FORM 2
THE PATENTS ACT, 1970
{39 of 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]
1. TITLE: REJUVENATING CORONARY ARTERY BY IMPROVING BLOOD FLOW
WITH THE HELP OF INSERTION OF NANO-BALLS (ENCAPSULATED
NANOPARTICLES) CONTAINING THERAPEUTIC AGENTS BY NON IMPLANTABLE
DEVICE FOR TISSUES AND THEREBY PROVIDING IN TISSUE RELEASE TO
ADDRESS THE REQUIRED CELL CYCLE
2. APPLICANTS:
1. Envision Scientific Private Limited ,
8, Narayan Darshan Apartment, Opp. Rupam Cinema, Salabatpura, Surat (Gujarat), INDIA , PIN- 395002 NATIONALITY : Indian
2. Concept Medical Research Private Limited
D-512A, International Trade Center, Near Majuragate, Ring Road, Surat (Gujarat), INDIA, PIN-395003 NATIONALITY : Indian

The following specification describes the invention
REJUVENATING CORONARY ARTERY BY IMPROVING BLOOD FLOW
WITH THE HELP OF INSERTION OF NANO-BALLS (ENCAPSULATED
NANOPARTICLES) CONTAINING THERAPEUTIC AGENTS BY NON
IMPLANTABLE DEVICE FOR TISSUES AND THEREBY PROVIDING IN
TISSUE RELEASE TO ADDRESS THE REQUIRED CELL CYCLE
FIELD OF THE INVENTION
[0001] The invention generally relates to a method and a device for administrating drug to a target site. More specifically, the invention relates to an insertable medical device coated with nano-encapsulated particles of one or more drugs for efficient delivery of the one or more drugs to a body vessel.
BACKGROUND
[0002] Human blood vessels, in some instances are prone to blockage due to accumulation of plaque within the blood vessels. Such blockages are treated using devices and procedures such as, stent angioplasty, balloon angioplasty, atherectomy devices, and lasers. For example, stent angioplasty using drug releasing stents is one of the well-known procedures for widening lumens of blood vessels that are blocked by accumulation of plaque. However, drug releasing stents generally cover only 10% to 20% of a portion of a lesion (blockage) in the blood vessels. Thus, delivery of a drug to the entire portion of the lesion cannot be guaranteed. Additionally, most of the drugs that are administered to a patient using the drug releasing stents are hydrophobic in nature and have affinity for body tissues. However, as the sizes of drug particles are in microns, very low amount of drug penetrates into tissue. As a result, a high amount of the drug needs to be loaded onto the drug releasing stents to achieve the desired therapeutic effect.

[0003] Other insertable devices, such as drug delivery catheters and related devices are used for localized delivery of drugs to a site of blockage in the blood vessels. However, these devices come in contact with the site of blockage for a short time of 60 to 90 seconds. Such a short time of 60 to 90 seconds may not be sufficient for an optimum uptake of the drug by the blood vessels to have a therapeutic effect. Therefore, the drug delivery catheters need to be loaded with a high dose of the drug. A substantial amount of the drug delivered by the drug delivery catheter may remain unabsorbed. The unabsorbed amount of the drug may get washed away in the blood stream thereby causing unwanted side effects. In instances when a balloon is used, the unabsorbed amount of the drug may stick to the balloon. Subsequently when the balloon comes in contact with target site, the unabsorbed drug is released from the balloon. This may lead to administration of higher dose of the drug than that is required which may result in toxicity followed by inflammation.
[0004] Additionally, in some instances, the drug delivery catheter and related devices use localized jetting of the drug at the site of blockage. Such localized jetting of drug at the site of blockage causes damage to the blood vessel. In addition, the localized jetting of drug may also produce toxicity of drugs with time.
[0005] Further, in the currently used drug releasing medical devices, the sizes of drug particles coated on the surface of these devices is in microns. Whereas, the sizes of the tissue pores of the blood vessel are in nanometers. This leads to insufficient penetration of the drug into the tissue pores. The penetration of the drug is further affected by the fact that the drug releasing medical devices.may come in contact with the target site for a short time of 60 to 90 seconds. Therefore, a substantial amount of drug remains unabsorbed by the target site. The unabsorbed drug may get washed away into the blood stream thereby causing unwanted side effects.

