheter was insert- animal is measured after 60 minutes, 1 day, 3 days, 31 ed into a target site in the coronary vasculature (LAD, days, 3 months, 6 months, 9 months and 12 months. 40 LCX and RCA) of a 25-45 pound pig. The balloon was [0291] Example 11 inflated to about 12 atm. The overstretch ratio (the ratio [0292] 150 mg (0.18 mmole) paclitaxel, 5 ml acetone of balloon diameter to vessel diameter) was about 1.15 (or ethylacetate or methyl ethyl ketone), 150 mg acetic -1.20. The drug delivered into the target tissue during anhydride or maleic anhydride or diglycolic anhydride, 30-60 seconds of inflation. The balloon catheter was then and 0.5 ml ethanol were mixed, then stirred until a solu- 45 deflated and was withdrawn from animal body. The target tion was obtained. 5 PTCA balloon catheters were blood vessel was harvested 0.25 -24 hours after the pro- sprayed or dipped in the solution, dried, and sprayed or cedure. The drug content in the target tissue and the dipped again until sufficient amount of drug on the balloon residual drug remaining on the balloon were analyzed by (3 microgram per square mm) is obtained. The coated tissue extraction and HPLC. balloon was then treated under high pH (range pH 8-11.5) 50 [0302] In some of these animal studies, a stent was conditions to hydrolyze the anhydride. This can be con- crimped on the drug coated balloon catheters prior to firmed by IR method. The hydrophilicity of the coating deployment. In chronic animal tests, angiography was was now increased. The coated balloons were then ster- performed before and after all interventions and at 28-35 ilized for animal test. days after the procedure. Luminal diameters were meas- [0293] Example 12 55 ured and late lumen loss was calculated. Late lumen loss [0294] The drug coated balloon catheters and uncoat- is the difference between the minimal lumen diameter ed balloon catheters (as control) were inserted via a bron- measured after a period of follow- up time (usually weeks choscope into the pulmonary airway in pigs. The balloon to months after an intervention, such as angioplasty and

36 71 EP 2 500 046 A2 72 stent placement in the case of this example) and the min- lumen loss was 0.33 (sd 0.14) mm. The diameter stenosis imal lumen diameter measured immediately after the in- was 6.7%. tervention. Restenosis may be quantified by the diameter [0308] The drug content of formulation 23 on the 3.5 stenosis, which is the difference between the mean lu- mm balloon catheters was 3.75 Pg/mm2. After the pro- men diameters at follow-up and immediately after the 5 cedure, residual drug on the balloon was 0.82 Pg, or 0.1 procedure divided by the mean lumen diameter immedi- % of the total drug load. The drug content in tissue har- ately after the procedure.The animal test results for For- vested 60 minutes after the procedure was 45.23 Pg, or mulation 16-23 are reported below. All data is an average 5.5% of the total drug load. After 28-35 days late lumen of five or six experimental data points. loss was 0.49 (sd 0.26) mm. The diameter stenosis was [0303] The drug content of the formulation 16 on the 10 11.3%. 3.5 mm balloon catheters was 3.26P g/mm2. After the [0309] The drug content of formulation 24 on the 3.5 procedure, the residual drug on the balloon was 15.92 mm balloon catheters was 3.35 Pg/mm2, After the pro- Pg, or 2.3% of the total drug loaded on the balloon. The cedure, the residual drug on the balloon was 62.07 Pg, drug content in tissue harvested 15-30 minutes after the or 7.5% of the total drug load, The drug content in tissue procedure was 64.79 Pg, or 9.2% of the total drug content 15 harvested 60 minutes after the procedure was 40.55 Pg, originally loaded on the balloon. When an 18 mm stent or 4.9% of the total drug load. After 28-35 days late lumen was deployed by the coated balloon, the residual drug loss was 0.47 (sd 0.33) mm. The diameter stenosis was on the balloon was 31.96 Pg, or 4.5% of drug load, and 9.9%. the drug content in tissue harvested 15-30 minutes after [0310] The drug content of the formulation 25 on the the procedure was 96.49 Pg, or 13.7% of drug load. The 20 3.5 mm balloon catheters was 3.41P g/mm2. After the stretch ratio is 1.3 in the procedure. The late lumen loss procedure, residual drug on the balloon was 50.0 Pg, or after 28-35 days was 0.10 (sd 0.2) mm. The diameter 6.0% of the total drug load. The drug content in tissue stenosis is 3.3%. harvested 60 minutes post procedure was 26.72 Pg, or [0304] The drug content of the formulation 19 on the 3.2% of the total drug load. After 28-35 days late lumen 3.5 mm balloon catheters was 3.08P g/mm2. After the 25 loss was 0.36 (sd 0.41) mm. The diameter stenosis was procedure, the residual drug on the balloon was 80.58 9.3%. Pg, or 11.4% of the total drug load. The drug content in [0311] The drug content of formulation 28 on the 3.5 tissue harvested 15-30 minutes after the procedure was mm balloon catheters was 3.10 Pg/mm2. After the pro- 42.23 Pg, or 6.0% of the total drug load. After 28-35 days cedure, residual drug on the balloon was 1.9% of the total late lumen loss was 0.30 (sd 0.23) mm. The diameter 30 drug load. The drug content in tissue harvested 2 hours stenosis was 5.4%. after the procedure was 34.17 Pg, or 5.0% of the total [0305] The drug content of formulation 20 on the 3.5 drug load. In tissue harvested 24 hours after the proce- mm balloon catheters was 3.61 Pg/mm2. After the pro- dure, the drug content in tissue was 28.92 Pg, or 4.2% cedure, the residual drug on the balloon was 174.24 Pg, of the total drug load. or 24.7% of the total drug load. The drug content in tissue 35 [0312] The drug content of control formulation (uncoat- harvested 15-30 minutes after the procedure was 83.83 ed balloon) on the 3.5 mm balloon catheters was 0.0 Pg, or 11.9% of the total drug load. When deployed with Pg/mm2. After the procedure, residual drug on the bal- a pre-crimped 18 mm stent, the residual drug on the bal- loon was 0% of the total drug load. The drug content in loon is 114.53 Pg, or 16.1 % of the total drug load, and tissue harvested 15 minutes after the procedure was 0 the drug content in tissue harvested 15-30 minutes post 40 Pg. In tissue harvested 24 hours after the procedure, the procedure was 147.95 Pg, or 18.1% of the total drug load. drug content in tissue was 0P g. after 28-35 days late The stretch ratio was 1.3 in the procedure. The late lumen lumen loss was 0.67 (sd 0.27) mm. The diameter stenosis loss after 28-35 days was 0.10 (sd 0.1) mm. The diameter is 20.8%. In the second repeat experiment, the stretch stenosis was 3.4%. ratio was 1.3. The late lumen loss was 1.1 (sd 0.1). The [0306] The drug content of formulation 21 on the 3.5 45 diameter stenosis was 37.5%. mm balloon catheters was 4.71 Pg/mm2. After the pro- [0313] The drug content of the comparison formulation cedure, the residual drug on the balloon was 44.39 Pg, 26 on the 3.5 mm balloon catheters was 3.21 Pg/mm2. or 6.3% of the total drug load. The drug content in the After the procedure, residual drug on the balloon was tissue harvested 15-30 minutes after the procedure was 13.62 Pg, or 1.9% of the total drug load. The drug content 77.87 Pg, or 11.0% of the total drug load. After 28-35 50 in the tissue was 28.32 Pg, or 4.0% of the total drug load. days late lumen loss was 0.23 (sd 0.44) mm. The diam- When the balloon was deployed with a pre-crimped 18 eter stenosis was 7.3%. mm stent, residual drug on the balloon was 26.45 Pg, or [0307] The drug content of the formulation 22 on the 3.7% of the total drug load. The drug content in tissue 3.5 mm balloon catheters was 3.85P g/mm2. After the was 113.79 Pg, or 16.1% of drug load. After 28-35 days, procedure, residual drug on the balloon was 24.59P g, 55 late lumen loss was 0.27 (sd 0.15) mm. The diameter or 3.5% of the total drug load. The drug content in tissue stenosis was 7.1 %. harvested 15-30 minutes after the procedure was 37.97 [0314] The drug content of the formulation 27 (without Pg, or 5.4% of the total drug load. After 28-35 days late additive) on the 3.5 mm balloon catheters was 4.22

37 73 EP 2 500 046 A2 74

Pg/mm2. After the procedure, residual drug on the bal- [0321] A formulation for a top coating layer was then loon was 321.97 Pg, or 45.6% of the total drug load. The prepared. The formulation of the top coating layer was drug content in the tissue was 12.83 Pg, or 1.8% of the paclitaxel, and one additive chosen from Tween 20, total drug load. Tween 80, polypropylene glycol-425 (PPG-425), and [0315] Suprisingly, the concentration of drug absorbed 5 polypropyl glycol-1000 (PPG-1000), in acetone. The bal- by porcine coronary artery tissue after deployment of bal- loon surface of the control catheters was only loaded with loons coated with formulations 18-25 and 28 according formulation 18. 25-50 mg of the top coating formulation to embodiments of the present invention was higher than (about 50% of paclitaxel by weight) in acetone was coat- that delivered by balloons coated with the comparison ed over the formulation 18 coating layer on the other bal- formulation 26 and higher than those coated with drug 10 loon surfaces. The coated balloons were dried for drug alone, formulation 27. The late lumen loss after 28-35 releasing testing in vitro. days follow up was less than the control (uncoated bal- [0322] The releasing experiment was designed to test loon). how much drug is lost during balloon inflation. Each of [0316] Example 16 the coated balloons were inflated to 12 atm. in 1% BSA [0317] 6 PTCA balloon catheters (3.5 and 3.0 mm in 15 solution at 37°C for 2 minutes. The drug, additive and diameter and 20 mm in length) were inflated at 1-3 atm. top coating were released. The residual drug on the bal- The inflated balloon was loaded with a formulation 18-25, loon catheters was analyzed by HPLC. The residual drug and 28 in example 1. A sufficient amount (3 Pg/mm2) of content of the control balloon catheter was 34% of the drug on the balloon surface was obtained. The inflated total drug loading. The residual drug content of of the balloon was dried. The drug coated balloon was then20 ballon catheter that included a top coating layer with loaded with a top coat. The top coating formulation in Tween 20, Tween 80, polypropylene glycol-425 (PPG- acetone or ethanol was chosen from gentisic acid, methyl 425) or polypropyl glycol-1000 (PPG-1000) was 47%, paraben, acetic acid, Tween 20, vanillin and aspirin. The 56%, 71 % and 81%, respectively. Thus, the top coating coated folded balloon was dried, then rewrapped and layer reduced drug loss in the tests in vitro during inflation sterilized for animal testing. 25 of the balloon components. [0318] A floating experiment was designed to test how [0323] Some preferred embodiments (EM) of the much drug is lost during balloon catheter insertion and invention are listed under points 1 to 149 below: transit to the target site prior to inflation. A control balloon catheter was coated with formulation 18. Top-coated 1. A medical device for delivering a therapeutic agent catheters also were prepared having a top coating of pro- 30 to a tissue, the device comprising a layer overlying pyl paraben. For top-coated catheters, the balloon cath- an exterior surface of the medical device, the layer eter was coated with formulation 18, then dried, 25-50 comprising a therapeutic agent and an additive, mg propyl paraben (about 50% of paclitaxel by weight) wherein the additive comprises a hydrophilic part in acetone was coated over the formulation 18 coating. and a drug affinity part, wherein the drug affinity part Each of the control and top- coated balloon catheters was 35 is at least one of a hydrophobic part, a part that has inserted in pig arteries. The floating time in pig arterial an affinity to the therapeutic agent by hydrogen vasculature was 1 minute. The drug, additive and top bonding, and a part that has an affinity to the thera- coating were released. The catheter was then withdrawn. peutic agent by van der Waals interactions, wherein The residual drug on the balloon catheters was analyzed the additive is water-soluble, wherein the additive is by HPLC. The residual drug content of the control balloon 40 at least one of a surfactant and a chemical com- catheters was 53% of the total drug loading. The residual pound, and wherein the chemical compound has a drug content of the top- coated balloon catheter was 88%. molecular weight of from 80 to 750. The top coat reduced drug loss in the vasculature, during conditions that simulate transit of the device to a site of 2. A medical device for delivering a therapeutic agent therapeutic intervention. The same animal tests were 45 to a tissue, the device comprising a layer overlying performed as in Example 15 with formulation 18 first coat- an exterior surface of the medical device, the layer ed on the balloon, and propyl paraben as a top coating comprising a therapeutic agent and an additive, layer overlying the first coating layer. The drug content wherein the additive comprises a hydrophilic part on the 3,5 mm balloon catheter was 3.39 Pg/mm2. After and a drug affinity part, wherein the drug affinity part the procedure, residual drug on the balloon was 64.5 Pg, 50 is at least one of a hydrophobic part, a part that has or 8.6% of the total drug load. The drug content in the an affinity to the therapeutic agent by hydrogen tissue was 28.42 Pg, or 4% of the total drug load. bonding, and a part that has an affinity to the thera- [0319] Example 17 peutic agent by van der Waals interactions, wherein [0320] 6 PTCA balloon components (3.5 and 3.0 mm the additive is at least one ofa surfactant and a chem- in diameter and 20 mm in length) were loaded with for- 55 ical compound, and wherein the chemical compound mulation 18 provided in Example 1. A sufficient amount has more than four hydroxyl groups. of drug (3 Pg/mm2) was obtained on the balloon surface. The balloon was dried. 3. The medical device according to EM 2, wherein

