FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
PROVISIONAL SPECIFICATION Section 10
1. TITLE OF THE INVENTION
"IMPLANTABLE MEDICAL DEVICES HAVING FORMULATIONS FOR TARGETED DRUG DELIVERY AND METHOD OF MANUFACTURE THEREOF"

2.

APPLICANT :


(a) Name
(b) Nationality
(c) Address
MERIL LIFE SCIENCES PRIVATE LIMITED
Indian
Plot No. 304/H-2, Kaldeep, Chanod Colony,
GIDC, Vapi - 396 195, Gujarat, India
3. PROVISIONAL SPECIFICATION
The following specification describes the invention.

FIELD OF THE INVENTION:
This invention relates to implantable medical devices loaded with formulations containing / comprising of affinity vehicle/s and additives, etc. along with therapeutic agent/s for targeted drug delivery and the method of manufacture to achieve desirable drug concentration ,and / or drug retention, and / or drug release in vivo. The invention relates to implantable stents, orthopedic implants, dental implants, etc. with porous and/or plain surface loaded with therapeutic formulation in which the drug is attached and/or encapsulated to/ with affinity vehicle/s to facilitate and/or enhance the effective drug delivery into the tissue of a mammalian blood vessel.
BACKGROUND OF THE INVENTION:
There are several methods that are known for the delivery of a pharmaceutical composition for the treatment of various medical conditions. The therapeutic agent in a pharmaceutical composition may be delivered to a human or veterinary patient by various routes of administration such as but not limited to subcutaneous, topical, oral, intraperitoneal, intradermal, intravenous, intranasal, rectal, intramuscular, and within the pleural cavity.
One of the method of administration of a drug is by introducing an implantable medical device containing the desired drug/therapeutic agent in a formulation, partly or completely into/ onto the respective site such as but not limited to esophagus, trachea, colon, biliary tract, urinary tract, vascular system or other locations within a human or veterinary patient wherein the medical device may be a stent, catheter, balloon, dental implants, orthopedic implants , etc.
Exposure, however, to a medical device which is implanted or inserted into the body of a patient can cause the body tissue to exhibit adverse physiological reactions. For instance, the insertion or implantation of certain catheters or stents can lead to the formation of emboli or clots in blood vessels. For example, when a medical device is introduced into and manipulated through the vascular system, the blood vessel walls can be disturbed or injured. Clot formation or thrombosis, and/or cell proliferation often results at the injured site, causing stenosis {i.e., closure) of the blood vessel. Additionally, if the medical device is left within the patient for an abnormal period of

time, thrombus may form on the device itself with subsequent cell proliferation, again causing stenosis.
Drug-Efuting Stents (DES) are made to resist stenosis or cell proliferation by coating them with therapeutic agents which elute at the target site at a desired rate and desired dose to achieve desired drug concentration in the vessel wall tissue. The rate of release of therapeutic agent in surrounding blood stream and on the surrounding tissue is very important to get desired clinical result, at the same time controlling adverse effects. To control the release rate, the therapeutic agents are coated on stents along with other components like polymers which are biodegradable or non¬biodegradable.
Treatment of damaged vascular tissue, thrombosis and restenosis, sees the need for administering therapeutic substances to the treatment site. For example, anticoagulants, antiplatelets and cytostatic agents are commonly used to prevent thrombosis of the coronary lumen, to inhibit development of restenosis, and to reduce post-angioplasty proliferation of the vascular tissue, respectively. In order to provide an efficacious concentration of therapeutic substances to the treated site, systemic administration of such medication is required which in turn produces adverse or toxic side effects for the patient. Such problem is overcome by way of local delivery wherein smaller levels of medication, as compared to systemic dosages, are concentrated at a specific site. Local delivery produces fewer side effects and achieves more effective results. Of the techniques applied for local delivery of the drugs, most common is through the use of medicated stents or drug eluting stents. One-proposed method of medicating stents is to seed the stent with endothelial cells (Dichek, D. A. et al.; Seeding of Intravascular Stents with Genetically Engineered Endothelial Cells; Circulation 1989; 80: 1347-1353).
Recently, various types of drug-coated stents have been used for the localized delivery of active pharmaceutical ingredients (APIs) to the wall of a body lumen to further prevent restenosis. The APIs used as part of the stent coating typically have one or more therapeutic activities such as antithrombotic activity, antiproliferative activity, anti-inflammatory activity, vasodilatory activity, or lipid-lowering activity. Generally, APIs are adhered to the stent surface in admixture with a carrier polymer.

