Title of Invention	A BALLOON CATHETER ASSEMBLY FOR TREATING BIFURCATION LESIONS
Abstract	The invention discloses a balloon catheter assembly for delivering nano-carriers to bifurcation lesions in one or more of a main branch and a side branch of a blood vessel bifurcation within 30 to 90 seconds. The balloon catheter assembly includes two or more balloons designed for use in the blood vessel bifurcation. A surface of one or more of the two or more balloons is coated with the nano-carriers. The nano-carriers include one or more drugs encapsulated with one or more biological agents.

Title of Invention

A BALLOON CATHETER ASSEMBLY FOR TREATING BIFURCATION LESIONS

Abstract

The invention discloses a balloon catheter assembly for delivering nano-carriers to bifurcation lesions in one or more of a main branch and a side branch of a blood vessel bifurcation within 30 to 90 seconds. The balloon catheter assembly includes two or more balloons designed for use in the blood vessel bifurcation. A surface of one or more of the two or more balloons is coated with the nano-carriers. The nano-carriers include one or more drugs encapsulated with one or more biological agents.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See section 10 and rule 13] 1. TITLE: A METHOD AND A BALLOON CATHETER ASSEMBLY FOR TREATING BIFURCATION LESIONS 2. APPLICANTS:- Concept Medical Research Private Limited 1-3, Silver Palm II, Near Sneh Milan Garden, Kadampalli, Nanpura, Surat (Gujrat) INDIA, PIN - 395001 NATIONALITY : Indian Envision Scientific Private Limited , 8, Narayan Darshan Apartment, Opp. Rupam Cinema, Salabatpura, Surat (Gujarat), INDIA, PIN - 395002 NATIONALITY : Indian A METHOD AND A BALLOON CATHETER ASSEMBLY FOR TREATING BIFURCATION LESIONS FIELD OF THE INVENTION The invention generally relates to a method and a balloon catheter assembly for treating bifurcation lesions of a main branch and a side branch of a blood vessel bifurcation. More specifically, the invention relates to a drug delivery system for delivering one or more drugs to the bifurcation lesions in the main branch and the side branch of the blood vessel bifurcation. BACKGROUND OF THE INVENTION The current methods for treatment of bifurcation lesions include V-stenting, simultaneous kissing stent technique, kissing balloon technique, stent deployment in a main branch followed by angioplasty of a side branch, Drug Eluting Stents (DESs) specially designed for the bifurcation lesions, T-stenting, crush technique, provisional stenting and the like. The current methods of treatment of bifurcation lesions involve use of medical devices specially designed for use in the bifurcation such as, Bare Metal Stents (BMSs), DESs, Drug Eluting Balloons (DEBs) and angioplasty balloons. When the BMSs are used for treating the bifurcation lesions, generally, the BMSs are deployed only in the main branch. The side branch is subjected to angioplasty or is left unattended. Alternatively, the BMSs are deployed in both the main branch and the side branch. Deploying the BMSs in both the main branch and the side branch may lead to metal overload in the bifurcation. The metal overload may further result in inflammation and thrombus formation. Also, owing to the complicated structure of the bifurcation, the BMSs may not be appropriate for treating the bifurcation lesions. Therefore, use of DEBs and DESs has gained significance in treatment of the bifurcation lesions. However, the currently used DEBs and DESs use polymer for loading the drugs on surfaces of the DEBs and the DESs. Owing to the use of polymers, the currently used DEBs and DESs are associated with phenomenon like an inflammation, restenosis, an acute thrombus formation, a sub-acute thrombus formation and a late thrombus formation. Furthermore, in case of the DESs. the amount of drug that is supplied to the lesions generally depends on a metal to artery ratio. The metal to artery ratio of the currently used DESs is 10% to 20%. Therefore, only 10% to 20% of a portion of the lesions is supplied with the drug. In addition, because of the complicated structure of the bifurcation, the metal to artery ratio in case of the bifurcation is generally less than the metal to artery ratio in a general non-bifurcated artery. In some instances, where the DEBs are used for treating the bifurcation lesions, the time for which the DEBs are exposed to the target site ranges from 30 to 90 seconds. The DEBs have to deliver an effective amount of the drug within these 30 to 90 seconds. In order to deliver the effective amount of the drug within these 30 to 90 seconds, a high amount of the drug has to be loaded on the DEBs. Even after loading a high amount of the drug, the DEBs may not deliver the desired amount of the drug in a short time of 30 to 90 seconds. Further, currently used DEBs can be loaded only with certain highly lipophilic drugs such as, paclitaxel. Whereas, the DEBs that can be loaded with a wider range of drugs are not available in the art. Additionally, in the currently used DEBs, a drug is coated on the surface of the balloon when the balloon is in a folded configuration. Therefore, a substantial portion of the DEB remains uncoated with the drug. When the DEB is inflated, the portion of the lesion that is exposed to the uncoated portion of the DEB is not supplied with the drug. Therefore, the currently used DEBs may not adequately cover the entire portion of the bifurcation lesions. Further, the particle size of the drugs as well as the polymers that are coated on the DESs and the DEBs are larger than the size of tissue pores at a target site. Therefore, a substantial amount of drug remains unabsorbed. The unabsorbed drug may be washed away in blood stream and may produce side effects. Therefore, there is a need in the art for an improved drug-delivering insertable medical device for treating the bifurcation lesions that is associated with reduced instances of restenosis, acute thrombus formation, sub-acute thrombus formation, and late thrombus formation. Further, there is need in the art for an improved drug-delivering insertable medical device that can deliver a desired amount of drug to the bifurcation lesions within 30 to 90 seconds with an optimum loading of the drug. BRIEF DESCRIPTION OF FIGURES FIG. 1 illustrates a schematic diagram showing a first balloon and a second balloon positioned in a main branch and a side branch of a blood vessel bifurcation in accordance with an embodiment of the invention. FIG. 2 illustrates size distribution of nano-particles of Lipoid E80 as detected by Malvern Zeta Sizer (ZS90) in accordance with Example 1. FIG. 3 illustrates size distribution of the nano-carriers as detected by Malvern ZS90 in accordance with Example 1. DETAILED DESCRIPTION OF THE INVENTION 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 delivery system. Accordingly, the components 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. 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, or device, 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, or device. 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. 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. The term "bifurcation" means a structure of a blood vessel where the blood vessel is divided into a main branch and a side branch. The term main branch means the blood vessel from which the side branch originates. Further, the term "bifurcation lesions" means the lesions present in one or more of the main branch, the side branch and a trunk of a blood vessel bifurcation. Pursuant to various embodiments, the invention discloses a drug delivery system for delivering one or more drugs to one or more of a first branch and a second branch of a blood vessel bifurcation. The first branch may be the main branch of the of the blood vessel bifurcation. Alternatively, the first branch may include a trunk and the main branch of the blood vessel bifurcation. Whereas, the second branch may be one or more of the side branch and the trunk of the blood vessel bifurcation. Further, one or more of the first branch and the second branch may have one or more of one or more lesions, one or more thrombus and one or more injuries. The one or more of the first branch and the second branch having one or more of one or more lesions, one or more thrombus and one or more injuries are hereinafter referred to as a target site. However, the target site may include any area inside the blood vessel bifurcation to which the one or more drugs may be delivered using the drug delivery system without departing from the scope of the invention. The drug delivery system includes a first balloon catheter assembly having a first balloon capable of passing through the blood vessel and being at least partially positioned in the first branch. The drug delivery system further includes a second balloon catheter assembly having a second balloon capable of passing through the blood vessel and being at least partially positioned in the second branch. One or more of the first catheter assembly and the second catheter assembly may include an angioplasty/angiography catheter and a thrombus aspiration catheter. The first balloon and the second balloon may be positioned at the target site in the main branch and the side branch respectively using methods and techniques known in the art. Thereafter, the first balloon and the second balloon may be inflated using methods and techniques known in the art. The first catheter assembly includes a catheter, a guide wire passing through the catheter, the first balloon mounted on a distal end of the catheter, and a mechanism for infusing fluid into the first balloon to inflate the first balloon. Similarly, second catheter assembly includes a catheter, a guide wire passing through the catheter, the second balloon mounted on a distal end of the catheter, and a mechanism for infusing fluid into the second balloon to inflate the second balloon. Alternatively, the drug delivering system may include a catheter assembly having a first catheter and a second catheter, a first guide wire and a second guide wire passing through the first catheter and the second catheter respectively, and a first balloon and a second balloon mounted on the first catheter and the second catheter respectively. In accordance with various embodiments, the first balloon may have one or more of a shape, a size and dimensions different from the second balloon. For example, the first balloon may have a conical shape with a proximal diameter smaller than a distal diameter of the first balloon. Whereas, the second balloon may have a proximal diameter smaller than or equal to a distal diameter of the second balloon. As such, the second balloon may have one of a conical shape and a cylindrical shape. Thus, owing to one or more of, different shapes, dimensions and sizes of the first balloon and the second balloon, distention of the trunk of the blood vessel bifurcation is prevented. This in turn prevents inflammation and injury to the blood vessel bifurcation. In an exemplary embodiment, the first balloon may have a generally conical shape with a tapering proximal portion. The tapering proximal portion may have a smaller diameter as compared to the diameter of a distal portion of the first balloon. Thus, the distal portion of the first balloon is suitable for being inserted into the side branch. Once inserted and positioned in the side branch, the first balloon is inflated. Whereas, a proximal portion of a second balloon of the two balloons may have a diameter equal to or greater than the diameter of a distal portion of the second balloon. Thus, the distal portion of the second balloon is suitable for being inserted and inflated in a distal portion of the main branch of the blood vessel bifurcation. FIG. 1 illustrates a schematic diagram showing a first balloon and a second balloon positioned in a main branch and a side branch of a blood vessel bifurcation in accordance with an embodiment of the invention. As illustrated in FIG. 1, a blood vessel bifurcation 100 has a first balloon 102 and a second balloon 104 positioned and inflated therein. A distal portion 106 of first balloon 102 is positioned in a side branch 108 and a distal portion 110 of second balloon 104 is positioned in a distal portion of main branch 112. Whereas, a proximal portion 114 of first balloon 102 and a proximal portion 116 of second balloon 104 are positioned side by side in a trunk 118 of blood vessel bifurcation 100. Trunk 118 in this case is a common artery. Thus, owing to the different proximal and distal diameters of one or more of the two balloons, distention of the common artery upon inflation of the first balloon and the second balloon may be avoided. When distal portion 106 of first balloon 102 and distal portion 110 of second balloon 104 comes in contact with a first lesion 120 and a second lesion 122, the one or more drugs (not illustrated in FIG. 1) are delivered to first lesion 120 and second lesion 122 respectively. In an embodiment, one or more of the first balloon and the second balloon may include a stepped balloon. A stepped balloon may have a proximal diameter smaller than a distal diameter. Alternatively, one or more of the first balloon and the second balloon may include any balloon with a shape that prevents distention of the common artery when the first balloon and the second balloon are positioned and inflated in the blood vessel bifurcation. Further, one or more of one or more portions of the first balloon and one or more portions of the second balloon are coated with a plurality of nano-carriers. A nano-carrier of the plurality of nano-carries (hereinafter referred to as "nano-carriers") includes one or more drugs