IE20130079A1 - Method for loading dilatable catheter balloons and dilatation catheters obtained therefrom - Google Patents

Abstract

The invention relates to a method for loading structured surfaces that are preferably made of a polymer material with the dithiolethione molecule, oltipraz, as well as the coated mecical products obtained by means of said method. The invention also relates to analogues of oltipraz that can be used as described above.

Description

Title Method for Loading Structured Surfaces Description The present invention relates to a method for loading textured surfaces, preferably such surfaces which are composed of a polymeric material, with the dithlolethlone molecule, oitipraz; and to the coated medical devices obtained by means of said method. The invention also includes analogues of oltipraz to be used in the methods described above. )0 Nowadays, implantation of vessel grafts such as stents has become a wellestablished surgical intervention for the treatment of stenoses. In this context, socalled restenosis (recurrent stenosis), i.e. the reccciusion of the vessel is a frequently occurring complication. There's no exact definition of the term restenosis to be found in literature. The most frequently used morphological definition of restenosis defines restenosis as a reduction of the vessel diameter to less than 50% of the normal value subsequent to successful PTA (percutaneous transluminal angioplasty). Said definition describes an empirically determined value and its hemodynamic meaning and association with clinical symptoms lack scientific background in practice, clinical deterioration in a patient is often considered a sign for the occurrence of restenosis in the previously treated vessel section.

Restenosis following stent implantation is one of the major causes for further hospitalization. Vessel traumas induced during stent implant ail on often cause inflammatory reactions which play a decisive role in the healing process during the first seven days. In the recent past, it has also been found that stents provided with a drug-eluting coating may cause late thromboses, i.e. in addition to restenosis the stent may also lead to long-term problems such as late thromboses.

To avoid such problems, a so-called biological stenting” may be performed using only a coated catheter balloon without any stent, i.e. the vessels are dilated at a constricted site by the dilatation of a coated catheter balloon, wherein, while the catheter balloon is dilated for a short period of time, a sufficient amount of pharmacological agent is transferred to the vessel wall to avoid re-constriction or reocclusion of the vessel due to the dilatation of the vessel and the delivery of active agents. 2IE 1 3 Ο Ο 7 9 Such coated catheter balloons are already known from WO 2005/089855 A1 and the international patent application WO 2004/028582 At discloses multifold balloons which are coated, especially within the folds, with a composition of a pharmacological agent and a contrast medium. A method for spray coating catheter balloons is described in WO 2004/006976 A1. it is an objective to apply the active agent oitipraz onto a catheter balloon in such manner that a coating is created which is easily detached from the balloon and can be effectively transferred to the vessel wall.

Said objective is resolved by the technical teaching of the independent claims Further advantageous embodiments of the invention result from the dependent ciaims and the description.

It has been found that a coating method of the following type is especially suited for resolving said objective.

Said method for loading or coating dilatable catheter balloons includes: I) providing a dilatable catheter balloon; II) providing a solution of oitipraz in acetone; III) texturing the surface of the dilatable catheter balloon; IV) wetting the surface of the dilatable catheter balloon with the solution of oitipraz in acetone; V) applying a solvent which is capable of precipitating oitipraz onio Ihe surface of the dilatable catheter balloon wetted with the solution of oitipraz in acetone; VI) drying the wetted surface of the dilatable catheter balloon; in another embodiment, multifold balloons are coated when in expanded state by a method that includes: I) providing a dilatable catheter balloon; Ila) providing a solution of oitipraz iri acetone; lib) expansion of the balloon that includes folds so that inner surfaces of the folds become accessible; III) texturing the surface of the dilatable, expanded catheter balloon; IV) wetting the surface of the dilatable catheter balloon with the solution of oitipraz in acetone; V) applying a solvent which is capable of precipitating oitipraz onto the surface of the dilatable catheter balloon wetted with the solution of oitipraz in acetone; Vi) drying the wetted surface of the dilatable catheter balloon; VB) refolding of the foldable balloon back into its compressed state. -3IEl 3 Ο Ο 7 9 The method for loading or coating catheter balloons and multifold balloons is carried out proceeding from step I) to VI) or respectively I) to Vfl), wherein it is evident that the order regarding steps I) and II) can be interchanged.

Moreover, steps IV) to VI) may be repeated several times. Step V) that includes the application of a solvent capable of precipitating oitipraz has to be performed at least once, but does not necessarily have to be repeated in a second coating process. Thus, it is aiso possible to perform steps IV) to VI) i.e. steps I) to VI) in the first coating process and to include only steps IV) to Vi) when the coating process is repeated.

In the above processes, acetone may be replaced with dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF).

Any commerciaify available dilatable catheter balloon may be used as catheter balloon. Preferably, so called multifold balloons are used, as described for example in the international patent application WO 94/23787 A1 by David H, Rammler, Labintetligence, USA; or the international patent application WO 03/059430 A1 by Sci med Life Sciences, Inc., USA; or the international patent application WO 2004/028582 A1 by Prof. Dr. Ulrich Speck or the European Patent No. EP 0519063 B1 by Medtronic Inc., USA.

Such balloons are provided with folds or wings forming essentially closed cavities when the balloon is in its compressed slate but bending outward during dilatation and being capable of releasing substances contained in the folds or respectively of pressing said substances against the vessel wall.

Such balloons are advantageous since the substances enclosed in the foids or respectively oitipraz enclosed in the folds are protected from being detached too soon during the insertion of the catheter.

To protect the active agent oitipraz from early detachment from the catheter bafloon, oitipraz may also be incorporated or embedded into a carrier substance, preferably a polymeric carrier. In order to apply said carrier or respectively polymeric carrier containing oitipraz onto the catheter balloon, the carrier substance is added to the ΙΕί 3 0 0 7 9 solution of acetone and oltipraz. Such acetone solutions containing oltipraz and the carrier substance are then applied onto the catheter balloon using conventionai methods, in particular spattering or dipping methods. Suitable carriers are such substances which are also used as balloon material, in particular polymeric and polymerizable substances as listed further below.

Aiso in such cases where the coating, i.e. the oltipraz, is not protected by the folds of a multifold balloon or where the oltipraz is not incorporated into a carrier, a sufficient amount of the pure active agent oltipraz, may be applied onto the catheter balloon so that even including a calculated amount of oltipraz in the range of about 30% of the total amount being detached prematurely during the insertion of the catheter balloon, there is still a sufficiently high and therapeutically active amount of oltipraz present on the balloon once it has reached its target, which amount can then be transferred to the vessel wall during dilatation.

IS Thus, it is preferred to protect the active agent oltipraz from premature detachment e.g. by application underneath the folds or by embedment into a carrier on the surface of the catheter balloon, although such a protection is not necessarily required.

Usually, the coating procedure is repeated one or two or three times, but said repetition is not obligatory. Even one coating procedure may be sufficient for the application of the required amount of oltipraz onto the catheter balloon.

Generally, an amount ΰΐ 0,5 pg io 50 pg of oltipraz per mm2 of the surface of trie balloon catheter to be coated and preferably an amount of 1 pg to 20 pg of oitipraz per mm2 of the surface of the balloon catheter to be coated is applied onto the surface of the balloon catheter. Preferably, 10 to 1000 pg of oltipraz are applied per catheter balloon and most preferably 20 pg to 400 pg are applied onto the balloon per catheter balloon.

Oltipraz (A-methyl-S-pyrazinyl-SH-l, 2-dlihiole-3“thione, CAS: 64224-21-1) is a synthetic member of the dithiolethiones family of molecules, whose chemical composition was first patented in 1963 by Rhone Poulenc. Oltipraz was initially developed as an anti-schistosoma! agent and first entered clinical trials in France in 1980, The chemical structure of oltipraz is: In certain embodiments of the invention, the metabolite of oltipraz, the pyrrolopyrazine derivative metabolite 3 (also known as M3) can be used.

In certain embodiments of the invention, the analogue of oltipraz, anethole trithione {5’-(p’-methoxyphenyJ)-3H-'t12-dithiole-3“thio)1 aiso known as anetol tritiona or SON I CU R ca n be used.