A method involves the use of a polymeric carrier coated onto the body of the stent, is disclosed in U.S. Pat. No. 5,464,650, U.S. Pat. No. 5,605,696, U.S. Pat. No. 5,865,814, and U.S. Pat. No. 5,700,286 .
US 5,843,172 and US6240616, report a medicated prosthesis, such as a stent, deployed in a human vessel. The metallic stent in consideration has a plurality of pores in the metal which are loaded with medication. When the stent is implanted into the vasculature of a patient, the medication in the stent dissipates into the tissue of the vasculature close to the stent. The stent may be formed from a porous metal in the form of a wire, tube, or metal sheet. Porous metal is formed by sintering metal particles. In some cases, sintering the particles or fibres is done in several layers.
In another recent prior art, US5972027, expandable intraluminal stents made of a powdered metal or polymer are provided as well as their method of manufacture. These stents are characterized by a desired porosity, with a drug compressed into the pores of the stent. The stents are formed by subjecting one or more powdered materials in a die cavity to a pressure treatment followed by a heat treatment. The material may be cast directly in a stent-like form or cast into sheets or tubes from which the inventive stents are produced. The so-formed porous metal or polymer stent is then loaded with one or more drugs.
US6379381 discloses an implantable stent capable of being loaded with substances. In one example, the prosthesis is a cylindrical-shaped body having depots or pores formed thereon. The depots can be formed at pre-selected locations on the body of the stent and can have a pre-selected depth, size, and shape. The depots can have various shapes including a cylindrical or a conical shape. Such depots are formed as laser trench. Laser fabrication and physical/chemical etching techniques well known to one of ordinary skill in the art have been used. Substances such as therapeutic substances, polymeric materials, polymeric materials containing therapeutic substances, radioactive isotopes, and radio-opaque materials can be deposited into the depots.
While the polymer provides the drug-coated stent with several important functions, the use of the polymer also burdens the stent with certain disadvantages. Often, coating the API with a polymer can result in drug entrapment within the polymer coating so that the API diffuses from the stent to the area to be treated too slowly and/or at too

low a concentration.. Moreover, conventional coating methods typically use a continuous phase coating such as a liquid carrier polymer phase to dispose the API on the stent. Such methods often result in disposing an excess amount of polymer on the stent surface. The presence of excess polymer is generally considered to be detrimental to tissue recovery, and a bare metal stent is believed to promote better vascular healing than a stent having a polymer finish.
Further, these polymers cause inflammation to the arterial wall leading to in-stent restenosis (ISR). Other distinct factors that cause ISR include neointimal hyperplasia and other well known cardiovascular complexities. Substantial research is being carried out to eliminate the negative/adverse effects of vascular stenting by eliminating the use of polymeric material for therapeutic coating of the stents.
Obstacles often encountered with the use of a polymeric coating include difficulties in coating a complicated geometrical structure, poor adhesion of the polymeric coating to the surface of a stent, and biocompatibility of the polymer.
The US patent application no. 2006/0085062 discloses an endolumenal stent system for promoting endothelialization of vascular injury sites, comprising: an endolumenal stent; a porous surface on the endolumenal stent having a plurality of pores; and a composite material located within each of the pores and comprising a bioerodable polymer in combination with a therapeutically effective amount of a bioactive agent US patent application no. 2003/0064965 discloses a medical device which comprises: a plurality of particles, which are supported within the matrix of a macrostructure, dispersed on the surface of the medical device, each particle comprising a therapeutic drug or a combination of therapeutic drugs having a nti-pral if era tive activity in the cardiovascular system, wherein the particles are selected from the group consisting of liposomes, microparticles, nanoparticles, and drug aggregates, and wherein the medical device is contacted with a tissue or circulation such that the drug is released from the particle, and into the surrounding tissue or circulation in less than 5 minutes after the contacting step. The macrostructure is selected from the group consisting of fibrin gels, hydrogels and glucose and the particles are supported within the matrix of a macrostructure. This formulation is specifically suitable for medical devices like balloon catheters which remain in the body for short time. This formulation can not be used where sustained release is required over a long period of time varying from a few days to 60 days.