[0006] There have been efforts to use expandable medical devices for localized delivery of drug to the site of blockage. However, efficiently releasing the drug from the surface of an expandable medical device when the balloon is in contact with the site of blockage, still remains a challenge.
[0007] Therefore, there is a need for an insertable medical device that can efficiently deliver the drug to the site of blockage within few seconds. In addition, there is a need for an insertable medical device that can efficiently deliver drug to the maximum area of a lesion and that provide for enhance bioavailability with a reduced amount of the drug loaded onto the device.
DETAILED DESCRIPTION
[0008] Before describing in detail embodiments that are in accordance with the invention, it should be observed that the embodiments reside primarily in combinations of components of a drug releasing medical device and method steps of preparing the same. Accordingly, the components and the method steps have been described to include only those specific details that are pertinent to understanding the embodiments of the invention so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having the benefit of the description herein.
[0009] In this document, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. An element preceded by "comprises ...a" does not, without more constraints, preclude the existence of additional identical elements in the process, method, article, or apparatus that comprises the element.

[0010] Further, before describing in detail embodiments that are in accordance with the invention, it should be observed that all the scientific and technical terms used in for describing the invention have same meanings as would be understood by a person skilled in the art.
[0011] Generally speaking, pursuant to various embodiments, the invention discloses a Drug Releasing Insertable Device (DRID) with nano-encapsulated particles of one or more drugs coated on one or more hydrophilic surfaces of the DRID. The invention also discloses a DRID with a porous bed on one or more non-hydrophilic surfaces such that, the nano-encapsulated particles are deposited in one or more pores of the porous bed. The nano-encapsulated particles include one or more of. one or more encapsulating mediums and one or more excipients. The one or more encapsulating mediums and the one or more excipients have one or more properties. The one or more properties include stabilizing the nano-encapsulated particles, affinity for blood vessel, and promoting healing of a site of blockage. The nanC-encapsulated particles are released upon coming in a close proximity of the site of blockage or upon change in pH.
[0012] Pursuant to the various embodiments of the invention, the DRID includes any medical device used for localized drug delivery at a target site in body. Examples of the DRID may include, but are not limited to, a catheter balloon, a guide wire, a catheter, a graft, diagnostic catheter, angiography catheter, endoscopy catheter, and any similar device. In an embodiment of the invention, the DRID is a catheter balloon. The catheter balloon has one or more surfaces. The one or more surfaces include, but are not limited to, one or more hydrophilic surfaces and one or more non-hydrophilic surfaces. The one or more surfaces are coated with nano-encapsulated particles of one or more drugs. The nano-encapsulated particles are released when the one or more surfaces of the catheter balloon come in a close proximity of a target site. It will be appreciated by a person skilled in the art that the target site includes any desired site in the body to which a drug has to be delivered. For example, the target site may include whole or part of, a body vessel. In an embodiment of the invention, the target site is a site of blockage in an artery.

