WO2012028310A2

WO2012028310A2 - Pharmaceutical compositions comprising a taxane

Info

Publication number: WO2012028310A2
Application number: PCT/EP2011/004384
Authority: WO
Inventors: Torsten Heilmann; Heiko Noack; Christian Richter; Sabine Post
Original assignee: Avidal Vascular Gmbh
Priority date: 2010-08-31
Filing date: 2011-08-31
Publication date: 2012-03-08
Also published as: WO2012028310A3

Abstract

The present invention relates inter alia to a pharmaceutical composition comprising a taxane, an antioxidant and a polyol and to a pharmaceutical composition comprising a taxane, a statin and a polyol. The pharmaceutical compositions of the invention can be used to coat medical devices such as implants. Such implant can be an expansible hollow part, having at least one opening, which consists of an elastic biocompatible material that comprises elongated micro-cavities in its surface. Medical devices coated with a pharmaceutical composition of the invention exhibit an enhanced transfer of taxane from the surface of said medical device into the target tissue.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING A TAXANE

BACKGROUND OF THE INVENTION

Taxanes are poorly water soluble alkaloids. Taxol has originally been isolated from several species of Western Yew. Taxanes exhibit antimitotic properties and are effective therapeutic agents. For example, taxol has been shown to be active against leukemia, colon, breast, melanoma, sarcomas, and Lewis lung tumor systems (see e.g. Tarr et al. (1987) Pharm. Res. 4: 162-165; Horwitz (1992) TIPS 13: 134-136). In vitro studies indicate that concentrations of taxol of 0.1-10.0 μg/ml stabilize microtubules, thus disrupting normal cell division (Rowinsky et al. (1990) J. Natl. Cancer Inst. 82:1247-1259).

Taxanes have also clinically been used to coat medical devices. For example for the treatment of a stenosis, implantation of taxane-coated vessel grafts such as stents have become a well-established surgical intervention. In this context, the taxane can reduce so-called restenosis (recurrent stenosis), i.e. the reocclusion 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). 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 implantation cause inflammatory reactions which play a decisive role in the healing process during the first seven days. As mentioned, it has also been found that stents provided with a taxane-eluting coating counteract restenosis.

But also 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. Such coated catheter balloons can be manufactured by directly applying the taxane to the surface of the balloon e.g. using known methods for spray coating as described in WO 2004/006976 Al .

One complication that frequently arises when using taxane coated medical devices is that the taxane is transferred into tissue only slowly and to a partial extent, due to its poor solubility in water and many oils. In an attempt to increase taxol's solubility and develop more feasible clinical formulations, investigators have modified the structure of taxanes, e.g. acylated carbons at the 7-position and 10-position of the taxene ring. These efforts have yielded compounds that retain their biological activity but are expensive and have further deficits such as their stability.

Thus, there is a need for improved therapeutic compositions comprising taxane that can be used to e.g. coat medical devices and that can be manufactured with relatively small effort and costs and which provide an improved transfer of the active substance, i.e. taxane to the target tissue compared with taxane-containing compositions available in the prior art.

SUMMARY OF THE INVENTION

To solve above-mentioned problems and further problems associated with the prior art compositions, the present invention provides a pharmaceutical composition comprising a taxane, an antioxidant and a polyol.

Also provided is a pharmaceutical composition comprising a taxane, a statin and a polyol. Further provided is a medical device comprising the pharmaceutical composition according to the invention.

In a further aspect the invention provides a pharmaceutical according to the invention for use in the treatment or prevention of diseases associated with or caused by hyperproliferation of cells.

DETAILED DESCRIPTION OF THE INVENTION

Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. One object of the present invention is to provide compositions which permit an improved transfer of a taxane from a medical device coated with the composition to a target tissue. Such compositions can for example be applied to vessel grafts such as stents but also to inflatable and expansible medical devices such as a balloon catheter or an expansible hollow part that can be used on the balloon of a balloon catheter. It is one unexpected finding of the present invention, that if an expansible hollow part, e.g. an expansible tube made of polyisoprene is coated with the pharmaceutical compositions of the invention, that up to 18-fold more taxane is transferred from the coat to the target tissue as compared to when comparable prior art medical devices comprising paclitaxel are used.

Thus, such coated devices will provide an effective means to counteract e.g. neointimal hyperplasia, restenosis, inflammation and thrombosis, solving the aforementioned problems with conventionally coated medical devices while providing the possibility of a controlled and improved delivery of the therapeutic substance.