Disadvantages associated with the aforementioned methods are (1) quite a lot of the drug is lost in the blood; (2) only a fraction of the drug is able to reach the target cell/ tissue, which necessitates incorporation of high drug dose on the medical devices e.g. stent to achieve efficacious drug dose in the target tissue; and (3) the drug and delivery vehicle residing for a long time or permanently on the stent surface after implantation causes inflammation, delayed healing and incomplete endothelialization which in turn results into acute, sub-acute and late thrombosis. In some cases, the entire quantity of drug and/or the vehicle is not released.
OBJECTS OF THE INVENTION
The object of the present invention is to provide an implantable medical device with a drug formulation capable of (a) delivering drug at the target site with very high or nearly complete drug availability to the target cell/ tissue (b) optimum retention of the drug on the stent and in the tissue to inhibit smooth muscle cell proliferation and also effect desired endothelialization.
A still further object of the present invention is to provide a formulation capable of being loaded onto the surface of the medical device that may be porous and / or plain.
A still further object of the present invention is to provide a formulation that, when applied to a medical device, covers the entire surface of a medical device uniformly and that adheres to the surface of the medical device with enough force to withstand forces applied to it during crimping and its implantation to the target site without damaging the coating.
A stiil further object of the present invention is to provide a formulation capable of delivering a therapeutic agent/s including drug, DNA. Genes, growth factors, etc, to the target site.
A still further object of the present invention is to provide an implantable medical device having ultra thin coating of the formulation .
A still further object of the present invention is to provide a formulation having anti¬inflammatory properties for coating on the implantable medical devices.

A still further object of the present invention is to provide a formulation which is removed completely from the surface of the implantable medical device over desired time period.
A still further object of the present invention is to provide an implantable medical device having porous surface.
Another object of the present invention is to be able to secure the therapeutic substance directly onto the surface of the stent body which may or may not be porous.
A still further object of the invention is to provide an implantable medical device in particular stents, which do not require the use of undesirable vehicle such as polymer thereby reducing or ejjmjnatmg artery waJJ inflammation.
Yet another object of the present invention is to provide an easy and simple method for pore formation and pre-loading methods.
Yet another object of the present invention is to provide a suitable porous surface which facilitates growth of tissue by cell anchoring without promoting adverse activation of platelets and leucocytes, thus promoting early endothelialization.
Yet another object of the present invention is to achieve desired drug concentration in the vessel wall tissue with considerably lower drug loading on the implantable medical devices compared to those currently in vogue.
SUMMARY OF THE INVENTION
The present invention has been described with particular reference to stents. However, the present Invention can be applied to all implantable devices, such as orthopedic & dental implants, etc.
In accordance with various aspects of the present invention, an implantable device is provided that is capable of being loaded with substances. The substances being loaded include, without being limited to, affinity vehicle/s and therapeutic agent/s.

Accordingly, in one aspect, the present invention provides an implantable medical device coated with a drug formulation capable of delivering drug at the target site with very high or nearly complete drug availability to the tissue and thereby providing an optimum retention of the drug on the stent and in the tissue to effect inhibit smooth muscle cell proliferation and desired endothelialization.
In accordance with the above aspect, an implantable medical device comprising of an endoluminal body having a porous surface consisting of plurality of pores/cavities with at least one therapeutic agent and at least one affinity vehicle together with an additive loaded onto the pores/cavities of said device for being released in a desired dosage for a desired period of time on the target site.
Further, the invention provides an implantable endoluminal body having a surface which is devoid of pores with at least one therapeutic agent and at least one affinity vehicle loaded onto the surface of said device for being released in a desired dosage for a desired period of time on the target site.
In another aspect, the invention provides a suitable porous surface prepared by easy and simple methods, which facilitates growth of tissue by cell anchoring without promoting adverse activation of platelets and leucocytes, thus promoting early endothelialization.
In another aspect, the invention provides pre-loading methods, which includes loading of the implantable medical device with the formulation comprising of one or more therapeutic agents with other substances like affinity vehicles and additives (henceforth termed as formulation). The formulation enters into and adsorbs onto the pore structure fully or partially depending on pore structure, molecular size of the components of the formulation and the formulation loading process. The pore structure and the mode of adsorption of the formulation play an important role in releasing the formulation adsorbed onto the pores.
In yet another aspect, the present invention provides a formulation which essentially comprises of at least one therapeutic agent with at least one affinity vehicle suitable for considerably lower drug loading onto the surface of the implantable endoluminal body compared to those currently in vogue, for being released in a desired dosage for a desired period of time on the target site