encapsulated with one or more biological agents. In an embodiment, a nano-carrier may include one or more of nano-crystals and micro-crystals of the one or more drugs surrounded by one or more of nano-particles and micro particles of the one or more biological agents. The one or more drugs may include, but not limited to, one or more of an antiproliferative agent, an anti-inflammatory agent, an anti-neoplastic agent, an anticoagulant agent, an anti-fibrin agent, an antithrombotic agent, an anti-mitotic agent, an antibiotic agent, an anti-allergic agent, an antioxidant, one or more flavonoids, an estrogen, a protease inhibitor, an antibody, an immunosuppressive agent, a cytostatic agent, a cytotoxic agent, a calcium channel blocker, a phosphodiesterase inhibitor, a prostaglandin inhibitor, a dietary supplement, a vitamin, an anti-platelet aggregating agent, and genetically engineered epithelial cells. The one or more flavonoids are selected from at least one of narigenin, naringin, eriodictyol, hesperetin, hesperidin (esperidine), kampferol, quercetin, rutin, cyanidol, meciadonol, catechin, epi-gallocatechin-gallate, taxifolin (dihydroquercetin), genistein, genistin, daidzein, biochanin, glycitein, chrysin, diosmin, luetolin, apigenin, tangeritin and nobiletin. Examples of the one or more drugs include, but not limited to, one or more of sirolimus, paclitaxel, tacrolimus, clobetasol, dexamethasone, genistein, heparin, beta-estradiol, rapamycin, everolimus, ethylrapamycin, zotarolimus, ABT-578, Biolimus A9, docetaxel, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, mitomycin, sodium heparin, low molecular weight heparin, heparinoid, hirudin, argatroban, forskolin, vapiprost, prostacyclin, prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone, dipyridamole, glycoprotein IIb/IIIa, recombinant hirudin, bivalirudin, nifedipine, colchicines, lovastatin, nitroprusside, suramin, serotonin blockers, a steroid, thioprotease inhibitors, triazolopyrimidine, nitric oxide ,nitric oxide donors, super oxide dismutase, super oxide dismutase mimetics, estradiol, aspirin, angiopeptin, captopril, cilazapril, lisinopril, permirolast potassium, alpha-interferon, and bioactive RGD and any salts or analogues thereof. In an embodiment, the one or more drugs are one of a sirolimus (rapamycin) and paclitaxel. Whereas, a biological agent of the one or more biological agents may include one or more of, but are not limited to, drug carriers, excipients, blood components, excipients derived from blood, phospholipids, solid lipid nano-particles, lipoids, vitamins and sugar molecules. Examples of the one or more biological agents may include, but are not limited to, a steroid, a vitamin, an estradiol, an esterified fatty acid, a non-esterified fatty acid, glucose, inositol, L-lactate, a lipoprotein, a carbohydrate, tricalcium phosphate, precipitated calcium phosphate, a substance derived from at least one of human, egg and soybean, phospholipon 80H, phospholipon 90H, Lipoid S75, Lipoid E80, Intralipid 20, Lipoid EPC, Lipoid E75, a lipid obtained from egg, a lipid obtained from soya, phosphatidylcholine, phosphatidylglycerol, phosphatidyl inositol, phosphatidylserine, phosphatidic acid, cardiolipin, and phosphatidylethanolamine. In an embodiment, the one or more biological agents are one of a phospholipid and Lipoid E80. Further, the one or more biological agents may exhibit one or more effects. The one or more effects include stabilizing the one or more drugs and affinity for tissues at the target site in the blood vessel bifurcation. Owing to the affinity of the one or more biological agents towards the tissues, the nano-carriers are rapidly absorbed by the tissues as compared to nano-particles containing a drug encapsulated by a polymer. The one or more biological agents may be soluble in a pH below 7.4. Therefore, when the nano-carriers come in contact with the tissues at the target site, the one or more biological agents are dissolved in the blood. The dissolution of the one or more biological agents results in release of the one or more drugs at the target site. Thus, a pH dependent release of the one or more drugs from the nano-carriers is achieved. The nano-carriers may include the nano-crystals of the one or more drugs encapsulated with the nano-particles of the one or more biological agents. The surface of the nano-carriers is devoid of the drug. The nano-carriers may be coated on one or more of the first balloon and the second balloon when they are in an unfolded configuration. Alternatively, the nano-carriers may be coated on the one or more of the first balloon and the second balloon when they are in a folded configuration. The nano-carriers may have an average diameter ranging from 10 nm to 5000 nm. Alternatively, the nano-carriers may include two or more sets of nano-carriers having two or more different average diameters. More specifically, the nano-carriers may include a first set of nano-carriers with a first average diameter and a second set of nano-carriers with a second average diameter. The first average diameter is different from the second average diameter. For example, the first average diameter may range from 10 nm to 700 nm and the second average diameter may range from 300 nm to 1000 nm. In an embodiment, the nano-carriers may include a first set of nano-carriers with a first average diameter, a second set of nano-carriers with a second average diameter, and a third set of nano-carriers with a third average diameter. The first average diameter may range from 10 nm to 500 nm, the second average diameter may range from 300 nm to 800 nm, and the third average diameter may range from 500 nm to 1000 nm. Any number of different sets of nano-carriers with varying average diameters may be used to achieve a particular therapeutic object without departing from the scope of the invention. For example, one or more of the first balloon and the second balloon are coated with a first set of nano-carriers, a second set of nano-carriers and a third set of nano-carriers. When the one or more of the first balloon and the second balloon are inflated and positioned in the blood vessel bifurcation, the first set of nano-carriers, the second set of nano-carriers and the third set of nano-carriers are released from the one or more of the first balloon and the second balloon. Thereafter, the first set of nano-carriers, the second set of nano-carriers and the third set of nano-carriers penetrate the tissue layers of the blood vessel bifurcation. The first set of nano-carriers includes nano-carriers having a first average diameter suitable for penetrating an intima layer of the blood vessel bifurcation. The second set of nano-carriers includes nano-carriers having a second average diameter suitable for penetrating a media layer of the blood vessel bifurcation through the intima layer and a vasa vasorum associated with the media layer. Further, the third set of nano-carriers includes nano-carriers with a third average diameter suitable for penetrating an adventitia layer of the blood vessel bifurcation through the intima layer and the vasa vasorum associated with the media layer and a vasa vasorum associated with the adventitia layer. In an embodiment, one or more of the first balloon and the second balloon have a hydrophilic surface and a non-hydrophilic surface. The hydrophilic surface may include any lubricous coating applied on the surface of one or more of the two balloons. Examples of the lubricious coating include, but are not limited to, polyalkylene glycols. alkoxy polyalkylene glycols, copolymers of methylvinyl ether and maleic acid poly(vinylpyrrolidone), poly(N-alkylacrylamide), poly(acrylic acid), poly(vinyl alcohol), poly(ethyleneimine), methyl cellulose, carboxymethyl cellulose, polyvinyl sulfonic acid, heparin, dextran, modified dextran and chondroitin sulphate and at least one anti-block agent. The hydrophilic surface may include one or more exposed hydrophilic surfaces. The one or more exposed hydrophilic surfaces may be created at one or more desired portions of an inflatable balloon such as, the first balloon and the second balloon, by not coating the nano-carriers on the one or more desired portions. In other words, the nano-carriers are coated on the entire hydrophilic surface except the one or more exposed hydrophilic surfaces. In an embodiment, the one or more exposed hydrophilic surfaces are created at one or more of one or more portions of a distal end of the hydrophilic surface and one or more portions of a proximal end of the hydrophilic surface. As such, the one or more exposed hydrophilic surfaces facilitate dissolution of the lubricious coating upon coming in contact with the blood at the target site. In response to the dissolution of the lubricious coating, the nano-carriers are released at the target site from the hydrophilic surface. Thus, the one or more exposed hydrophilic surfaces facilitate the release of the nano-carriers from the two balloons. When one or more of the two balloons are inflated at the target site, about 30% to 80% of the nano-carriers are released from the hydrophilic surface within 15 to 90 seconds. The nano-carriers coated on one or more portions of the hydrophilic surface are released rapidly as compared to the release of nano-carriers from the surface of a balloon without the lubricious coating. Thus, a burst release of the nano-carriers from the hydrophilic surface may be achieved within a short period for which the two balloons come in contact with the target site in the blood vessel bifurcation. In an exemplary embodiment, about.70% to 80% of the nano-carriers are released from the hydrophilic surface within about 60 seconds when the first balloon and the second balloon are inflated at the target site. In another embodiment, one or more of the first balloon and the second balloon are coated with an outer layer of nano-carriers and an inner layer of nano-carriers. The outer layer may include the third set of nano-carriers. The inner layer may include one or more of the second set of nano-carriers and the first set of nano-carriers. Further, a drug present in the outer layer may be same or different from a drug present in the inner layer. In an exemplary embodiment, the drug present in the outer layer is an anti-inflammatory agent. Whereas, the drug present in the inner layer may include one or more of an anti-thrombogenic agent and an anti-proliferative agent. In accordance with various embodiments, the first set of nano-carriers and the second set of nano-carriers may include a same or a different drug. In addition, the second set of nano-carriers and the third set of nano-carriers may include a same or a different drug. Further, an average diameter of the first set of nano-carriers may range from 800 nm to 1500 nm, an average diameter of the second set of nano-carriers may range from 300 nm to 800 nm and an average diameter of the third set of nano-carriers may range from 10 nm to 300 nm. In yet another embodiment, a surface of one or more of the first balloon and the second balloon has a hydrophilic layer coated on the surface. The nano-carriers are coated on one or more portions of the hydrophilic layer. The hydrophilic layer enables release of the nano-carriers from the hydrophilic layer within 30 to 90 seconds when the one or more of the two balloons are inflated at the target site. Alternatively, the hydrophilic layer is coated with a second layer. The second layer includes one or more of the biological agents and a polymer. Further, one or more pores are present in the second layer and one or more nano-carriers of the nano-carriers are deposited in the one or more pores. When one or more of the first balloon and the second balloon are inflated upon coming in proximity of the target site in the blood vessel bifurcation, the one or more nano-carriers are released from the one or more pores. In an embodiment, one or more nano-carriers of the plurality of nano-carriers further include nano-particles of the one or more drugs encapsulated with nano-particles of the one or more biological agents and nano-particles of one or more polymers. The one or more polymers include one or more of a biodegradable polymer, a non-degradable polymer, a bioderodable polymer, an excipient, a drug, and a polymer matrix. Examples of the one or more polymers include, but are not limited to, poly(l-lactide), racemic polylactide, poly(l-lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co-caprolactone poly(d, 1 -lactide-co-caprolactone), poly(l -lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate). When the one or more polymers and the one or more biological agents are used to encapsulate the one or more drugs, the one or more polymers may be covalently attached to one or more of the one or more drugs and the one or more biological agents. In another embodiment, the nano-carriers, the nano-particles of the one or more drugs, the nano-particles of the one or more biological agents, and one or more excipients are deposited in a polymer matrix coated on at least one of the hydrophilic surface and the non-hydrophilic surface. Examples: Example 1: Preparation of the nano-carriers: Lipoid E80 was obtained from Lipoid GMBH, Batch No.: 776114-1/906. Sirolimus was obtained from Biocon Ltd. (India), Batch No.: EH-B10-01-000982/0133 7. The water, other solvents and reagents used were of HPLC grade. A polyamide catheter system (Yangtze μ5b PTCA cathater) with COPAN Co-Polyamide dedicated angioplasty balloons for blood vessel bifurcation (hereinafter referred to as "the balloon system") coated with Hydraflow® Hydrophilic coating (hereinafter referred to as "the hydrophilic surface") was obtained from Minvasys, Paris, France. Lipoid E80 was dissolved in methanol. 