FIELD OF THE INVENTION

The present invention relates to a pharmaceutical formulation comprising sirolimus. The present invention more particularly relates to a process for the preparation of controlled drug formulation and method of coating comprising sirolimus which enhances stability and re-endothelialization.

BACKGROUND OF THE INVENTION

The fact that stents are widely accepted and used in the cure of coronary occlusions in to-day's angioplasty is well known. Stents are reticular metal prostheses positioned in the portion of the vessel subject to stenosis, which remain at the site of the lesion after the release system and balloon system have been retracted. Thus the stent compresses the plaque and provides a mechanical support for the vessel wall to maintain the vessel diameter re-established by expansion of the balloon and to prevent collapse of the vessel. However, the long-term efficacy of the use of intracoronary stents still presents the major problem of post-angioplasty coronary instent restenosis, which is the phenomenon of reocclusion of the coronary vessel.

The stenosis caused by insertion of the stent is due to hyperplasia of the newly-formed intima. In particular, mechanical damage caused to the artery wall by the stent and the foreign body reaction induced by the presence of the stent give rise to a chronic inflammatory process in the vessel. This phenomenon in turn gives rise to the release of cytokines and growth factors which promote activation of the proliferation and migration of smooth muscle cells (SMC). The growth of these cells together with the production of extra-cellular matrix results in increase in the cross-section of the vessel occupied by the neointema and therefore a process of reducing the lumen of the vessel, bringing about the abovementioned restenosis.

Numerous pharmacological approaches attempted via the systemic route have not yielded useful results in terms of reducing the level of instent- restenosis after angioplasty. The prob-lem with this method of administration can in fact be identified in the low concentration of the pharmacologically active ingredient which reaches the stenotic lesion. An alternative ap-proach to prevent the problem of instent - restenosis, which brings about greater release of active ingredient in the zone requiring treatment, is provided by the use of coated stents, used as a local source capable of releasing drugs (DES, drug eluting stent) . For example, in the article by Takeshi Suzuki et al. “Stent-Based Delivery of Sirolimus Reduces Neointimal For-mation in a Porcine Coronary Model” Circulation 2001;104:1188-1193, stents coated with a non-degradable polymer matrix based on poly-n-butyl methacrylate and polyethylene-vinyl acetate containing a therapeutic concentration of active ingredient, designed to reduce hy-perplasia of the neointima, are described.

U.S. Pat no. 2008/0033037 issued to Greenpharma and Bioalternatives describes the use of silymarin, or of the main constituents thereof alone or as a mixture, chosen from silybin (or 2,3-dihydro-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-6-(3,5,7-trihydroxy-4 oxoben-zopyran-2-yl)benzodioxine), isosilybin, silydianin, silychristin, silandrin, silymonin and taxifolin, isolated enantiomers thereof and also salts thereof, for the manufacture of compositions for inducing, restoring or stimulating pigmentation of the skin, body hair or head hair. The invention also relates to the use of these agents for the manufacture of compositions for pre-serving the integrity of the hair, for limiting its loss and for stimulating hair regrowth. Silymarin or the constituents thereof alone or as a mixture are obtained by extraction of a plant of the genus Silybum Sylimarin is an antioxidant, anti inflammatory and hepatoprotective.

U.S Pat no. 2010/0268187 issued to Ranbaxy Laboratories Ltd, describes a packaging kit used for the stabilization of sirolimus particles wherein the packaging kit is in the form of a vacuum sealed impermeable container. It further relates to a method for stabilization of sirolimus particles as well as composition comprising the particles.

Sirolimus apart from its stability problems also inhibits circulating Endothelial Progenitor Cells (EPC) that aid in re- enothelization of the stented segment of the vessel. Poor re-endothelialization with sirolimus eluting stents is one of the major problems that lead to late stent thrombosis and death.

Hence, there is a need of formulation and method of enhancing stability and re-endothelialization of sirolimus in in-stent restenosis.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a formulation comprising sirolimus.

It is an object of the present invention to provide an implantable medical device that provides a controlled release of the drug formulation comprising sirolimus there by enhancing the stability, wherein the implantable medical device may be selected from the group consisting of stents, vascular implants, vascular supports, tissue adhesives, tissue sealants, tissue scaffolds and intraluminal devices, clamps, clips, sutures, suture anchors, electrodes, catheters, leads, grafts, dressings, pacemakers, pacemaker housings, prostheses, ear drainage tubes, ophthalmic implants, orthopedic devices, vertebral disks, bone substitutes, anastomotic de-vices, perivascular wraps, hemostatic barriers.