Thus, in a first aspect, the invention provides a pharmaceutical composition comprising a taxane, an antioxidant and a polyol. As shown in the examples below, a medical device coated with a composition according to the first aspect of the invention was capable of transferring up to about 18-fold more paclitaxel into target tissue than prior art balloon catheters that were formulated with a matrix of pure paclitaxel (e.g. compare fig. 1 "WOMBAT la" with "ELU"). An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. For the purpose of the invention, any antioxidant may be used. Antioxidants are also capable of removing free radical intermediates. They do this by being oxidized themselves, so antioxidants are often reducing agents such as thiols, ascorbic acid or polyphenols.

Taxanes are diterpenes which are mitotic inhibitors and include e.g. paclitaxel (Taxol) and docetaxel. As used herein, a polyol refers to an alcohol preferably an alkyl alcohol, aryl alcohol, a heterocyclic alcohol or a cycloalkyl alcohol, containing multiple, preferably between 2 and 20 (i.e. 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20), more preferably between 2 and 5 (i.e. 2, 3, 4 or 5) and most preferably between 2 and 3 hydroxyl groups. In one embodiment of the first and second aspect of the invention the polyol is an alcohol with between 2 and 10 (i.e. 2, 3, 4, 5, 6, 7, 8, 9 or 10) hydroxyl groups.

Thus, suitable polyols that can be used in the composition of the invention include e.g. pentaerythritol, erythritol, glycol (preferably ethylene glycol) and glycerol. In a most preferred embodiment glycerol is used in the compositions of the invention.

In a preferred embodiment of the first aspect, the molar ratio between the taxane and said antioxidant is between 6: 1 and 0.1 : 1 , preferably between 3:1 and 0.5: 1 and most preferably between 2.6:1 and 0.5:1. Further preferred ratios are also shown in the examples and fig. 1.

In a further preferred embodiment of the pharmaceutical composition of the invention, the antioxidant has a larger Log P value than the taxane. The symbol "P" of "Log P" is the calculated partition coefficient of a chemical substance, which is a measure of the way in which a compound will partition itself between the octanol and water phases in a two-phase octanol- water system, and thus an indicator of certain types of biological activity. Specifically, P is the ratio of the concentration (in moles per liter) of the compound in the octanol phase to that in the water phase at infinite dilution. The solubility is usually expressed as base 10 logarithm of the partition coefficient, Log P. Log P and methods for calculating it are well known to those skilled in the art. The Log P value can be calculated e.g. by the method described in Hansch C. and Leo A. "Substituent Constants for Correlation Analysis in Chemistry and Biology" Wiley, N.Y., 1979. Thus, Log P is a widely used parameter for correlating biological effects of organic substances. It is a property of the two-phase system in which water and 1 -octanol are in equilibrium at a fixed temperature and the substance is distributed between the water-rich and octanol-rich phases. Generally, the greater the Log P value of a compound or agent, the less hydrophilic the compound or agent. In a therapeutic composition of the invention, the antioxidant preferably has a Log P value of at least 3.1 , more preferably at least 5.1 and most preferably of at least 8. Preferred antioxidants that can be used in the composition of the invention are selected from the group consisting of tocopherol, a tocopherol ester, tocotrienol, tocotrienol ester, probucol, glutathione, vitamin C, an ester of vitamin C, ubiquinol, a carotene, uric acid, lipoic acid and a flavonoid such as resveratrol. If a tocopherol ester is used it is preferably selected from the group consisting of tocopheryl nicotinate, tocopheryl linolate, tocopheryl acetate and tocopheryl succinate. Most preferably the antioxidant is probucol or tocopheryl nicotinate. Probucol (4,4'- [propane-2,2-diylbis(thio)]bis(2,6-di-tert-butylphenol)) is an anti-hyperlipidemic drug. Probucol is also a powerful antioxidant which inhibits the oxidation of cholesterol in LDLs; this for example slows the formation of foam cells, which contribute to atherosclerotic plaques.

In a second aspect the invention provides a pharmaceutical composition comprising a taxane, a statin and a polyol. The meaning of "taxane" and "polyol" has already been described above and naturally applies also to the second aspect of the invention. In a preferred embodiment the molar ratio between the taxane and said statin is between 5: 1 and 0.01 : 1 , preferably between 3:1 and 0.1 :1 and most preferably between 2:1 and 0.4:1. Further preferred ratios are also shown in the examples and fig. 1.