100 ml HPLC grade water and Tween 80 (5 mg) was added to obtain an aqueous solution of Lipoid E80. The aqueous solution Lipoid E80 (10 ml) was subjected to ultrasonic homogenization for 20 to 25 minutes in an ice-cold water bath to obtain Solution Al. The Solution Al thus obtained contained nano-particles of Lipoid E80. The solution Al was subsequently analyzed for particle size detection using Malvern Zeta Sizer (ZS90) [Malvern, UK] size detector. FIG. 2 illustrates the size distribution of nano-particles of Lipoid E80 as detected by Malvern Zeta Sizer (ZS90). Z-average diameter of the nano-particles of the Lipoid E80 was found to be 242.8074 nm. Sirolimus (20 mg) was dissolved in minimum quantity of methanol. HPLC grade water containing 0.5 % w/w of Tween 80 was added to obtain an aqueous solution of sirolimus by re-precipitation. The aqueous solution of sirolimus (100 ml) was subjected to ultrasonic homogenization for 100 to 200 minutes in an ice-cold water bath to obtain Solution A2. The Solution A2 thus obtained contained nano-crystals of sirolimus. The solution A2 was subsequently analyzed for particle size detection using Malvern ZS90 (Malvern, UK) size detector. 10 ml solution Al was added to Solution A2 drop by drop slowly under a ultrasonic homogenization process. The resultant mixture was subjected to ultrasonic homogenization for another 20 minutes after complete addition to obtain Solution A3. Solution A3 was then stirred with a magnetic stirrer (2MLH hot plate heater cum stirrer, Accumax, INDIA) for 20 minutes. Solution A3 thus obtained contained nano-carriers (nano-crystals of sirolimus surrounded by nano-particles of Lipoid E80). Solution A3 was subsequently analyzed for particle size detection using Malvern ZS90 (Malvern, UK) size detector. FIG. 3 illustrates size distribution of the nano-carriers as detected by Malvern ZS90. The average diameters of nano-carriers were found to be 245.493 nm. Solution A3 (Aqueous solution of nano-carriers) was further subjected to extraction with dichloromethane. Solution A3 (about 100 ml) was transferred to a 250 ml separating funnel. 50 ml of dichloromethane was added to the 250 ml separating funnel. The resultant mixture was shaken for 15 minutes and then allowed to stand. Thereafter, two layers i.e., an aqueous layer and a dichloromethane layer were observed in the 250 ml separating funnel. The dichloromethane layer was separated from the aqueous layer. The solution was evaporated up to a volume of 50 ml. The dichloromethane layer i.e., solution of the nano-carriers was stored in an amber colored small measuring flask with a batch number. Subsequently, the solution of the nano-carriers was used for coating the balloon system. Example 2: Preparation of the drug delivery system (The balloon system): Yangtze μsb PTCA catheter of the size 2.5 mm * 10 mm was used for the coating. The solution of the nano-carriers (about 3 ml) was fed into reservoir of a coating machine. The balloons of the balloon system were mounted on a rotating mandrel of the coating machine one by one. Each balloon of the balloon system was exposed to an atomization nozzle of the coating machine separately. The balloon system was rotated at a speed varying from 5 rpm to 40 rpm by rotating the mandrel. Simultaneously, the solution of nano-carriers was sprayed over the balloons at an inert gas pressure varying from 0.5 psi to 4.0 psi in two oscillations. Thus, the balloons coated with the nano-carriers (hereinafter referred to as "the coated balloon system") was obtained. The coated balloon system was then removed and checked under a high-resolution microscope for the coating surface smoothness and any foreign particles. Various embodiments of the invention provide a medical device and a method for delivering one or more drugs to bifurcation lesions in a main branch and a side branch of the blood vessel bifurcation within 30 to 90 seconds. Further, the invention provides a medical device specially designed for treating the bifurcation lesions that is associated with reduced instances of a restenosis, an acute thrombus formation, a sub-acute thrombus formation, and a late thrombus formation. 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. 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. CLAIMS What is claimed is: 1. A drug delivery system for delivering at least one drug to at least one of a first branch and a second branch of a blood vessel bifurcation, the drug delivery system comprising: a first balloon catheter assembly having a first balloon capable of passing through the blood vessel and being at least partially positioned in the first branch; and a second balloon catheter assembly having a second balloon capable of passing through the blood vessel and being at least partially positioned in the second branch. wherein at least one of the first balloon and the second balloon is coated with a plurality of nano-carriers, the plurality of nano-carriers comprising at least one drug encapsulated with at least one biological agent, the at least one of the first balloon and the second balloon capable of delivering the plurality of nano-carriers to at least one of the first branch and the second branch upon being positioned and inflated in the at least one of the first branch and the second branch respectively. 2. The drug delivery system of claim 1, wherein a proximal diameter of the second balloon is smaller than a distal diameter of the second balloon in an inflated state and a proximal diameter of the first balloon is smaller than or equal to a distal diameter of the first balloon in an inflated state. 3. The drug delivery system of claim 1, wherein the first balloon has at least one of a shape, a size and dimensions different from the second balloon. 4. The drug delivery system of claim 1, wherein at least one of the first balloon and the second balloon comprises a hydrophilic surface and a non-hydrophilic surface, the hydrophilic surface being coated with the plurality of nano-carriers, wherein a set of nano-carriers of the plurality of nano-carriers is released from the hydrophilic surface within a predetermined duration in response to inflating the at least one of the first balloon and the second balloon at a target site in the at least one of the first branch and the second branch respectively. 5. The drug delivery system of claim 4. wherein the predetermined duration ranges from 30 to 90 seconds. 6. The drug delivery system of claim 4, wherein the hydrophilic surface have a layer coated thereon, the layer comprising nano-particles of at least one of the at least one biological agent and at least one polymer. 7. The drug delivery system of claim 6, wherein the layer further comprises a plurality of pores, wherein at least one nano-carrier of the plurality of nano-carriers is deposited in at least one pore of the plurality of pores, wherein the hydrophilic surface is exposed through the plurality of pores and the at least one nano-carrier is in direct contact with the hydrophilic surface. 8. The drug delivery system of claim 1, wherein the at least one biological agent exhibits an effect, the effect is at least one of stabilizing the at least one drug, and affinity for tissues of the blood vessel bifurcation. 9. The drug delivery system of claim 1, wherein the plurality of nano-carriers have an average diameter ranging between 1 nm to 1000 nm. 10. The drug delivery system of claim 1, wherein the plurality of nano-carriers further comprise a first set of nano-carriers having a first average diameter and a second set of nano-carriers having a second average diameter, the first average diameter being different from the second average diameter. 11. The drug delivery system of claim 10, wherein the first average diameter ranges from 1 nm to 700 nm and the second average diameter ranges from 300 nm to 1000 nm. 12. The drug delivery system of claim 1, wherein the plurality of nano-carriers further comprise a first set of nano-carriers with a first average diameter, a second set of nano-carriers with a second average diameter, and a third set of nano-carriers with a third average diameter. 13. The drug delivery system of claim 12, wherein the first average diameter ranges from 1 nm to 500 nm, the second average diameter ranges from 300 nm to 800 nm, and the third average diameter ranges from 500 nm to 1000 nm. 14. The drug delivery system of claim 1, wherein the at least one biological agent is selected from a group comprising drug carriers, excipients, blood components, excipients derived from blood, phospholipids, solid lipid nano-particles, lipoids, vitamins and sugar molecules. 15. The drug delivery system of claim 1, wherein the at least one biological agent is selected from at least one of a steroid, a vitamin, an estradiol, an esterified fatty acid, a non-esterified fatty acid, glucose, inositol, L-lactate, a lipoprotein, a carbohydrate, tricalcium phosphate, precipitated calcium phosphate, a substance derived from at least one of human, egg and soybean, phospholipon 80H, phospholipon 90H, Lipoid S75, Lipoid E80, Intralipid 20, Lipoid EPC, Lipoid E75, a lipid obtained from egg, a lipid obtained from soya, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid, cardiolipin, and pho sphatidylethanolamine. 16. The drug delivery system of claim 1, wherein at least one nano-carrier of the plurality of nano-carriers further comprises at least one nano-particle of the at least one drug encapsulated with nano-particles of the at least one biological agent and nano- particles of at least polymer, the at least one polymer comprising at least one of a biodegradable polymer, a non-degradable polymer, a bioderodable polymer, an excipient, a drug, and a polymer matrix. 17. The drug delivery system of claim 16, wherein the at least one polymer is selected from at least one of poly(l-lactide), racemic polylactide, poly(l-lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co-caprolactone poly(d, 1-lactide-co-caprolactone), poly(l-lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate), and wherein the at least one polymer is covalently attached to at least one of the at least one drug and the at least one biological agent. 18. The drug delivery system of claim 1, wherein the at least one drug is selected from at least one of an anti-proliferative agent, an anti-inflammatory agent, an anti-neoplastic agent, an anti-coagulant agent, an anti-fibrin agent, an antithrombotic agent, an anti-mitotic agent, an antibiotic agent, an anti-allergic agent, an antioxidant, at least one flavonoid, an estrogen, a protease inhibitor, an antibody, an immunosuppressive agent, a cytostatic agent, a cytotoxic agent, a calcium channel blocker, a phosphodiesterase inhibitor, a prostaglandin inhibitor, a dietary supplement, a vitamin, an anti-platelet aggregating agent, andgenetically engineered epithelial cells, wherein the at least one flavonoids is selected from at least one of narigenin, naringin, eriodictyol, hesperetin, hesperidin (esperidine), kampferol. quercetin, rutin, cyanidol, meciadonol, catechin, epi-gallocatechin-gallate, taxifolin (dihydroquercetin), genistein, genistin, daidzein, biochanin, glycitein, chrysin, diosmin, Iuetolin, apigenin, tangeritin and nobiletin. 19. The drug delivery system of claim 1, wherein the at least one drug is selected from a group comprising sirolimus, paclitaxel, tacrolimus, clobetasol, dexamethasone, genistein, heparin, beta-estadiol, rapamycin, everolimus, ethylrapamycin, zotarolimus, ABT-578, Biolimus A9, docetaxel, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, mitomycin, sodium heparin, low molecular weight heparin, heparinoid, hirudin, argatroban, forskolin, vapiprost, prostacyclin, prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone, dipyridamole, glycoprotein IIb/IIIa, recombinant hirudin, bivalirudin, nifedipine, colchicines, lovastatin, nitroprusside, suramin, serotonin blockers, a steroid, thioprotease inhibitors, triazolopyrimidine, nitric oxide ,nitric oxide donors, super oxide dismutase, super oxide dismutase mimetics, estradiol, aspirin, angiopeptin. captopril, cilazapril, lisinopril, permirolast potassium, alpha-interferon, and bioactive RGD. 20. The drug delivery system of claim 1, wherein the at least one drug is Sirolimus. 21. The drug delivery system of claim 1, wherein the at least one drug is Pacliaxel. 22. The drug delivery system of claim 1, wherein the drug delivery system is used to treat a medical condition associated with the blood vessel bifurcation, wherein the medical condition is at least one of stenosis, restenosis, blockage in an artery, thrombus in an artery, acute myocardial infarction, and arterial lesions. 23. The drug delivery system of claim 4, wherein the hydrophilic surface and the non-hydrophilic surface are coated with the plurality of nano-carriers. 24. The drug delivery system of claim 23, wherein at least one of the plurality of nano-carriers, the nano-particles of the at least one drug, the nano-particles of the at least one biological agent, and at least one excipient are deposited in a polymer matrix coated on at least one of the hydrophilic surface and the non-hydrophilic surface.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]
1. TITLE: A METHOD AND A BALLOON CATHETER ASSEMBLY FOR TREATING BIFURCATION LESIONS
2. APPLICANTS:-
Concept Medical Research Private Limited
1-3, Silver Palm II, Near Sneh Milan Garden, Kadampalli, Nanpura, Surat (Gujrat) INDIA, PIN - 395001 NATIONALITY : Indian
Envision Scientific Private Limited ,
8, Narayan Darshan Apartment, Opp. Rupam Cinema, Salabatpura, Surat (Gujarat), INDIA, PIN - 395002 NATIONALITY : Indian

