FIELD OF THE INVENTION

The present invention relates to a pharmaceutical formulation comprising of 40-O-(2-hydroxyethyl) derivative of sirolimus (Everolimus) and coating on the implantable medical 5 devices including coronary stents. The present invention particularly relates to a process for the preparation of controlled drug formulation, stability and method of coating.

BACKGROUND OF THE INVENTION

10 The implantation of a medical device into a patient's body can cause the body to exhibit ad¬verse physiological reactions. The reactions may range from infections to the formation of emboli or clots in blood vessels. One particularly adverse physiological reaction is the result of epithelial damage to the cardio vasculature. That is, the vasculature can be damaged dur¬ing procedures such as percutaneous transluminal coronary angioplasty (PCTA). As a result 15 of damage to the epithelium of the vasculature, a cascade of physiological events may result in the re-narrowing (restenosis) of the vessel. Restenosis may be the result of smooth mus¬cle cell proliferation in the intimal layers of the vessel.

Restenosis of an artherosclerotic coronary artery after PTCA occurs in 10-50% of patients undergoing this procedure and subsequently requires either further angioplasty or coronary 20 artery bypass graft. In order to maintain the patency of the vessel, intravascular stents have been developed as a mechanical means of preventing the collapse or abrupt closure of the dilated segment of the artery.
Compared to PTCA, coronary stenting has a reduced restenosis rate. The angiographic res-tenosis rate for coronary stenting is about 10 to 20% in short lesions and large vessels. In-25 stent restenosis, however, occurs in over 30% to 60% of patients with diabetes, diffuse le¬sions, or lesions that occur in small vessels or are located at a bifurcation (Mehran R, et al. Circulation 1999; 100:1872-8). It is known that stenting prevents restenosis by eliminating negative remodeling and elastic recoil. However, stents fail to prevent neointimal proliferative response due to vessel injury. Studies have shown that stent-induced neointimal formation is 30 more extensive and protracted than that provoked by PTCA (Schwartz R S. J Invas Cardiol 1996; 8:386-7; Rogers C, et al. Circulation 1993; 88:1215-21). In particular, intimal hyperpla-sia is the major component of late lumen loss after stent implantation.

Numerous pharmacological approaches attempted via the systemic route have not yielded 35 useful results in terms of reducing the level of instent- restenosis after angioplasty. The prob-2

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, 5 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 Formation 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-10 perplasia of the neointima, are described.
Despite a high rate of procedural success with drug eluting stent implantation, an unaccepta-bly high (approximately 25%) rate of stent thrombosis is also experienced (Serruys P W et al. N Engl J Med 1991; 324: 13-7; Schatz R A et al. Circulation 1991; 83:148-61). With the use of aggressive and precise anti-platelet and anti-coagulation therapy along with the implemen-15 tation of high pressure balloon expansion, recent studies have shown thrombosis rates of less than 2% when stents are implanted electively and thrombosis rates of less than 5% in the treatment of abrupt closure (Lablanche J M, et al. Eur Heart J 1996; 17:1373-80; Goods C M, et al. Circulation 1996; 93:1803-8). Although thrombosis rates are lower as compared to the results from the early studies, stent thrombosis is a disastrous complication that carries a 20 high risk of ischemic sequelae (Mak K H et al. J Am Coll Cardiol 1996; 2 7:494-503). Addi¬tionally, systemic anti-platelet and anti-coagulation therapy increases the incidence of bleed¬ing complications. Accordingly, there still remains a need for solution to stent thrombosis. One approach to improve the biocompatibility of stents is to incorporate bioactive or pharma¬cological agents onto the stents. The approach involves physically blending or dispersing 25 bioactive agent(s) with inert polymers. These “inert” polymers do not possess any known pharmacological activity and only serve as a carrier or binder for the bioactive agent(s). For instance, bioactive compounds such as heparin have been applied to stent surfaces utilizing inert polymers such as thermoplastic polyurethane, silicone, polycaprolactone, polylactic ac¬id, polyethylene-vinyl acetate and cellulose-based polymers. 30

To address these problems, stents are being developed to provide for the local delivery of agents like anti thrombotic and anti restenosis agents. One method of local delivery includes coating the surface of the device such as a stent with a polymeric carrier and attaching an agent to, or blending it with, polymeric carrier. Agents can be used alone, and in combina-35 tion. There is continual need for novel ways to control the release rate of an agent from coat-3

ing and also stability of the drug. The present invention provides with a potent anti-restenosis agent with a polymeric carrier.