In a further aspect, the invention provides a preparation method of inventive formulations useful for loading on to the surface of the implantable medical devices such as stents, orthopedic & dental implants, etc.
DETAILED DESCRIPTION OF THE INVENTION
For the purpose of this invention, the expression "endoluminal body"; "implantable medical device" and "stent" are used interchangeably.
The stent is made from biocompatible materials like metals such as stainless steel, Cobalt-chromium alloy (L-605), Nickel-Titanium alloy (Nitinol), Titanium, Platinum, Magnesium, etc. and polymers by standard and well known stent forming methods. The metallic stent surface can be treated to make it suitable for pore formation process.
According to the present invention, the surface of the implantable metallic medical device is treated to make it porous in nature. A porous surface would mean a surface containing cavities which are nanometers to micrometers in dimensions. These cavities are also referred to as "pores". The porous surface is so tailored as to hold specific quantity of desired formulation of affinity vehicle/s and/or other therapeutic agents including drug/s and/or also to facilitate growth of tissue by cell anchoring without promoting adverse activation of platelets and leucocytes, thus promoting early endothelialization.
The said cavities or pores on the surface carry a therapeutic dosage of an agent or in the alternative; the therapeutic agent is encapsulated in or attached to a carrier
vehicle.
The therapeutic agent of choice or combinations of therapeutic agents may be formulated or encapsulated in such a way as to increase it's bioavailability to produce the desired effect and for site specific delivery when loaded onto the stent surface which may be porous or not.
The methods for preparing the formulations include use of lipids and liposomes for site specific delivery of therapeutic agent/s, particularly for preventing artery inflammation
*

and stenosis. The carrier vehicle stores the therapeutic agent as well as allows the agent to diffuse uniformly and in a controlled manner into the lumen of the tissue in which the medical device has been implanted. The carrier vehicle can be designed to effect delivery of the therapeutic agent in the target tissue minimizing the loss of drug into the blood stream.
The preferred embodiment of the present invention comprises of an implantable medical device which comprises of a endoluminal body with a surface having plurality of randomly or unrandomly distributed pores/cavities. The therapeutic agent loaded onto this device is either adsorbed into the said cavities in such a way that the formulation enters into the pores or coated onto the surface of the body of the medical device. The said formulation may be attached to the affinity vehicle and then applied In an appropriate manner onto the surface of the device.
In another aspect of the present invention, surface modification of implantable medical device is disclosed. The surface modification process includes pore formation and loading of the therapeutic formulation over the said pores. The method for manufacturing porous implantable medical devices includes the pore formation process.
Accordingly, a method of manufacturing an implantable medical device with porous surface for providing local delivery of therapeutic agent at an implantation site, comprises of:
a) treating the surface of the implantable medical device with specific chemicals along with or without electrochemical process to make it porous by providing a plurality of porous holding cavities open to one side;
b) optionally, subjecting the said device with pores to post treatment methods, and
c) loading the therapeutic agent(s) and affinity vehicle(s) together with additive onto the cavities formed on the surface.
The manufacturing process as mentioned supra comprising the pore formation process which includes treating the bare metal stent with specific chemicals including

but not limited to mineral acids, organic acids, alkalies, salt solutions, oxidizing agents, reducing agents, etc. either individually or in combination, with a specific sequence under inert or normal atmosphere, under programmed and strictly controlled time-temperature profiles for each individual step. The processing is once through or repetitive over several cycles with the same or different time-temperature profiles. The process may or may not include electrochemical step in combination with chemical contacting or separately using electrolytic solutions. The electrolytes are selected from a variety of inorganic and organic salts and salt mixtures with ionic bonds having compatible ions. The choice also depends on the relative positions of these ions in the electrochemical series. The electrolytes are maintained at specific pH to achieve desired etching. The electrochemical step may be a single step or repeated several times in series or alternating with chemical contacting steps. The current passed in electrochemical step may be constant, variable, intermittent or in step wise manner to achieve desired results. The time for applying electric current has also pronounced effect on the pore structure and can be used as a control parameter. Composition of the electrolyte, temperature of electrolytic bath, the process environment and processing time in electrochemical step/s are manipulated to get desired results.
Depending on pore structure requirement, the medical device may also be subjected to one or more heat treatments at specific temperature and specific time duration. All these processes yield desired pore structure. The porous surface may have a uniform or random pore structure or an oriented or directional grain porous structure or a mixture of these types.
The further process step comprises of suitable post treatments tike cleaning, passivation, heating, aging and physical treatment in media like, but not limited to, de-ionized water, organic solvents with promotional additives.
The processing etches the stent surface in preferential manner with no or partial oxidation of metal atoms on the surface. This processing creates cavities on the surface that are within a particular size and depth. The porosity of the medicai devices surface may vary in a particular range of the surface of the medical device. The size distribution of pores and surface coverage can be controlled by manipulating the process conditions. The pore size distribution is made suitable to the formulation of the therapeutic agents and desired loading philosophy to achieve desired release kinetics.