A METHOD AND A BALLOON CATHETER ASSEMBLY FOR TREATING
BIFURCATION LESIONS
FIELD OF THE INVENTION
The invention generally relates to a method and a balloon catheter assembly for treating bifurcation lesions of a main branch and a side branch of a blood vessel bifurcation. More specifically, the invention relates to a drug delivery system for delivering one or more drugs to the bifurcation lesions in the main branch and the side branch of the blood vessel bifurcation.
BACKGROUND OF THE INVENTION
The current methods for treatment of bifurcation lesions include V-stenting, simultaneous kissing stent technique, kissing balloon technique, stent deployment in a main branch followed by angioplasty of a side branch, Drug Eluting Stents (DESs) specially designed for the bifurcation lesions, T-stenting, crush technique, provisional stenting and the like. The current methods of treatment of bifurcation lesions involve use of medical devices specially designed for use in the bifurcation such as, Bare Metal Stents (BMSs), DESs, Drug Eluting Balloons (DEBs) and angioplasty balloons.
When the BMSs are used for treating the bifurcation lesions, generally, the BMSs are deployed only in the main branch. The side branch is subjected to angioplasty or is left unattended. Alternatively, the BMSs are deployed in both the main branch and the side branch. Deploying the BMSs in both the main branch and the side branch may lead to metal overload in the bifurcation. The metal overload may further result in inflammation and thrombus formation. Also, owing to the complicated structure of the bifurcation, the BMSs may not be appropriate for treating the bifurcation lesions. Therefore, use of DEBs and DESs has gained significance in treatment of the bifurcation lesions.