In a dose-dependent fashion, everolimus reduced human coronary artery smooth muscle cell (HCASMC) proliferation without toxicity in a bimodal fashion, with accentuated potency oc-5 curring at 10 µM. Everolimus arrested the majority of HCASMCs in G1-phase, while reducing the fraction of cells in S-phase. Moreover, everolimus-induced inhibition of the mammalian target of rapamycin complex 1 (mTORC1) and regulation of cyclin-mediated cell-cycle pro¬gression actions likely account for the anti-proliferative effects of this compound on HCASMCs.
U.S Pat no. 5,665,772 describes the novel derivatives of rapamycin, particularly 9-deoxorapamycins, 26-dihydro-rapamycins, and 40-0-substituted and 28,40-0,0-di-substituted rapamycins, which are found to have pharmaceutical utility, particularly as immunosuppres-sants. U.S Pat no. 20100082095 describes a coating on the surface of a substrate and the coated
substrates. The coating includes a polymer, an olimus drug (sirolimus, everolimus, zo-tarolimus, etc.), and a dexamethasone derivative. The polymer may be a hydrophobic poly¬mer, preferably a fluoropolymer, and more preferably a fluoropolymer with at least 25% vi-nylidene fluoride by weight.
U.S Pat no. 7,297,703 describes a mixture comprising a poly-ene macrolide and an antioxi-dant. Preferably, the poly-ene macrolide is rapamycin and the antioxidant is 2, 6-di-tert.-butyl-4-methylphenol. The presence of the antioxidant improves the stability of the poly-ene macrolide to oxidation
U.S Pat no. 20100094408 describes an intravascular stent and method for inhibiting resteno-sis, following vascular injury.. The stent has an expandable, linked-filament body and a drug-release coating formed on the stent-body filaments, for contacting the vessel injury site when the stent is placed in-situ in an expanded condition. The coating releases, for a period of at least 4 weeks, a restenosis-inhibiting amount of the macrocyclic triene immunosuppressive
compound everolimus. The stent, when used to treat a vascular injury, gives good protection against clinical restenosis, even when the extent of vascular injury involves vessel over¬stretching by more than 30% diameter. Also disclosed is a stent having a drug-release coat¬ing composed of (i) 10 and 60 weight percent poly-dl-lactide polymer substrate and (ii) 40-90 weight percent of an anti-restenosis compound, and a polymer undercoat having a thickness
of between 1-5 microns.

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 siro-5 limus particles as well as composition comprising the particles.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a formulation comprising everoli-10 mus.

It is an object of the present invention to provide an implantable medical device that provides a controlled release of the drug formulation comprising everolimus thereby enhancing the stability, wherein the implantable medical device may be selected from the group consisting of stents, vascular implants, vascular supports, tissue scaffolds, intraluminal devices, grafts, 15 dressings, pacemakers, pacemaker housings, prostheses, ear drainage tubes, ophthalmic implants, orthopedic devices, vertebral disks, bone substitutes, anastomotic devices, peri-vascular wraps, hemostatic barriers.

It therefore appears obvious that with this invention it is possible to obtain advantageously 20 stents comprising a drug layer with everolimus, at least one stabilizing agent with a biode¬gradable polymer. The coating process is done on the luminal and abluminal side and ablu-minal side alone and 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. 25 One aspect of the present invention is to provide a pharmaceutical formulation comprising everolimus wherein the formulations are in form of multi-particulate may be in matrix and/or reservoir forms.