In certain embodiments of the invention, the compound 1,2-dithiole-3-thione (D3T) or an analogue thereof, can be used. Typically, the 1,2-dithiole-3-thione analogue has the following formula: wherein: in the case of 5-substituted analogues: R1 is H, R2 is phenyl and X is S, Ri is H, R- is 4-methoxyphenyl and X is S, Ri is H, R2 is 2-pyranzinyl and X Is O or Ri is H, Ra is 2-(5,B-dimethyl) pyrazinyl and X is S; in the case of 5-substituted-4-methyl analogues: Ri is CH3l R2 is 2’-pyridyi and X is S, Ri is CH3, Rj> is 3-pyridyi and X is S, -61E1 3 Ο Ο 7 9 Ri is CHa, R2 is 4-pyridyi and X is S, R1 is CHSl R2 is 3-pyridazinyl and X is S, R, is CHa, R2 is 2-thiofuranyl and X is S or, R, is CH3, R2 is 2-(2-pyrazinyi) ethylene and X is S; in the case of 4-substituied-5-(2-pyrazinyl) analogues: Rq is CH3l R? is 2-pyrazinyl and X is S, Rt is CH3l R2 is 2-pyraziny I and X is O, Rt is CH2OH, R2 is 2-pyrazinyi and X is S, Rt is CH2CH3, R2 is 2-pyrazinyl and X is S or Rt is (CH2)3CH3, R2 is 2-pyrazinyl and X is S; in the case of miscellaneous analogues: Rt is CO2C2H5, R2 is 2-pyridyl and X is S, Rt is CO2C2H5i Rj> is 4-pyridyl and X is S, Rd is Cl, R2 is [4-(2-propyl)phenyl] amino and X is S, Rq is Ci, R2 is [4-(2- propyl)phenyl] amino and X is 0, R1 is CH2CO2C2HGl R is 5-pyrimidyl and X is S, Rt is CJ-ISCONECH(CH3)2]2, R2 is 5-pyrimidyl and X is S, Rt is phenethyl, R2 is 3-pyridazinyi and X is S, R, is H, R2 is 4-pyridyl and X is N-O-(CH2)3N(CH3)2 or R1 is (CH3)3CH3l R2 is 3-(S-di methyl a mi no) pyridezinyl and X is S.

In certain further embodiments, R1 is fluorine or bromine, and R2 and X are selected from the substituents listed above.

In certain further embodiments, the analogue can be selected from 3H-1,2-dithioie-3thione, anethole trithione (5-(4-methoxyphenyi)-3H-1 ,2-dithiole-3-thione), ADT, ADO, 1,2- dithiole-3-thione, 1,2-dithiolane, 1 ,3-dithioIe-2-thione, malotiiate, 4-(3,5diisopropyl-4-hydroxyphenyl)-1,2-dit-hiote-3-thione; 4(3,5-di-t-buty l-4-hydroxy pheny J)35 1 ,2-dithiole-3-thione; 4-[3,5brs(l J-dimethylpropyl )-4-hydroxyphenyl]-1 ,2-dithi-ole-3thione; 4- [3,5bis(l,l-dimethylbutyt )-4-hydroxypheny 1]-1,2-dithiole-3-thione; 4-[3,5-7IEl 3 0 0 7 9 bis(1,1,3,3-tetramethy I butyl )-4-hyd roxy phenyl]-1,2-dithole3-th ion-e; 4-[3,5-bis(lmethyicyciohexyl)-4-hydroxyphenyi]-1 32-dEthto1e-3-tbione; 4- {3,5-bis(t dimethyl benzyl )-4-hydroxyphenyi]1 ,2 -dithiole-3-thione; 4-(3t -butyM-hydroxy-Sisopropylphenyl)- 1 ,2-dithiole-3-thione; 4-(3 t-bu t y l-4-hy d rax y-5-m ethyl phony 1)-1,25 d it hiole-3-throne; 4-(3(1, 1-dimethyipropyl)-4-hydroxy.-5isopropyiphenyl]-1 ,2-dithiole3-thi-one; 4-(3(1, 'l-dimethyibenzyl)4-hydroxy-5-isopropylphenylj-1 ,2-d it hiole-3thione; 5-benzy It h io4- (3.5-d i-t-buty i-4-h y d roxy ph en y I) -1,2-dithole -3-thione; 5benzy Ith i o-4-f 3,5- bis( I, i -d i methy Ipro py I )-4-h y d roxy-pheny I]-1 ,2- d i th io I e-3-thi on e; 5hexylth ΐ 0-4-(3 ,5-d i-t-butyl-4-hydroxyphenyl)1 ,2-dithde-3—thione; 5-hexylth 10-4-(3,510 bis(l,l-dimethylbutyl)-4hydroxy-phenyl]-1 ,2-d i-th lole-3-thione; Ξ-octadecylth io-4-{3 , 5 -d it- buty I -4-hy d roxy p heny I)-1 ,2-di- th i 0 le-3-th ro ne; 5- oda decy Ithio- 4-[3,5-biS(l,l· di methy lb enzy I) -4-hy d roxy ph e n y ipf, 2-d ith io!e-3thione; 5-aliylthro-4-(3,5“di“t-butyl-4hyd roxy ph en y-1)-1,2-dithio le-3-t h io ne; 5-cy cl o hexy It h i 0-4-(3,5-di-t- but y 1-4hydroxyphenyl}-1,2-d ithio le-3-th rone; arid 4-(3,5-di-sec-buty l-4hyd roxy pheny 1)-1 ,2-di15 thiole-3-thione.

Oitipraz is highly soluble in acetone, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) and methanol as well as in anhydrous ethanol, but is comparatively poorly soluble in water.

Acetone is used as a solvent for oitipraz. Acetone dissolves the required amounts of oitipraz ensuring sufficient amounts of the compound are available to coat the balloon catheter. Materials used for the balloon catheter are such materials as listed further below, wherein the following polymers are particularly preferred; polyamides, block copolymers of polyamide, poly ether and polyester, polyurethanes, polyesters and polyolefins.

Furthermore, by successively increasing its water content acetone can slowly reduce the solubility of oitipraz in acetone to a point where oitipraz starts to precipitate or to crystallize. The structure of the precipitated oitipraz is not clear but it has been shown that an oitipraz coating obtained by the embodiments disclosed herein detaches particularly well from the catheter balloon and can be particularly well transferred to the vessel wall.

In the acetone, oitipraz is soluble in amounts of up to 150 mg/ml. Preferably 1 mg -8IE 1 3 0 0 7 9 150 mg, more preferably 10 mg to 90 mg and most preferably 40 mg to 60 mg of oitipraz are dissolved in one mi of acetone.

As already mentioned before, a carrier for the active agent oitipraz may be added to 5 the acetone solution. Preferably, the carrier is a biostable or biodegradable polymer, preferably selected from the group of polymers disclosed further below as materials for the catheter balloon. The carrier substance(s) used may include a weight percentage of up to 70% by weight, preferably up to 50% by weight, more preferably up to 30% per weight with respect to the total weight of the solution.

According to the inventive methods, the surface of the catheter balloon is textured mechanically, chemically, electronically and/or by means of radiation to allow for an improved adhesion of oitipraz and to assist the precipitation or crystallization of the oitipraz.

By the texturing of the surface of the catheter balloon the surface of the catheter balloon is to be modified in the range from nanometers to micrometers, i.e. a kind of micro-rough surface structure is to be provided. Surface texturing is preferably applied to the whole area to be coated of the catheter balloon and may result in organized or random structures.