However, the currently used DEBs and DESs use polymer for loading the drugs on surfaces of the DEBs and the DESs. Owing to the use of polymers, the currently used DEBs and DESs are associated with phenomenon like an inflammation, restenosis, an acute thrombus formation, a sub-acute thrombus formation and a late thrombus formation. Furthermore, in case of the DESs. the amount of drug that is supplied to the lesions generally depends on a metal to artery ratio. The metal to artery ratio of the currently used DESs is 10% to 20%. Therefore, only 10% to 20% of a portion of the lesions is supplied with the drug. In addition, because of the complicated structure of the bifurcation, the metal to artery ratio in case of the bifurcation is generally less than the metal to artery ratio in a general non-bifurcated artery.
In some instances, where the DEBs are used for treating the bifurcation lesions, the time for which the DEBs are exposed to the target site ranges from 30 to 90 seconds. The DEBs have to deliver an effective amount of the drug within these 30 to 90 seconds. In order to deliver the effective amount of the drug within these 30 to 90 seconds, a high amount of the drug has to be loaded on the DEBs. Even after loading a high amount of the drug, the DEBs may not deliver the desired amount of the drug in a short time of 30 to 90 seconds. Further, currently used DEBs can be loaded only with certain highly lipophilic drugs such as, paclitaxel. Whereas, the DEBs that can be loaded with a wider range of drugs are not available in the art.
Additionally, in the currently used DEBs, a drug is coated on the surface of the balloon when the balloon is in a folded configuration. Therefore, a substantial portion of the DEB remains uncoated with the drug. When the DEB is inflated, the portion of the lesion that is exposed to the uncoated portion of the DEB is not supplied with the drug. Therefore, the currently used DEBs may not adequately cover the entire portion of the bifurcation lesions.
Further, the particle size of the drugs as well as the polymers that are coated on the DESs and the DEBs are larger than the size of tissue pores at a target site. Therefore,

a substantial amount of drug remains unabsorbed. The unabsorbed drug may be washed away in blood stream and may produce side effects.
Therefore, there is a need in the art for an improved drug-delivering insertable medical device for treating the bifurcation lesions that is associated with reduced instances of restenosis, acute thrombus formation, sub-acute thrombus formation, and late thrombus formation. Further, there is need in the art for an improved drug-delivering insertable medical device that can deliver a desired amount of drug to the bifurcation lesions within 30 to 90 seconds with an optimum loading of the drug.
BRIEF DESCRIPTION OF FIGURES
FIG. 1 illustrates a schematic diagram showing a first balloon and a second balloon positioned in a main branch and a side branch of a blood vessel bifurcation in accordance with an embodiment of the invention.
FIG. 2 illustrates size distribution of nano-particles of Lipoid E80 as detected by Malvern Zeta Sizer (ZS90) in accordance with Example 1.
FIG. 3 illustrates size distribution of the nano-carriers as detected by Malvern ZS90 in accordance with Example 1.
DETAILED DESCRIPTION OF THE INVENTION
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 delivery system. Accordingly, the components 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.

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, or device, 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, or device. 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.
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. The term "bifurcation" means a structure of a blood vessel where the blood vessel is divided into a main branch and a side branch. The term main branch means the blood vessel from which the side branch originates. Further, the term "bifurcation lesions" means the lesions present in one or more of the main branch, the side branch and a trunk of a blood vessel bifurcation.
Pursuant to various embodiments, the invention discloses a drug delivery system for delivering one or more drugs to one or more of a first branch and a second branch of a blood vessel bifurcation. The first branch may be the main branch of the of the blood vessel bifurcation. Alternatively, the first branch may include a trunk and the main branch of the blood vessel bifurcation. Whereas, the second branch may be one or more of the side branch and the trunk of the blood vessel bifurcation.
Further, one or more of the first branch and the second branch may have one or more of one or more lesions, one or more thrombus and one or more injuries. The one or more of the first branch and the second branch having one or more of one or more lesions, one or more thrombus and one or more injuries are hereinafter referred to as a target site. However, the target site may include any area inside the blood vessel

bifurcation to which the one or more drugs may be delivered using the drug delivery system without departing from the scope of the invention.
The drug delivery system includes a first balloon catheter assembly having a first balloon capable of passing through the blood vessel and being at least partially positioned in the first branch. The drug delivery system further includes a second balloon catheter assembly having a second balloon capable of passing through the blood vessel and being at least partially positioned in the second branch. One or more of the first catheter assembly and the second catheter assembly may include an angioplasty/angiography catheter and a thrombus aspiration catheter. The first balloon and the second balloon may be positioned at the target site in the main branch and the side branch respectively using methods and techniques known in the art. Thereafter, the first balloon and the second balloon may be inflated using methods and techniques known in the art.
The first catheter assembly includes a catheter, a guide wire passing through the catheter, the first balloon mounted on a distal end of the catheter, and a mechanism for infusing fluid into the first balloon to inflate the first balloon. Similarly, second catheter assembly includes a catheter, a guide wire passing through the catheter, the second balloon mounted on a distal end of the catheter, and a mechanism for infusing fluid into the second balloon to inflate the second balloon. Alternatively, the drug delivering system may include a catheter assembly having a first catheter and a second catheter, a first guide wire and a second guide wire passing through the first catheter and the second catheter respectively, and a first balloon and a second balloon mounted on the first catheter and the second catheter respectively.
In accordance with various embodiments, the first balloon may have one or more of a shape, a size and dimensions different from the second balloon. For example, the first balloon may have a conical shape with a proximal diameter smaller than a distal diameter of the first balloon. Whereas, the second balloon may have a proximal diameter smaller than or equal to a distal diameter of the second balloon. As such, the second balloon may have one of a conical shape and a cylindrical shape. Thus, owing to one or