According to further features in preferred embodiments of the invention described below, the 30 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, 10 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, 15 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 configu¬rations 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 em-25 bodiments of the present invention, the coat is made of a biodegradable polymer.

The term "biodegradable" as used in the context of the present invention, describes a mate¬rial which can decompose under physiological and/or environmental conditions into break¬down products. Such physiological and/or environmental conditions include, for example, hy-30 drolysis (decomposition via hydrolytic cleavage), enzymatic catalysis (enzymatic degrada¬tion), and mechanical interactions. This term typically refers to substances that decompose under these conditions such that 50 weight percents of the substance decompose within a time period shorter than one year.

The term stabilizing agent as used in the context of the present invention, describes the sta¬bility of everolimus in the formulation. The stabilizing agents like e.g. ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, 5 sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, toco-pherol hemisuccinate, TPGS or other tocopherol derivatives and natural antioxidants like fla-vonoids e.g quercetin, rutin genistein, apigenin . The concentration of an antioxidant agent in the formulation is normally from about 0.1% w/w to about 1% w/w.

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 com¬pletely dissolvable in such solvents or reaches its maximal saturation concentration in water, aqueous solutions and/or other polar solvents, while the remainder of the substance is in the

form of a suspension of small solid particles in the solvent. Hydrophilic agents are therefore typically water-soluble agents, in which the dissolvability of the molecule in water, aqueous solutions and polar solvents is higher than its dissolvability in oils, organic solvents and other non-polar solvents. The term "hydrophilic", as used and defined herein, also encompasses amphiphilic or amphiphatic agents, which are characterized by a part of the molecule that is
hydrophilic and hence renders the molecule dissolvable, at least to some extent, in water and aqueous solutions.

The term “inert core” 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 25 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. 30

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 inven¬tion. Accordingly, the description of a range should be considered to have specifically dis-35 closed 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 specif¬ically 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. 5

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 10 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 15 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 20 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 25 and procedures either known to, or readily developed from known manners, means, tech¬niques 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 fol¬lowing description, taken in conjunction with the accompanying drawings in which:

FIGURE - 1 is a graphical illustration of the drug elution (release) profile of stents coated with different formulations of everolimus

FIGURES - 2 to 5 are graphical illustrations of the drug elution (release) profile of stents at accelerated conditions coated with formulations F-1 to F-4

FIGURE - 6 is a graphical illustration of the drug elution (release) profile of stents coated with formulation F- 4 and packed with nitrogen at accelerated conditions 10

DETAILED DESCRIPTION

The invention is herein described, by way of example only, with reference to the accompany-15 ing drawings. With specific reference now to the drawings in detail, it is stressed that the par¬ticulars shown are by way of example and for purposes of illustrative discussion of the pre¬ferred embodiments of the present invention only, and are presented in the cause of provid¬ing 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 20 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.

Briefly described according to one of the embodiment, everolimus as a perfect anti resteno-25 sis agent but with stability concerns. To improve the stability of everolimus atleast on stabiliz¬ing agent is incorporate in the formulation and coated on the stents. The coated implantable medical devices were also packed with nitrogen along the formulation containing a stabilizing agent. The stents coated with different formulations were evaluated for its stability and re¬lease kinetics. 30 EXAMPLES
The following non limiting examples provide a process for the preparation of controlled drug formulation comprising everolimus which enhanced stability according to the teachings of the present invention.

EXAMPLE 1

FIG. 1 is a graphical illustration of the drug elution (release) profile of stents coated with dif¬ferent formulations of everolimus. The illustration determines the release kinetics where in the cumulative percentage release of everolimus vs. time is projected 5

EXAMPLE 2

Accelerated stability studies:

This example describes experiments that demonstrate the stability studies as conducted in accordance with ICH Q1A (R2) guidelines for the finished products. 10
Table: 1 Everolimus content on the stents coated with different formulations at accelerated conditions

Test Carried Initial 1 month 2 month 3 month
% Everolimus Content ERL(F1) 98.24±1.2 87.46±2.1 76.81 ±2.5 69.37±2.8