The pore structure and formulation composition can be designed to achieve nearly 100% availability of therapeutic agent/s.
The pore formation is controlled in such a way that the mechanical properties of the medical device are not changed. The properties of the medical devices like radial strength, pushability, trackability, elastic recoil, etc. remain essentially unaltered. The pore forming process is controlled so that it does not affect the corrosion properties of the device material adversely.
The porous surface can be designed to facilitate growth of tissue by cell anchoring without promoting adverse activation of platelets and leucocytes, thus promoting early endothelialization.
The implantable medical device is then loaded with the formulation of one or more therapeutic agents with other substances like affinity vehicles & additives (henceforth termed as formulation). The formulation enters into and adsorbs onto the pore structure fully or partially depending on pore structure, molecular size of the components of the formulation and the formulation loading process. The pore structure and the mode of adsorption of the formulation play an important role in releasing the formulation adsorbed onto the pores. The release rate of the formulation depends on the difference between the driving force exerted by the surrounding environment and the affinity of the formulation towards the pores and pore structure. Larger the difference, faster is the release of the formulation. A threshold value of this difference is required to start the release process. In extreme cases on either side, the formulation may not get released at all or may release instantaneously. The affinity of the formulation and the driving force can both be further manipulated by presence of other materials like affinity vehicles. The release kinetics can thus be tailored to suit the clinical requirements by modifying the pore structure and the formulation.
The hydrophilicity and hydrophobicity of the formulation play a very important role in the release kinetics and target delivery of therapeutic agent/s into the tissue. The formulation can be tailored to adjust these properties favorably such that the device delivers maximum therapeutic agent/s in to the tissue with very little loss to the blood stream. This tailoring of the formulation becomes efficacious even at doses of therapeutic agent/s which are much lower than those currently in vogue. This will result in to a coating which is comparatively thinner.

The formulations and the coating methods can be designed to make them effective and suitable for the plain non-porous stent surface without compromising on the positive aspects of the stents with pores.
The method of coating of the formulation and the properties of the formulation are optimized to provide uniform thin coating over the entire surface. The adhesion of the formulation to the stent surface (which may or may not be porous) is strong enough to withstand forces applied during crimping of the stent on the balloon catheter and handling during its deployment in the artery.
The desired therapeutic agents may be chosen from a host of products known to have the right effect on prevention of stenosis. These therapeutic agents may include anti¬proliferative agents, anti-inflammatory agents and anti-thrombotic agents. The drugs may include paclitaxel and its analogs, drugs of the Monocyclic lactone family (for example, Sirolimus, Evrolimus, their other analogs, etc) and other such drugs.
Examples of therapeutic agents include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof {manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I ., , actinomycin X 1 , and actinomycin C 1 . The drug can also fall under the genus of antineoplastic, antiinflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such antineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®, from Aventis SA, Frankfurt, Germany), methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn, Peapack, N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.) Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein llb/llla platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.) Examples of such cytostatic or antiproliferative agents include angiopeptin, angiotensin converting