more of, different shapes, dimensions and sizes of the first balloon and the second balloon, distention of the trunk of the blood vessel bifurcation is prevented. This in turn prevents inflammation and injury to the blood vessel bifurcation.
In an exemplary embodiment, the first balloon may have a generally conical shape with a tapering proximal portion. The tapering proximal portion may have a smaller diameter as compared to the diameter of a distal portion of the first balloon. Thus, the distal portion of the first balloon is suitable for being inserted into the side branch. Once inserted and positioned in the side branch, the first balloon is inflated. Whereas, a proximal portion of a second balloon of the two balloons may have a diameter equal to or greater than the diameter of a distal portion of the second balloon. Thus, the distal portion of the second balloon is suitable for being inserted and inflated in a distal portion of the main branch of the blood vessel bifurcation.
FIG. 1 illustrates a schematic diagram showing a first balloon and a second balloon positioned in a main branch and a side branch of a blood vessel bifurcation in accordance with an embodiment of the invention. As illustrated in FIG. 1, a blood vessel bifurcation 100 has a first balloon 102 and a second balloon 104 positioned and inflated therein. A distal portion 106 of first balloon 102 is positioned in a side branch 108 and a distal portion 110 of second balloon 104 is positioned in a distal portion of main branch 112. Whereas, a proximal portion 114 of first balloon 102 and a proximal portion 116 of second balloon 104 are positioned side by side in a trunk 118 of blood vessel bifurcation 100. Trunk 118 in this case is a common artery. Thus, owing to the different proximal and distal diameters of one or more of the two balloons, distention of the common artery upon inflation of the first balloon and the second balloon may be avoided. When distal portion 106 of first balloon 102 and distal portion 110 of second balloon 104 comes in contact with a first lesion 120 and a second lesion 122, the one or more drugs (not illustrated in FIG. 1) are delivered to first lesion 120 and second lesion 122 respectively.
In an embodiment, one or more of the first balloon and the second balloon may include a stepped balloon. A stepped balloon may have a proximal diameter smaller than

a distal diameter. Alternatively, one or more of the first balloon and the second balloon may include any balloon with a shape that prevents distention of the common artery when the first balloon and the second balloon are positioned and inflated in the blood vessel bifurcation.
Further, one or more of one or more portions of the first balloon and one or more portions of the second balloon are coated with a plurality of nano-carriers. A nano-carrier of the plurality of nano-carries (hereinafter referred to as "nano-carriers") includes one or more drugs encapsulated with one or more biological agents. In an embodiment, a nano-carrier may include one or more of nano-crystals and micro-crystals of the one or more drugs surrounded by one or more of nano-particles and micro particles of the one or more biological agents.
The one or more drugs may include, but not limited to, one or more of an antiproliferative agent, an anti-inflammatory agent, an anti-neoplastic agent, an anticoagulant agent, an anti-fibrin agent, an antithrombotic agent, an anti-mitotic agent, an antibiotic agent, an anti-allergic agent, an antioxidant, one or more flavonoids, an estrogen, a protease inhibitor, an antibody, an immunosuppressive agent, a cytostatic agent, a cytotoxic agent, a calcium channel blocker, a phosphodiesterase inhibitor, a prostaglandin inhibitor, a dietary supplement, a vitamin, an anti-platelet aggregating agent, and genetically engineered epithelial cells. The one or more flavonoids are selected from at least one of narigenin, naringin, eriodictyol, hesperetin, hesperidin (esperidine), kampferol, quercetin, rutin, cyanidol, meciadonol, catechin, epi-gallocatechin-gallate, taxifolin (dihydroquercetin), genistein, genistin, daidzein, biochanin, glycitein, chrysin, diosmin, luetolin, apigenin, tangeritin and nobiletin.
Examples of the one or more drugs include, but not limited to, one or more of sirolimus, paclitaxel, tacrolimus, clobetasol, dexamethasone, genistein, heparin, beta-estradiol, rapamycin, everolimus, ethylrapamycin, zotarolimus, ABT-578, Biolimus A9, docetaxel, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, mitomycin, sodium heparin, low molecular weight heparin, heparinoid,

hirudin, argatroban, forskolin, vapiprost, prostacyclin, prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone, dipyridamole, glycoprotein IIb/IIIa, recombinant hirudin, bivalirudin, nifedipine, colchicines, lovastatin, nitroprusside, suramin, serotonin blockers, a steroid, thioprotease inhibitors, triazolopyrimidine, nitric oxide ,nitric oxide donors, super oxide dismutase, super oxide dismutase mimetics, estradiol, aspirin, angiopeptin, captopril, cilazapril, lisinopril, permirolast potassium, alpha-interferon, and bioactive RGD and any salts or analogues thereof. In an embodiment, the one or more drugs are one of a sirolimus (rapamycin) and paclitaxel.
Whereas, a biological agent of the one or more biological agents may include one or more of, but are not limited to, drug carriers, excipients, blood components, excipients derived from blood, phospholipids, solid lipid nano-particles, lipoids, vitamins and sugar molecules. Examples of the one or more biological agents may include, but are not limited to, a steroid, a vitamin, an estradiol, an esterified fatty acid, a non-esterified fatty acid, glucose, inositol, L-lactate, a lipoprotein, a carbohydrate, tricalcium phosphate, precipitated calcium phosphate, a substance derived from at least one of human, egg and soybean, phospholipon 80H, phospholipon 90H, Lipoid S75, Lipoid E80, Intralipid 20, Lipoid EPC, Lipoid E75, a lipid obtained from egg, a lipid obtained from soya, phosphatidylcholine, phosphatidylglycerol, phosphatidyl inositol, phosphatidylserine, phosphatidic acid, cardiolipin, and phosphatidylethanolamine. In an embodiment, the one or more biological agents are one of a phospholipid and Lipoid E80.
Further, the one or more biological agents may exhibit one or more effects. The one or more effects include stabilizing the one or more drugs and affinity for tissues at the target site in the blood vessel bifurcation. Owing to the affinity of the one or more biological agents towards the tissues, the nano-carriers are rapidly absorbed by the tissues as compared to nano-particles containing a drug encapsulated by a polymer. The one or more biological agents may be soluble in a pH below 7.4. Therefore, when the nano-carriers come in contact with the tissues at the target site, the one or more biological agents are dissolved in the blood. The dissolution of the one or more biological agents

results in release of the one or more drugs at the target site. Thus, a pH dependent release of the one or more drugs from the nano-carriers is achieved.
The nano-carriers may include the nano-crystals of the one or more drugs encapsulated with the nano-particles of the one or more biological agents. The surface of the nano-carriers is devoid of the drug. The nano-carriers may be coated on one or more of the first balloon and the second balloon when they are in an unfolded configuration. Alternatively, the nano-carriers may be coated on the one or more of the first balloon and the second balloon when they are in a folded configuration.
The nano-carriers may have an average diameter ranging from 10 nm to 5000 nm. Alternatively, the nano-carriers may include two or more sets of nano-carriers having two or more different average diameters. More specifically, the nano-carriers may include a first set of nano-carriers with a first average diameter and a second set of nano-carriers with a second average diameter. The first average diameter is different from the second average diameter. For example, the first average diameter may range from 10 nm to 700 nm and the second average diameter may range from 300 nm to 1000 nm.
In an embodiment, the nano-carriers may include a first set of nano-carriers with a first average diameter, a second set of nano-carriers with a second average diameter, and a third set of nano-carriers with a third average diameter. The first average diameter may range from 10 nm to 500 nm, the second average diameter may range from 300 nm to 800 nm, and the third average diameter may range from 500 nm to 1000 nm. Any number of different sets of nano-carriers with varying average diameters may be used to achieve a particular therapeutic object without departing from the scope of the invention.
For example, one or more of the first balloon and the second balloon are coated with a first set of nano-carriers, a second set of nano-carriers and a third set of nano-carriers. When the one or more of the first balloon and the second balloon are inflated and positioned in the blood vessel bifurcation, the first set of nano-carriers, the second set of nano-carriers and the third set of nano-carriers are released from the one or more of the