A statin is a HMG-CoA reductase inhibitor. Statins can have both antioxidant and antiinflammatory properties (A. Tavridou et al., European Journal of Clinical Pharmacology, Volume 62, Number 6 / Juni 2006, p. 485-489). Preferably, the statin of the composition of the invention is selected from the group consisting of atorvastatin, bombrestatin, cerivastatin, fluvastatin, lovastatin, mevastatin, nystatin, pancratistatin, pentostatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Most preferably, the statin is simvastatin. Simvastatin (l S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-l,2,3,7,8,8a- hexahydronaphthalen-l -yl 2,2-dimethylbutanoat) is an antihyperlipidemic agent, capable of decreasing low density lipoprotein (LDL) levels.

In a preferred embodiment of the first and second aspect of the invention the molar ratio between the taxane and said polyol (preferably glycerol), of the pharmaceutical composition according to the invention is between 1 :3 to 1 :250 and preferably between 1 :6 to 1 :120 and most preferably between 1 :25 to 1 :35. Further preferred ratios are also shown in the examples and fig. 1. These ratios proved to be most effective to provide a stable and even coating on medical devices and at the same time enhanced the transfer of the taxane from the medical device into the target tissue. With ratios smaller than 1 :3 only a poor transfer of paclitaxel into tissue was observed. With ratios exceeding 1 :250 paclitaxel was washed off of the medical device in the blood vessel prematurely. When preparing a coating solution, wherein the ingredients of the compositions of the invention are preferably dissolved in ethanol (see also examples below), it is preferred that such coating solution comprises glycerol in the final amount of between 3% and 7%, more preferably between 4% and 6% and most preferably in the amount of about 5% (v/v). Such coating solutions are also within the ambit of the invention.

The pharmaceutical composition according to the first and second aspect may in preferred embodiments also comprise an additional active compound selected from the following group: abciximab, acemetacin, acetylvismione B, aclarubicin, ademetionine, adriamycin, aescin, afromosone, akagerine, aldesleukin, amidorone, aminoglutethimide, amsacrine, anakinra, anastrozole, anemonin, anopterine, antimycotics, antithrombotics, apocymarin, argatroban, aristolactam-AII, aristolochic acid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, combrestatin, Boswellic acids and derivatives thereof, bruceanol A, B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin, capecitabine, o-carbamoyl-phenoxyacetic acid, 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, 1,1 l-dimethoxycanthin-6-one, docetaxel, doxorubicin, daunamycin, epirubicin, epothilone A and B, erythromycin, estramustine, etoposide, everolimus, filgrastim, fluoroblastin, fluvastatin, fludarabine, fludarabine-5'-dihydrogen phosphate, fluorouracil, folimycin, fosfestrol, gemcitabine, ghalakinoside, ginkgol, ginkgolic acid, glycoside la, 4- hydroxyoxycyclo phosphamide idarubicin, ifosfamide, josamycin, lapachol, lomustine, lovastatin, melphalan, midecamycin, mitoxantrone, nimustine, pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, pegaspargase, exemestane, letrozole, formestane, mitoxantrone, mycophenolate mofetil, [beta]-lapachone, podophyllotoxin, podophyllic acid 2-ethylhydrazide, molgramostim (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 -hydroxy- 1 1 -methoxycanthin-6-one, scopoletin, NO donors, pentaerythrityl tetranitrate and sydnoimines, 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, verapamil, tyrosine kinase inhibitors (tyrphostins), paclitaxel and derivatives thereof, 6-[alpha]-hydroxy-paclitaxel, taxoteres, mofebutazone, lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, [beta] -sitosterol, myrtecaine, polidocanol, nonivamide, levomenthol, ellipticine, D-24851 (Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, bacitracin, vitronectin receptor antagonists, azelastine, 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 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, dipyramidole, trapidil, nitroprussides, PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon [alpha], [beta] und [gamma], histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, halofuginone, nifedipine, tocopherol, tranilast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, dicloxacillin, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecamide, propafenone, sotalol, natural and synthetically obtained steroids such as bryophyllin A, inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances ( SAIDS) such as fenoprofen, fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, antiviral agents, acyclovir, ganciclovir zidovudine, clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprotozoal agents, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17- hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelic acid baccharinoids Bl, B2, B3 and B7, tubeimoside, bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A,B C and D, ursolic acid, hyptatic acid A, iso- iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-[alpha]-senecioyloxychaparrin, taxamairin A and B, regenilol, triptolide, cymarin, hydroxyanopterine, protoanemonin, cheliburin chloride, sinococuline A and B, dihydronitidine, nitidine chloride, 12-[beta]-hydroxypregnadien-3,20- dione, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin A and B, larreatin, malloterin, mallotochromanol, isobutyrylmallotochromanol, marchantin A, maytansin, lycoridicin, margetine, pancrati statin, liriodenine, oxoushinsunine, periplocoside A, deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, chromones of spathelia, stizophyllin, dihydrousambaraensine, hydroxyusambarine, strychnopentamine, strychnophylline, usambarine, usambarensine, liriodenine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, sirolimus (rapamycin), somatostatin, tacrolimus, roxithromycin, ^-oleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, teniposide, vinorelbine, trofosfamide, treosulfan, temozolomide, thiotepa, tretinoin, spiramycin, umbelliferone, desacetylvismione A, vismione A and B and zeorin.