enzyme inhibitors such as captopril (e.g. Capoten® and Capozide®from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co., Inc., Whitehouse Station, N.J.), calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, macrocyclic lactones like rapamycin and its analogs like tacrolimus, dexamethasone, and other structural derivatives or functional analogs thereof, such as 40-O-{2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUS available from Novartis), 40-O-{3-hydroxy)propyl-rapamycin, 40-O-[2-{2-hydroxy)ethoxyJ ethyl -rapamycin, and 40-O-tetrazole-rapamycin.
The dosage or concentration of the therapeutic agent required to inhibit the desired cellular activity of the vascular region can depend upon factors such as the particular circumstances of the patient; the nature of the trauma, the nature of the therapy desired, the time over which the ingredient administered resides at the vascular site; and if other therapeutic agents are employed, the nature and type of the substance or combination of substances. Therapeutic effective dosages can be determined empirically, for example by infusing vessels from suitable animal model systems and using immunohistochemicaf, fluorescent or electron microscopy methods to detect the agent and its effects, or by conducting suitable in vitro studies. Standard pharmacological test procedures to determine dosages are understood by one of ordinary skill in the art.
In a further embodiment, the medical device may also carry therapeutic agents, such as, for example, anti-spasmodic, anti-thromoogenic, and anti-platelet agents, antibiotics, steroids, and the like, in conjunction with the anti-proliferative agent, to provide local administration of additional medication.

The therapeutic agents may be formulated in normal way or may be encapsulated in the agents like oils, long chain fatty acids, lipids or liposomes, etc.
The method of coating the stent with therapeutic agents that may be lipid encapsulated is designed so as to have proper distribution of coating onto the pores and on the surface to ensure desired pharmacokinetics and target delivery into the tissue. The proportions inside the pores and on the surface can be varied to suit the pore structure as well as pharmacokinetics.
Thus, a preferred embodiment comprises of a therapeutic formulation comprising of therapeutic agent/s bound with affinity vehicle/s together with suitable additives capable of being coated on the surface (porous or non-porous) of implantable medical devices to deliver the desired concentration of therapeutic agent/s to the target site at doses of therapeutic agents lower than those in vogue and retaining the therapeutic agent for desired period of time.
The suitable lipid or a mixture of lipids for the purpose of the present invention may include phospholipids, mono, di and triglycerides of long chain fatty acids or any oil which is suitable for the purpose such as fats, waxes, cholesterol, sterols, fat-so!uble vitamins (such as vitamins A, D, E and K), and others. This may also include a lipid or a mixture of lipids which are triglycerides of long chain fatty acids like vegetable oils (which may include Soya, Safflower, Castor, Sunflower oils or similar other oils) with varying amounts of free fatty acid and triglycerides.
Additives may be a low molecular weight alkylated aromatic compound or a mixture of such compounds which may include but not limited to tertiary butyl phenols, tertiary butyl catechols, tertiary butyl cresols, etc.
A low molecular weight alcohol (C1 to C6) or a mixture of such alcohols are used as solvents to from homogeneous solution of all the components. In case the compounds are not soluble {fully or partially) in the solvent, they are emulsified using biocompatible emulsifiers or used as homogeneous slurry.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way

of example and for purpose of illustrative discussion of preferred embodiments of the invention.
The example described below demonstrates the efficacy of the formulation of therapeutic agent/s coated on plain surface of the medical device like a coronary stent. The improved efficacy of the invention is demonstrated by comparison between coronary stents coated with conventional formulations containing higher dose of therapeutic agent in polymers as vehicles and stents coated with invented formulation.
Though the example is for coronary stent with rapamycin as therapeutic agent, the invented formulation and imparting porosity to the surface are equally applicable to all medical devices and all other therapeutic agents as described supra. Similarly, the other components are not limited to lipids as described in the given example. The method is applicable to other components described in this patent application.
For clarity, the 'formulation' refers to the invented formulation and 'conventional formulation' refers to the formulation of therapeutic agent in polymers as vehicle. Similarly, the 'stent' refers to the stent coated with invented formulation and 'conventional stent' refers to the stent coated with formulation of therapeutic agent in polymers as vehicle. The conventional stents used for comparison are with plain surface.
The method of coating the stents with the formulation is also described below. This method gives uniform thin coating of the formulation over the entire surface of the stent.
Example 1
The formulation: The preferred formulation includes, but is not limited to, the following components.
1. The therapeutic agent/s.
2. A lipid or a mixture of lipids which are triglycerides of long chain fatty acids like vegetable oils (which may include Soya, Safflower, Castor, Sunflower oils or similar other oils) with varying amounts of free fatty acid and triglycerides.