first balloon and the second balloon. Thereafter, the first set of nano-carriers, the second set of nano-carriers and the third set of nano-carriers penetrate the tissue layers of the blood vessel bifurcation. The first set of nano-carriers includes nano-carriers having a first average diameter suitable for penetrating an intima layer of the blood vessel bifurcation. The second set of nano-carriers includes nano-carriers having a second average diameter suitable for penetrating a media layer of the blood vessel bifurcation through the intima layer and a vasa vasorum associated with the media layer. Further, the third set of nano-carriers includes nano-carriers with a third average diameter suitable for penetrating an adventitia layer of the blood vessel bifurcation through the intima layer and the vasa vasorum associated with the media layer and a vasa vasorum associated with the adventitia layer.
In an embodiment, one or more of the first balloon and the second balloon have a hydrophilic surface and a non-hydrophilic surface. The hydrophilic surface may include any lubricous coating applied on the surface of one or more of the two balloons. Examples of the lubricious coating include, but are not limited to, polyalkylene glycols. alkoxy polyalkylene glycols, copolymers of methylvinyl ether and maleic acid poly(vinylpyrrolidone), poly(N-alkylacrylamide), poly(acrylic acid), poly(vinyl alcohol), poly(ethyleneimine), methyl cellulose, carboxymethyl cellulose, polyvinyl sulfonic acid, heparin, dextran, modified dextran and chondroitin sulphate and at least one anti-block agent.
The hydrophilic surface may include one or more exposed hydrophilic surfaces. The one or more exposed hydrophilic surfaces may be created at one or more desired portions of an inflatable balloon such as, the first balloon and the second balloon, by not coating the nano-carriers on the one or more desired portions. In other words, the nano-carriers are coated on the entire hydrophilic surface except the one or more exposed hydrophilic surfaces. In an embodiment, the one or more exposed hydrophilic surfaces are created at one or more of one or more portions of a distal end of the hydrophilic surface and one or more portions of a proximal end of the hydrophilic surface.

As such, the one or more exposed hydrophilic surfaces facilitate dissolution of the lubricious coating upon coming in contact with the blood at the target site. In response to the dissolution of the lubricious coating, the nano-carriers are released at the target site from the hydrophilic surface. Thus, the one or more exposed hydrophilic surfaces facilitate the release of the nano-carriers from the two balloons.
When one or more of the two balloons are inflated at the target site, about 30% to 80% of the nano-carriers are released from the hydrophilic surface within 15 to 90 seconds. The nano-carriers coated on one or more portions of the hydrophilic surface are released rapidly as compared to the release of nano-carriers from the surface of a balloon without the lubricious coating. Thus, a burst release of the nano-carriers from the hydrophilic surface may be achieved within a short period for which the two balloons come in contact with the target site in the blood vessel bifurcation. In an exemplary embodiment, about.70% to 80% of the nano-carriers are released from the hydrophilic surface within about 60 seconds when the first balloon and the second balloon are inflated at the target site.
In another embodiment, one or more of the first balloon and the second balloon are coated with an outer layer of nano-carriers and an inner layer of nano-carriers. The outer layer may include the third set of nano-carriers. The inner layer may include one or more of the second set of nano-carriers and the first set of nano-carriers. Further, a drug present in the outer layer may be same or different from a drug present in the inner layer. In an exemplary embodiment, the drug present in the outer layer is an anti-inflammatory agent. Whereas, the drug present in the inner layer may include one or more of an anti-thrombogenic agent and an anti-proliferative agent.
In accordance with various embodiments, the first set of nano-carriers and the second set of nano-carriers may include a same or a different drug. In addition, the second set of nano-carriers and the third set of nano-carriers may include a same or a different drug. Further, an average diameter of the first set of nano-carriers may range from 800 nm to 1500 nm, an average diameter of the second set of nano-carriers may

range from 300 nm to 800 nm and an average diameter of the third set of nano-carriers may range from 10 nm to 300 nm.
In yet another embodiment, a surface of one or more of the first balloon and the second balloon has a hydrophilic layer coated on the surface. The nano-carriers are coated on one or more portions of the hydrophilic layer. The hydrophilic layer enables release of the nano-carriers from the hydrophilic layer within 30 to 90 seconds when the one or more of the two balloons are inflated at the target site. Alternatively, the hydrophilic layer is coated with a second layer. The second layer includes one or more of the biological agents and a polymer. Further, one or more pores are present in the second layer and one or more nano-carriers of the nano-carriers are deposited in the one or more pores. When one or more of the first balloon and the second balloon are inflated upon coming in proximity of the target site in the blood vessel bifurcation, the one or more nano-carriers are released from the one or more pores.
In an embodiment, one or more nano-carriers of the plurality of nano-carriers further include nano-particles of the one or more drugs encapsulated with nano-particles of the one or more biological agents and nano-particles of one or more polymers. The one or more polymers include one or more of a biodegradable polymer, a non-degradable polymer, a bioderodable polymer, an excipient, a drug, and a polymer matrix. Examples of the one or more polymers include, but are not limited to, poly(l-lactide), racemic polylactide, poly(l-lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co-caprolactone poly(d, 1 -lactide-co-caprolactone), poly(l -lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate). When the one or more polymers and the one or more biological agents are used to encapsulate the one or more drugs, the one or more polymers may be covalently attached to one or more of the one or more drugs and the one or more biological agents.
In another embodiment, the nano-carriers, the nano-particles of the one or more drugs, the nano-particles of the one or more biological agents, and one or more excipients

are deposited in a polymer matrix coated on at least one of the hydrophilic surface and the non-hydrophilic surface.
Examples:
Example 1:
Preparation of the nano-carriers:
Lipoid E80 was obtained from Lipoid GMBH, Batch No.: 776114-1/906. Sirolimus was obtained from Biocon Ltd. (India), Batch No.: EH-B10-01-000982/0133 7. The water, other solvents and reagents used were of HPLC grade. A polyamide catheter system (Yangtze μ5b PTCA cathater) with COPAN Co-Polyamide dedicated angioplasty balloons for blood vessel bifurcation (hereinafter referred to as "the balloon system") coated with Hydraflow® Hydrophilic coating (hereinafter referred to as "the hydrophilic surface") was obtained from Minvasys, Paris, France.
Lipoid E80 was dissolved in methanol. 100 ml HPLC grade water and Tween 80 (5 mg) was added to obtain an aqueous solution of Lipoid E80. The aqueous solution Lipoid E80 (10 ml) was subjected to ultrasonic homogenization for 20 to 25 minutes in an ice-cold water bath to obtain Solution Al. The Solution Al thus obtained contained nano-particles of Lipoid E80. The solution Al was subsequently analyzed for particle size detection using Malvern Zeta Sizer (ZS90) [Malvern, UK] size detector. FIG. 2 illustrates the size distribution of nano-particles of Lipoid E80 as detected by Malvern Zeta Sizer (ZS90). Z-average diameter of the nano-particles of the Lipoid E80 was found to be 242.8074 nm.
Sirolimus (20 mg) was dissolved in minimum quantity of methanol. HPLC grade water containing 0.5 % w/w of Tween 80 was added to obtain an aqueous solution of sirolimus by re-precipitation. The aqueous solution of sirolimus (100 ml) was subjected to ultrasonic homogenization for 100 to 200 minutes in an ice-cold water bath to obtain