The close proximity includes for example, but not limited to, a physical contact of the catheter balloon with the target site and any distance less than 1 mm between the catheter balloon and the target site. In an embodiment of the invention, proximity includes physical contact between the catheter balloon and the target site. The catheter balloon may come in the close proximity of the target site upon positioning and inflating the catheter balloon at the target site. When the one or more surfaces of the catheter balloon come in close proximity of the target site, the nano-encapsulated particles are released from the one or more surfaces.
[0013] The nano-encapsulated particles include one or more of, but not limited to, one or more drugs, one or more encapsulating mediums, and one or more excipients. The one or more drugs may include, one or more of, but not limited to, an anti-inflammatory agent, an anti-thrombotic agent, an anti-proliferative agent, estrogens, thrombolytics, an antimitotic, a smooth muscle cell inhibitor, a fibrinolytic, a anti-antigenic agent, a healing promoter, an antibiotic, a protease inhibitor, one or more antibodies, an anti-mitotic agent, an immunosuppressive agent, a cytostatic agent, a cytotoxic agent, a calcium channel blocker, an antioxidant and an anti-platelet aggregating agent. For example, the one or more drugs may be one or more of, but not limited to, paclitaxel, sirolumus, dexamethasone, genistine, flavenoids like flavanones, neoflavones, aurones, chalcones, dihydrochalcones, flavonols, dihydroflavonols, flavones, flavanols, isoflavones, anthocyanidins, proanthocyanidins, isoflavanes, heparin, beta-estradiol, and rapamycin.
[0014] Further, the one or more drugs may include one or more of but not limited to, analogues of the one more drugs and substitutes of the one or more drugs. The one or more drugs may be, for example, but not limited to, everolimus, zotralimus, biolimusA9, mayolimus, novalimus, pemecrolimus, and tacrolimus.
[0015] The nano-encapsulated particles include nano-particles of a drug. In accordance with various embodiments of the invention, the nano-particles may be prepared by known methods. Alternatively, the nano-particles of the drug that are readily available may be

used for encapsulation. The nano-particles are encapsulated with the one or more encapsulating mediums.
[0016] In accordance with the various embodiments of the invention, the one or more encapsulating mediums may have one or more properties. The one or more properties include, but are not limited to, stabilizing the nano-encapsulated particles, affinity for blood vessel, and promoting healing of a site of blockage after treating it or opening it. The one or more encapsulating mediums include, one or more of, but not limited to, excipients obtained from blood and one or more phospholipids. The one or more phospholipids may include one or more phospholipids obtained from natural source and one or more phospholipids synthesized chemically. For example, the one or more phospholipids may be one or more of obtained from soya, phospholipids obtained from egg, but not limited to, phosphatidylcholines (lecithins), phosphatidylglycerol, phosphatidylinositoL phosphatidylserine, phosphatide acid, cardiolipin, phosphatidylethanolamine, Phospholipon 80H, Phospholipon 90H, Lipoids S75, Lipoids E80, Intralipid 20, Lipoid EPC, and Lipoids E75. In an embodiment of the invention, the nano-particles of the drug are encapsulated with the excipient obtained from blood to get the nano-encapsulated particles. The nano-encapsulated particles thus obtained show better affinity for the target site. The nano-encapsulated particles are attracted by the target site because of the better affinity for the target site.
[0017] The better affinity of the nano-encapsulated particles for the target site may be attributed to the use of the one or more encapsulating mediums and the one or more excipients used for preparing the nano-encapsulated particles. For example, the use of one or more excipients obtained from blood as the one or more encapsulating mediums, enhances the affinity of the nano-encapsulated particles for the target site. Further, the affinity of the nano-encapsulated particles for the target site is enhanced by the use of the one or more phospholipids with one hydrophilic head and two hydrophobic tails. When the catheter balloon is inflated, the nano-encapsulated particles are released from the one or more surfaces of the catheter balloon. Further, when the physiological pH changes, the

one or more excipients get dissolved in blood thereby releasing the one or more drugs from the nano-encapsulated particles. The one or more drugs thus released provide for diffusion of the one or more drugs in to the target site. Therefore, the nano-encapsulated particles facilitate better absorption of one or more drugs by the target site.
[0018] Further, in accordance with the various embodiments of the invention, the one or more excipients may have one or more properties. The one or more properties may include, but are not limited to, stabilizing the nano-encapsulated particles, affinity for blood vessel, and promoting healing of a site of blockage. The one or more excipients may include, one or more of, but not limited to, excipients obtained from blood, one or more phospholipids. The one or more phospholipids may be obtained from natural source or may be synthesized chemically. For example, the one or more excipients may be one or more of, but not limited tof phosphatidylcholines (lecithins), phospholipids obtained from soya, phospholipids obtained from egg lecithin, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatide acid, cardiolipin, phosphatidylethanolamine, Phospholipon 80H, Phospholipon 90H, Lipoids S75, Lipoids E80, Intralipid 20, Lipoid EPC, and Lipoids E75. In an embodiment of the invention, the one or more excipients include the excipient obtained from blood. The nano-encapsulated particles with the excipient obtained from blood, show better affinity for the target site. Therefore, the nano-encapsulated particles provide for a better absorption of one or more drugs by the target site.
[0019] In another embodiment of the invention, the one or more excipients or the one or more encapsulation mediums include one or more phospholipids. The one or more phospholipids may have one hydrophilic head and two hydrophobic tails. The one or more phospholipids provide stability to one or more of the nano-particles of one or more drugs and the nano-encapsulated particles. Further, the one or more phospholipids may provide for a rapid release of the nano-encapsulated particles from the DRID. The rapid release of the nano-encapsulated particles from the DRID is achieved because of the one hydrophilic head of the one or more phospholipids. The one hydrophilic head gets