The catheter balloons may he composed of the following materials: paryiene C, parylene D, parylene M, parylene F, polyvaferolaciones, poly-epsilon.decalactone, poiylactonic acid, polyglycolic acid, pofyfactides, polyglycolides, copolymers of the polylactides and polyglycolides, poly . epsi I on.-ca pro lactone, poly hydroxy butyric acid, poiyhydroxy butyrates, poly hydroxy val erates, p oly h yd roxy b uty rate-co-va le rate, po ly (1,4-dioxane-2-d tone), ρα I y (1,3-dioxa n e-2-one), poly-para-dioxanone, polyanhydrides, poly maleic acid anhydride, polyh yd roxymeth acrylates, fibrin, polycyanoacrylate, polyca pro Eactone di methylacrylates, poly-.beta-maleic acid, polyca pro lactone butyl acrylates, multiblock polymers from ol ig oca prolacton edio les and ο I igodioxa no nedioles, poly ether ester multi block polymers from PEG and polyfbutylene terephthalate), poly pi votola clones, polyglycolic acid tri methyl carbonates, poly capro lactone glycolides, poly (.gamma-ethyl glutamate) poiy(DTH-iminocarbonate), poly(DTE-co35 DT-carbonate), poly(bisphenol A-tminocarbonate), poiyorthoesters, polyglycolic acid trimethyl-carbonate, polytrimethyl carbonates, poiyiminocarbonates, pofy(N-vinyl)-9IE 1 3 0 0 7 9 pyrrol· done, polyvinyl alcohols, polyester amides, glycolized polyesters, poly phosp hoesters, poiyph osphazenes, poly [p-carboxyphen oxy) propane], poly hydroxy pentanoic acid, polya nhydrides, polyethylene oxide propylene oxide, soft polyurethanes, polyurethanes having amino acid residues in the backbone, poiyether ester, polyethylene oxide, polyalkene oxalates, poly orthoesters as well as their copolymers, lipids, carrageenans, fibrinogen, starch, collagen, protein based polymers, polyamino acids, synthetic patyamino acids, zein, polyhydroxyalkanoates, pectic acid, actinic acid, car boxy methy I sulfate, albumin, hyaluronic acid, chitosan and derivatives thereof, heparan sulfates and derivatives thereof, he pari ns, iO chondroitin sulfate, dextran, .beta.-cyclodextrin5. copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatine, collagen N-hydroxysuccinimide, phospholipids, polyacrylic acid, polyacrylates, polym ethyl methacrylate, polybutyl methacrylate, polyacrylamide, polyacrylonitriles, polyamides, polyetheramides, polyethylene amine, polyimides, polycarbonates, poiycarbourethanes, polyvinyl ketones, polyvinyl halogenides, poly vinylidene halogenides, polyvinyl ethers, polyj so butylenes, polyvinyi aromatics, polyvinyl esters, polyvinyl pyrrolidones, poly oxy methylenes, polytetramethylene oxide, polyethylene, polypropylene, polytetrafiuoroethylene, polyurethanes, polyether urethanes, silicone poiyether urethanes, silicone polyurethanes, silicone polycarbonate urethanes, polyolefin elastomers, EPDM gums, flu orosi iicones, car boxy methyl chitosans, polya ryletheretherketones, polyetheretherketones, polyethylene terephthalate, poly vale rates, carb oxy methy I cellulose, cellulose, rayon, rayon triacetates, cellulose nitrates, cellulose acetates, hydroxyeihyl cellulose, cellulose butyrates, cellulose acetate butyrates, ethyl vinyl acetate copolymers, poiysulfones, epoxy resins, ASS resins, silicones, polysiloxanes, polydimethylsiloxanes, polyvinyi halogens and copolymers, cellulose ethers, cellulose tri acetates, chitosans and copolymers and/or mixtures of the aforementioned poly mere.

Polyamides, block copolymers of polyamide-polyether-poly ester, polyurethanes, polyester and polyolefins are preferred. it is of importance to avoid all damage to the catheter balloons while the balloon surface is textured and to ensure that their capability to expand is not dis advantageously affected. Thus, the methods for micro texturing the balloon surface must not Jead to the formation of holes, micropores or fissures in the balloon -10IE 1 3 0 0 7 9 material. Ideally, only the outer surface of the balloon, i.e. to a maximum depth of 1 pm, is textured.

The dilatable catheter balloon may be textured mechanically by making use of a 5 rasp-like device, a rasp or a blasting method employing solid particles, such as a sand blasting procedure.

In a chemical-mechanical procedure a suspension or a dispersion of solid particles in & solvent, in particular in water, is used. Such methods are also referred to as chemical polishing methods. By rubbing such compositions onto the surface of the balloon material the material is roughened without deep fissures or holes being created.

In a purely chemical texturing method, acids, bases, etching chemicals and/or oxidizing chemicals corroding the surface of the balloon material are used. Such chemicals, however, are to be used with caution, as the balloon material couid be damaged if the exposition period is io long or too intense.

When an electrical or electronic procedure is used for texturing the surface of the dilatable catheter balloon, texturing is performed by means of conductors which are heated by current flow. For example, a fine, warm, hot or glowing needle may be used to melt the surface of the balloon material by means of which certain patterns cart be created on the surface, especially when the needle is moved along the surface of the catheter balloon.

An elegant method for generating organized textures, espa ci ally in form of micro depressions or micro channels, may include the use of lasers or basically of strongly focused radiation. Said radiation means are very accurate and may be especially used for the generation of defined textures such as grids, spirals or lines, Such a structuring of the surface results in an extension of the surface and thereby enables a higher loading of the active agent compared to an unstructured surface.

The microstructuring of the catheter balloon thereby creates a three dimensional surface, which can be foaded with a bigger amount of oltipraz. Furthermore compared to the flat untreated surface of the balloon, the structured surface also - 11 IE 1 3 Ο Ο 7 9 enables a better adhesion of the active agent, which then is better protected against being removed by washing and dissolution in the biood stream, as it is at least partly incorporated in the so generated pores.

The textured or micro modified to nano-mod if ied surface of the catheter balloon may be wetted by using all common methods For example, the soiution of oltipraz in acetone may be applied onto the balloon surface by means of spattering, dipping, plasma deposition, brushing or spraying. While the whole surface of the catheter balloon is usually coated when a dipping method or plasma disposition are used, spattering, brushing and spraying may be used when only a portion of the balloon surface is to be coated.

According to an embodiment, the catheter balloon does not have to be completely coated. Partial coating of or loading of certain texture elements onto the surface of the catheter balloon may be sufficient. A special catheter balloon including microneedles or micro-pores or micro-chambers is disclosed in the international patent application no. WO 02/043796 A2 issued to Scimed Life Systems, Inc,, USA, wherein inflatable and textured areas are present on the balloon surface. In said embodiment, loading or inflating certain portions of the balloon surface would be sufficient to achieve the desired therapeutic success, wherein it is also possible, evidently, that the whole surface is coated.

Furthermore, another possibility inciudes coating the catheter balloon partially, i.e. certain sections of the catheter balloon and, successively, additional areas until a completely coated catheter ba I io on is obtained, if desired.

It has been found that upon complete or partial wetting of the surface of the catheter balloon the desired coating cannot be generated by mere evaporation of the solvent. Thus, step V) of the inventive coating method in which a solvent capable of precipitating oltipraz is applied onto the wetted surface immediately after the wetting process or immediately after the application of the solution of oltipraz in acetone and before the acetone has evaporated to an extent of 50%, preferably 25% and more preferably 10% is particularly essential. Said additional solvent is added to the acetone and is intended to reduce the solubility of oltipraz in acetone. Said addition solvent is typically designed such that oltipraz is only poorly soluble or insoluble - 12ΙΕ ί 3 0 f) .7 9 therein, so that the solubility product of oitipraz in acetone is reduced when said solvent is added to the acetone.

Said additional solvent is used for precipitating oitipraz and is preferably dispersed 5 homogenously in the acetone. Precipitating agent is added, preferabiy by spattering or brushing or pipetting, until a slight clouding is caused or until oitipraz visibly starts to precipitate. At this point, some more precipitating solvent may be added or the solvent mixture of acetone and precipitating solvent is left to evaporate. Evidently, the drying process of the coating may be accelerated by applying negative pressure or vacuum; air drying, however, is to be preferred.

The inventive oitipraz coating which is hard to characterize is thus obtained.

Preferably, such solvents which have a poor solubility of oitipraz are used as a 15 precipitating solvent for oitipraz. Generally, the solubility of oitipraz in such solvents should be characterized by no more than 1 mg of oitipraz per 1 ml of solvent being soluble.

Water is particularly suited as precipitating solvent, due to the fact that oitipraz is only 20 very poorly soluble therein and as water is both physiologically acceptable and harmless to the balloon material.

In the best case, distilled, desalted and deionized water which can be obtained by common ion exchange chromatography is used.

It is additionally preferred that the water has a phi in the range of from 2 io 6, preferabiy from 3 to 5 and more preferably form 3,5 to 4.5. The pH may be adjusted using organic acids and salts of said organic acids, wherein generally as small an amount of buffer in form of acids and conjugated bases as possible is to be used.