In a third aspect the invention provides a medical device comprising a pharmaceutical composition according to the invention as described above. Particularly preferred medical devices are selected from the group consisting of implants such as stents, a balloon catheter (in particular for percutaneous transluminal coronary angioplasty) and an expansible hollow part. The expansible hollow part is useful to be e.g. used on a balloon catheter. If the medical device is an expansible hollow part, it preferably has at least one and more preferably at leas two openings (e.g. a tube) and it consists of an elastic biocompatible material that comprises micro-cavities in its surface that are preferably elongated. In a further preferred embodiment of the medical device, the medical device is a hollow part as described, wherein more than 50% of a pharmaceutical composition of the invention is located in said micro-cavities. Preferably, the material of the expansible hollow part consists, comprises or essentially consists of a material selected from the group consisting of:

natural rubber, polyisoprene, a copolymer of isobutylene and isoprene, a halogenated butyl rubber, a polybutadiene, a styrene-butadiene rubber, a copolymer of polybutadiene and acrylonitrile, a hydrogenated nitrile rubber, a chloroprene rubber, a polychloroprene, latex, a neoprene, a baypren, latex, parylene, polyvalerolactone, poly-s-decalactone, polylactic acid, polyglycol acid, polylactide, polyglycolide, co-polymer of polylactide and polyglycolide, poly- ε-caprolactone, polyhydroxy butyric acid, polyhydroxybutyrate, polyhydroxyvalerate, polyhydroxybutyrate-co-valerate, poly(l ,4-dioxan-2,3-dione), poly(l,3-dioxan-2-one), poly- para-dioxanone, polyanhydride, polymaleicacidanhydride, polyhydroxymethacrylate, fibrin, polycyanoacrylate, polycaprolactondimethylacrylate, poly-fi-maleic acid, polycaprolactonbutylacrylate, multiblockpolymers made of oligocaprolactondiole and oligodioxanondiole, polyetherestermultiblockpolymers made from PEG and polybutylenterephtalate, polypivotolactone, poly-glycolic acid trimethylcarbonate polycaprolactonglycolide, poly(g-ethylglutamate), poly(dth-iminocarbonate), poly(dte-co-dt- carbonat), poly( bisphenol A-iminocarbonate), polyorthoester, poly- glycolic acid - trimethylcarbonate, polytrimethylcarbonate polyiminocarbonate, poly(n-vinyl)-pyrrolidone, polyvinylalcohols, polyesteramide, glycolized polyester, polyphosphoester, polyphosphazene, poly(p-carboxyphenoxy)propane], polyhydroxypentanoic acid, polyethylenoxidpropylenoxid, polyurethane, polyurethane comprising amino acids, polyetherester like polyethyleneoxide, polyalkeneoxalate, polyorthoester, lipids, carrageenane, fibrinogen, starch, collagene, protein- based polymers, polyaminoacids, zein, polyhydroxyalkanoate, pectic acid, actinic acid, carboxymethylsulfate, albumine, hyaluronic acid, chitosane, heparanesulfate, heparine, chondroitinsulfate, dextrane, β-cyclodextrine, copolymers comprising PEG and polypropyleneglycole, gummi arabicum, guar, gelatine, collagen-n-hydroxysuccinimide, phospholipids, polyacrylic acid, polyacrylate, polymethylmethacrylate, polybutylmethacrylate, polyacrylamide, polyacrylonitrile, polyamide, polyetheramide, polyethyleneamine, polyimide, polycarbonate, polycarbourethane, polyvinylketone, polyvinylhalogenide, polyvinylidenhalogenide, polyvinylether, polyisobutylene, aromatic compounds comprising a polyvinyl functional group, polyvinylester, polyvinylpyrollidone, polyoxymethylene, polytetramethyleneoxide, polyethylen, polypropylen, polytetrafluorethylen, polyetherurethane, silicon- polyetherurethane, silicon-polyurethane, silicon-polycarbonat-urethane, polyolefin- elastomers, epdm-rubber, fluorosilicone, carboxymethylchitosane, polyaryletheretherketone, polyetheretherketone, polyethylenterephtalate, polyvalerate, carboxymethylcellulose, cellulose, rayon, rayontriacetate, cellulosenitrate, celluloseacetate, hydroxyethylcellulose, cellulosebutyrate, celluloseacetatebutyrate, ethyl vinyl acetate, polysulfone, epoxy-resin, abs- resin, silicone like polysiloxane, polydimethylsiloxane, polyvinylhalogens, cellulose-ether, cellulose-triacetate, copolymers mixtures and derivatives thereof.