38 75 EP 2 500 046 A2 76 the chemical compound having more than four hy- 12. A medical device for delivering a therapeutic droxyl groups has a melting point of 120°C or less, agent to a tissue, the device comprising a layer over- and wherein the chemical compound is an alcohol lying an exterior surface of the medical device, the or an ester. layer comprising a therapeutic agent and an additive, 5 wherein the additive comprises a hydrophilic part 4. The medical device according to EMs 1 or 2, and a drug affinity part, wherein the drug affinity part wherein the layer does not include an iodine covalent is at least one of a hydrophobic part, a part that has bonded contrast agent. an affinity to the therapeutic agent by hydrogen bonding, and a part that has an affinity to the thera- 5. The medical device according to EMs 1 or 2,10 peutic agent by van der Waals interactions, and wherein the chemical compound is chosen from ami- wherein the additive is chosen from p-isononylphe- no alcohols, hydroxyl carboxylic acid, ester, anhy- noxypolyglycidol, PEG laurate, Tween 20, Tween drides, hydroxyl ketone, hydroxyl lactone, hydroxyl 40, Tween 60, PEG oleate, PEG stearate, PEG glyc- ester, sugar phosphate, sugar sulfate, ethyl oxide, eryl laurate, PEG glyceryl oleate, PEG glyceryl stea- ethyl glycols, amino acids, peptides, proteins, sorb- 15 rate, polyglyceryl laurate, plyglyceryl oleate, polyg- itan, glycerol, polyalcohol, phosphates, sulfates, or- lyceryl myristate, polyglyceryl palmitate, polyglycer- ganic acids, esters, salts, vitamins, combinations of yl-6 laurate, plyglyceryl- 6 oleate, polyglyceryl- 6 myr- amino alcohol and organic acid, and their substituted istate, polyglyceryl-6 palmitate, polyglyceryl-10 lau- molecules. rate, plyglyceryl-10 oleate, polyglyceryl-10 myr- 20 istate, polyglyceryl-10 palmitate PEG sorbitan mon- 6. The medical device according to EMs 1 or 2, olaurate, PEG sorbitan monolaurate, PEG sorbitan wherein the surfactant is chosen from ionic,nonionic, monooleate, PEG sorbitan stearate, PEG oleyl aliphatic, and aromatic surfactants, PEG fatty esters, ether, PEG laurayl ether, octoxynol, monoxynol, ty- PEG omega-3 fatty esters, ether, and alcohols, glyc- loxapol, sucrose monopalmitate, sucrose monolau- erol fatty esters, sorbitan, fatty esters, PEG glyceryl 25 rate, decanoyl-N-methylglucamide, n-decyl - β -D- fatty esters, PEG sorbitan, fatty esters, sugar fatty glucopyranoside, n-decyl - β -D-maltopyranoside, n- esters, PEG sugar esters, and derivatives thereof. dodecyl - β -D-glucopyranoside, n-dodecyl - β -D- maltoside, heptanoyl-N-methylglucamide, n-heptyl- 7. The medical device according to EM 1, wherein β -D-glucopyranoside, n-heptyl - β -D-thioglucoside, the chemical compound has one or more hydroxyl, 30 n-hexyl - β -D-glucopyranoside, nonanoyl-N-meth- amino, carbonyl, carboxyl, acid, amide or ester ylglucamide, n-noyl - β -D-glucopyranoside, oc- groups. tanoyl-N-methylglucamide, n-octyl- β -D-glucopyra- noside, octyl - β -D-thioglucopyranoside; cystine, ty- 8. The medical device according to EM 7, wherein rosine, tryptophan, leucine, isoleucine, phenyla- the surfactant is chosen from ionic, nonionic, aliphat- 35 lanine, asparagine, aspartic acid, glutamic acid, and ic, and aromatic surfactants, PEG fatty esters, PEG methionine; acetic anhydride, benzoic anhydride, omega-3 fatty esters, ether, and alcohols, glycerol ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodi- fatty esters, sorbitan fatty esters, PEG glyceryl fatty um pyrrolidone carboxylate, ethylenediamine- esters, PEG sorbitan fatty esters, sugar fatty esters, tetraacetic dianhydride, maleic and anhydride, suc- PEG sugar esters and derivatives thereof. 40 cinic anhydride, diglycolic anhydride, glutaric anhy- dride, acetiamine, benfotiamine, pantothenic acid; 9. The medical device according to EM 7, wherein cetotiamine; cycothiamine, dexpanthenol, niacina- the chemical compound having one or more hy- mide, nicotinic acid, pyridoxal 5-phosphate, nicoti- droxyl, amino, carbonyl, carboxyl, acid, amide or es- namide ascorbate, riboflavin, riboflavin phosphate, ter groups is chosen from amino alcohols, hydroxyl 45 thiamine, folic acid, menadiol diphosphate, menadi- carboxylic acid, ester, anhydrides, hydroxyl ketone, one sodium bisulfite, menadoxime, vitamin B12, vi- hydroxyl lactone, hydroxyl ester, sugar phosphate, tamin K5, vitamin K6, vitamin K6, and vitamin U; al- sugar sulfate, ethyl oxide, ethyl glycols, amino acids, bumin, immunoglobulins, caseins, hemoglobins, lys- peptides, proteins, sorbitan, glycerol, polyalcohol, ozymes, immunoglobins, a-2-macroglobulin, fi- phosphates, sulfates, organic acids, esters, salts, vi- 50 bronectins, vitronectins, firbinogens, lipases, benza- tamins, combinations of amino alcohol and organic lkonium chloride,benzethonium chloride,docecyl tri- acid, and their substituted molecules. methyl ammonium bromide, sodium docecylsul- fates, dialkyl methylbenzyl ammonium chloride, and 10. The medical device according to EMs 1 or 2, dialkylesters of sodium sulfonsuccinic acid, L-ascor- wherein the additive is not a therapeutic agent. 55 bic acid and its salt, D-glucoascorbic acid and its salt, tromethamine, triethanolamine, dieth- 11. The medical device according to EM 10, wherein anolamine, meglumine, glucamine, amine alcohols, the additive is not salicylic acid or salts thereof. glucoheptonic acid, glucomic acid, hydroxyl ketone,

39 77 EP 2 500 046 A2 78 hydroxyl lactone, gluconolactone, glucoheptonolac- wherein the device further comprises a top layer tone, glucooctanoic lactone, gulonic acid lactone, overlying the surface of the layer overlying the exte- mannoic lactone, ribonic acid lactone, lactobionic ac- rior surface of the medical device to reduce loss of id, glucosamine, glutamic acid, benzyl alcohol, ben- drugduring transit through a body to the target tissue. zoic acid, hydroxybenzoic acid, propyl 4-hydroxy- 5 benzoate, lysine acetate salt, gentisic acid, lactobi- 19. The medical device according to EM 18, wherein onic acid, lactitol, sinapic acid, vanillic acid, vanillin, the top layer comprises an additive that is less hy- methyl paraben, propyl paraben, sorbitol, xylitol, cy- drophilic than the additive in the layer overlying the clodextrin, (2-hydroxypropyl)-cyclodextrin, acetami- exterior surface of the medical device, and wherein nophen, ibuprofen, retinoic acid, lysine acetate, gen- 10 the additive of the top layer is chosen from p-isono- tisic acid, catechin, catechin gallate, tiletamine, ket- nylphenoxypolyglycidol, PEG laurate, Tween 20, amine, propofol, lactic acids, acetic acid, salts of any Tween 40, Tween 60, PEG oleate, PEG stearate, organic acid and organic amine, polyglycidol, glyc- PEG glyceryl laurate, PEG glyceryl oleate, PEG glyc- erol, multiglycerols, galactitol, di (ethylene glycol), tri eryl stearate, polyglyceryl laurate, plyglyceryl oleate, (ethylene glycol), tetra(ethylene glycol), penta(eth- 15 polyglyceryl myristate, polyglyceryl palmitate, poly- ylene glycol), poly(ethylene glycol) oligomers, di glyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl- (propylene glycol), tri(propylene glycol), tetra(pro- 6 myristate, polyglyceryl-6 palmitate, polyglyceryl- pylene glycol, and penta (propylene glycol), poly (pro- 10 laurate, plyglyceryl-10 oleate, polyglyceryl-10 pylene glycol) oligomers, a block copolymer of pol- myristate, polyglyceryl-10 palmitate PEG sorbitan yethylene glycol and polypropylene glycol, and de- 20 monolaurate, PEG sorbitan monolaurate, PEG sorb- rivatives and combinations thereof. itan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, ty- 13. The medical device according to EMs 1 or 2, loxapol, sucrose monopalmitate, sucrose monolau- wherein the tissue includes tissue of one of coronary rate, decanoyl-N-methylglucamide, n-decyl - β -D- vasculature, peripheral vasculature, cerebral vascu- 25 glucopyranoside, n-decyl - β -D-maltopyranoside, n- lature, esophagus, airways, sinus, trachea, colon, dodecyl - β -D-glucopyranoside, n-dodecyl - β -D- biliary tract, urinary tract, prostate, and brain pas- maltoside, heptanoyl-N-methylglucamide, n-heptyl- sages. β -D-glucopyranoside, n-heptyl - β -D-thioglucoside, n-hexyl - β -D-glucopyranoside, nonanoyl-N-meth- 14. The medical device according to EMs 1 or 2,30 ylglucamide, n-noyl - β - D-glucopyranoside, oc- wherein the device includes one of a balloon cathe- tanoyl-N-methylglucamide, n-octyl- β -D-glucopyra- ter, a perfusion balloon catheter, an infusion cathe- noside, octyl - β -D-thioglucopyranoside; cystine, ty- ter, a cutting balloon catheter, a scoring balloon cath- rosine, tryptophan, leucine, isoleucine, phenyla- eter, a laser catheter, an atherectomy device, a de- lanine, asparagine, aspartic acid, glutamic acid, and bulking catheter, a stent, a filter, a stent graft, a cov- 35 methionine; acetic anhydride, benzoic anhydride, ered stent, a patch, a wire, and a valve. ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodi- um pyrrolidone carboxylate, ethylenediamine- 15. The medical device according to EMs 1 or 2, tetraacetic dianhydride, maleic and anhydride, suc- wherein the therapeutic agent is one of paclitaxel cinic anhydride, diglycolic anhydride, glutaric anhy- and analogues thereof, rapamycin and analogues 40 dride, acetiamine, benfotiamine, pantothenic acid; thereof, beta-lapachone and analogues thereof, bi- cetotiamine; cycothiamine, dexpanthenol, niacina- ological vitamin D and analogues thereof, and a mix- mide, nicotinic acid, pyridoxal 5-phosphate, nicoti- ture of these therapeutic agents. namide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadi- 16. The medical device according to EMs 1 or 2,45 one sodium bisulfite, menadoxime, vitamin B12, vi- wherein the therapeutic agent is in combination with tamin K5, vitamin K6, vitamin K6, and vitamin U; al- a second therapeutic agent, wherein the therapeutic bumin, immunoglobulins, caseins, hemoglobins, lys- agent is one of paclitaxel, rapamycin, and analogues ozymes, immunoglobins, a-2-macroglobulin, fi- thereof, and wherein the second therapeutic agent bronectins, vitronectins, firbinogens, lipases, benza- is one of beta-lapachone, biological active vitamin 50 lkonium chloride,benzethonium chloride,docecyl tri- D, and their analogues. methyl ammonium bromide, sodium docecylsul- fates, dialkyl methylbenzyl ammonium chloride, and 17. The medical device according to EMs 1 or 2, dialkylesters of sodium sulfonsuccinic acid, L-ascor- wherein the device further comprises an adherent bic acid and its salt, D-glucoascorbic acid and its layer between the exterior surface of the medical de- 55 salt, tromethamine, triethanolamine, dieth- vice and the layer. anolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxyl ketone, 18. The medical device according to EMs 1 or 2, hydroxyl lactone, gluconolactone, glucoheptonolac-