Particularly suited acids for adjusting the pH include: formic acid, acetic acid, propionic acid, oxalic acid, salicylic acid, tartaric acid, fumaric acid, gluconic acid, lactic acid, malic acid, ascorbic acid, maleic acid, malonic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, giutaric acid, camphors uifonic acid or china acid {quinic acid). Additionally, saits of said acids, such as sodium acetate, calcium oxalate or lithium malonate may be used, if required. - 13 ΙΕ* λ 0 o 'i g Furthermore, another active agent may be added to the soiution of oltipraz in acetone, which agent may, for exampie, be selected from the following group: abciximab, acemetacin, acetyivismione B, aclarubicin, ademetionine, adriamycin, aescin, afromosorte, akagerine, aldesleukin, amidorone, aminoglutethimide, amsacrine, anakinra, anastrozoie, anemonin, anopterine, antimycotics, antithrombotics, apocymarin, argatroban, aristoiactam-AII, aristofochic acid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basilrximab, bendamustine, benzocaine, berberine, betulin, betulinlc acid, bilobol, bisparthenoiidine, bleomycin, com bre statin, Bosweliic acids and derivatives thereof, bruceanol A, B and C, bryophyllin A, busulfan, antithrombin, bivaiirudin, cadherins, camptothecin, capecitabine, α-carbamoyl-phenoxyacetic acid, carboplatin, camnustine, celecoxib, cepharanthin, cerlvastatin, CETR inhibitors, chiorambucii, chloroquine phosphate, cicutoxin, ciprofloxacin, cisplatin, cla dri bine, clarithromycin, colchicine, concanamycin, coumadin, G-type natriuretic peptide (CNP), cudraisoflavone A, curcumin, cyclophosphamide, ciclosporin A, cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone, daunorubicin, diclofenac, 1,11d i methoxy canthin-6-one, docetaxei, doxorubicin, daunamycin, epirubicin, epothilorte A and B, erythromycin, estramustine, etoposide, everolimus, filgrastim, fluoroblastin, fluvastatin, fludarabine, fiudara bi ne-5'-di hydrogen phosphate, fluorouracil, f ol i my ci n, fosfestrol, gemcitabine, ghalakinosrde, ginkgol, ginkgolic acid, glycoside 1a, 4hydroxyoxycyclo phosphamide idarubicin, ifosfamrde, josamycin, Japachol, Iomustine, lovastatin, melphalan, mid ecarnycin, mitoxantrone, nimustine, pita vast atiri, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxajiplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, pegaspargase, exemestane, letrozole, formestane, mitoxantrone, myoophenolate mofetil, beta -lapachone, podophyllotoxin, podophyliic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon alpha.-2b, lenograstim (r-HuG-CSF), macrogof, select!n (cytokine antagonist), cytokinin inhibitors, COX-2 inhibitor, angiopeptin, monoclonal antibodies inhibiting muscle cel! proliferation, bFGF antagonists, probucol, prostaglandins, 1 -hy d roxy-11 -methoxy canth in-6-on e, scopoletin, NO donors, pentaerythrityl tetranitrate and sydnolmines, S-nitroso derivatives, tamoxifen, staurosporine, .beta.-estradiol, .alpha.-estradiol, estriol, estrone, ethinyl estradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids used in cancer therapy, - 14“ IEl 3 0 0 7 9 verapamil, tyrosine kinase inhibitors (tyrphostins), taxoteres, mofebutazone, lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meioxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, .betasitosterol, myrtecaine, polidocano!, nonivamide, tevomenthol, eilipticine, D-24S51 (Cal biochem), colcemid, cytochalasin A-E, indanocine, nocod azole, bacitracin, vitronectin receptor antagonists, azeiastine, guanidyl cyclase stimulator, tissue inhibitor of metal proteinase-1 and -2, free nucleic acids, nucleic acids Incorporated into virus transmitters, DNA and RNA fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, antisense oligonucleotides, VEGF inhibitors, IGF-1, active agents from fhe group of antibiotics, cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamicin, penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole, e noxa pari n, heparin, hirudin, PPACK, protamine, pro urokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidole, trapidil, nitroprussides, PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captoprll, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, Interferon alpha, beta and gamma, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, haiofuginone, nifedipine, tocopherol, tranilast, molsidomine, tea polyphenols, epicat echin gallate, epigallocatechin gallate, leffunomide, etanercept, sulfasalazine, dicloxacillin, tetracycline, triamcinolone, mutamycin, procain imide, retinoic acid, quinidine, drsopyrimide, flecamide, propafenone, sotalol, natural and synthetically obtained steroids such as bryophyllin A, inotodioi, maquiroside A, ghalaklnoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances (NSAIDS) such as fenoprofen, fe noprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, antiviral agents, acyclovir, ganciclovir zidovudine, clotrimazole, flucytosine, griseofuivtn, ketoconazole, miconazole, nystatin, terbinafine, antiprotozoal agents, chloroquine, mefloquine, quinine, natural terpenoids, hippocaescufin, barringtogenol-C21a ng elate, 14-dehydroagrostisiachin, agroskerin, agrostisiachin, 17hydroxyagrosti sta chin, ovatodiolids, 4,7-oxycyc!oanisome!ic acid baccharinoids B1, 82, B3 and B7, tubeimoside, bruce anti noside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and 8, ooranarin A,B C and D, ursoiic acid, hyptatic acid A, iso-irldogermanai, maytertfoiioi, effusantin A, excisanin A and δ, Jongikaurin B, scuiponeatin C, kamebaunin, ieukamenin A and 8, 13,18-dehydro-6alpha-senecloyloxychaparrin, taxamairin A arid B, regeniiol, triptolide, cymarin, hydroxyanopterine, protoanemonin, chetiburin chloride, sin ococu line A and B, dihydronitidine, nitidine chloride, 12“beta“hydroxypregnadien-3,20-dione, helenaiin, - 15IE * 3 Ο Ο 7 9 indicine, indicine-N-oxide, lasiocarpine, irtotodiol, podophyllotoxin, justicidin A and B, larreatin, mailoterin, malfotochromanol, isobutyrylmailotochromanol, marchantin A, maytansin, lycoridicin, margetine, pancratistatin, iiriodenine, oxoush insu nine, peripio coside A, deoxypsorospermin, psychorubin, rich A, sanguinarine, manwu wheat acid, methy Isorbifoiin, chromones of spathelia, stizophyllin, dihydrousambaraensine, hydroxyusambarirte, strychnopentamine, strychnophylline, usambarine, usambarensine, liriodenine, dap h no retin, lariciresinol, meth oxy larici resin oi, syringaresinol, sirolirrius (raparnycin), somatostatin, tacrolimus, roxithromycin, troleandornycin, simvastatin, rosuvasiatin, vinblastine, vincristine, vindesine, teniposide, vinorelbine, irofosfamide, ireosulfan, ternozolomide, ihiotepa, tretinoin, spiramycin, umbelliferone, desacetylvismione A, vismione A and B, zeorin, N6-isopenteny! adenosine r furfuryladenine (kinetin), 6-(3-hydroxymethyl),3meth y I a Hy J (zeatin), 5-[2-py raztn y i]-4-methy I-1,2-dithi o-3-th ione (oltipraz), pyrrolopyrazine derivative metabolite 3 (M3), 5-(p-methoxy phenyl) “3H“l,2-dith io ie-315 thio (anethole trihione), 1,2-dithiole-3-thione (D3T) Further embodiments relate to catheter baiioons and in particular to multifold balloons for catheters coated according to the methods disclosed herein.

The catheter baiioons are coated with essentially pure oitipraz. Thus, the catheter baiioons carry a layer that includes an active agent in form of oitipraz only, wherein in said layer only traces of acetone and possibly of another solvent and minimum residue of the acid used and possibly of its conjugated base are contained.

Due to the inventive coating method, the oitipraz dried at the surface of the catheter balloon has a special consistence, which is hard to characterize but seems io be essential for the transfer to the ceil wall and the incorporation, especially into the smooth muscle ceils.

In the case of multifold baiioons, one part of the oltipraz -containing coating is provided underneath the folds when the balioon is in its compressed state. Said amount is sufficient to achieve the desired therapeutic success even if the remaining uncovered balloon surface is not coated with active agent.

Thus, embodiments also relate to catheters that include a catheter balloon coated according to the methods disclosed herein. - 16IE 1 3 0 0 7 9 Such catheters are preferably used for treating constricted vessel segments, particularly of blood vessels and for the treatment and prophylaxis of stenosis, restenosis, arteriosclerosis, atherosclerosis and fibrotic vessel constriction.

Furthermore, catheter balloons which are coated according to the methods disclosed herein are suited for the treatment and/or prophylaxis of in-stent restenosis, i.e a reoccurring vessel constriction within an already implanted stent in such cases where the placement of an additional stent within an already implanted stent would prove to '10 be very problematic or even impracticable from a medical point of view. Such in-stent restenosis can be effectively treated without an additional stent having to be implanted by applying active agent with the help of a catheter coated according to the methods disclosed herein or respectively a catheter balloon of a dilatation catheter which balloon is coated according to the methods disclosed herein.

Furthermore, the catheter balloons coated according to the methods disclosed herein are particularly suited for the treatment of small vessels, preferably such vessels having a vessel diameter of less than 2,25 mm.