It therefore appears obvious that with this invention it is possible to obtain advantageously stents comprising a) a base coat comprising a hydrophilic polymer with silymarin; b) drug layer comprising a drug layer comprising sirolimus and at least one surface modifying agent with a biodegradable polymer surrounding the core; c) optionally, a barrier layer over the drug coated core containing silymarin and all the coating process is done on the abluminal side and which has a thickness compatible with an association with an active ingredient which will be delivered and released in a controlled way and over periods which are clinically useful.

It one aspect of the present invention to provide a pharmaceutical formulation comprising si-rolimus wherein the formulations are in form of multi-particulate may be in matrix and/or re-servoir forms.

According to further features in preferred embodiments of the invention described below, the coat is capable of releasing the bioactive agent encapsulated in the coat in a pre-determined release rate.

DEFINITIONS

When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles “a”, “an”, “the” and “said”are intended to mean that there are one or more of the elements. When employed in the present disclosure, the terms “comprises” ”comprising,” “including” and “having,” and other derivatives from the root terms “comprise,” “include” and “have” are intended to be open-ended terms that specify the presence of any stated features, elements, integers, steps, or components, and are not intended to preclude the presence or addition of one or more other features, elements, integers, steps, components, or groups thereof.

As used herein, the term “polymer” generally includes but is not limited to, homopolymers, copolymers, including block, graft, random and alternating copolymers, terpolymers, etc. and blends and modifications thereof. Furthermore, unless otherwise specifically limited, the term “polymer” shall include all possible geometrical configurations of the material. These configurations include, but are not limited to, isotactic, syndiotactic and atactic symmetries.

The term “polymer”, as used herein, encompasses organic and inorganic polymer and further encompasses one or more of a polymer, a copolymer or a mixture thereof (a blend).

While any polymer, copolymer or a mixture of polymers and/or copolymers can be used for producing the core and coat of the structures described herein, according to preferred embodiments of the present invention, the coat is made of a biodegradable polymer.

The term “hydrophilic” as used herein, describes a trait of a molecule or part of a molecule which renders the molecule dissolvable, at least in part, in water, aqueous solutions and/or other polar solvents. The phrase “at least in part” means that the substance is either completely dissolvable in such solvents or reaches its maximal saturation re” as used herein comprises a pharmacologically inactive tablet, core, or inert beads or spheres which comprise one or more of soluble or insoluble inert materials and the like, or mixtures thereof. The cores may be optionally seal coated to increase the strength of the core to withstand the mechanical pressures during processing.
The term “stability” as used in the invention refers to physical stability and chemical stability, wherein physical stability refers to retaining an original form in the composition and chemical stability refers to resistance to drug degradation and/or impurity generation.

The terms “surface modifying agent,” “surfactant,” and “wetting agent” are synonymous and as used herein include agents which are used to disperse the drug in a particular solvent and also enhance wetting properties of the drug.

Throughout this disclosure, various aspects of this invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

As used herein throughout, the term “comprising” means that other steps and ingredients that do not affect the final result can be added. This term encompasses the terms “consisting of” and “consisting essentially of”

As used herein, the phrase “substantially retaining” and/or “substantially maintaining” refers to a protein's specific activity, dissolvability and other biochemical properties essential to its biological activity, which are retained and or maintained at significant levels subsequent to the chemical modifications, described in the present invention, carried out so to obtain a metal-coat on the protein and intermediates to that end.

The term “method” or “process” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, bio-chemical and medical arts.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity in the appended claims. The invention itself, however, both as to organization and methods of operation, together with further objects and advantages thereof, may be best understood by reference to the following description, taken in conjunction with the accompanying drawings in which:

FIG. 1 is a perspective view of a stent having a base coat (Sirolimus with PLGA) in accordance with the present invention.

FIG. 2 is a perspective view of a stent having a base coat (Sirolimus with PLGA) and a top coat (Silymarin with PVP) in accordance with the present invention.

FIG. 3 is a perspective view of a stent having a base coat (Silymarin with PVP), a middle coat (sirolimus with PGLA) and a top coat (Silymarin with PVP) in accordance with the present invention.

FIG. 4 is a graphical illustration of the drug elution (release) profile of stents coated with sirolimus as single layer.

FIG. 5 is a graphical illustration of the drug elution (release) profile of stents coated with sirolimus as base coat and silymarin as top coat.