40 79 EP 2 500 046 A2 80 tone, glucooctanoic lactone, gulonic acid lactone, bility of at least 1 mg/ml, and wherein the therapeutic mannoic lactone, ribonic acid lactone, lactobionic ac- agent is not water-soluble. id, glucosamine, glutamic acid, benzyl alcohol, ben- zoic acid, hydroxybenzoic acid, propyl 4-hydroxy- 29. A medical device for delivering a therapeutic benzoate, lysine acetate salt, gentisic acid, lactobi- 5 agent to a tissue, the device comprising a layer over- onic acid, lactitol, sinapic acid, vanillic acid, vanillin, lying an exterior surface of the medical device, the methyl paraben, propyl paraben, sorbitol, xylitol, cy- layer comprising a therapeutic agent and at least two clodextrin, (2-hydroxypropyl)-cyclodextrin, acetami- additives, wherein each of the additives comprises nophen, ibuprofen, retinoic acid, lysine acetate, gen- a hydrophilic part and a drug affinity part, wherein tisic acid, catechin, catechin gallate, tiletamine, ket- 10 the drug affinity part is at least one of a hydrophobic amine, propofol, lactic acids, acetic acid, salts of any part, a part that has an affinity to the therapeutic organic acid and organic amine, polyglycidol, glyc- agent by hydrogen bonding, and a part that has an erol, multiglycerols, galactitol, di (ethylene glycol), tri affinity to the therapeutic agent by van der Waals (ethylene glycol), tetra(ethylene glycol), penta(eth- interactions, and wherein each additive is soluble in ylene glycol), poly(ethylene glycol) oligomers, di 15 polar organic solvent and is soluble in water. (propylene glycol), tri(propylene glycol), tetra(pro- pylene glycol, and penta (propylene glycol), poly (pro- 30. The medical device according to EM 29, wherein pylene glycol) oligomers, a block copolymer of pol- the polar organic solvent is chosen from methanol, yethylene glycol and polypropylene glycol, and de- ethanol, isopropanol, acetone, dimethylformide, tet- rivatives and combinations thereof. 20 rahydrofuran, methylethyl ketone, dimethylsulfox- ide, acetonitrile, ethyl acetate, and chloroform, and 20. The medical device according to EMs 1 or 2, mixtures of these polar organic solvents with water. wherein the device further comprises a dimethylsul- foxide solvent layer, wherein the dimethylsulfoxide 31. The medical device according to EM 29, wherein solvent layer is overlying the surface of the layer. 25 the device further comprises a top layer overlying the surface of the layer overlying the exterior surface 21. The medical device according to EMs 1 or 2, of the medical device to reduce loss of drug during wherein the device is capable of releasing the ther- transit through a body to the target tissue. apeutic agent and the additive and delivering the therapeutic agent to the tissue in about 0.1 to 2 min- 30 32. A medical device for delivering a therapeutic utes. agent to a tissue, the device comprising a layer over- lying an exterior surface of the medical device, the 22. The medical device according to EMs 1 or 2, layer comprising a therapeutic agent and an additive, wherein the layer consists essentially of the thera- wherein the additive comprises a hydrophilic part peutic agent and the additive. 35 and a drug affinity part, wherein the drug affinity part is at least one of a hydrophobic part, a part that has 23. The medical device according to EMs 1 or 2, an affinity to the therapeutic agent by hydrogen wherein the concentration of the therapeutic agent bonding, and a part that has an affinity to the thera- in the layer is from 1 to 20 Pg/mm2. peutic agent by van der Waals interactions, wherein 40 the additive reduces crystal size and number of par- 24. The medical device according to EMs 1 or 2, ticles of the therapeutic agent, and wherein the ad- wherein the concentration of the therapeutic agent ditive is water-soluble and the therapeutic agent is in the layer is from 2 to 10 Pg/mm2. not water-soluble.

25. The medical device according to EMs 1 or 2,45 33. A medical device for delivering a therapeutic wherein the therapeutic agent is not water-soluble. agent to a tissue, the device comprising a layer over- lying an exterior surface of the medical device, the 26. The medical device according to EMs 1 or 2, layer comprising a therapeutic agent and an additive, wherein the additive enhances release of the thera- wherein the additive comprises a hydrophilic part peutic agent off the medical device and wherein both 50 and a drug affinity part, wherein the drug affinity part the therapeutic agent and the additive are released. is at least one of a hydrophobic part, a part that has an affinity to the therapeutic agent by hydrogen 27. The medical device according to EMs 1 or 2, bonding, and a part that has an affinity to the thera- wherein the additive enhances penetration and ab- peutic agent by van der Waals interactions, wherein sorption of the therapeutic agent in tissue. 55 the additive has a fatty chain of an acid, ester, ether, or alcohol, wherein the fatty chain can directly insert 28. The medical device according to EMs 1 or 2, into lipid membrane structures of the tissue, and wherein the additive has a water and alcohol solu- wherein the therapeutic agent is not water-soluble.

41 81 EP 2 500 046 A2 82

34. A medical device for delivering a therapeutic affinity to the therapeutic agent by van der Waals agent to a tissue, the device comprising a layer over- interactions, wherein the additive is water-soluble, lying an exterior surface of the medical device, the and wherein theadditive is at least one of asurfactant layer comprising a therapeutic agent and an additive, and a chemical compound, and wherein the chemi- wherein the additive comprises a hydrophilic part 5 cal compound has a molecular weight of from 80 to and a hydrophobic part, wherein the additive can 750. penetrate into and rearrange lipid membrane struc- tures of the tissue, and wherein the therapeutic agent 41. A balloon catheter for delivering a therapeutic is not water-soluble and is not enclosed in micelles agent to a blood vessel, the catheter comprising a or encapsulated in polymer particles. 10 layer overlying an exterior surface of the medical de- vice, the layer comprising a therapeutic agent and 35. A stent coating for delivering a therapeutic agent an additive, wherein the additive comprises a hy- to a tissue, the stent coating comprising a layer over- drophilic part and a drug affinity part, wherein the lying a surface of the stent, the layer comprising a drug affinity part is at least one of a hydrophobic part, therapeutic agent, an additive, and a polymer matrix, 15 a part that has an affinity to the therapeutic agent by wherein the therapeutic agent is dispersed, but not hydrogen bonding, and a part that has an affinity to encapsulated, as particles in the polymer matrix, the therapeutic agent by van der Waals interactions, wherein the additive comprises a hydrophilic part wherein the additive is at least one of a surfactant and a drug affinity part, wherein the drug affinity is and a chemical compound, and wherein the chemi- at least one of a hydrophobic part, a part that has an 20 cal compound has more than four hydroxyl groups. affinity to the therapeutic agent by hydrogen bond- ing, and a part that has an affinity to the therapeutic 42. The balloon catheter according to EM 41, where- agent by van der Waals interactions. in the chemical compound having more than four hydroxyl groups has a melting point of 120°C or less, 36. The stent according to EM 35, wherein the ad- 25 and wherein the chemical compound is an alcohol ditive improves the compatibility of the therapeutic or an ester. agent and the polymer matrix, wherein the additive reduces the particle sizes and improves uniformity 43. The balloon catheter according to EMs 40 or 41, of distribution of the therapeutic agent in the polymer wherein the layer does not include an iodine covalent matrix, and wherein the additive enhances rapid re- 30 bonded contrast agent. lease of drug from the polymer matrix. 44. The balloon catheter according to EMs 40 or 41, 37. A medical device coating for delivering a drug to wherein the surfactant is chosen from ionic,nonionic, a tissue, the coating prepared from a mixture com- aliphatic, and aromatic surfactants, PEG fatty esters, prising an organic phase containing drug particles 35 PEG omega-3 fatty esters, ether, and alcohols, glyc- dispersed therein and an aqueous phase containing erol fatty esters, sorbitan fatty esters, PEG glyceryl a water-soluble additive. fatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugar esters, and derivatives thereof. 38. The medical device coating according to EM 37, wherein preparation of the mixture includes homog- 40 45. The balloon catheter according to EM 40, where- enization under high shear conditions and optionally in the chemical compound has one or more hydroxyl, under pressure. amino, carbonyl, carboxyl, acid, amide or ester groups. 39. The medical device coating according to EM 37, wherein the water-soluble additive is chosen from 45 46. The balloon catheter according to EM 45, where- polyethylene glycol, polyvinyl alcohol, polyvinylpyr- in the surfactant is chosen from ionic, nonionic, rolidinone, polypeptides, water-soluble surfactants, aliphatic, and aromatic surfactants, PEG fatty esters, water-soluble vitamins, and proteins. PEG omega-3 fatty esters, ether, and alcohols, glyc- erol fatty esters, sorbitan fatty esters, PEG glyceryl 40. A balloon catheter for delivering a therapeutic 50 fatty esters, PEG sorbitan fatty esters, sugar fatty agent to a blood vessel, the catheter comprising a esters, PEG sugar esters and derivatives thereof. coating layer overlying an exterior surface of a bal- loon, the coating layer comprising a therapeutic 47. The balloon catheter according to EM 45, where- agent and an additive, wherein the additive compris- in the chemical compound having one or more hy- es a hydrophilic part and a drug affinity part, wherein 55 droxyl, amino, carbonyl, carboxyl, acid, amide or es- the drug affinity part is at least one of a hydrophobic ter groups is chosen from amino alcohols, hydroxyl part, a part that has an affinity to the therapeutic carboxylic acid, ester, and anhydrides, hydroxyl ke- agent by hydrogen bonding, and a part that has an tone, hydroxyl lactone, hydroxyl ester, sugar phos-

42 83 EP 2 500 046 A2 84 phate, sugar sulfate, ethyl oxide, ethyl glycols, amino ide solvent layer is overlying the surface of the coat- acids, peptides, proteins, sorbitan, glycerol, polyal- ing layer. cohol, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohol and 59. The balloon catheter according to EMs 40 or 41, organic acid, and their substituted molecules. 5 wherein the balloon catheter is capable of releasing the therapeutic agent and the additive and delivering 48. The balloon catheter according to EMs 40 or 41, the therapeutic agent to the blood vessel in about wherein the additive is not a therapeutic agent. 0.1 to 2 minutes.