attracted by the tissue thereby resulting in the rapid release of the nano-encapsulated particles.
[0020] In accordance with the various embodiments of the invention, the nano-encapsulated particles may have an average diameter ranging between 10 to 1200 nano¬meters. Preferably, the average diameter of the nano-encapsulated particles ranges from 300 to 900 nanometer. More preferably, the average diameter of the nano-encapsulated particles ranges from 400 to 600 nanometer. In an embodiment, the average diameter of the nano-encapsulated particles is 400 nanometer. It will be appreciated by a person skilled in the art that any size of the nano-encapsulated particles may be used to achieve particular therapeutic objectives, without deviating from the scope of the invention.
[0021] In one of the embodiments of the invention, the nano-encapsulated particles are coated on the one or more hydrophilic surfaces of the DRID. These nano-encapsulated particles are rapidly released from the DRID. Further, one or more excipients may be coated on the one or more non-hydrophilic surfaces to form a porous bed on the one or more non-hydrophilic surfaces.
[0022] Examples of the one or more excipients used to form the porous bed may include, but not limited to, one or more biodegradable excipients, one or more bioerodable excipients, one or more bioabsorbable excipients, one or more polymers, and one or more celluloses. For example, the one or more excipients used to form the porous bed may be, one or more of, but not limited to, phosphatidylcholines (lecithins), phospholipids obtained from soya, phospholipids obtained from egg lecithin, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatide acid, cardiolipin, phosphatidylethanolamine, Phospholipon 80H, Phospholipon 90H, Lipoids S75, Lipoids E80, Intralipid 20, Lipoid EPC, and Lipoids E75.
[0023] The porous bed includes a thin layer of the one or more excipients. In an embodiment of the invention, the thin layer is made up of the one or more polymers. The thin layer further has one or more pores. The one or more pores store the one or more

nano-encapsulated particles. The one or more nano-encapsulated particles are released from the one or more pores upon coming in the close proximity of the target site or in response to change in pH at the target site. Alternatively, the nano-encapsulated particles may be released from the one or more pores upon inflation of the catheter balloon. The porous bed may be created using known methods. In an embodiment of the invention, the porous bed is created by coating the one or more non-hydrophilic surfaces of the DRID with the one or more polymers to form a thin layer on the one or more surfaces. The thin layer is further subjected to vacuum drying to create one or more pores in the thin layer thereby forming the porous bed.
[0024] In yet another embodiment of the invention, the DRID is a catheter balloon. The catheter balloon has one or more hydrophilic surfaces. The one or more hydrophilic surfaces are coated with nano-encapsulated particles. The nano-encapsulated particles include one or more of, but not limited to, an anti-inflammatory agent, an anti-thrombogenic agent, and a prohealer. Further, the DRID includes a stent mounted or crimped on the catheter balloon. Thus, two or more drugs can be delivered to the target site to produce two or more therapeutic effects. In an embodiment of the invention, the catheter balloon is coated with nano-encapsulated particles of the anti-inflammatory agent and the stent is coated with nano-encapsulated particles of the anti-proliferative agent. Thus, a combination of an anti-inflammatory agent and an anti-proliferative agent can be delivered to the target site to achieve two or more therapeutic objectives. The two or more therapeutic objectives include, for example, but not limited to, reducing the instances of restenosis, reducing inflammation, and reducing thrombus formation. It will be appreciated by one skilled in the art that any different combinations of drugs can be coated on the catheter balloon and the stent to achieve one or more therapeutic objectives, without deviating from the scope of the invention.
[0025] In an embodiment of the invention, of one or more medical devices of, but not limited to, a drug releasing stent, a bare metal stent, a biodegradable stent, and any other insertable medical device may be mounted or crimped on the DRID. The DRID may then