The catheter balloons coated according to the methods disclosed herein are preferably used in the cardiovascular area, but the catheter balloons coated according to the methods disclosed herein are also suited for the treatment of vessel constrictions of biliary tracts, esophagus, urinary tracts, pancreas, renai tracts, pulmonary tracts, trachea, small intestine and large intestine.

Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention, it is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled In the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the claims. - 17It 1 3 Ο ϋ 7 9 Example One Month in vivo Efficacy Comparison between Oitipraz and Paclitaxel Coated Drug-Eluting Stents in Rabbit Iliac Artery Drug Eluting Stent Coating Materia! and Methods: (i) Stents: 32 metal stents (316L stainless steel, 13mm length) (ii) Drugs: Paclitaxel and Oitipraz if} (iii) Coating Polymer: PLGA (iv) Solvents: THF and Acetone Stent Coating: Sixteen stents were spray-coated with paclitaxel and 16 stents were spray-coated 15 with oitipraz. For the paclitaxel stents, both the drug and the PLGA polymer were dissolved in tetra hydrofuran (THF), for oitipraz stents, both the drug and PLGA polymer were dissolved in acetone. Table 1 is a summary of drug loaded onto each stent. - 18IB1 3 0 0 7 9 Table 1: Summary of Drug Loaded Onto Each Stent Oitipraz and Paciltaxet Drug Coated Stent Infoimation Groups Stent# Pre-Coat (mg) After Coat (mg) Total Loaded .. Drug Loaded (pg) Oitipraz coating formulation: 1 mg PLGA 1 10.016 16.236 0.22 0.11 2 15.93 16.046 0-216 0.103 3 16,74 16.96 0.22 0.11 4 16 384 16.572 0.188 0.094 5 16.002 17.016 0.214 0.107 6 16.814 17,056 0.242 0.121 7 15.252 15.468 0.216 0.103 and 1 mg e 15.104 15.322 0.218 0.109 Oitipraz in 1 ml Acetone 9 10 11 15.574 15.32 15.796 15.533 0.222 0.218 0,111 0409 17.02 17.25 0.23 0415 12 15,46 15.636 0.226 0.113 13 15.766 15.98 0.214 0.107 0414 14 15.584 15.812 0.228 15 16.042 16.258 0.216 0.108 16 16.004 16,222 0 213 0,109 Mean 15.932 16.201 0.219 0,110 Paclitaxel coating Ϊ7 15.124 15 374 0.25 0 125 10 ' 19 16.62 16.82 0,2 0.1 15.77 15.972 0.202 0.101 '0402 20 16.892 17 096 0.204 21 15.813 16.022 0.204 0.102 22 15.568 15.772 0.204 0.102 23 15.616 15.338 0.222 0.111 24 15.55 15.762 0,212 0.106 formulation: 1mg PLGA and 1mg Paclitaxel in 1 ml THF 25 17.078 17.32 0.242 0.121 26 15.09 15.294 0.204 0.102 0.11 ”....... 0413 27 20 16.08 15.46 16.3 15.686 0.22 0.226 29 .........30' 31 16.S Stent 16.126 17.02 Broken 16.366 ' 15.5 98 0.22 0.24 0.11 ’θ42 32 Mean 15.388 15.59163 0.21 0405 15.806625 0.21733333 0.109 Ste/tf Gt imping: Al! coated stents (total 31 stents, stent #30 was broken) were crimped on 3 0mm x 30 15mm balloon catheters and sterilised with ETO prior to implantation.

Rabbit Iliac Arterial Implantation Total of 28 drug coated stents, 14 from oitipraz coated stents and 14 from paclitaxel coated stents were implanted randomly into 14 New England white rabbit iliac arteries, ra bbits wel g hed 2.5-kg, m a le or fema !e. - 19IEl 3 0 0 7 9 Stent implantation: Stent Implantation was performed under sterile conditions using fluoroscopic imaging system. Anaesthesia was induced in New Zealand white rabbits with intravenous xylazine (2.2mg/kg) and ketamine (22mg/kg) and maintained with 1-2% isoflurane in oxygen after endotracheal intubation. Rabbits were allowed to breath spontaneously during the procedure A 5-Fr introducer sheath was inserted into the left carotid artery through a small incision and a fluid-filled 5-l-r JR 3.5-5 soft tip guide catheter preloaded with a guide wire was advanced into the distal descending aorta The guide wire was advanced into the proximal portion of the right iliac artery and the IO guide catheter was carefully removed while the wire remained in place. The premounted stent-delivery system was advanced into the distal portion of the iliac artery where the stent-artery ratio is 1.1:1 to 1,2:1, The stent was deployed with pressure of 8 atm for 30 seconds, intravenous heparin (100 U/kg) was administered immediately after stent deployment. Successful deployment was verified by angiography. Each rabbit received two stents, one in the left iliac artery and one in the right iliac artery. Once the stent was implanted, the carotid artery was ligated, the incision was dosed in layers and the rabbit was allowed to emerge from anaesthesia. Intramuscular buprenorphine (0.05 mg/kg bid) was used for postoperative analgesia. Rabbits received antibiotic prophylaxis (5mg/kg enrofloxacin) for 4 days after stent implantation and aspirin in their drinking water (20 mg/day) for the duration of the experimental protocol.

Animal Sacrifice: At 23 days post stent implantation, all rabbits that underwent iliac stent implantation as described above were sacrifice. On the day of sacrifice, rabbits were anaesthetised as previously described, the chest was opened by a midline sternotomy and the pericardium was incised. The apex of the left ventricle was perfused at a mean arterial pressure of 100 mm Hg with lactated Ringer s solution, followed by neutralised formalin solution. All the stents were carefully excised and fixed in neutralised formalin solution for 24 hours. Samples were then plastic embedded, sectioned and H-E stained for histological analysis.

Histological Analysis: Ail histopathological analysis was completed by an investigator who was blinded to the treatment. Sectional areas of the lumen, neointima, media, adventia and the whole vessel were measured. The area within the Internal Elactic Lamina (IEL) was IE 1 3 0 0 7 9 -20considered the norma! lumen area. The IEL area and residual area was traced using Nikon 50i Imaging Analysis System (Nikon, Worcester, MA}, The percentage of new intima was defined as [(IEL area - residual lumen area)/IEL] x 100. Neointima area was determined by subtracting the area of residua! lumen from the area within the internal elastic lumen.

Two rabbits died, one from the oitipraz group {stent # 3 and 4) and one from the paclitaxel group (stent # 18 and 1S) within the first week after stent implantation due to the surgical procedures (mostly related to anaesthesia, bleeding or acute KJ thrombosis). One rabbit (stent # 20 and 21) from the paclitaxel group died on week 4 (23rd day) after surgery, reasons unknown. All other animals (6 from oitipraz group and 5 from paclitaxel group) survived through the 26 days study period and the stented arteries were harvested as described above.

A total of 22 stented arteries (12 from oitipraz group and 10 from paclitaxel group) were subjected to pathoiogicai analysis. One stent sample (stent # 1 from oitipraz group) did not polymized well during plastic embedding process and was excluded from further measurement and analysis. All other samples (11 from oitipraz group and 10 from the paclitaxel group) were included in the final pathoiogicai analysis.

Tabie 2 is the summary of morphometric data for ail samples.