49. The balloon catheter according to EM 48, where- 10 60. The balloon catheter according to EMs 40 or 41, in the additive is not salicylic acid or salts thereof. wherein the concentration of the therapeutic agent in the coating layer is from 1 to 20 Pg/mm2. 50. The balloon catheter according to EMs 40 or 41, wherein the additive is soluble in an organic solvent 61. The balloon catheter according to EMs 40 or 41, and in water. 15 wherein the concentration of the therapeutic agent in the coating layer is from 2 to 10 Pg/mm2. 51. The balloon catheter according to EMs 40 or 41, wherein the therapeutic agent is not water-soluble. 62. A balloon catheter for delivering a therapeutic agent to a blood vessel, the catheter comprising a 52. The balloon catheter according to EMs 40 or 41, 20 coating layer overlying the exterior surface of a bal- wherein the additive enhances penetration and ab- loon, the coating layer comprising a therapeutic sorption of the therapeutic agent in tissue of a blood agent and an additive, wherein the additive compris- vessel. es a hydrophilic part and a drug affinity part, wherein the drug affinity part is at least one of a hydrophobic 53. The balloon catheter according to EMs 40 or 41, 25 part, a part that has an affinity to the therapeutic wherein the additive has a water and alcohol solu- agent by hydrogen bonding, and a part that has an bility of at least 1 Pg/ml, and wherein the therapeutic affinity to the therapeutic agent by van der Waals agent is not water-soluble. interactions, wherein the additive is chosen from p- isononylphenoxypolyglycidol, PEG laurate, Tween 54. The balloon catheter according to EMs 40 or 41, 30 20, Tween 40, Tween 60, PEG oleate, PEG stearate, wherein the therapeutic agent is one of paclitaxel PEG glyceryl laurate, PEG glyceryl oleate, PEG glyc- and analogues thereof, rapamycin and analogues eryl stearate, polyglyceryl laurate, plyglyceryl oleate, thereof, beta-lapachone and analogues thereof, bi- polyglyceryl myristate, polyglyceryl palmitate, poly- ological vitamin D and analogues thereof, and a mix- glyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl- ture of these therapeutic agents. 35 6 myristate, polyglyceryl-6 palmitate, polyglyceryl- 10 laurate, plyglyceryl-10 oleate, polyglyceryl-10 55. The balloon catheter according to EMs 40 or 41, myristate, polyglyceryl-10 palmitate PEG sorbitan wherein the therapeutic agent is in combination with monolaurate, PEG sorbitan monolaurate, PEG sorb- a second therapeutic agent, wherein the therapeutic itan monooleate, PEG sorbitan stearate, PEG oleyl agent is one of paclitaxel, rapamycin, and analogues 40 ether, PEG laurayl ether, octoxynol, monoxynol, ty- thereof, and wherein the second therapeutic agent loxapol, sucrose monopalmitate, sucrose monolau- is one of beta-lapachone, biological active vitamin rate, decanoyl-N-methylglucamide, n-decyl - β -D- D, and their analogues. glucopyranoside, n-decyl - β D-maltopyranoside, n- dodecyl - β -D-glucopyranoside, n-dodecyl- β -D- 56. The balloon catheter according to EMs 40 or 41, 45 maltoside, heptanoyl-N-methylglucamide, n-heptyl- wherein the catheter further comprises an adherent β -D-glucopyranoside, n-heptyl - β -D-thioglucoside, layer between the exterior surface of the balloon and n-hexyl - β -D-glucopyranoside, nonanoyl-N-meth- the coating layer. ylglucamide, n-noyl - β -D-glucopyranoside, oc- tanoyl-N-methylglucamide, n-octyl- β -D-glucopyra- 57. The balloon catheter according to EMs 40 or 41, 50 noside, octyl - β -D-thioglucopyranoside; cystine, ty- wherein the catheter further comprises a top layer rosine, tryptophan, leucine, isoleucine, phenyla- overlying the coating layer, wherein the top layer re- lanine, asparagine, aspartic acid, glutamic acid, and duces loss of the therapeutic agent during transit methionine; acetic anhydride, benzoic anhydride, through a body to the blood vessel. ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodi- 55 um pyrrolidone carboxylate, ethylenediamine- 58. The balloon catheter according to EMs 40 or 41, tetraacetic dianhydride, maleic and anhydride, suc- wherein the catheter further comprises a dimethyl- cinic anhydride, diglycolic anhydride, glutaric anhy- sulfoxide solvent layer, wherein the dimethylsulfox- dride, acetiamine, benfotiamine, pantothenic acid;

43 85 EP 2 500 046 A2 86 cetotiamine; cycothiamine, dexpanthenol, niacina- the additive is at least one of a surfactant and a mide, nicotinic acid, pyridoxal 5-phosphate, nicoti- chemical compound, and wherein the chemical namide ascorbate, riboflavin, riboflavin phosphate, compound has a molecular weight of from 80 to thiamine, folic acid, menadiol diphosphate, menadi- 750, one sodium bisulfite, menadoxime, vitamin B12, vi- 5 and tamin K5, vitamin K6, vitamin K6, and vitamin U; al- wherein the catheter is capable of releasing the bumin, immunoglobulins, caseins, hemoglobins, lys- therapeutic agent and the additive and deliver- ozymes, immunoglobins, a-2-macroglobulin, fi- ing the therapeutic agent to tissue of the blood bronectins, vitronectins, firbinogens, lipases, benza- vessel in less than about 2 minutes. lkonium chloride,benzethonium chloride,docecyl tri- 10 methyl ammonium bromide, sodium docecylsul- 64. The balloon catheter according to EM 63, where- fates, dialkyl methylbenzyl ammonium chloride, and in the balloon catheter further comprises a top layer dialkylesters of sodium sulfonsuccinic acid, L-ascor- overlying the coating layer, wherein the top layer bic acid and its salt, D-glucoascorbic acid and its maintains integrity of the coating layer during transit salt, tromethamine, triethanolamine, 15 dieth- through a blood vessel to the target site for thera- anolamine, meglumine, glucamine, amine alcohols, peutic intervention. glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolac- 65. The balloon catheter according to EM 63, where- tone, glucooctanoic lactone, gulonic acid lactone, in the concentration of the therapeutic agent in the mannoic lactone, ribonic acid lactone, lactobionic ac- 20 coating layer is from 2.5 to 6 Pg/mm2. id, glucosamine, glutamic acid, benzyl alcohol, ben- zoic acid, hydroxybenzoic acid, propyl 4-hydroxy- 66. The balloon catheter according to EM 63, where- benzoate, lysine acetate salt, gentisic acid, lactobi- in the surfactant is chosen from ionic, nonionic, onic acid, lactitol, sinapic acid, vanillic acid, vanillin, aliphatic, and aromatic surfactants, PEG fatty esters, methyl paraben, propyl paraben, sorbitol, xylitol, cy- 25 PEG omega-3 fatty esters, ether, and alcohols, glyc- clodextrin, (2-hydroxypropyl)-cyclodextrin, acetami- erol fatty esters, sorbitan fatty esters, PEG glyceryl nophen, ibuprofen, retinoic acid, lysine acetate, gen- fatty esters, PEG sorbitan fatty esters, sugar fatty tisic acid, catechin, catechin gallate, tiletamine, ket- esters, PEG sugar esters and derivatives thereof. amine, propofol, lactic acids, acetic acid, salts of any organic acid and organic amine, polyglycidol, glyc- 30 67. The balloon catheter according to EM 63, where- erol, multiglycerols, galactitol, di (ethylene glycol), tri in the chemical compound has one or more hydroxyl, (ethylene glycol), tetra(ethylene glycol), penta(eth- amino, carbonyl, carboxyl, acid, amide or ester ylene glycol), poly(ethylene glycol) oligomers, di groups. (propylene glycol), tri(propylene glycol), tetra(pro- pylene glycol, and penta (propylene glycol), poly (pro- 35 68. The balloon catheter according to EM 67, where- pylene glycol) oligomers, a block copolymer of pol- in the surfactant is chosen from ionic, nonionic, yethylene glycol and polypropylene glycol, and de- aliphatic, and aromatic surfactants, PEG fatty esters, rivatives and combinations thereof. PEG omega-3 fatty esters, ether, and alcohols, glyc- erol fatty esters, sorbitan fatty esters, PEG glyceryl 63. A balloon catheter for delivering a therapeutic 40 fatty esters, PEG sorbitan fatty esters, sugar fatty agent to a blood vessel, the catheter comprising: esters, PEG sugar esters and derivatives thereof.

an elongate member having a lumen and a distal 69. The balloon catheter according to EM 67, where- end; in the chemical compound having one or more hy- an expandable balloon attached to the distal end 45 droxyl, amino, carbonyl, carboxyl, acid, amide or es- of the elongate member and in fluid communi- ter groups is chosen from amino alcohols, hydroxyl cation with the lumen; and carboxylic acid, ester, and anhydrides, hydroxyl ke- a coating layer overlying an exterior surface of tone, hydroxyl lactone, hydroxyl ester, sugar phos- the balloon, the coating layer comprising a ther- phate, sugar sulfate, ethyl oxide, ethyl glycols, amino apeutic agent and an additive, 50 acids, peptides, proteins, sorbitan, glycerol, polyal- wherein the additive comprises a hydrophilic cohol, phosphates, sulfates, organic acids, esters, part and a drug affinity part, wherein the drug salts, vitamins, combinations of amino alcohol and affinity part is at least one of a hydrophobic part, organic acid, and their substituted molecules. a part that has an affinity to the therapeutic agent by hydrogen bonding, and a part that has an 55 70. The balloon catheter according to EM 67, where- affinity to the therapeutic agent by van der Waals in the chemical compound has more than four hy- interactions, droxyl groups and has a melting point of 120°C or wherein the additive is water-soluble, wherein less, and wherein the chemical compound is an al-