In a most preferred embodiment, the elastic biocompatible material of the expansible hollow part according to the invention is polyisoprene or latex, especially Guayule (Parthenium argentatum) latex which is hypoallergenic.

As used herein "micro-cavity" refers to either a hole or a furrow such as a groove. The cross-section of said furrow can have any shape. If the micro-cavity is a hole, the hole is a pit that can also have any shape but a micro-cavity that is a hole is not a perforation, i.e. not an opening connecting the outer and inner surface of the hollow part of the invention. Thus, if an expansible hollow part of the invention comprises micro-cavities these cavities according to the invention do not penetrate the material of the hollow part, e.g. to connect any outer surface with an inner surface of the material. This is advantageous since the cavities do not substantially weaken the material which is thus, resilient against mechanical stress and can undergo a substantial expansion without tear. For the same reason it is preferred that the surface of the expansible hollow part may preferably not comprise a plurality of perforations through which liquid can penetrate when the expansible hollow part of the invention is in its expanded state. It is, thus also preferred that the surface of the expansible hollow part of the invention is substantially impermeable to liquid and/or gas. The micro-cavities in the surface of the expansible hollow part can be generated by e.g. blasting the surface with sand, glass beads, or water. Preferably the micro-cavities are cut utilizing laser or plasma eroding techniques.

If the micro-cavities are elongated then they are preferably selected from the group consisting of crescent-shaped furrows, sinuous furrows, circular furrows, elliptical furrows, furrows comprising one or more bends, straight furrows, bifurcated furrows and combinations thereof. In one preferred embodiment, the elongated micro-cavities have a length of not more than 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, or more than 6 mm. Irrespective of whether the micro-cavities are holes or furrows, it is preferred that their depth is between 5 μιη and 500 μηι, which allows good mechanical strength and good loading capacities of the biologically active substance which is as further detailed below preferably loaded into the micro-cavities. As already mentioned, it is preferred that the cavities do not penetrate the surface of the hollow part and, thus, the cavity depth is preferably smaller than the thickness of the wall of the expansible hollow part of the invention.

As used herein "expansible" refers to the ability of the material of the expansible hollow part according to the invention to reversibly expand its surface when exposed to mechanical stress, i.e. a force causing deformation. Thus, the surface will return to its original, i.e. "relaxed" configuration, when the stress is removed. As used herein "relaxed" means in the absence of any external forces except the average atmospheric pressure present on earth at an altitude of between zero and 500 m above sea level. If in a preferred embodiment the expansible hollow part of the invention is a tubular structure, it is preferred that "expansible" means that the tubular structure can be reversibly expanded in its circumference. In a preferred embodiment, the expansible hollow part of the invention is expansible to at least 1 10%, 1 15%, 120%, 140%, 160%, 180%, 200%, 400%, 600%, 800%, 1000%, 1200%, 1400%, 1600%, 1800% or to at least 2000% of the circumference of its non-expanded state. Preferably the expansible hollow part according to the invention has an inner diameter smaller than 3, 2.5, 2.0, 1.5, 1 , 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2 or smaller than 0.1 cm in its non-expanded state. Most preferably, the inner diameter is smaller than 1 cm in its non-expanded state when measured at its narrowest section.