FIG. 6 is a graphical illustration of the telomerase activity of endothelial progenitor cells (EPCs) with sirolimus and silymarin and in combinations.

FIG. 7 is a graphical illustration of the ß- Galactosidase activity of endothelial progenitor cells (EPCs) with sirolimus and silymarin and in combinations.

FIG. 8 is a graphical illustration of the proliferation of endothelial progenitor cells (EPCs) with sirolimus and silymarin and in combinations.

DETAILED DESCRIPTION

The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

In one embodiment of the present invention as illustrated in FIG. 1, the Stent (100) having a base coat (103), wherein the base coat is a sirolimus with PLGA.

In one embodiment of the present invention as illustrated in FIG. 2, the stent (100) having
base coat (103) wherein the base coat is a sirolimus with PLGA and a top coat (101), wherein the top coat is silymarin with PVP.

In one embodiment of the present invention as illustrated in FIG.3, the stent (100) having a top coat (101), wherein the top coat is silymarin with PVP, a middle coat (102), wherein the middle coat is sirolimus with PLGA and a base coat (103) , wherein the base coat is silymarin with PVP.

Briefly described according to one of the embodiment, the drug eluted stents (DES’s) reduce neointima area and in-stent restenosis but delay reendothelialization. Pharmacological expansion and functional enhancement of endothelial progenitor cells (EPCs) can be achieved by treatment with a silymarin even for feeble cells derived from coronary artery disease patients. Sirolimus an antiproliferative agent used on drug eluting stents induces endothelial progenitor cells (EPCs) senescence through telomerase inactivation and may impair the reendothelization of an injured arterial wall, leading to thrombosis. Initially, we examined whether silymarin, a complex of flavonolignans with hepatoprotective and antioxidative properties can protect EPCs against sirolimus-induced senescenece.

Further, silymarin has increased telomerase activity 3-fold, reduced the number of senesce-net cells, and increased EPC proliferative activity (upto 64%) in comparison with cells cultured with sirolimus alone. Moreover, silymarin partially prevented impairment of tubular-like structure formation in matrigel by sirolimus. These findings suggest that silymarin counteracts the inhibitory effects of sirolimus in EPCs. Silymarin may protect EPCs against the anti-proliferative effects of sirolimus and restore their reconstructive ability.

Further, Silymarin treatment enhanced EPC adhesion via up-regulated expression of the a-4 intrgrin amehorated re-endothelialization and reduced neointima formation. The instability of sirolimus and its formulations was also a concern because of its affinity to undergo oxidation and photolysis. A formulation comprising silymarin and sirolimus with a biodegradable and a hydrophilic polymer were used for coating the stents to address these unresolved problems.

EXAMPLES

The following non limiting examples provide a process for the preparation of controlled drug formulation comprising sirolimus which enhances stability for the according to the teachings of the present invention.

EXAMPLE 1
Accelerated stability studies:
This example describes experiments that demonstrate the stability studies were conducted in accordance with ICH 1Q2A guidelines for the finished products. Total sirolimus / silymarin content, release kinetics, degradation profile were studied.

As can be seen in Table.1, the sirolimus content is carried out in percentage basis with regard to the duration in month as single coat, top and base coat and top, middle and base coat.

FIG. 4 is a graphical illustration of the drug elution (release) profile of stents coated with sirolimus as single layer. The illustration determines the release kinetics where in the cumulative % release of sirolimus vs. the number of days (months).

FIG. 5 is a graphical illustration of the drug elution (release) profile of stents coated with sirolimus as base coat and silymarin as top coat. The illustration determines the release kinetics of the stents where in the cumulative % release of sirolimus vs. number of days (months).

EXAMPLE 2

Telomerase activity:

The example describes endothelial progenitor cells (EPCs) treated with sirolimus and/or silymarin were harvested at day 7 of cultivation and then the quantitative analysis of telomerase activity was performed using Telo TAG PCR ELISA Plus Kit (Roche Diagnostics).

FIG. 6 is a graphical illustration of the telomerase activity of endothelial progenitor cells when treated with (EPCs) with sirolimus and silymarin and in combinations. The illustration deter-mines the % of telomerase activity of EPCs vs. use of sirolimus and silymarin and in combinations.