44 87 EP 2 500 046 A2 88 cohol or an ester. methyl paraben, propyl paraben, sorbitol, xylitol, cy- clodextrin, (2-hydroxypropyl)-cyclodextrin, acetami- 71. The balloon catheter according to EM 63, where- nophen, ibuprofen, retinoic acid, lysine acetate, gen- in the additive is chosen from p-isononylphenoxy- tisic acid, catechin, catechin gallate, tiletamine, ket- polyglycidol, PEG laurate, Tween 20, Tween 40, 5 amine, propofol, lactic acids, acetic acid, salts of any Tween 60, PEG oleate, PEG stearate, PEG glyceryl organic acid and organic amine, polyglycidol, glyc- laurate, PEG glyceryl oleate, PEG glyceryl stearate, erol, multiglycerols, galactitol, di (ethylene glycol), tri polyglyceryl laurate, plyglyceryl oleate, polyglyceryl (ethylene glycol), tetra(ethylene glycol), penta(eth- myristate, polyglyceryl palmitate, polyglyceryl- 6 lau- ylene glycol), poly(ethylene glycol) oligomers, di rate, plyglyceryl-6 oleate, polyglyceryl-6 myristate, 10 (propylene glycol), tri(propylene glycol), tetra(pro- polyglyceryl-6 palmitate, polyglyceryl-10 laurate, pl- pylene glycol, and penta (propylene glycol), poly (pro- yglyceryl-10 oleate, polyglyceryl-10 myristate, poly- pylene glycol) oligomers, a block copolymer of pol- glyceryl-10 palmitate PEG sorbitan monolaurate, yethylene glycol and polypropylene glycol, and de- PEG sorbitan monolaurate, PEG sorbitan mo- rivatives and combinations thereof. nooleate, PEG sorbitan stearate, PEG oleyl ether, 15 PEG laurayl ether, octoxynol, monoxynol, tyloxapol, 72. A pharmaceutical composition comprising a ther- sucrose monopalmitate, sucrose monolaurate, de- apeutic agent and an additive, wherein the additive canoyl-N-methylglucamide, n-decyl - β -D-glucop- comprises a hydrophilic part and a drug affinity part, yranoside, n-decyl - β -D-maltopyranoside, n-do- wherein the drug affinity part is at least one of a hy- decyl - β -D-glucopyranoside, n-dodecyl - β -D-mal- 20 drophobic part, a part that has an affinity to the ther- toside, heptanoyl-N-methylglucamide, n-heptyl- β apeutic agent by hydrogen bonding, and a part that -D-glucopyranoside, n-heptyl - β -D-thioglucoside, has an affinity to the therapeutic agent by van der n-hexyl - β -D-glucopyranoside, nonanoyl-N-meth- Waals interactions, wherein the additive is water- sol- ylglucamide, n-noyl - β - D-glucopyranoside, oc- uble, wherein the additive is at least one of a sur- tanoyl-N-methylglucamide, n-octyl- β -D-glucopyra- 25 factant and a chemical compound, and wherein the noside, octyl - β -D-thioglucopyranoside; cystine, ty- chemical compound has a molecular weight of from rosine, tryptophan, leucine, isoleucine, phenyla- 80 to 750. lanine, asparagine, aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoic anhydride, 73. The pharmaceutical composition according to ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodi- 30 EM 72, wherein the composition does not include an um pyrrolidone carboxylate, ethylenediamine- iodine covalent bonded contrast agent or a polymer, tetraacetic dianhydride, maleic and anhydride, suc- and wherein the therapeutic agent is not encapsu- cinic anhydride, diglycolic anhydride, glutaric anhy- lated in miscelles or particles. dride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; cycothiamine, dexpanthenol, niacina- 35 74. The pharmaceutical composition according to mide, nicotinic acid, pyridoxal 5-phosphate, nicoti- EM 72, wherein the chemical compound has one or namide ascorbate, riboflavin, riboflavin phosphate, more hydroxyl, amino, carbonyl, carboxyl, acid, thiamine, folic acid, menadiol diphosphate, menadi- amide or ester groups. one sodium bisulfite, menadoxime, vitamin B12, vi- tamin K5, vitamin K6, vitamin K6, and vitamin U; al- 40 75. The pharmaceutical composition according to bumin, immunoglobulins, caseins, hemoglobins, lys- EM 72, wherein the surfactant is chosen from ionic, ozymes, immunoglobins, a-2-macroglobulin, fi- nonionic, aliphatic, and aromatic surfactants, PEG bronectins, vitronectins, firbinogens, lipases, benza- fatty esters, PEG omega-3 fatty esters, ether, and lkonium chloride,benzethonium chloride,docecyl tri- alcohols, glycerol fatty esters, sorbitan fatty esters, methyl ammonium bromide, sodium docecylsul-45 PEG glyceryl fatty esters, PEG sorbitan fatty esters, fates, dialkyl methylbenzyl ammonium chloride, and sugar fatty esters, PEG sugar esters and derivatives dialkylesters of sodium sulfonsuccinic acid, L-ascor- thereof. bic acid and its salt, D-glucoascorbic acid and its salt, tromethamine, triethanolamine, dieth- 76. The pharmaceutical composition according to anolamine, meglumine, glucamine, amine alcohols, 50 EM 74, wherein the surfactant is chosen from ionic, glucoheptonic acid, glucomic acid, hydroxyl ketone, nonionic, aliphatic, and aromatic surfactants, PEG hydroxyl lactone, gluconolactone, glucoheptonolac- fatty esters, PEG omega-3 fatty esters, ether, and tone, glucooctanoic lactone, gulonic acid lactone, alcohols, glycerol fatty esters, sorbitan fatty esters, mannoic lactone, ribonic acid lactone, lactobionic ac- PEG glyceryl fatty esters, PEG sorbitan fatty esters, id, glucosamine, glutamic acid, benzyl alcohol, ben- 55 sugar fatty esters, PEG sugar esters and derivatives zoic acid, hydroxybenzoic acid, propyl 4-hydroxy- thereof. benzoate, lysine acetate salt, gentisic acid, lactobi- onic acid, lactitol, sinapic acid, vanillic acid, vanillin, 77. The pharmaceutical composition according to

45 89 EP 2 500 046 A2 90

EM 74, wherein the chemical compound having one bronectins, vitronectins, firbinogens, lipases, benza- or more hydroxyl, amino, carbonyl, carboxyl, acid, lkonium chloride,benzethonium chloride,docecyl tri- amide or ester groups is chosen from amino alco- methyl ammonium bromide, sodium docecylsul- hols, hydroxyl carboxylic acid, ester, and anhy- fates, dialkyl methylbenzyl ammonium chloride, and drides, hydroxyl ketone, hydroxyl lactone, hydroxyl 5 dialkylesters of sodium sulfonsuccinic acid, L-ascor- ester, sugar phosphate, sugar sulfate, ethyl oxide, bic acid and its salt, D-glucoascorbic acid and its ethyl glycols, amino acids, peptides, proteins, sorb- salt, tromethamine, triethanolamine, dieth- itan, glycerol, polyalcohol, phosphates, sulfates, or- anolamine, meglumine, glucamine, amine alcohols, ganic acids, esters, salts, vitamins, combinations of glucoheptonic acid, glucomic acid, hydroxyl ketone, amino alcohol and organic acid, and their substituted 10 hydroxyl lactone, gluconolactone, glucoheptonolac- molecules. tone, glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonic acid lactone, lactobionic ac- 78. The pharmaceutical composition according to id, glucosamine, glutamic acid, benzyl alcohol, ben- EM 74, wherein the chemical compound has more zoic acid, hydroxybenzoic acid, propyl 4-hydroxy- than four hydroxyl groups and has a melting point of 15 benzoate, lysine acetate salt, gentisic acid, lactobi- 120°C or less, and wherein the chemical compound onic acid, lactitol, sinapic acid, vanillic acid, vanillin, is an alcohol or an ester. methyl paraben, propyl paraben, sorbitol, xylitol, cy- clodextrin, (2-hydroxypropyl)-cyclodextrin, acetami- 79. The pharmaceutical composition according to nophen, ibuprofen, retinoic acid, lysine acetate, gen- EM 72, wherein the additive is chosen from p-isono- 20 tisic acid, catechin, catechin gallate, tiletamine, ket- nylphenoxypolyglycidol, PEG laurate, Tween 20, amine, propofol, lactic acids, acetic acid, salts of any Tween 40, Tween 60, PEG oleate, PEG stearate, organic acid and organic amine, polyglycidol, glyc- PEG glyceryl laurate, PEG glyceryl oleate, PEG glyc- erol, multiglycerols, galactitol, di (ethylene glycol), tri eryl stearate, polyglyceryl laurate, plyglyceryl oleate, (ethylene glycol), tetra(ethylene glycol), penta(eth- polyglyceryl myristate, polyglyceryl palmitate, poly- 25 ylene glycol), poly(ethylene glycol) oligomers, di glyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl- (propylene glycol), tri(propylene glycol), tetra(pro- 6 myristate, polyglyceryl-6 palmitate, polyglyceryl- pylene glycol, and penta (propylene glycol), poly (pro- 10 laurate, plyglyceryl-10 oleate, polyglyceryl-10 pylene glycol) oligomers, a block copolymer of pol- myristate, polyglyceryl-10 palmitate PEG sorbitan yethylene glycol and polypropylene glycol, and de- monolaurate, PEG sorbitan monolaurate, PEG sorb- 30 rivatives and combinations thereof. itan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, ty- 80. A method for treating a diseased body lumen or loxapol, sucrose monopalmitate, sucrose monolau- cavity after a surgical or interventional procedure rate, decanoyl-N-methylglucamide, n-decyl - β -D- comprising delivering a pharmaceutical composition glucopyranoside, n-decyl - β - D-maltopyranoside, 35 at a surgical site by injection or spraying with a cath- n-dodecyl - β -D-glucopyranoside, n-dodecyl - β -D- eter, wherein the composition comprises a therapeu- maltoside, heptanoyl-N-methylglucamide, n-heptyl- tic agent and an additive, wherein the additive com- β -D-glucopyranoside, n-heptyl - β -D-thioglucoside, prises a hydrophilic part and a drug affinity part, n-hexyl - β -D-glucopyranoside, nonanoyl-N-meth- wherein the drug affinity part is at least one of a hy- ylglucamide, n-noyl - β - D-glucopyranoside, oc- 40 drophobic part, a part that has an affinity to the ther- tanoyl-N-methylglucamide, n-octyl- β D-glucopyran- apeutic agent by hydrogen bonding, and a part that oside, octyl - β -D-thioglucopyranoside; cystine, ty- has an affinity to the therapeutic agent by van der rosine, tryptophan, leucine, isoleucine, phenyla- Waals interactions, wherein the additive is at least lanine, asparagine, aspartic acid, glutamic acid, and one of a surfactant and a chemical compound, and methionine; acetic anhydride, benzoic anhydride, 45 wherein the chemical compound has a molecular ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodi- weight of from 80 to 750. um pyrrolidone carboxylate, ethylenediamine- tetraacetic dianhydride, maleic and anhydride, suc- 81. The method according to EM 80, wherein the cinic anhydride, diglycolic anhydride, glutaric anhy- chemical compound has one or more hydroxyl, ami- dride, acetiamine, benfotiamine, pantothenic acid; 50 no, carbonyl, carboxyl, acid, amide or ester groups. cetotiamine; cycothiamine, dexpanthenol, niacina- mide, nicotinic acid, pyridoxal 5-phosphate, nicoti- 82. The method according to EM 80, wherein the namide ascorbate, riboflavin, riboflavin phosphate, additive is water-soluble, and wherein the composi- thiamine, folic acid, menadiol diphosphate, menadi- tion does not include an iodine covalent bonded con- one sodium bisulfite, menadoxime, vitamin B12, vi- 55 trast agent. tamin K5, vitamin K6, vitamin K6, and vitamin U; al- bumin, immunoglobulins, caseins, hemoglobins, lys- 83. The method according to EM 80, wherein the ozymes, immunoglobins, a-2-macroglobulin, fi- surfactant is chosen from ionic, nonionic, aliphatic,

46 91 EP 2 500 046 A2 92 and aromatic surfactants, PEG fatty esters, PEG acid, and their substituted molecules. omega-3 fatty esters, ether, and alcohols, glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty 90. The solution according to EM 85, wherein the esters, PEG sorbitan fatty esters, sugar fatty esters, therapeutic agent is paclitaxel or rapamycin or ana- PEG sugar esters, and derivatives thereof. 5 log or derivative thereof.