Preferably the wall thickness of the expansible hollow part of the invention is between

200 μιη and 1000 μπι and the hollow part comprises micro-cavities that have a maximal depth of 100 nm, 1 μ^ηι, 10 μιη, 20 μιη, 30 μηι, 40 μπι, 50 μιη, 60 μιη, 70 μηι, 80 μπι, 90 μπι or ΙΟΟμπι.

Preferred expansible hollow parts that can be used according to the invention, their making and coating has also been described in WO 2009/121565 incorporated herein by reference in its entirety. Expansible hollow parts, preferably in tube-form, coated with a composition of the invention can be used with a balloon catheter which is covered by the expansible hollow part. Thus, when the balloon catheter is inflated, the expansible hollow part of the invention is expanded and the paclitaxel is transferred to the vessel or organ wall by contact. This allows an efficient transfer of the biologically active substance from the hollow part to the tissue.

In a further preferred embodiment of the medical device of the invention, at least part of said device is coated with said pharmaceutical composition such that the average taxane concentration on said coated surface is between 2 and 10 μg taxane / mm², preferably between 2 and 6 μg taxane / mm² and most preferably between 3 and 5 μg taxane / mm².

In a further aspect the invention relates to a pharmaceutical composition according to the invention for use in the treatment or prevention of diseases associated with or caused by hyperproliferation of cells. In this context it is preferred that the disease is selected from stenosis, restenosis, stricture, defective bypass craft, thrombosis, dissection, tumor, calcification, arteriosclerosis, inflammation, autoimmune response, necrosis, injured anastomosis, lesion, allergy, wart, hyperproliferation, infection, scald, edema, coagulation, cicatrization, burn, frostbite and lymphangitis.

Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.

The following figures and examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention as indicated by the appended claims in any way.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1: Efficiency of transfer of the therapeutic substance paclitaxel into tissue

A hollow tube made from polyisoprene was coated as described in the examples below with a mixture of paclitaxel and a matrix component. In vivo data using coronary arteries from swine show the amount of paclitaxel substance that is effectively transferred into the artery tissue. Also shown is the amount of matrix compound that is co-transferred into the tissue. Surprisingly, the matrix substance tocopherylnicotinate significantly enhances paclitaxel transfer but is itself not transferred into the tissue. This is an advantage as it is not for all patients desirable that tocopherylnicotinate which is a biologically active substance (see above) is transferred into the tissue.

EXAMPLES Example 1: Production of drug-eluting therapeutic devices

The following therapeutic stock solutions on ethanol basis were prepared in order to be combined later to provide the final spray solution:

Simvastatin: 40 mg/ml ethanol

Paclitaxel: 40 mg/ml ethanol

Probucol: 40 mg/ml ethanol

Tocopheryl-Nicotinat 40 mg/ml ethanol

Production of the spray-solution:

For the production of the individual spray solutions, the stock solutions were combined as shown in table 1 below, diluted with absolute ethanol and combined with glycerol to give a final glycerol concentration of 5% (v/v).

For example:

Production of 20 ml of a solution comprising Simvastatin + Paclitaxel + glycerol which can be used for the spraying process and with which a coat can be sprayed onto e.g. expansible hollow tubes or balloon catheters to result in a surface concentration of 1 μg/mm² simvastatin and 4 μg/mm² paclitaxel:

10 ml paclitaxel stock-solution (40mg/ml)

+ 2.5 ml simvastatin stock-solution

+ 1 ml glycerol

+ 6.5 ml ethanol abs.

mix well An amount of 5% glycerol in conjunction with the addition of an antioxidant or a statin was shown to strongly improve the amount of paclitaxel that can be transferred from the surface of the therapeutic device (hollow part or balloon cathether) into the target tissue. Using paclitaxel at a concentration of 20 mg/ml and a total concentration of glycerol of about 5% (v/v), the molar ratio between glycerol and paclitaxel is about 30:1 which is considered to, without being bound by theory, permit a molecular segregation of individual paclitaxel molecules, thereby reducing the hydrophobic interaction of neighboring paclitaxel molecules resulting in an improved transfer rate and an increased amount transferred into tissue.