ERL +AA(F2) 98.26±1.8 92.38±1.9 88.16±2.1 85.22±2.9

ERL +T(F3) 98.31 ±1.5 93.45±1.8 89.43±2.3 86.18±2.7

ERL + BHT(F4) 98.28±1.7 96.51 ±2.0 95.34±2.6 94.85±3.0

ERL + BHT ( F4) Under nitrogen packing 98.37±1.9 97.15±2.3 96.38±2.7 96.1 6±3.1
ERL: Everolimus; AA: Ascorbic acid; T: Tocopherol; BHT: Butylatedhydroxytoulene 15

As can be seen in Table.1, the Everolimus content is carried out in percentage basis with re¬gard to the duration in months with different formulations.

From FIG. 2 to 6, the graphical illustrations of the drug elution (release) profile of stents on 20 accelerated conditions coated with F1 to F4 and formulation under nitrogen packing. The illu¬stration determines the release kinetics where in the cumulative percentage release of evero-limus vs. time

Non-limiting examples of biodegradable polymers composing the core and coat of the com-25 posite structure described herein, respectively, include homo-polymers and co-polymers

such as aliphatic polyesters made of glycolide (glycolic acid), lactide (lactic acid), caprolac-tone, p-dioxanone, trimethylene carbonate, hydroxybutyrate, hydroxyvalerate, polypeptide made of natural and modified amino acids, polyethers made of natural and modified saccha-rides, polydepsipeptide, biodegradable nylon copolyamides, polydihydropyrans, polyphos-5 phazenes, poly(ortho-esters), poly(cyano acrylates), polyanhydrides and any combination thereof.

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 in¬tended to be limiting.

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 en-hancers, humectants, chelating agents, preservatives, occlusive agents, emollients, permea¬tion 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-25 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), 30 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, wal-35 nuts, 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, isohexade-5 cane, isononyl isononanoate, PPG Ethers, petrolatum, lanolin, safflower oil, castor oil, coco¬nut 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 gly-col 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, glycyrrhiz-ic 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 con-strued 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 inven¬tion 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 5 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 embodi-10 ment. 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 subcom-bination.

This invention includes all modifications and equivalents of the subject matter recited in the 15 claims appended hereto as permitted by applicable law.

CLAIMS

I/ We claim:
1. A coated implantable medical device, comprising: a pharmacologically active
core; a drug layer comprising everolimus and at least one stabilizing agent agent with a bio-degradable polymer surrounding the said core; optionally, a barrier layer over the drug coated core containing hydrophylic polymer
2. The coated implantable medical device of claim 1, wherein said stabilizing agent
comprises at least one of the antioxidant
3. The coated implantable medical device of claim 1, wherein said stabilizing agent
comprises of at least one antioxidant and the implantable devices are packed with nitrogen
4. The coated implantable medical device of claim 1, wherein said barrier layer com-
prises one or more of a methylcellulose, an ethylcellulose, a hydroxymethylcellulose, a hy-droxyethylcellulose, a hydroxypropylcellulose, a hydroxymethyl ethylcellulose, a hydroxy-15 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.
5. 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).
6. The coated implantable medical device of claim 1, wherein said biodegradable
polymer is combination of PLA and PLGA.
7. The coated implantable medical device of claim 1, wherein said hydrophilic poly-
mer is essential polyvinyl pyrolidne (PVP, 30K).
8. The coated implantable medical device of claim 1, wherein everolimus with biode-
gradable polymer is used as single layered coat.

9. The coated implantable medical device of claim 1, wherein hydophylic polymer as top coat and everolimus with biodegradable polymer as base coat
10. The coated implantable medical device of claim 1, wherein said coating process is done on the luminal and abluminal site
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 scaffolds,
intraluminal devicescatheters, 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.

ABSTRACT
The present invention relates to a process for the preparation of controlled drug for¬mulation and method of coating comprising everolimus. The invention also relates to a 5 coated implantable medical device, comprising a drug layer with everolimus, at least one stabilizing agent with a biodegradable polymer.