IE 1 3 0 0 7 9 -21 Table 2: Summary of Morphometric Data Stent OiOijpi Animal # itenl# STdes Read [ptemal Elastic Area Residual Aren ΤΪ Restenosis (1EL- RAJi'lELxtOQ Averages Id stent Averages Groups p-viiluc Ρ,ιρΙιΙηϊίΙ Coated Stsnts KU 2? 1 1of2 184922 170057 8 UZHsSfe 5.093259 56.99222 Ϊ2οΪ2 ΙΗβλϋ Π73Ϊ324' 7.9376^792 2 1of2 163321 170399 4:32738202 7. 2of2 “196095· 176510 3 55764^57 3 lot? iuioG9 “172970' 7.33865827 3 2of2 187343 179225 4^54758 2Ϊ 1 ΙηΓ2 2023*19 19086i 5 57731998 4.795552 1 TOR 197757'' 106934 5.45353527 2 iof2 196C07 167497 '4.34263166 2 2al2 196215 167396 4.09^2746 3 1oS2 204748 195639 4.42395839 3'2ΰ<2 ' 203279 ' 193333 4.36316609 AB 2i Γ2αΤ2 196890 172931 13 0784224 6.269137 2 lofc ifl^l N i .91445483 5'5o!5 189977 lW04i T7WTI7 3 iat2 194*19.1 195661 4.54152327 3 2ef2 19^474 ι'/ΐιώ 8.*1218O'345 25 1 1<42 205260 134276 10.2231316 6.675235Ll2o^ ' '211494 ' 133307 13.3275549 ? 1ci2 “WT7“ lU)!Zili 3.05796173 3toG 192354 189942 3 2ol2 ιϋϋέ 136960' R3 25 1 1of2 '' WST 161575 ϊΜ!Κ^ΐ6ιά 1 2ot2 185277 156167 14,6375427 t94505 “17A57&' O.i4i7t6ii 'FSB· 'ΤΐϊΓίΤ- 1774/)4 7:23992759 10.61369 3 1oG 205515 185945 9.475625 3 2ol2 203075 133961 9.46152399 27 1 lali Τ5317£$ΙΪ 1 2et2 175161 18301 69.6112079 2 io12 187777 10533 94.3830241 9? 92571 2 2οΪ2 1153949 —ιϊόίύ 93.4606976 3 id? 191247 5436 97.1581254 3 2eS2 183636 4376 '97.6156296' Hl 28 1 lot? 20G844 164835 19.9216326 1 2d2 202701 150424 20.8563285 2 1of2 ' Ί'9'39'93' 175272 9:65934321 13.21591 iioli 1914^5 i7iih ΌΤτΤΪΤ? 3 1qF2 165197 147945 10.4426836 3 2ef2 ' 107492' 150666 9.92644425 29 '' Γ I ό!2' 192472 177246 2 lot? 185524 159769 13.8823009 2 2oE? 18Θ891 163310 13.2730281 13.1866 3 lof2 1(W 149761 15.6761¼ 3 ?t>F2 164317 139365 15.1852821 r: 31 HoR 191492 160597 ' '16.1294534 l2of2“ 191161 Ιϊέίΐί Τΐάίΐ Ί'έ?4&' 'iWiii J.93 734954' 946CO76 2^2 137340 179404 4.23614818 ......floE” 179466 £^iWl2 Wi ' 19^54 179493 6.52970918 32 1 1af2 177096' ' 162413 '—rsr- .....MW 158519 '070048(1868' ΐ'ϊόβ1 194244 17&ii 7.ϊ?76ϋάΐ 7.315873 TSt2 19450/) 177929 ¢.6653037 3 1of2 ' 169134' ' ' '159018 '6.64457023' 32oQ ' W 1£fi474 7.fli44!X16 22IEl 3 0 0 7 9 Ο -.:γλζ toat-jj ' Λ 1C· Π to.· sr t 1 dF2 157446 1J0731 13.1568619 9.705912 H JoFO Ϊ592-5Π 137556 13.5127319 2 I of2 153220 150376 7.£027iEBS 2 2 2oF2 102322 150636 7.36224024 3 1nF2 156603 ;4ai7i 7.3369454-1 3 2e?3 1OD073 U5761 3.29096195 R:3 1 ic/2 1770112 164533 0 .p 1 jo 1 ca 5 ^73220 1 5ci; 17SQ10 105666 6.63746173 C. 2 2o12 169941 17Ε737 7.479 111*2 2.1RC lcf2 1695 64 196510 6.50052 103 3 1RC I5S335 107394 Q.55741343 3.IRC 3*ί2 130917 ΙΪ4532 9.0203434^ c 2 Icl2 :8f3c? 173314 *.33650204 £ 442523 2.1 FIC 2oF2 ' 8I 312 171355 5.1 607 ! 744 3 2dF2 :7cC-io '67843 4.63723052 ?JRC 1of2 175E5-3 '61176 £?400ES0D 3. I RC 2of 170&2J 162652 7.7 329 6507 R7 7 OF2 1407451 13022 24.1204755 23.21:34'·' 1 2ύΓ2 15DD84 Ί34 60 244023347 2 :□?? 150134 119-.62 5J. .2956-120 2 2c'2 1515Ώ5 117034 2 2.2045 Ε B2 3 1ϋί2 1*0341 12553a 23.822643 3 2&?2 1*7025 127211 23.63715015 1 li-ί 2 165102 15 2796 17.4DB5P01 1 5,72361 1 2cf2 1 £:2232 15181ι 16 5935551 2 1of2 17fi723 154509 12jO?6264S 2 2of2 175253 1E5H4 714742665 3 1*12 I 633 CO 1 £4θϋ ϊΰ.¢551063 S2oF2 ΐΕί!60 153592 18.9930151 R5 R4 y 1 1*f2 ΐ01β11 61330 43.464045 1 2nf2 157E01 Β04Β4 42.550206 38.E£TS2 2 iof2 τ37551 1piSOfi 20.1321255 2 2*12 Γ35763 ι00605 3140072 Ϊ 1*F2 :ΕΟ3IQ 79120 48.0254946 '1 3cf2 15Ο2Ϊ-Ϊ 75-214 47.2754303 ·: 2of2 '74655ρ25243 2E.37C304 CP'5-·. 2 Iol2 '77261 '.43771 lfi 2ΪΕΘΕ55 2 20F2 '75454 '42345 10.6576 !51 3 :dF2 13101-3 142-122 2-3.7*74 £45J 1 dF2 '7OE3J 131017 22.2:75233 ·? 2<.f 2 170186 402 11 ?J 7524513 2 ! ofi 15767C -40-74 7.29117773 2 ΣϋΓΣ li'3E3Qρ4ί· Dio 5.52576733 3 1 dF2 1C73SEp3aa5? 17.0337221 3 3uf2 105663 :39133 1ΕΌ732Β97 1 lof? 191555 13 313422 i 2of2 1*6295 165427 : 3.722361« 2 poF2 2O?149 :04-57-5 1OJ992£7OS ' ·.£'<':ύ : '.nFi 207541 131243 1 2.306 B 221 3 3of2 207051 19227S 13.1022144 R12 jj 1 :of2 104403 155405 4 30770791? 1 2of2 151664 155763 3.7*921363 2 lc?2 1*8619 101568 4.2826933 4.249755 2 Ξΰ?2 1Έ-3591 1318(14 4J0178D70& 3 ϊοΌ' 1&41Ϊ10 17B249 4.33120937 14 1 'of 2 224700 21:345 ί 0Ϊ10 5372 1 2cf2 226050 213600 «.*5793495 3 lcf2 2298Ϊ1 215607 ¢2:4620403 5.633154 3 20/2 224424 215404 5.9607 20*4 □.439D02

Claims (16)

Claims

1. Method for loading dilatable catheter balloons comprising: I) providing a diiatable catheter balloon; ll) providing a solution of oltipraz in acetone; 111) texturing the 5 surface of the diiatable catheter balloon; IV) wetting the surface of the dilatable catheter balloon with the solution of oltipraz in acetone; V) applying a solvent which is capable of precipitating oltipraz onto the surface of the dilatable catheter balloon wetted with the solution of oftipraz in acetone; VI) drying the wetted surface of the dilatable catheter balloon; [()

2. Method according to claim 1, wherein the dilatable catheter balloon is a multifold balloon

3. Method according to claim 1, wherein the diiatable catheter balloon is coated in its 15 expanded state

4. Method according to claim 2, wherein the dilatable multifold balloon is coated in its expanded state 20 5. Method according to claim 1 further comprising step VII): VH) Refolding of the multifold balloon into its compressed state

5. Method according to claim 1, wherein the solution oi oltipraz in scetone contains from 1 mg to 150 mg of oltipraz per Ί mi of acetone.