be used to deliver the one or more medical device at a target site. For example, but not limited to, the DRID may be used for delevering the drug releasing stent to prevent loss of drug while handling the drug releasing stent.
[0026] In accordance with the various embodiments of the invention, the nano-encapsulated particles may be released from the DRID at once, upon coming in the close proximity of the target site. Alternatively, the nano-encapsulated particles may be released from the DRID in more than one time. For releasing the nano-encapsulated particles in more than one times, the DRID is brought into the close proximity of the target site for more than one times. For example, when the DRJD is brought into the close proximity of the target site for a first time, some of the nano-encapsulated particles are released. When the DRID is brought into the close proximity of the target site for a second time, a remaining amount of the nano-encapsulated particles is released from the DRID.
[0027J In accordance with the various embodiments of the invention, the one or more pores of the porous bed may store, one or more of, but not limited to, nano-particles of the one or more drugs, nano-particles of the one or more excipients, the nano-encapsulated particles of the one or more drugs.
[0028] Pursuant to the various embodiments, the invention discloses a method for preparing a DRID. The method includes, encapsulating nano-particles of one or more drug with one or more encapsulation mediums. The one or more encapsulating mediums include, one or more of, but not limited to, excipients obtained from blood, one or more naturally occurring phospholipids, and one or more lipoids. The method further includes depositing the nano-encapsulated particles on one or more hydrophilic surfaces of the DRID. The nano-encapsulated particles may be deposited on the one or more hydrophilic surfaces by known methods. In an embodiment of the invention, the nano-encapsulated particles are deposited on the one or more hydrophilic surfaces by spray coating.

[0029] Pursuant to another embodiments, the invention discloses a method for preparing a DRID. The method includes coating one or more non-hydrophilic surfaces of the DRID to form a thin layer on the one or more non-hydrophilic surfaces. One or more of, but not limited to, one or more biodegradable excipients, one or more bioerodable excipients, one or more bioabsorbable excipients, one or more polymers, and one or more celluloses may be used for the coating. Further, one or more pores are formed in the thin layer by using an appropriate process. Example of the appropriate process may include, but not limited to, vacuum drying. The one or more pores are created in the thin layer using vacuum drying to form a porous bed on the one or more non-hydrophilic surfaces of the DRID. Nano-encapsulated particles of one or more drugs are deposited in the one or more pores of the porous bed. The nano-encapsulated particles are released when the porous bed comes in a close proximity of tissues of a target site.
[0030] Various embodiments of the invention provide a DRID and a method for preparing the same. The DRID provides for a penetration of one or more drugs into a target site to achieve better in-tissue diffusion and in-tissue drug release. The DRID also provides for a rapid release of the one or more drugs at the target site. Further, the DRID provides for uniform distribution of the one or more drugs across the target site. The invention also provides a DRID that exhibits enhanced bioavailability and biocompatibility of the one or more drugs. Various embodiments of the invention provide a DRID that enhances healing process of an affected target site by use of excipients that have healing properties
[0031] Those skilled in the art will realize that the above-recognized advantages and other advantages described herein are merely exemplary and are not meant to be a complete rendering of all of the advantages of the various embodiments of the invention.
[0032] In the foregoing specification, specific embodiments of the invention have been described. However, one of ordinary skill in the art appreciates that various modifications and changes can be made to the invention without deviating from the scope of the

invention. Accordingly, the specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of the invention.