84. The method according to EM 81, wherein the 91. The solution according to EM 85, wherein the chemical compound having one or more hydroxyl, additive is chosen from p-isononylphenoxypolyglyc- amino, carbonyl, carboxyl, acid, amide or ester idol, PEG laurate, Tween 20, Tween 40, Tween 60, groups is chosen from amino alcohols, hydroxyl car- 10 PEG oleate, PEG stearate, PEG glyceryl laurate, boxylic acid, ester, and anhydrides, hydroxyl ketone, PEG glyceryl oleate, PEG glyceryl stearate, polyg- hydroxyl lactone, hydroxyl ester, sugar phosphate, lyceryl laurate, plyglyceryl oleate, polyglyceryl myr- sugar sulfate, ethyl oxide, ethyl glycols, amino acids, istate, polyglyceryl palmitate, polyglyceryl-6 laurate, peptides, proteins, sorbitan, glycerol, polyalcohol, plyglyceryl-6 oleate, polyglyceryl-6 myristate, poly- phosphates, sulfates, organic acids, esters, salts, vi- 15 glyceryl-6 palmitate, polyglyceryl-10 laurate, plyg- tamins, combinations of amino alcohol and organic lyceryl-10 oleate, polyglyceryl-10 myristate, polyg- acid, and their substituted molecules. lyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan mo- 85. A solution for coating a medical device, the so- nooleate, PEG sorbitan stearate, PEG oleyl ether, lution comprising an organic solvent, a therapeutic 20 PEG laurayl ether, octoxynol, monoxynol, tyloxapol, agent, and an additive, wherein the additive com- sucrose monopalmitate, sucrose monolaurate, de- prises a hydrophilic part and a drug affinity part, canoyl-N-methylglucamide, n-decyl - β -D-glucop- wherein the drug affinity part is at least one of a hy- yranoside, n-decyl - β -D-maltopyranoside, n-do- drophobic part, a part that has an affinity to the ther- decyl - β -D-glucopyranoside, n-dodecyl - β -D-mal- apeutic agent by hydrogen bonding, and a part that 25 toside, heptanoyl-N-methylglucamide, n-heptyf- β has an affinity to the therapeutic agent by van der -D-glucopyranoside, n-heptyl - β -D-thioglucoside, Waals interactions, wherein the additive is water- sol- n-hexyl - β -D-glucopyranoside, nonanoyl-N-meth- uble, wherein the additive is at least one of a sur- ylglucamide, n-noyl - β - D-glucopyranoside, oc- factant and a chemical compound, and wherein the tanoyl-N-methylglucamide, n-octyl- β -D-glucopyra- chemical compound has a molecular weight of from 30 noside, octyl - β -D-thioglucopyranoside; cystine, ty- 80 to 750. rosine, tryptophan, leucine, isoleucine, phenyla- lanine, asparagine, aspartic acid, glutamic acid, and 86. The solution according to EM 85, wherein the methionine; acetic anhydride, benzoic anhydride, solution does not include an iodine covalent bonded ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodi- contrast agent. 35 um pyrrolidone carboxylate, ethylenediamine- tetraacetic dianhydride, maleic and anhydride, suc- 87. The solution according to EM 85, wherein the cinic anhydride, diglycolic anhydride, glutaric anhy- chemical compound has one or more hydroxyl, ami- dride, acetiamine, benfotiamine, pantothenic acid; no, carbonyl, carboxyl, acid, amide or ester groups. cetotiamine; cycothiamine, dexpanthenol, niacina- 40 mide, nicotinic acid, 88. The solution according to EM 85, wherein the pyridoxal 5-phosphate, nicotinamide ascorbate, ri- surfactant is chosen from ionic, nonionic, aliphatic, boflavin, riboflavin phosphate, thiamine, folic acid, and aromatic surfactants, PEG fatty esters, PEG menadiol diphosphate, menadione sodium bisulfite, omega-3 fatty esters, ether, and alcohols, glycerol menadoxime, vitamin B12, vitamin K5, vitamin K6, fatty esters, sorbitan fatty esters, PEG glyceryl fatty 45 vitamin K6, and vitamins U; albumin, immunoglobu- esters, PEG sorbitan fatty esters, sugar fatty esters, lins, caseins, hemoglobins, lysozymes, immu- PEG sugar esters, and derivatives thereof. noglobins, a-2-macroglobulin, fibronectins, vit- ronectins, firbinogens, lipases, benzalkonium chlo- 89. The solution according to EM 85, wherein the ride, benzethonium chloride, docecyl trimethyl am- chemical compound having one or more hydroxyl, 50 monium bromide, sodium docecylsulfates, dialkyl amino, carbonyl, carboxyl, acid, amide or ester methylbenzyl ammonium chloride, and dialkylesters groups is chosen from amino alcohols, hydroxyl car- of sodium sulfonsuccinic acid, L-ascorbic acid and boxylic acid, ester, and anhydrides, hydroxyl ketone, its salt, D-glucoascorbic acid and its salt, trometh- hydroxyl lactone, hydroxyl ester, sugar phosphate, amine, triethanolamine, diethanolamine, meglu- sugar sulfate, ethyl oxide, ethyl glycols, amino acids, 55 mine, glucamine, gamine alcohols, glucoheptonic peptides, proteins, sorbitan, glycerol, polyalcohol, acid, glucomic acid, hydroxyl ketone, hydroxyl lac- phosphates, sulfates, organic acids, esters, salts, vi- tone, gluconolactone, glucoheptonolactone, glu- tamins, combinations of amino alcohol and organic cooctanoic lactone, gulonic acid lactone, mannoic

47 93 EP 2 500 046 A2 94 lactone, ribonic acid lactone, lactobionic acid, glu- drug affinity part, wherein the drug affinity part cosamine, glutamic acid, benzyl alcohol, benzoic ac- is at least one of a hydrophobic part, a part that id, hydroxybenzoic acid, propyl 4-hydroxybenzoate, has an affinity to the therapeutic agent by hy- lysine acetate salt, gentisic acid, lactobionic acid, drogen bonding, and a part that has an affinity lactitol, sinapic acid, vanillic acid, vanillin, methyl pa- 5 to the therapeutic agent by van der Waals inter- raben, propyl paraben, sorbitol, xylitol, cyclodextrin, actions, wherein the additive is water-soluble, (2-hydroxypropyl)-cyclodextrin, acetaminophen, wherein the additive is at least one of a sur- ibuprofen, retinoic acid, lysine acetate, gentisic acid, factant and a chemical compound, and wherein catechin, catechin gallate, tiletamine, ketamine, pro- the chemical compound has a molecular weight pofol, lactic acids, acetic acid, salts of any organic 10 of from 80 to 750. acid and organic amine, polyglycidol, glycerol, mul- tiglycerols, galactitol, di(ethylene glycol), tri (ethylene 97. The two layer coating according to EM 96, where- glycol), tetra(ethylene glycol), penta(ethylene gly- in the first layer does not include an iodine covalent col), poly(ethylene glycol) oligomers, di(propylene bonded contrast agent. glycol), tri(propylene glycol), tetra(propylene glycol, 15 and penta(propylene glycol), poly(propylene glycol) 98. The two layer coating according to EM 96, where- oligomers, a block copolymer of polyethylene glycol in the top layer further comprises a therapeutic and polypropylene glycol, and derivatives and com- agent. binations thereof. 20 99. A method for preparing a medical device, the 92. A medical device for delivering a therapeutic method comprising: agent to a tissue, the device comprising: (a) preparing a coating solution comprising an a first layer applied to an exterior surface of the organic solvent, a therapeutic agent, and an ad- medical device, and 25 ditive, wherein the additive comprises a hy- a second layer overlying the first layer, drophilic part and a drug affinity part, wherein wherein the first layer comprises a therapeutic the drug affinity part is at least one of a hydro- agent, and phobic part, a part that has an affinity to the ther- wherein the second layer comprises an additive, apeutic agent by hydrogen bonding, and a part wherein the additive comprises a hydrophilic 30 that has an affinity to the therapeutic agent by part and a drug affinity part, wherein the drug van der Waals interactions, wherein the additive affinity part is at least one of a hydrophobic part, is water-soluble, wherein the additive is at least a part that has an affinity to the therapeutic agent one of a surfactant and a chemical compound, by hydrogen bonding, and a part that has an and wherein the chemical compound has a mo- affinity to the therapeutic agent by van der Waals 35 lecular weight of from 80 to 750; interactions. (b) applying the coating solution to a medical device; and 93. The medical device according to EM 92, wherein (c) drying the coating solution, forming a coating the first layer further comprises an additive, wherein layer. the additive is water-soluble, and the layer does not 40 include an iodinated contrast agent. 100. The method according to EM 99, wherein the coating layer does not includes an iodine covalent 94. The medical device according to EM 92, wherein bonded contrast agent. the second layer further comprises a therapeutic agent. 45 101. The method according to EM 99, wherein the coating solution is applied by dipping a portion of the 95. The medical device according to EM 92, wherein exterior surface of the medical device in the coating the first layer further comprises an additive and the solution. second layer further comprises a therapeutic agent. 50 102. The method according to EM 99, wherein the 96. A two layer coating comprising: coating solution is applied by spraying a portion of the exterior surface of the medical device with a coat- a first layer comprising a therapeutic agent and ing solution. an additive, and a top layer comprising an additive, wherein the 55 103. The method according to EM 99, wherein steps top layer is overlying the first layer, (b) and (c) are repeated until a therapeutically effec- wherein the additive in both the first layer and in tive amount of the therapeutic agent in the coating the top layer comprises a hydrophilic part and a layer is deposited on the surface of the medical de-

48 95 EP 2 500 046 A2 96 vice. removing plaques from the body passage; inserting a medical device comprising a coating 104. The method according to EM 99, wherein the layer into the body passage, total thickness of the coating layer is from about 0.1 wherein the coating layer comprises a therapeu- to 200 microns. 5 tic agent and an additive, wherein the additive comprises a hydrophilic part and a drug affinity 105. The method according to EM 99, further com- part, wherein the drug affinity part is at least one prising applying a dimethylsulfoxide solvent to the of a hydrophobic part, a part that has an affinity dried coating layer obtained in step (c). to the therapeutic agent by hydrogen bonding, 10 and a part that has an affinity to the therapeutic 106. A method for preparing a drug coated balloon agent by van der Waals interactions, wherein catheter, the method comprising: the additive is at least one of a surfactant and a chemical compound, and wherein the chemical (a) preparing a coating solution comprising an compound has a molecular weight of from 80 to organic solvent, a therapeutic agent, and an ad- 15 750; and ditive, releasing the therapeutic agent and the additive wherein the additive comprises a hydrophilic and delivering the therapeutic agent into the tis- part and a drug affinity part, wherein the drug sue of the body passage in 2 minutes or less. affinity is at least one of a hydrophobic part, a part that has an affinity to the therapeutic agent 20 110. A method for treating tissue of a body compris- by hydrogen bonding, and a part that has an ing: affinity to the therapeutic agent by van der Waals interactions, wherein the additive is at least one bringing a medical device comprising a coating of a surfactant and a chemical compound, and layer into contact with tissue of the body, wherein the chemical compound has a molecu- 25 wherein the coating layer comprises a therapeu- lar weight of from 80 to 750; tic agent and an additive, wherein the additive (b) applying the coating solution to an inflated comprises a hydrophilic part and a drug affinity balloon catheter; and part, wherein the drug affinity part is at least one (c) deflating and folding the balloon catheter and of a hydrophobic part, a part that has an affinity drying the coating solution to increase uniformity 30 to the therapeutic agent by hydrogen bonding, of drug coating. and a part that has an affinity to the therapeutic agent by van der Waals interactions, wherein 107. Amethod for treating a blood vessel comprising: the additive is water-soluble, wherein the addi- tive is at least one of a surfactant and a chemical inserting a medical device comprising a coating 35 compound, and wherein the chemical com- layer into the blood vessel, pound has a molecular weight of from 80 to 750; wherein the coating layer comprises a therapeu- and tic agent and an additive, wherein the additive releasing the therapeutic agent and the additive comprises a hydrophilic part and a drug affinity and delivering the therapeutic agent into the tis- part, wherein the drug affinity is at least one of 40 sue in 2 minutes or less. a hydrophobic part, a part that has an affinity to the therapeutic agent by hydrogen bonding, and 111. The method according to EM 110, wherein the a part that has an affinity to the therapeutic agent coating layer does not include an iodine covalent by van der Waals interactions, wherein the ad- bonded contrast agent. ditive is water-soluble, wherein the additive is at 45 least one of a surfactant and a chemical com- 112. The method for treating according to EM 110, pound, and wherein the chemical compound wherein the tissue includes tissue of one of coronary has a molecular weight of from 80 to 750; and vasculature, peripheral vasculature, cerebral vascu- releasing the therapeutic agent and the additive lature, esophagus, airways, sinus, trachea, colon, and delivering the therapeutic agent into the tis- 50 biliary tract, urinary tract, prostate, and brain pas- sue of the blood vessel in 2 minutes or less. sages.