For the purpose of the invention any medical device can be coated with a therapeutic composition of the invention. For the following examples balloon catheters and expansible hollow tubes made of polyisoprene have been coated with compositions of the invention and the respective amount of therapeutic substance transferred into the target tissue has been examined.

Expansible drug-eluting hollow parts that can be used on a balloon catheter to deliver increased amounts of paclitaxel into tissue that is to be treated were spray-coated as follows:

(1) A flexible hollow tube made of polyisoprene as mentioned was slipped on the balloon part of a balloon catheter and afixed to the catether.

(2) Upon complete expansion of the balloon using a standard inflation device, the inflation port of the balloon catheter was temporarily sealed and the inflation device was removed.

(3) The coating was applied to the hollow part in the expanded state using an ultrasonic sound spray system (Sono-Tek Corporation) and a therapeutic composition of the invention. In this method the therapeutic composition is dispersed using ultrasonic sound producing a fine spray of liquid which was applied onto the expanded hollow part under constant rotation of said part at 240 rpm.

(4) Step (3) was repeated a total of 3 times with intermittent drying phases to permit evaporation of the ethanol solvent from the surface.

Using spray solutions (see above) with a concentration of paclitaxel of 20 mg/ml a coating was obtained on the hollow parts with a paclitaxel concentration of 4 ± 0.2 μg/mm² surface.

The therapeutic potential of the following coatings have been analyzed in vivo using a swine model system as outlined below:

Claims

1. A pharmaceutical composition comprising a taxane, an antioxidant and a polyol.

2. The pharmaceutical composition according to claim 1 , wherein the molar ratio between the taxane and said antioxidant is between 6:1 and 0.1 :1 and preferably between 3: 1 and 0.5: 1.

3. The pharmaceutical composition according to claim 1 or 2, wherein the antioxidant has a larger Log P value than the taxane.

4. The pharmaceutical composition according to any of claims 1-3, wherein the antioxidant has a Log P value of at least 3.1 , more preferably at least 5.1 and most preferably of at least 8.

5. The pharmaceutical composition according to any of claims 1-4, wherein the antioxidant is selected from the group consisting of tocopherol, a tocopherol ester, tocotrienol, tocotrienol ester, probucol, glutathione, vitamin C, an ester of vitamin C, ubiquinol, a carotene, uric acid, lipoic acid and a flavonoid.

6. The pharmaceutical composition according to any of claims 1-5, wherein the tocopherol ester is selected from the group consisting of tocopheryl nicotinate, tocopheryl linolate, tocopheryl acetate and tocopheryl succinate.

7. A pharmaceutical composition comprising a taxane, a statin and a polyol.

8. The pharmaceutical composition according to claim 7, wherein the molar ratio between the taxane and said statin is between 5: 1 and 0.01 :1 and preferably between 2: 1 and 0.5:1.

9. The pharmaceutical composition according to claim 7 or 8, wherein the statin is selected from the group consisting of atorvastatin, bombrestatin, cerivastatin, fluvastatin, lovastatin, mevastatin, nystatin, pancratistatin, pentostatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.

10. The pharmaceutical composition according to any of claims 1 -9, wherein the taxane is paclitaxel or docetaxel.

11. The pharmaceutical composition according to any of claims 1-10, wherein the polyol is an alcohol containing between 2 and 10 hydroxyl groups.

12. The pharmaceutical composition according to claim 1 1 , wherein the polyol is selected from the group of alcohols consisting of glycerol, ethylene glycol, erythritol and pentaerythritol.

13. The pharmaceutical composition according to any of claims 1-12, wherein the molar ratio between the taxane and said polyol is between 1 :3 to 1 :250 and preferably between 1 :6 to 1 : 120 and most preferably between 1 :25 to 1 :35.

14. A medical device comprising the pharmaceutical composition according to any of claims 1-13.

15. The medical device according to claim 14, wherein the device is an expansible hollow part, having at least one opening, which consists of an elastic biocompatible material that comprises micro-cavities in its surface.

16. The medical device of claim 15, wherein more than 50% of the pharmaceutical composition is located in said micro-cavities.