6. 7. Method according to claim 6, wherein the solution of oltipraz in acetone contains from 40 mg to 60 mg of oltipraz per 1 ml of acetone,

7. 8. Method according to claim 1, wherein the acetone used has a water content of 30 iess than 5 percent by volume,

8. 9. Method according to claim 1, wherein the acetone used may contain an additional solvent in an amount of up to 10 percent by volume. 35 10. Method according to eiaim 1, wherein at least one carrier substance is added to the solution of oltipraz in acetone. -24IE 1 3 0 0 7 9 11. Method according to claim 10, wherein the at least one carrier substance is selected from the group consisting of: parylene C, parylene D, parylene N, parylene F, poiyvalerofactones, poly-.epsflon.-decalactone, polylactonic acid, polyglycoiic acid, 5 polyiactides, polyglycoiides, copolymers of the polylactides and polyglycoiides, poly .epsilon.-capra lactone, polyhydroxybutyric acid, poiyhydroxybutyrates, po I yh yd roxy va le rates, p olyhyd roxybutyrate-co -valerate, poly(1,4-d i oxa ne-2,3 -di ο π e), polyO^-dioxane-S-one), poiy-para-dioxanone, polya nhydrides, polymaleic acid anhydride, poiy hydroxy meth acrylates, fibrin, poiycya no aery late, polycaprolactone

9. 10 di methyl acrylates, poly-beta-maleic acid, polycaprolactone butyl acrylates, multi block polymers from oligocaprolactonedioles and oligodioxanonedioies, poiyether ester multiblock polymers from PEG and poiy (butylene terephthalate), polypivotolactones, polyglycoiic acid trimethy! carbonates, polycaprolactone glycolides, poly(,gamma ethyl g I utam ate), p oly ( DTH 4 m inc ca rb on ate), poiy(DT E-co-DT-ca rbonate), 15 poly (bisphenol A-iminocarbonate), polyorthoesters, polyglycoiic acid thmethyfcarbonate, poiytri methyl carbonates, polyimi nocarbonates, poly(N-vinyi)-pyrrolidone, polyvinyl alcohols, polyester amides, glycolized polyesters, polyphosphoesters, polyp hosphazenes, polyfp-carb oxy phenoxy)pro pane], poly hydroxy pentanoic acid, polya nhydrides, polyethylene oxide propylene oxide soft polyurethanes, 20 polyurethanes having amino acid residues in the backbone, poiyether esters, polyethylene oxide, poiyaikene oxaiates, polyorthoesters as well as their copolymers, lipids, carrageenans, fibrinogen, starch, collagen, protein based polymers, poiyamino acids, synthetic poiyamino acids, zein, polyhydroxyalkanoates, pectic acid, actinic acid, carboxy methy I sulfate, albumin, hyaluronic acid, chitosan and derivatives 25 thereof, heparan sulfates and derivatives thereof, heparins, chondroitin sulfate, dextran, beta-cyolodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen N-hydroxysuccinimtde, phospholipids, polyacrylic acid, polyacrylates, polymethyl methacrylate, polybutyl methacrylate, polyacrylamide, polyacrylonitriles, polyamides, polyetheramides, polyethylene amine, polyimides, 30 polycarbonates, poiycarbourethanes, polyvinyl ketones, polyvinyl halogenides, polyvinylidene halogenides, polyvinyl ethers, poly iso butylenes, polyvinyl aromatics, polyvinyl esters, polyvinyl pyrrolidones, poly oxy methylene, polytetramethylene oxide, polyethylene, polypropylene, polytetrafiuoroethylene, polyurethanes, poiyether urethanes, silicone poiyether urethanes, silicone polyurethanes, silicone 35 polycarbonate urethanes, polyolefin elastomers, EPDM gums, fiuoros ill cones, carboxymethyl chitosans, polyaryletherether ketones, polyetheretherketones, IE 1 3 0 0 7 9 -25polyethylene terephthalate, poly valerates, carboxymethylcelluiose, cellulose, rayon, rayon triacetates, cellulose nitrates, cellulose acetates, hydroxyethyl cellulose, celluiose butyrates, cellulose acetate butyrates, ethyl vinyl acetate copolymers, polysulfones, epoxy resins, ABS resins, silicones, polysiloxanes, 5 polydimethyislloxanes, polyvinyl halogens and copolymers, cellulose ethers, celluiose tri acetates, chitosans and copolymers and/or mixtures of the aforementioned polymers.

10. 12. Method according to claim '1, wherein the surface of the dilatable catheter balloon 10 is textured mechanically, chemically, electronically and/or by means of radiation,

11. 13. Method according to claim 12, wherein the mechanical texturing of the surface of the dilatable catheter balloon is achieved by means of a sandblasting process or by using a rasp.

12. 14. Method according to claim 12, wherein the chemical texturing of the surface of the dilatable catheter balloon is achieved by means of acidic, basic, etching or oxidizing chemicals. 20 15. Method according to claim 12, wherein the electrical texturing of the surface of the dilatable catheter balloon is achieved by means of conductors heated by current flow. 16. Method according io claim 12, wherein the texturing of the surface of the dilatable 25 catheter balloon is achieved by means of laser radiation or by means of strongly focus able radiation. 17. Method according to claim 1, wherein the wetting of the surface of the dilatable catheter balloon is completely or partially achieved by means of spraying, dipping, 30 plasma deposition, brushing or spattering. 18. Method according to ciaim 1, wherein steps IV) to VI) are repeated several times. 19. Method according to claim 1, wherein the solvent capable of precipitating oltipraz 35 has a solubility of oltipraz in said solvent of less than 1 mg of oltipraz per 1 ml of solvent. -26IEl 3 ΰ Ο7 9 20. Method according to claim 1, wherein the solvent capable of precipitating oltipraz is water. 5 21. Method according to claim 20, wherein the water is distilled, desalted or deionized water. 22. Method according to claim 20, wherein the water has a pH of from 3 to 5. 10 23. Method according to claim 22, wherein the pH of the water is adjusted by means of formic acid, acetic acid, propionic acid, oxalic acid, salicylic acid, tartaric acid, fumaric acid, gluconic acid, lactic acid, malic acid, ascorbic acid maleic acid, malonic acid, hydroxy maleic acid, pyruvic acid, phenylacetic acid, benzoic acid, glutaric acid, camphorsulfonic acid or china acid (quinic acid). 24. Method according to claim 1, wherein the solvent capable of precipitating oltipraz is added by means of spray injection, spraying or pipetting. 25. Method according to ciaim 1, wherein the drying process of the wetted surface of 20 the dilatable catheter balloon is accelerated by a vacuum. 26. Method according to claim 1, wherein the dilatable catheter balloon includes a material or a mixture of materials, wherein the material or the mixture of materials is selected from the following group of materials: parylene C, pa ry lens D, p arylene M, 25 parylene F, polyvaiero lactones, poly-, epsilon.-decal a clone, polylactonic acid, polyglycolic acid, polylactides, polyglycolides, copolymers of the poly la elides and polygiy coli des, poly-epsilon-c a prolactone, polyhydroxybutyric acid, polyhydroxybutyrates, polyhydroxyvalerates, poiy hy d roxy buty rate-co-vale rate, poly(1,4’-dioxane-2,3-’dione) I poly(1,3-dioxane-2-one), poiy-para-dioxanone, 30 polyan hydrides, poly maleic acid anhydride, potyhydroxymethacrylates, fibrin, poly cyanoacrylate, polyca pro lactone di methyl acrylates, poiy-beta-maieic acid, polycaprolactone buty! acrylates, multiblock polymers from oligocaprolactonedioles and oligodioxanonedioles, polyether ester multiblock polymers from PEG and poly(butytene terephthalate), polypivotolactcnes, polyglycolic acid tri methyl 35 carbonates, polycaprolactone glycol ides, polyt gamma,-ethyl glutamate) poly(DTHiminocarbonate), poly (DTEco-DT-car bona te), poiy (bisphenol A-iminocarbonate), IE I 3 Ο Ο 7 9 -27poly orthoesters, polygiycolic acid trimethyl-carbonate, poly trim ethyl carbonates, polyiminocarbonates, poly(N-vinyl)-pyrrolidone, polyvinyl alcohols, polyester amides, glycohzed polyesters, poly phos phoesters, poly phos phazenes, polyfpcarboxyphen oxy) propane], polyhydroxy psntanoic acid, polyanhydrides, polyethylene 5 oxide propylene oxide, soft polyurethanes, polyurethanes having amino acid residues in the backbone, polyether ester, polyethylene oxide, polyalkene oxalates, poly ortho esters as well as their copolymers, lipids, carrageenans, fibrinogen, starch, collagen, protein based polymers, polyamino acids, synthetic polyamino acids, zein, polyh yd roxyalkan oates, pectic acid, actinic acid, carboxy methyl sulfate, albumin, 10 hyaluronic acid, chitosan and derivatives thereof, heparan sulfates and derivatives thereof, heparin s, chondroitin sulfate, dextran, beta-cyclo dextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatine, collagen Nhydroxysuccinimide, phospholipids, polyacrylic acid, polyacrylates, poly methyl methacrylate, polybutyi methacrylate, polyacrylamide, polyacrylonitriles, polyamides,

13. 15 polyetheramides, polyethylene amine, polyimides, polycarbonates, polycarbourethanes, polyvinyl ketones, polyvinyl halogen ides, polyvinylidene halogen ides, polyvinyl ethers, poly isobutyl ones, polyvinyl aromatics, polyvinyl esters, polyvinyl pyrrolidones, poly oxy methylene, poiytetram ethylene oxide, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, poiyether urethanes, silicone