EXAMPLE 3

ß- Galactosidase activity:

The example describes the ß- Galactosidase activity when the endothelial progenitor cells are treated with sirolimus and/or silymarin where harvested at day 7 of cultivation and then senescence-associated (SAB-gal) activity was measured using senenscence ß- Galactosidase staining kit (cell signalling technology)

FIG. 7 is a graphical illustration of the ß- Galactosidase activity of endothelial progenitor cells when treated with (EPCs) with sirolimus and silymarin and in combinations. The illustration determines the % of ß- Galactosidase activity of EPCs vs. use of sirolimus and silymarin and in combinations.

EXAMPLE 4

Proliferative activity Assay:
The example describes the Mitogenic assay was performed using a colorimetric MTS (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenol)-2-(4-sulfophenyl)-2H-Tetrazolium) assay (Cell titer 96AQ, Promega)

FIG. 8 is a graphical illustration of the proliferation of endothelial progenitor cells (EPCs) with sirolimus and silymarin and in combinations.

As described in Fig. 6 7 and 8, the term ng refers to nanogram(s) and µg refers to micro-grams(s).

Non-limiting examples of biodegradable polymers composing the core and coat of the composite structure described herein, respectively, include homo-polymers and co-polymers such as aliphatic polyesters made of glycolide (glycolic acid), lactide (lactic acid), caprolactone, p-dioxanone, trimethylene carbonate, hydroxybutyrate, hydroxyvalerate, polypeptide made of natural and modified amino acids, polyethers made of natural and modified saccharides, polydepsipeptide, biodegradable nylon copolyamides, polydihydropyrans, polyphosphazenes, poly(ortho-esters), poly(cyano acrylates), polyanhydrides and any combination thereof.

Exemplary hydrophilic substances include, without limitation, compounds comprising one or more charged or polar groups such as one or more carboxyl groups (e.g., organic acids), one or more hydroxyl groups (e.g., alcohols), one or more amino groups (e.g., primary, secondary, tertiary and quaternary amines), and any combination thereof. Such groups are present, for example, in peptides and saccharides and in many other naturally occurring and synthetic substances.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

One group of additional agents which may contribute to the final microstructure of the coat includes surfactants or surface active agents, as these are defined herein below. As demonstrated in the examples section that follows, the addition of a surfactant at the preparation stage of the coat material affects the porosity thereof and in some cases is essential to the formation of the coat.

The coat can further include, in addition to the bioactive agent, additional agents that may improve the performance of the bioactive agent. These include, for example, penetration enhancers, humectants, chelating agents, preservatives, occlusive agents, emollients, permeation enhancers, and anti-irritants. These agents can be encapsulated within the pores of a porous coat or can be doped within the polymer forming the coat.

Representative examples of humectants include, without limitation, allantoin, urazole, poly-hydroxy alcohols such as sorbitol, glycerol, hexanetriol, propylene glycol, butylene glycol, hexylene glycol and the like, polyethylene glycols, sugars and starches, sugar and starch de-rivatives (for example, alkoxylated glucose), hyaluronic acid, lactamide monoethanolamine, acetamide monoethanolamine and , guanidine, glycolic acid and glycolate salts (for example ammonium slat and quaternary alkyl ammonium salt) and any combination thereof.

Non-limiting examples of chelating agents include ethylenediaminetetraacetic acid (EDTA), EDTA derivatives, or any combination thereof.

Non-limiting examples of occlusive agents include petrolatum, mineral oil, beeswax, silicone oil, lanolin and oil-soluble lanolin derivatives, saturated and unsaturated fatty alcohols such as behenyl alcohol, hydrocarbons such as squalane, and various animal and vegetable oils such as almond oil, peanut oil, wheat germ oil, linseed oil, jojoba oil, oil of apricot pits, walnuts, palm nuts, pistachio nuts, sesame seeds, rapeseed, cade oil, corn oil, peach pit oil, poppyseed oil, pine oil, castor oil, soybean oil, avocado oil, safflower oil, coconut oil, hazelnut oil, olive oil, grape seed oil and sunflower seed oil.

Non-limiting examples of emollients include dodecane, squalane, cholesterol, isohexadecane, isononyl isononanoate, PPG Ethers, petrolatum, lanolin, safflower oil, castor oil, coconut oil, cottonseed oil, palm kernel oil, palm oil, peanut oil, soybean oil, polyol carboxylic acid esters, derivatives thereof and mixtures thereof.

Non-limiting examples of penetration enhancers include dimethylsulfoxide (DMSO), dimethyl formamide (DMF), allantoin, urazole, N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C10 MSO), polyethylene glycol monolaurate (PEGML), propylene glycol (PG), propylene glycol monolaurate (PGML), glycerol monolaurate (GML), lecithin, the 1-substituted azacyclo-heptan-2-ones. The permeation enhancer may also be a vegetable oil. Such oils include, for example, safflower oil, cottonseed oil and com oil.