17. The medical device of any of claims 14-16, wherein the elastic biocompatible material consists, comprises or essentially consists of a material selected from the group consisting of:

natural rubber, polyisoprene, a copolymer of isobutylene and isoprene, a halogenated butyl rubber , a polybutadiene, a styrene-butadiene rubber, a copolymer of polybutadiene and acrylonitrile, a hydrogenated nitrile rubber, a chloroprene rubber, a polychloroprene, latex, a neoprene, a baypren, latex, parylene, polyvalerolactone, poly-e-decalactone, polylactic acid, polyglycol acid, polylactide, polyglycolide, copolymer of polylactide and polyglycolide, poly-8-caprolactone, polyhydroxy butyric acid, polyhydroxybutyrate, polyhydroxyvalerate, polyhydroxybutyrate-co-valerate, poly( 1 ,4-dioxan-2,3-dione), poly( 1 ,3-dioxan-2-one), poly-para-dioxanone, polyanhydride, polymaleicacidanhydride, polyhydroxymethacrylate, fibrin, polycyanoacrylate, polycaprolactondimethylacrylate, poly-B-maleic acid, polycaprolactonbutylacrylate, multiblockpolymers made of oligocaprolactondiole and oligodioxanondiole, polyetherestermultiblockpolymers made from PEG and polybutylenterephtalate, polypivotolactone, poly-glycolic acid trimethylcarbonate polycaprolactonglycolide, poly(g-ethylglutamate), poly(dth-iminocarbonate), poly(dte-co-dt-carbonat), poly( bisphenol A-iminocarbonate), polyorthoester, poly- glycolic acid -trimethylcarbonate, polytrimethylcarbonate polyiminocarbonate, poly(n-vinyl)-pyrrolidone, polyvinylalcohols, polyesteramide, glycolized polyester, polyphosphoester, polyphosphazene, poly(p-carboxyphenoxy)propane], polyhydroxypentanoic acid, polyethylenoxidpropylenoxid, polyurethane, polyurethane comprising amino acids, polyetherester like polyethyleneoxide, polyalkeneoxalate, polyorthoester, lipids, carrageenane, fibrinogen, starch, collagene, protein-based polymers, polyaminoacids, zein, polyhydroxyalkanoate, pectic acid, actinic acid, carboxymethylsulfate, albumine, hyaluronic acid, chitosane, heparanesulfate, heparine, chondroitinsulfate, dextrane, β-cyclodextrine, copolymers comprising PEG and polypropyleneglycole, gummi arabicum, guar, gelatine, collagen-n- hydroxysuccinimide, phospholipids, polyacrylic acid, polyacrylate, polymethylmethacrylate, polybutylmethacrylate, polyacrylamide, polyacrylonitrile, polyamide, polyetheramide, polyethyleneamine, polyimide, polycarbonate, polycarbourethane, polyvinylketone, polyvinylhalogenide, polyvinylidenhalogenide, polyvinylether, polyisobutylene, aromatic compounds comprising a polyvinyl functional group, polyvinyl ester, polyvinylpyrollidone, polyoxymethylene, polytetramethyleneoxide, polyethylen, polypropylen, polytetrafluorethylen, polyetherurethane, silicon- polyetherurethane, silicon-polyurethane, silicon- polycarbonat-urethane, polyolefin-elastomers, epdm-rubber, fluorosilicone, carboxymethylchitosane, polyaryletheretherketone, polyetheretherketone, polyethylenterephtalate, polyvalerate, carboxymethylcellulose, cellulose, rayon, rayontriacetate, cellulosenitrate, celluloseacetate, hydroxyethylcellulose, cellulosebutyrate, celluloseacetatebutyrate, ethyl vinyl acetate, polysulfone, epoxy- resin, abs-resin, silicone like polysiloxane, polydimethylsiloxane, polyvinylhalogens, cellulose-ether, cellulose-triacetate, copolymers mixtures and derivatives thereof.

18. The medical device of any of claims 15-17, wherein at least part of said device is coated with said pharmaceutical composition such that the average taxane concentration on said coated surface is between 2 and 10 μg taxane / mm².

19. Pharmaceutical composition according to claims 1 to 13 for use in the treatment or prevention of diseases associated with or caused by hyperproliferation of cells.

20. Pharmaceutical composition of claim 19, wherein the disease is selected from stenosis, restenosis, stricture, defective bypass craft, thrombosis, dissection, tumor, calcification, arteriosclerosis, inflammation, autoimmune response, necrosis, injured anastomosis, lesion, allergy, wart, hyperproliferation, infection, scald, edema, coagulation, cicatrization, burn, frostbite and lymphangitis.