14. 20 poiyether urethanes, silicone polyurethanes, silicone polycarbonate urethanes, polyolefin elastomers, EPDM gums, fluorosilicones, carboxymethyl chitosans, polyaryletheretherketones, polyetheretherketones, polyethylene terephthalate, poly valerates, car boxy methylcellulose, cellulose, rayon, rayon triacetates, cellulose nitrates, cellulose acetates, hydroxyethyl cellulose, cellulose butyrates, cellulose 25 acetate butyrates, ethyl vinyl acetate copolymers, polysulfones, epoxy resins, ABS resins, silicones, polysiloxanes, polydimethylsiloxanes, polyvinyl halogens and copolymers, cellulose ethers, cellulose triacetates, chitosans arid copolymers and/or mixtures of the aforementioned polymers. 30 27. Method according to claim 1, wherein an additional active agent is incorporated into the solution of oltipraz in dimethyl sulfoxide, selected from the group consisting of: abciximab, acemetacin, acetylvismione B, aclarubicin, ademetionine, adriamycin, aescin, afromosone, akagerine, aldesleukin, am Ido rone, ami nogluteth imide, amsacrine, anakinra, anastrozole, anemonin, anopterine, antimycotics 35 antithrombotics, apocymarin, argatroban, aristolactam-AII, aristotochic acid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, -28IE' 3 0 0 7 9 baccatin, bafilomycin, baslliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenoiidine, bieomycin, combrestatin, Soswellic acids and derivatives thereof, bruceanol A, B and C, bryophyllin A, busulfan, antithrombin, bivaiirudin, cadherins, camptothecin, capecitabine, o-carbamoyl-phenoxy acetic acid, 5 carboplatin, carmustine, celecoxib, cepharanthin, cerivastatin, CETP inhibitors, chlorambucil, chloroquine phosphate, cicutoxin, ciprofloxacin, cisplatin, cladribine, clarithromycin, colchicine, concanamycin, coumadin, C-type natriuretic peptide (CNP), cudraisoflavone A, curcumin, cyclophosphamide, ciclosporin A, cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone, daunorubicin, diclofenac, 1,1110 dimethoxycanthin-6-one, docetaxei, doxorubicin, daunamycin, epirubicin, epothilone A and B, erythromycin, estramustine, etoposide, everolimus, filgrastim, fluoroblastin, fluvastatin, fludarabine, fludara bi ne-5'-dihydrogen phosphate, fluorouracil, folimycin, fosfestrol, gemcitabine, ghaiakinoside, ginkgol, ginkgolic acid, glycoside 1a, 4hydroxyoxycyclo phosphamide, idarubicin, ifosfamide, josamycin, lapachol, 15 Iomustine, lovastatin, melphalan, midecamycin, mitoxantrone, nimustine, pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, pegaspargase, exemestane, letrozole, formestane, my cophenolate mofetil, .betalapachone, podophyllotoxin, podophyliic acid-2-ethyl hydrazide, molgramostim 20 (rhuGM-CSF), peginterferon alpha,-2b, lenograstim (r-HuG-CSF), macrogol, selectin (cytokine antagonist), cytokinin inhibitors, COX-2 inhibitor, angiopeptin, monoclonal antibodies inhibiting muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1-h y drox y-11-m ethoxy c a nth in-6-one, scopoletin, NO donors, pentaerythrityl tetranitrate and sydnoimines, S-nitroso derivatives, tamoxifen, 25 staurosporine, beta-estradiol, alpha-estradiol, estriol, estrone, ethinyl estradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), taxoteres, mofebutazone, lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, 30 hydroxychloroquine, sodium aurothiomalate, oxaceprol, beta-sitosterol, myrtecaine, polidocancl, nonivamide, levomenthol, ellipticine, D-24851 (Caibiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, bacitracin, vitronectin receptor antagonists, azeiastine, guanidyl cyclase stimulator, tissue inhibitor of metal proteinase-1 and -2, free nucleic acids, nucleic acids incorporated into virus 35 transmitters, DNA and RNA fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, antisense oligonucleotides, VEGF inhibitors, IGF-1, -29ΙΕΙ 3 0 0 7 9 active agents from the group of antibiotics, cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamicin, penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxaparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidoie, trapidil, nitroprussides, 5 PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captopril, cilazapril, lisirtoprii, enaiaprii, losarian, thioprotease inhibitors, prostacyclin, vapiprost, interferon alpha, beta and gamma, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, haiofuginone, nifedipine, tocopherol, tranilast, molsidomine, tea polyphenols, epicatechin galiate, epigallocatechin gallate, 10 leflunomide, etanercept, sulfasalazine, tetracycline, triamcinolone, mutamycin, pro ca inimide, retinoic acid, quinidine, disopyrimide, flecamide, propafenone, sotalol, natural and synthetically obtained steroids such as bryophyllin A, inotodiol, maquiroside A, ghalakinostde, mansortine, strebioside, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances (NSAIDS), fe no profen, 15 ibuprofen, indomethacin, naproxen, phenylbutazone, antiviral agents, acyclovir, ganciclovir zidovudine, clotrimazole, flucytosine, grrseofuivin, ketoconazole, miconazole, nystatin, terbinafine, antiprotozoal agents, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, bar ringtog e no I-C21-angel ate, 14dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, 20 ovatodiolids, 4,7-oxycycioanisomelic acid baccharinoids B1, B2, B3 and B7, tubeimoside, brucea nt i noside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A,B C and D, ursolic acid, hyptatic acid A, isoiridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,13-dehydro-S-alpha25 senecioyloxychaparrin, taxamairin A and B, regen ilol, triptoiide, cymarin, hydroxyanopterine, proto a nemo n in, cheiiburin chloride, sinococuline A and B. d i hydro nitid ine, n it i d in e chloride, 12-. beta, -hyd roxyp reg n ad ien-3,2 0- dione, heie nal i n, indicine, in dici ne-N-oxide, lasiocarpine, inotodiol, podophy liotoxin, Justicidin A and B. larreatin, malloterin, mallotochromanol, isobutyrylmallotochromanoi, marchantin A, 30 maytansln, lycoridicin, margetine, pancratistatin, liriodentne, oxoushinsunine, peripiocoside A, deoxypsorospermin, psychombin, ricin A, sanguinarine, manwu wheat acid, methyl sorbifoiin, chromones of spatheiia, stizophyllin, di hydro usambaraen sine, hydroxyusa mbar ine, strychnopentamine, strychnophylline, usambarine, usambarensine, 1 iriode nine, daphrto retin, lariciresinol, 35 methoxylariciresinol, syringaresinol, sirolimus (rapamycin), somatostatin, tacrolimus, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, -30ΙΕί 3 0 0 7 9 vindesine, teniposide, vinorelbine, trofosfamide, treosulfan, ternozolomide, thiotepa, tretinoin, spiramycin, umbelliferone, desacetylvismione A, vismione A and B, zeorin, N6-tsopentenyl adenosine (IPA), furfuryladenine (kinetin), 6-(3-hydroxymethy!),3methyl allyl (zeatin), 5-(2-pyrazinyl]-4-methyl-1,2-dithio-3-thione (oltipraz), 5 pyrrolopyrazine derivative metabolite 3 (M3), 5-(p- methoxy phenyl)-3H-1,2-d ith iole-3thio (anethole trihione), 1,2-dithioie-3-thione (D3T).

15. 23. Coated dilatable catheter balloon which can be obtained by the method according to claim 1. JO 29. Dilatation catheter comprising the coated dilatable catheter balloon according to ciaim 28. 30. Dilatation catheter according to claim 29 further comprising a coated or uncoated 15 stent attached to the coated dilatable catheter balloon. 31. Method of preparing a drug eluting meta! stents loaded with Oltipraz. Metal stents are spray coated with Oltipraz solubilised in acetone and the coating Polymer PLGA is aiso dissolved in acetone. Oltipraz formulation used in example presented within 20 thus patent is 1mg PLGA (Polymer) and 1mg Oltipraz in 1mg of acetone to achieve Oltipraz loading of 0.10 ~ 0.12 mg per stent. 32. Method of preparing a drug eluting metal stents loaded with S-(p-rnethoxyphenyl)3H-1,2-dithiole-3“thio (Anethole trihione). Metal stents are spray coated with Anethole

16. 25 trihione solubilised in acetone and the coating Polymer PLGA is also dissolved in acetone. Anethole trihione formulation used in example presented within thus patent is 1mg PLGA (Polymer) and 1mg Anethole trihione in lmg of acetone to achieve Anethole trihione loading of 0.10 - 0.12 mg per stent.