3. A low molecular weight alkylated aromatic compound or a mixture of such compounds (referred to as "additive/s" hereinafter).
4. A low molecular weight alcohol or a mixture of such alcohols used as solvents to from homogeneous solution of all the components.
The lipid/s and the additive/s can be chosen from a host of chemical compounds keeping in mind their (a) biocompatibility (b) physical affinity to the therapeutic agent/s and with each other (c) chemical compatibility to the therapeutic agent/s and with each other to prevent unwanted side reactions (d) hydrophilicity and hydrophobicity of the overall formulation and (e) the physical and chemical affinity of the formulation to the surface of the medical device which may be plain or porous. The solvent can be chosen from a number of candidates keeping in mind its solvent properties, biocompatibility and volatility. The formulation should have desired adhesion to the surface of the medical device when coated and after evaporation of the solvent. Adhesion should be sufficiently strong to withstand physical forces during mounting the stent onto the balloon catheter and also prevent the formulation release during implantation of the stent. At the same time, the coating should have desired release properties after the implantation of the medical device. The components should have no undesired interactions with each other when they are being processed and also during the shelf life of the medical device.
Example 2
The coating process: The formulation coating process is performed using a micromist medicoat spray coating machine obtained from SONO-TEK Corporation, USA. To achieve good coating efficiency, high accuracy, overall control over the amount, uniform thickness of coating and uniform distribution of the therapeutic agent over the entire surface of the medical device, the spray-coating process is required to be controlled by an efficient programming of the entire process. The Spray coating machine is provided with one micro mist nozzle (located in vertical direction) which carries an inert gas like nitrogen (used as carrier) and two side nozzles (located in horizontal direction). The former is for spraying formulation and the latter are for wetting with the solvent/s to remove the excess therapeutic agent/s and lipid from the medical device to ensure uniformity in coating. The process sequence typically

consists of first purging of inert gas to remove the foreign particles, if any. This is followed by repeat cycles of spraying the formulation followed by wetting. The number of cycles depends on specific coating requirements. This sequence should be well validated to achieve desired results and it should be controlled by automated operation program. The invented coating method is efficient and can be validated to achieve very uniform thin coating on a medical device even if it has complicated surfaces. The coating formulation, comprising of therapeutic agent/s, lipid/s, additive/s and solvent/s, can be applied to the surface of a medical device using a single feed ultrasonic nozzle. This machine has a medicoat bench top glove box type enclosure. The formulation and wetting solution syringes are fitted to pumps located on one side of the coating chamber. The formulation is placed into the syringe and the syringe is fitted to the pump. Electrostatically charged finely divided droplets of coating formulation are created through the nozzle and deposited onto the grounded surface of the medical device to form a coating on its surface. The coating produced by the method of present Invention is completely uniform. \n particular, when a coating formulation is applied to a stent having a tubular sidewall and openings therein, the coating on both the inside and outside surfaces of the stent's sidewall is uniform.
There is another advantage of the coating method of the present invention. Because the atomization in the gas is conducted solely using electrostatic forces, each droplet has very little tendency to deviate from the path to which it is directed. Accordingly, a spray mist containing such droplets is less likely to miss the target surface. This provides a much more efficient means for applying a coating formulation to the surface of a medical device. More specifically, a major portion of the coating formulation that is sprayed gets deposited on the surface minimizing the losses and environmental contamination.
The coated medical devices are kept in the vacuum oven at required reduced pressure for minimum 12 hrs to maximum 24 hrs at appropriate temperature for vacuum drying. This operation removes the solvent/s from the coating. The coating machine and the coating process are made suitable and well validated for the specific formulation and specific surface of the device.
Example 3
Comparison with conventional stents and the study method

The stents coated with invented formulation were implanted in left and right iliac arteries of rabbits and tissue was examined after the intervals of 1, 3, 14 and 28 days. Drug elution and blood samples at various time points were also examined. Conventional stent-1 were also implanted along with these stents as control for comparison.
The comparison was made with two types of conventional stents as under.
Conventional stent -1
The same bare metal stents (with plain surface) were coated with rapamycin formulated in biodegradable polymers. The drug dose was 0.7 micrograms per mm2 of the stent area. The total loading of rapamycin on the stent of 3 mm dia, 13 mm length was 40 micrograms. The formulation had 36-37% rapamycin and 63-64% bio degradable polymers Poly(L-lactide) and Poly(DL-lactide-co-glycolide) in the ratio 3.5:1. These stents were implanted in rabbits as control samples along with stents coated with invented formulation.
Conventional stent- 2
Comparison was also made with conventional stent coated with conventional formulation of rapamycin in polymers as vehicle for which the data was obtained from literature. The dose of rapamycin in these stents was 1.4 micrograms per mm2 of stent surface area. For the stent surface area same as Conventional stent-1, the drug dose would amount to 80 micrograms. Though the available literature data was for porcine model, the comparison of results obtained on rabbit iliac gives a clear conclusion on superiority of the invented formulation.
Inventive stent with formulation - 3
This example demonstrates the superior efficacy of the invented formulation coated on plain surface of coronary stent compared to conventional stents coated with conventional formulations using same therapeutic agent but polymer/s as vehicle for controlled release.