108. The method according to EM 107, wherein the 113. A balloon catheter produced by a process com- coating layer does not include an iodine covalent prising: contrast agent. 55 preparing a solution comprising an organic sol- 109. A method for treating a total occlusion or nar- vent, a therapeutic agent, and an additive, rowing of a body passage comprising: wherein the additive comprises a hydrophilic

49 97 EP 2 500 046 A2 98

part and a drug affinity part, wherein the drug layer comprising a therapeutic agent and an additive, affinity is at least one of a hydrophobic part, a wherein the additive is one of sorbitan fatty esters, part that has an affinity to the therapeutic agent and PEG sorbitan esters. by hydrogen bonding, and a part that has an affinity to the therapeutic agent by van der Waals 5 120. The medical device according to EM 113, interactions, wherein the additive is water- solu- wherein the additive is chosen from sorbitan monol- ble, wherein the additive is at least one of a sur- aurate, sorbitan monopalmitate, sorbitan mo- factant and a chemical compound, and wherein nooleate, sorbitan monostearate, PEG-20 sorbitan the chemical compound has a molecular weight monolaurate, PEG-20 sorbitan monopalmitate, of from 80 to 750; 10 PEG-20 sorbitan monooleate, and PEG- 20 sorbitan applying the solution to the balloon catheter; and monostearate. evaporating the solvent. 121. A medical device for delivering a therapeutic 114. The balloon catheter according to EM 113, agent to a tissue, the device comprising a layer over- wherein the solution does not contain an iodinated 15 lying an exterior surface of the medical device, the contrast agent. layer comprising a therapeutic agent and an additive, wherein the additive is a chemical compound con- 115. A medical device for delivering a therapeutic taining a phenol moiety. agent to a tissue, the device comprising a layer over- lying an exterior surface of the medical device, the 20 122. The medical device according to EM 121, layer comprising a therapeutic agent and an additive, wherein the additive is chosen from p-isononylphe- wherein the additive is one of PEG fatty ester, PEG noxypolyglycidol, octoxynol, monoxynol, tyloxapol, fatty ether, and PEG fatty alcohols. octoxynol-9, and monoxynol-9.

116. The medical device according to EM 115,25 123. A medical device for delivering a therapeutic wherein the additive is chosen from PEG-8 laurate, agent to a tissue, the device comprising a layer over- PEG-8 oleate, PEG- 8 stearate, PEG-9 oleate, PEG- lying an exterior surface of the medical device, the 10 laurate, PEG-10 oleate, PEG-12 laurate, PEG- layer comprising a therapeutic agent and an additive, 12 oleate, PEG-15 oleate, PEG- 20 laurate, PEG-20 wherein the additive is chosen from sucrose monol- oleate, PEG-20 dilaurate, PEG-20 dioleate, PEG- 20 30 aurate, decanoyl-N-methylglucamide, n-decyl - β -D- distearate, PEG-32 dilaurate and PEG-32 dioleate. glucopyranoside, n-decyl - β -D-maltopyranoside, n- dodecyl - β -D-glucopyranoside, n-dodecyl - β -D- 117. A medical device for delivering a therapeutic maltoside, heptanoyl-N-methylglucamide, n-heptyl- agent to a tissue, the device comprising a layer over- β -D-glucopyranoside, n- heptyl - β - D- thioglucoside, lying an exterior surface of the medical device, the 35 n-hexyl - β -D-glucopyranoside, nonanoyl-N-meth- layer comprising a therapeutic agent and an additive, ylglucamide, n-noyl - β -D-glucopyranoside, oc- wherein the additive is one of glycerol and polyglyc- tanoyl-N-methylglucamide, n-octyl- fl -D-glucopyra- erol fatty esters and PEG glycerol fatty esters. noside, octyl -β -D-thioglucopyranoside, D-glu- coascorbic acid and its salt, tromethamine, glu- 118. The medical device according to EM 117,40 camine, glucoheptonic acid, glucomic acid, hydroxyl wherein the additive is chosen from polyglyceryl ketone, hydroxyl "lactone, gluconolactone, gluco- oleate, polyglyceryl-2 dioleate, polyglyceryl-10 tri- heptonolactone, glucooctanoic lactone, gulonic acid oleate, polyglyceryl stearate, polyglyceryl laurate, lactone, mannoic lactone, ribonic acid lactone, lac- polyglyceryl myristate, polyglyceryl palmitate, poly- tobionic acid, and glucosamine. glyceryl linoleate, polyglyceryl-10 laurate, polyglyc- 45 eryl-10 oleate, polyglyceryl-10 mono, dioleate, pol- 124. A medical device for delivering a therapeutic yglyceryl-10 stearate, polyglyceryl-10 laurate, poly- agent to a tissue, the device comprising a layer over- glyceryl-10 myristate, polyglyceryl- 10 paimitate, pol- lying an exterior surface of the medical device, the yglyceryl-10 linoleate, polyglyceryl-6 stearate, poly- layer comprising a therapeutic agent and an additive, glyceryl-6 laurate, polyglyceryl-6 myristate, polyg- 50 wherein the additive is an ionic surfactant. lyceryl-6 palmitate, and polyglyceryl- 6 linoleate, pol- yglyceryl polyricinoleates, PEG-20 glyceryl laurate, 125. The medical device according to EM 124, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, wherein the additive is chosen from benzalkonium PEG-20 glyceryl oieate, and PEG- 30 glyceryl oleate. chloride, benzethonium chloride, cetylpyridinium 55 chloride, docecyl trimethyl ammonium bromide, so- 119. A medical device for delivering a therapeutic dium docecylsulfates, dialkyl methylbenzyl ammoni- agent to a tissue, the device comprising a layer over- um chloride, edrophonium chloride, domiphen bro- lying an exterior surface of the medical device, the mide, dialkylesters of sodium sulfonsuccinic acid,

50 99 EP 2 500 046 A2 100 sodium dioctyl sulfosuccinate, sodium cholate, and layer comprising a therapeutic agent and an additive, sodium taurocholate. wherein the additive includes a combination or mix- ture of both a surfactant and a chemical compound, 126. A medical device for delivering a therapeutic wherein the chemical compound has one or more agent to a tissue, the device comprising a layer over- 5 hydroxyl, amino, carbonyl, carboxyl, acid, amide or lying an exterior surface of the medical device, the ester groups. layer comprising a therapeutic agent and an additive, wherein the additive is a vitamin or a vitamin deriv- 133. The medical device according to EM 132, ative. wherein the surfactant is chosen from ionic,nonionic, 10 aliphatic, and aromatic surfactants, PEG fatty esters, 127. The medical device according to EM 126, PEG omega-3 fatty esters, ether, and alcohols, glyc- wherein the additive is chosen from acetiamine, ben- erol fatty esters, sorbitan fatty esters, PEG glyceryl fotiamine, pantothenic acid, cetotiamine, cycothia- fatty esters, PEG sorbitan fatty esters, sugar fatty mine, dexpanthenol, niacinamide, nicotinic acid and esters, PEG sugar esters and derivatives thereof. its salts, pyridoxal 5- phosphate, nicotinamide ascor- 15 bate, riboflavin, riboflavin phosphate, thiamine, folic 134. The medical device according to EM 132, acid, menadiol diphosphate, menadione sodium bi- wherein the chemical compound having one or more sulfite, menadoxime, vitamin B12, vitamin K5, vita- hydroxyl, amino, carbonyl, carboxyl, acid, amide or min K6, vitamin K6, vitamin U, ergosterol, 1-alpha- ester groups has a molecular weight of from 80 to hydroxycholecal- ciferol, vitamin D2, vitamin D3, al- 20 750. pha-carotene, beta-carotene, gamma-carotene, vi- tamin A, fursultiamine, methylolriboflavin, octo- 135. The medical device according to EM 134, tiamine, prosultiamine, riboflavine, vintiamol, dihy- wherein the chemical compound is chosen from ami- drovitamin K1, menadiol diacetate, menadiol dibu- no alcohols, hydroxyl carboxylic acid, ester, and an- tyrate, menadiol disulfate, menadiol, vitamin K1, vi- 25 hydrides, hydroxyl ketone, hydroxyl lactone, hy- tamin K1 oxide, vitamins K2, and vitamin K--S(II). droxyl ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids, sorbitan, glycerol, 128. A medical device for delivering a therapeutic polyalcohol, phosphates, sulfates, organic acids, es- agent to a tissue, the device comprising a layer over- ters, salts, vitamins, combinations of amino alcohol lying an exterior surface of the medical device, the 30 and organic acid, and their substituted molecules. layer comprising a therapeutic agent and an additive, wherein the additive is an amino acid, an amino acid 136. The medical device according to EM 132, salt, or an amino acid derivative. wherein the chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or 129. The medical device according to EM 128,35 ester groups is chosen from acetic acid and anhy- wherein the additive is chosen from alanine, ar- dride, benzoic acid and anhydride, diethylenetri- ginine, asparagine, aspartic acid, cysteine, glutamic aminepentaacetic acid dianhydride, ethylenediami- acid, glutamine, glycine, histidine, proline, isoleu- netetraacetic dianhydride, maleic acid and anhy- cine, leucine, lysine, methionine, phenylalanine, ser- dride, succinic acid and anhydride, diglycolic acid ine, threonine, tryptophan, tyrosine, valine, and de- 40 and anhydride, glutaric acid and anhydride, ascorbic rivatives thereof. acid, citric acid, tartaric acid, lactic acid, oxalic acid aspartic acid, nicotinic acid, L-ascorbic acid and its 130. A medical device for delivering a therapeutic salt, D-glucoascorbic acid and its salt, trometh- agent to a tissue, the device comprising a layer over- amine, triethanolamine, diethanolamine, meglu- lying an exterior surface of the medical device, the 45 mine, glucamine, amine alcohols, glucoheptonic ac- layer comprising a therapeutic agent and an additive, id, glucomic acid, hydroxyl ketone, hydroxyl lactone, wherein the additive is a peptide, an oligopeptide, or gluconolactone, glucoheptonolactone, glucooctano- a protein. ic lactone, gulonic acid lactone, mannoic lactone, ri- bonic acid lactone, lactobionic acid, glucosamine, 131. The medical device according to EM 130,50 glutamic acid, benzyl alcohol, benzoic acid, hydroxy- wherein the additive is chosen from albumins, im- benzoic acid, propyl 4-hydroxybenzoate, lysine ac- munoglobulins, caseins, hemoglobins, lysozymes, etate salt, gentisic acid, lactobionic acid, lactitol, immunoglobins, a-2-macroglobulin, fibronectins, vit- sorbitol, glucitol, sugar phosphates, glucopyranose ronectins, firbinogens, and lipases. phosphate, sugar sulphates, sinapic acid, vanillic ac- 55 id, vanillin, methyl paraben, propyl paraben, xylitol, 132. A medical device for delivering a therapeutic 2-ethoxyethanol, cyclodextrin, hydroxypro- (2- agent to a tissue, the device comprising a layer over- pyl)-cyclodextrin, acetaminophen, ibuprofen, retino- lying an exterior surface of the medical device, the ic acid, lysine acetate, gentisic acid, catechin, cate-