Non-limiting examples of anti-irritants include steroidal and non steroidal anti-inflammatory agents or other materials such as aloe vera, chamomile, alpha-bisabolol, cola nitida extract, green tea extract, tea tree oil, licoric extract, allantoin, caffeine or other xanthines, glycyrrhizic acid and its derivatives.

Non-limiting examples of preservatives include one or more alkanols, EDTA salts, EDTA fatty acid conjugates, disodium EDTA (ethylenediamine tetraacetate), isothiazolinone, parabens such as methylparaben and propylparaben, propylene glycols, sorbates, urea derivatives such as diazolindinyl urea, or any combinations thereof. The composite structures according to the present embodiments are particularly beneficial when it is desired to encapsulate bio-active agents which require delicate treatment and handling, and which cannot retain their biological and/or therapeutic activity if exposed to conditions such as heat, damaging sub-stances and solvents and/or other damaging conditions. Such bioactive agents include, for example, peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, cells and prodrugs.

All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and/or enforceability of such patent documents.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

CLAIMS

We claim:

1. A coated implantable medical device, comprising: a pharmacologically active core; a base coating comprising a hydrophilic polymer with silymarin; a drug layer comprising sirolimus and at least one surface modifying agent with a biodegradable polymer surrounding the said core; optionally, a barrier layer over the drug coated core containing silymarin.

2. The coated implantable medical device of claim 1, wherein said surface modifying agent comprises at least one of a polyoxyethylene castor oil derivative, a polyoxyethylene sorbitan fatty acid ester, a poloxamer, and a poloxamine.

3. The coated implantable medical device of claim 1, wherein said barrier layer comprises one or more of a methylcellulose, an ethylcellulose, a hydroxymethylcellulose, a hy-droxyethylcellulose, a hydroxypropylcellulose, a hydroxymethyl ethylcellulose, a hydroxy-propyl methylcellulose, a sodium carboxymethyl cellulose, a cellulose acetate phthalate, a cellulose acetate trimellitate, a methylhydroxypropylcellulose phthalate, a polyvinyl acetate phthalate, a dextrin, a starch, a starch derivative, a natural gum, gum Arabic, a xanthan, an alginate, a polyacrylic acid, a polyvinylalcohol, a polyvinyl acetate, a polyvinylpyrrolidone, a polymethacrylate or derivative thereof, and chitosan or a derivative thereof.

4. The coated implantable medical device of claim 1, wherein said biodegradable polymer is biodegradable polyester selected from the group consisting of PLA (polylactic acid), PGA (poly glycolic acid) and PLGA (Poly (lactic co glycolic acid).

5. The coated implantable medical device of claim 1, wherein said biodegradable polymer is combination of PLA and PLGA.

6. The coated implantable medical device of claim 1, wherein said hydrophilic polymer is essential polyvinyl pyrolidne (PVP, 30K).

7. The coated implantable medical device of claim 1, wherein silymarin with Hydrophilic polymer is used as single layered coat.

8. The coated implantable medical device of claim 1, wherein sirolimus with biodegradable polymer is used as single layered coat.

9. The coated implantable medical device of claim 1, wherein silymarin with hydophylic polymer as the base coat and sirolimus with biodegradable polymer may be used as top coat or vice- versa.

10. The coated implantable medical device of claim 1, wherein silymarin with hydophylic polymer as the base and top coat and sirolimus with biodegradable polymer may be used as middle coat.

11. The coated implantable medical device of claim 1, wherein said coating process is done on the abluminal site.

12. The coated implantable medical device according to claim 1, may be selected from the group consisting of stents, vascular implants, vascular supports, tissue adhesives, tissue sealants, tissue scaffolds and intraluminal devices, clamps, clips, sutures, suture anchors, electrodes, catheters, leads, grafts, dressings, pacemakers, pacemaker housings, prostheses, ear drainage tubes, ophthalmic implants, orthopedic devices, vertebral disks, bone substitutes, anastomotic devices, perivascular wraps, hemostatic barriers.

13. The coated implantable medical device of claim 12, wherein said coating process is done on the abluminal site with a porous nano- carbon hypotube inserted in to the lumen of the stent during the process of coating.

14. The coated implantable medical device of claim 13, wherein said coating process is done on the abluminal site with a porous nylon balloon inserted in to the lumen of the stent during the process of coating.