The formulation was made using a lipid, rapamycin as therapeutic agent and a low molecular weight alkyl cresol with alkyl chain containing 3 to 6 carbon atoms as additive; all dissolved in ethyl alcohol as solvent.
This formuialion was coated on the surface of a coronary stent 3 mm dia and 13 mm long made from cobalt chromium alloy. The coating process as described above was used to achieve uniform thin coating of the formulation with rapamycin dose of 0.56 micrograms per mm2 of the stent surface. The stent surface was plain and did not have pores. The total loading of rapamycin on the stent was 31.5 micrograms.
The stents were implanted in left and right iliac arteries of rabbits and tissue was examined after the intervals of 1, 3, 14 and 28 days. Blood samples and drug elution at various time points were also examined. Following results were obtained.
1. For the stent, more than 80% of the drug was released at day 1 and 97% at
day 7. The stent did not show any coating at the end of 7 days showing
exposed metal.
In comparison, the Conventional stent-1 showed release of 25% at day 1 and 77% at day 7. It reaches 88% at day 14 and 95% at day 28.
The Conventional stent-2 reports release of -18% at day 1 and 45% at day 7. It reaches 80% at day 28 and 95% at day 90.
This comparison shows that the release of invented formulation is much faster than from conventional stents.
2. For the stent, the concentration of rapamycin in blood stream of the animal
(rabbit) was very low throughout the trial. This concentration dropped
substantially after 24 hrs of implantation (0,56 ng/ml).
In comparison, for the Conventional stent-1, rapamycin concentration in the blood of the animal (rabbit) reached 3.1 ng/ml in 24 hours of implantation.
For Conventional stent-2, the rapamycin concentration in the blood of the animal (swine) reaches 0.4 ng/ml in 24 hours of implantation. This comparison

is not very accurate because this data for Conventional stent-2 is reported for swine model.
3. The artery homogenate showed substantially high concentration of drug for
the stent compared to conventional stent. On day 1, for the Stent, the drug concentration was - 210 ng/mg. This concentration reduced to 180, 50, 40 and 26 ng/mg on day 3, 7, 14 and 28 respectively. It is evident that even on day 28, the drug concentration in artery homogenate is considerably high.
In comparison, the Conventional stent-1 showed tissue concentration of 12 ng/mg on day 1. This concentration reduced to 1.2, 1.5, 6.8 and 0.7 ng/mg on day 3, 7, 14 and 28 respectively.
The Conventional stent-2 reports tissue concentration of 10 ng/mg on day 1. This concentration reduced to 8, 4, 8 and 2 ng/mg on day 3, 7, 14 and 28 respectively.
This shows that the tissue concentration for the stent coated with invented formulation is substantially higher over the conventional models.
Thus, the invented formulation and coating method result in target drug delivery with very little loss to the blood stream. In addition, the drug availability is nearly total. The dose of rapamycin (0.56 micrograms/mm2) is much lower than conventional doses of 0.7 and 1.4 micrograms/mm2. Even at such high doses, drug concentrations in artery homogenate are much lower for conventional formulations.
The therapeutic formulation according to the present invention is capable of being removed completely from the surface of the implantable medical device over desired time period.
The implantable medical device according to the present invention, the said affinity vehicle allows the therapeutic agent to be retained into the tissue of the vessel wall for desired period of time and to diffuse uniformly in a controlled manner into the tissue of the vessel wall.

It is to be understood that the embodiments and variations shown and described herein are merely illustrative of the principles of the present invention. Therefore, various adaptations and modifications may be implemented by those skilled in the art without departing from the spirit and scope of the present invention.
Dated this 21st day of January, 2009

To,
The Controller of Patents
The Patent Office
Mumbai