51 101 EP 2 500 046 A2 102 chin gallate, tiletamine, ketamine, propofol, lactic ac- ethyl glycols, amino acids, peptides, proteins, sug- ids, acetic acid, salts of any organic acid and amine ars, glucose, sucrose, sorbitan, glycerol, polyalco- described above, polyglycidol, glycerol, multiglycer- hol, phosphates, sulfates, organic acids, esters, ols, galactitol, di(ethylene glycol), tri(ethylene gly- salts, vitamins, combinations of amino alcohol and col), tetra(ethylene glycol), penta(ethylene glycol), 5 organic acid, and their substituted molecules. poly(ethylene glycol) oligomers, di(propylene gly- col),tri (propyleneglycol), tetra (propyleneglycol, and 143. The pharmaceutical formulation according to penta(propylene glycol), poly(propylene glycol) oli- EM 139,wherein the chemical compound havingone gomers, a block copolymer of polyethylene glycol or more hydroxyl, amino, carbonyl, carboxyl, acid, and polypropylene glycol, and derivatives and com- 10 amide or ester groups is chosen from L- ascorbic acid binations thereof. and its salt, D-glucoascorbic acid and its salt, tromethamine, triethanolamine, diethanolamine, 137. The medical device according to any one of meglumine, glucamine, amine alcohols, glucohep- EMs 115, 117, 119, 121, 123, 124, 126, 128, 130, tonic acid, glucomic acid, hydroxyl ketone, hydroxyl 132, wherein the tissue includes tissue of one of cor- 15 lactone, gluconolactone, glucoheptonolactone, glu- onary vasculature, peripheral vasculature, cerebral cooctanoic lactone, gulonic acid lactone, mannoic vasculature,esophagus, airways, sinus, trachea, co- lactone, ribonic acid lactone, lactobionic acid, glu- lon, biliary tract, urinary tract, prostate, and brain cosamine, glutamic acid, benzyl alcohol, benzoic ac- passages. id, hydroxybenzoic acid, propyl 4-hydroxybenzoate, 20 lysine acetate salt, gentisic acid, lactobionic acid, 138. The medical device according to any one of lactitol, sorbitol, glucitol, sugar phosphates, glucop- EMs 115, 117, 119, 121, 123, 124, 123, 128, 130, yranose phosphate, sugar sulphates, sinapic acid, and 132, wherein the device includes one of a bal- vanillic acid, vanillin, methyl paraben, propyl pa- loon catheter, a perfusion balloon catheter, an infu- raben, xylitol, 2-ethoxyethanol, sugars, galactose, sion catheter, a cutting balloon catheter, a scoring 25 glucose, ribose, mannose, xylose, sucrose, lactose, balloon catheter, a laser catheter, an atherectomy maltose, arabinose, lyxose, fructose, cyclodextrin, device, a debulking catheter, a stent, a filter, a stent (2-hydroxypropyl)-cyclodextrin, acetaminophen, graft, a covered stent, a patch, a wire, and a valve. ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, pro- 139. A pharmaceutical formulation for administration 30 pofol, lactic acids, acetic acid, salts of any organic to a mammal comprising: paclitaxel or rapamycin or acid and amine described above, polyglycidol, glyc- derivatives thereof; and a combination of both a sur- erol, multiglycerols, galactitol, di (ethylene glycol), tri factant and a chemical compound, wherein the (ethylene glycol), tetra(ethylene glycol), penta(eth- chemical compound has one or more hydroxyl, ami- ylene glycol), poly(ethylene glycol) oligomers, di no, carbonyl, carboxyl, acid, amide or ester groups. 35 (propylene glycol), tri(propylene glycol), tetra(pro- pylene glycol, and penta (propylene glycol), poly (pro- 140. The pharmaceutical formulation according to pylene glycol) oligomers, a block copolymer of pol- EM 139, wherein the surfactant is chosen from ionic, yethylene glycol and polypropylene glycol, and de- nonionic, aliphatic, and aromatic surfactants, PEG rivatives and combinations thereof. fatty esters, PEG omega-3 fatty esters, ether, and 40 alcohols, glycerol fatty esters, sorbitan fatty esters, 144. A pharmaceutical formulation for administration PEG glyceryl fatty esters, PEG sorbitan fatty esters, to a mammal comprising: paclitaxel or rapamycin or sugar fatty esters, PEG sugar esters and derivatives derivatives thereof; and a chemical compound with thereof. one or more hydroxyl, amino, carbonyl, carboxyl, ac- 45 id, amide or ester groups; wherein the chemical com- 141. The pharmaceutical formulation according to pound with one or more hydroxyl, amino, carbonyl, EM 139,wherein the chemical compound havingone carboxyl, acid, amide or ester groups has a molec- or more hydroxyl, amino, carbonyl, carboxyl, acid, ular weight of from 80 to 750. amide or ester groups has a molecular weight of from 80 to 750. 50 145. The pharmaceutical formulation according to EM 144, wherein the chemical compound with one 142. The pharmaceutical formulation according to or more hydroxyl, amino, carbonyl, carboxyl, acid, EM 139,wherein the chemical compound havingone amide, or ester groups is chosen from hydroxyl ke- or more hydroxyl, amino, carbonyl, carboxyl, acid, tone, hydroxyl lactone, gluconolactone, glucohep- amide, or ester groups is chosen from amino alco- 55 tonolactone, glucooctanoic lactone, gulonic acid lac- hols, hydroxyl carboxylic acid, ester, and anhy- tone, mannoic lactone, ribonic acid lactone, sugar drides, hydroxyl ketone, hydroxyl lactone, hydroxyl phosphate, sugar sulfate, catechin, catechin gallate, ester, sugar phosphate, sugar sulfate, ethyl oxide, and combinations of amino alcohol and organic acid.

52 103 EP 2 500 046 A2 104

146. The pharmaceutical formulation according to no, carbonyl, carboxyl, acid, amide or ester groups. EM 145, wherein the amino alcohol is chosen from tromethamine, triethanolamine, diethanolamine, 2. The composition of claim 1, wherein the chemical meglumine, glucamine, glucosamine,lysine, and de- compound has a molecular weight of from 80 to 750. rivatives thereof; and the organic acid is chosen from 5 glucoheptonic acid, glucomic acid, glutamic acid, 3. The composition of claims 1 or 2, wherein the com- benzoic acid, hydroxybenzoic acid, gentisic acid, position does not include an iodine covalent-bonded lactobionic acid, vanillic acid, lactic acids, acetic acid, contrast agent or a polymer, and wherein the thera- and derivatives thereof. peutic agent is not enclosed in micelles or encapsu- 10 lated in particles. 147. A pharmaceutical formulation for administration to a mammal comprising: paclitaxel or rapamycin or 4. The composition of claims 1 to 3, wherein the sur- derivatives thereof; and a combination of amino al- factant is chosen from ionic, nonionic, aliphatic, and cohol and organic acid, wherein the amino alcohol aromatic surfactants, PEG fatty esters, PEG omega- is chosen from tromethamine, triethanolamine, di- 15 3 fatty esters, ether, and alcohols, glycerol fatty es- ethanolamine, meglumine, glucamine, glu- ters, sorbitan fatty esters, PEG glyceryl fatty esters, cosamine, lysine, and derivatives thereof; and the PEG sorbitan fatty esters, sugar fatty esters, PEG organic acid is chosen from glucoheptonic acid, glu- sugar esters and derivatives thereof. comic acid, glutamic acid, benzoic acid, hydroxyben- zoic acid, gentisic acid, lactobionic acid, vanillic acid, 20 5. The composition of claim 4, wherein the surfactant lactic acids, acetic acid, and derivatives thereof. is chosen from Tween 20, Tween 40, Tween 60, Tween 80, PEG laurate, PEG oleate, PEG stearate, 148. A medical device for delivering a therapeutic PEG glyceryl laurate, PEG glyceryl oleate, PEG glyc- agent to a tissue, the device comprising a layer over- eryl stearate, PEG sorbitan monolaurate, PEG sorb- lying an exterior surface of the medical device, the 25 itan monooleate, PEG sorbitan stearate, PEG sorb- layer comprising a therapeutic agent and an additive, itan laurate, PEG sorbitan oleate, PEG sorbitan wherein the additive is chosen from hydroxyl ketone, palmitate, and combinations thereof. hydroxyl lactone, gluconolactone, glucoheptonolac- tone, glucooctanoic lactone, gulonic acid lactone, 6. The composition of claims 1 or 2, wherein the chem- mannoic lactone, ribonic acid lactoneand lactobionic 30 ical compound is chosen from sorbitol, sorbitan, xy- acid. litol, gluconolactone, glucoheptonolactone, glu- cooctanoic lactone, gulonic acid lactone, mannoic 149. A medical device for delivering a therapeutic lactone, ribonic acid lactone, lactobionic acid, cate- agent to a tissue, the device comprising a layer over- chin, catechin gallate, pentaerythritol, amides, or- lying an exterior surface of the medical device, the 35 ganic acids, esters, ethers, anhydrides, poly(ethyl- layer comprising a therapeutic agent and an additive, ene glycol) oligomers, poly(propylene glycol) oli- wherein the therapeutic agent is paclitaxel and an- gomers, di(ethylene glycol), tri (ethylene glycol), tetra alogues thereof or rapamycin and analogues there- (ethylene glycol), penta(ethylene glycol), di(propyl- of, and the additive is chosen from sorbitol, diethyl- ene glycol), tri(propylene glycol), tetra(propylene ene glycol, triethylene glycol, tetraethylene glycol, 40 glycol, penta(propylene glycol), a block copolymer polyethylene glycol oligomers, polypropylene glycol of polyethylene glycol and polypropylene glycol, and oligomers, block copolymer oligomers of polyethyl- polyvinylpyrrolidinone. ene glycol and polypropylene glycol, xylitol, 2-ethox- yethanol, sugars, galactose, glucose, mannose, xy- 7. The composition of claims 1 to 5, wherein the chem- lose, sucrose, lactose, maltose, Tween 20, Tween 45 ical compound is chosen from sorbitol, sorbitan, xy- 40, Tween 60, and their derivatives, wherein the ratio litol, gluconolactone, glucoheptonolactone, glu- by weight of drug to additive is from 0.5 to 3, wherein cooctanoic lactone, gulonic acid lactone, mannoic the therapeutic agent and the additive are simulta- lactone, ribonic acid lactone, lactobionic acid, cate- neously released. chin, catechin gallate, pentaerythritol, amides, or- 50 ganic acids, esters, ethers, anhydrides, poly(ethyl- ene glycol) oligomers, poly(propylene glycol) oli- Claims gomers, di(ethylene glycol), tri (ethylene glycol), tetra (ethylene glycol), penta(ethylene glycol), di(propyl- 1. A composition comprising paclitaxel, a paclitaxel an- ene glycol), tri(propylene glycol), tetra(propylene alogue, rapamycin, and a rapamycin analogue or de- 55 glycol and penta(propylene glycol). rivatives thereof; and a combination of both a sur- factant and a chemical compound, wherein the 8. The composition according to any of the proceeding chemical compound has one or more hydroxyl, ami- claims, wherein the composition consists of only the

53 105 EP 2 500 046 A2 106

therapeutic agent, the surfactant, the chemical com- pound, and optionally a solvent.

9. The composition according to claim 8, wherein the solvent is ethanol, methanol, or acetone. 5

10. The composition according to any of the preceding claims, wherein the ratio by weight of the therapeutic agent to the first and second additives in the com- position is from about 0.1 to 5. 10

11. The composition according to any of the preceding claims, for use in a method of treating a diseased body lumen or cavity. 15 12. The composition for use according to claim 11, wherein the method of treatment includes delivering the composition to tissue by injection, spraying, or coating release with a catheter. 20 13. Use of the composition according to any of the pro- ceeding claims for coating a medical device.

14. The use according to claim 13, wherein the medical device is a balloon catheter, a cutting balloon cath- 25 eter, a scoring balloon catheter, a laser catheter, an atherectomy device, a debulking catheter, a stent, a filter, a stent graft, a covered stent, a patch, a wire, or a valve. 30 15. A medical device coated with the composition of claims 1 to 12.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 11942452 B [0001] • US 90447307 P [0001] • US 86008406 P [0001] • US 92685007 P [0001] • US 88074207 P [0001] • US 98138007 P [0001] • US 89742707 P [0001] • US 98138407 P [0001] • US 90352907 P [0001]

Non-patent literature cited in the description

• SCHOTT. J, Pharm. Sciences, 1990, vol. 79 (1), 87-88 [0117]

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