Solution A2. The Solution A2 thus obtained contained nano-crystals of sirolimus. The solution A2 was subsequently analyzed for particle size detection using Malvern ZS90 (Malvern, UK) size detector.
10 ml solution Al was added to Solution A2 drop by drop slowly under a ultrasonic homogenization process. The resultant mixture was subjected to ultrasonic homogenization for another 20 minutes after complete addition to obtain Solution A3. Solution A3 was then stirred with a magnetic stirrer (2MLH hot plate heater cum stirrer, Accumax, INDIA) for 20 minutes. Solution A3 thus obtained contained nano-carriers (nano-crystals of sirolimus surrounded by nano-particles of Lipoid E80). Solution A3 was subsequently analyzed for particle size detection using Malvern ZS90 (Malvern, UK) size detector. FIG. 3 illustrates size distribution of the nano-carriers as detected by Malvern ZS90. The average diameters of nano-carriers were found to be 245.493 nm.
Solution A3 (Aqueous solution of nano-carriers) was further subjected to extraction with dichloromethane. Solution A3 (about 100 ml) was transferred to a 250 ml separating funnel. 50 ml of dichloromethane was added to the 250 ml separating funnel. The resultant mixture was shaken for 15 minutes and then allowed to stand. Thereafter, two layers i.e., an aqueous layer and a dichloromethane layer were observed in the 250 ml separating funnel. The dichloromethane layer was separated from the aqueous layer. The solution was evaporated up to a volume of 50 ml. The dichloromethane layer i.e., solution of the nano-carriers was stored in an amber colored small measuring flask with a batch number. Subsequently, the solution of the nano-carriers was used for coating the balloon system.
Example 2:
Preparation of the drug delivery system (The balloon system):
Yangtze μsb PTCA catheter of the size 2.5 mm * 10 mm was used for the coating. The solution of the nano-carriers (about 3 ml) was fed into reservoir of a coating

machine. The balloons of the balloon system were mounted on a rotating mandrel of the coating machine one by one. Each balloon of the balloon system was exposed to an atomization nozzle of the coating machine separately. The balloon system was rotated at a speed varying from 5 rpm to 40 rpm by rotating the mandrel. Simultaneously, the solution of nano-carriers was sprayed over the balloons at an inert gas pressure varying from 0.5 psi to 4.0 psi in two oscillations. Thus, the balloons coated with the nano-carriers (hereinafter referred to as "the coated balloon system") was obtained. The coated balloon system was then removed and checked under a high-resolution microscope for the coating surface smoothness and any foreign particles.
Various embodiments of the invention provide a medical device and a method for delivering one or more drugs to bifurcation lesions in a main branch and a side branch of the blood vessel bifurcation within 30 to 90 seconds. Further, the invention provides a medical device specially designed for treating the bifurcation lesions that is associated with reduced instances of a restenosis, an acute thrombus formation, a sub-acute thrombus formation, and a late thrombus formation.
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.
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.

CLAIMS
What is claimed is:
1. A drug delivery system for delivering at least one drug to at least one of a first branch
and a second branch of a blood vessel bifurcation, the drug delivery system
comprising:
a first balloon catheter assembly having a first balloon capable of passing through the blood vessel and being at least partially positioned in the first branch; and
a second balloon catheter assembly having a second balloon capable of passing through the blood vessel and being at least partially positioned in the second branch. wherein at least one of the first balloon and the second balloon is coated with a plurality of nano-carriers, the plurality of nano-carriers comprising at least one drug encapsulated with at least one biological agent, the at least one of the first balloon and the second balloon capable of delivering the plurality of nano-carriers to at least one of the first branch and the second branch upon being positioned and inflated in the at least one of the first branch and the second branch respectively.
2. The drug delivery system of claim 1, wherein a proximal diameter of the second balloon is smaller than a distal diameter of the second balloon in an inflated state and a proximal diameter of the first balloon is smaller than or equal to a distal diameter of the first balloon in an inflated state.
3. The drug delivery system of claim 1, wherein the first balloon has at least one of a shape, a size and dimensions different from the second balloon.
4. The drug delivery system of claim 1, wherein at least one of the first balloon and the second balloon comprises a hydrophilic surface and a non-hydrophilic surface, the hydrophilic surface being coated with the plurality of nano-carriers, wherein a set of nano-carriers of the plurality of nano-carriers is released from the hydrophilic surface within a predetermined duration in response to inflating the at least one of the first

balloon and the second balloon at a target site in the at least one of the first branch and the second branch respectively.
5. The drug delivery system of claim 4. wherein the predetermined duration ranges from 30 to 90 seconds.
6. The drug delivery system of claim 4, wherein the hydrophilic surface have a layer coated thereon, the layer comprising nano-particles of at least one of the at least one biological agent and at least one polymer.
7. The drug delivery system of claim 6, wherein the layer further comprises a plurality of pores, wherein at least one nano-carrier of the plurality of nano-carriers is deposited in at least one pore of the plurality of pores, wherein the hydrophilic surface is exposed through the plurality of pores and the at least one nano-carrier is in direct contact with the hydrophilic surface.
8. The drug delivery system of claim 1, wherein the at least one biological agent exhibits an effect, the effect is at least one of stabilizing the at least one drug, and affinity for tissues of the blood vessel bifurcation.
9. The drug delivery system of claim 1, wherein the plurality of nano-carriers have an average diameter ranging between 1 nm to 1000 nm.
10. The drug delivery system of claim 1, wherein the plurality of nano-carriers further comprise a first set of nano-carriers having a first average diameter and a second set of nano-carriers having a second average diameter, the first average diameter being different from the second average diameter.
11. The drug delivery system of claim 10, wherein the first average diameter ranges from 1 nm to 700 nm and the second average diameter ranges from 300 nm to 1000 nm.

12. The drug delivery system of claim 1, wherein the plurality of nano-carriers further comprise a first set of nano-carriers with a first average diameter, a second set of nano-carriers with a second average diameter, and a third set of nano-carriers with a third average diameter.
13. The drug delivery system of claim 12, wherein the first average diameter ranges from 1 nm to 500 nm, the second average diameter ranges from 300 nm to 800 nm, and the third average diameter ranges from 500 nm to 1000 nm.
14. The drug delivery system of claim 1, wherein the at least one biological agent is selected from a group comprising drug carriers, excipients, blood components, excipients derived from blood, phospholipids, solid lipid nano-particles, lipoids, vitamins and sugar molecules.
15. The drug delivery system of claim 1, wherein the at least one biological agent is selected from at least one of a steroid, a vitamin, an estradiol, an esterified fatty acid, a non-esterified fatty acid, glucose, inositol, L-lactate, a lipoprotein, a carbohydrate, tricalcium phosphate, precipitated calcium phosphate, a substance derived from at least one of human, egg and soybean, phospholipon 80H, phospholipon 90H, Lipoid S75, Lipoid E80, Intralipid 20, Lipoid EPC, Lipoid E75, a lipid obtained from egg, a lipid obtained from soya, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid, cardiolipin, and
pho sphatidylethanolamine.
16. The drug delivery system of claim 1, wherein at least one nano-carrier of the plurality
of nano-carriers further comprises at least one nano-particle of the at least one drug
encapsulated with nano-particles of the at least one biological agent and nano-
particles of at least polymer, the at least one polymer comprising at least one of a
biodegradable polymer, a non-degradable polymer, a bioderodable polymer, an
excipient, a drug, and a polymer matrix.

17. The drug delivery system of claim 16, wherein the at least one polymer is selected from at least one of poly(l-lactide), racemic polylactide, poly(l-lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co-caprolactone poly(d, 1-lactide-co-caprolactone), poly(l-lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate), and wherein the at least one polymer is covalently attached to at least one of the at least one drug and the at least one biological agent.
18. The drug delivery system of claim 1, wherein the at least one drug is selected from at least one of an anti-proliferative agent, an anti-inflammatory agent, an anti-neoplastic agent, an anti-coagulant agent, an anti-fibrin agent, an antithrombotic agent, an anti-mitotic agent, an antibiotic agent, an anti-allergic agent, an antioxidant, at least one flavonoid, an estrogen, a protease inhibitor, an antibody, an immunosuppressive agent, a cytostatic agent, a cytotoxic agent, a calcium channel blocker, a phosphodiesterase inhibitor, a prostaglandin inhibitor, a dietary supplement, a vitamin, an anti-platelet aggregating agent, andgenetically engineered epithelial cells, wherein the at least one flavonoids is selected from at least one of narigenin, naringin, eriodictyol, hesperetin, hesperidin (esperidine), kampferol. quercetin, rutin, cyanidol, meciadonol, catechin, epi-gallocatechin-gallate, taxifolin (dihydroquercetin), genistein, genistin, daidzein, biochanin, glycitein, chrysin, diosmin, Iuetolin, apigenin, tangeritin and nobiletin.
19. The drug delivery system of claim 1, wherein the at least one drug is selected from a group comprising sirolimus, paclitaxel, tacrolimus, clobetasol, dexamethasone, genistein, heparin, beta-estadiol, rapamycin, everolimus, ethylrapamycin, zotarolimus, ABT-578, Biolimus A9, docetaxel, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, mitomycin, sodium heparin, low molecular weight heparin, heparinoid, hirudin, argatroban, forskolin, vapiprost, prostacyclin, prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone, dipyridamole, glycoprotein IIb/IIIa, recombinant hirudin, bivalirudin, nifedipine, colchicines, lovastatin, nitroprusside, suramin, serotonin blockers, a steroid, thioprotease inhibitors, triazolopyrimidine, nitric oxide ,nitric

oxide donors, super oxide dismutase, super oxide dismutase mimetics, estradiol, aspirin, angiopeptin. captopril, cilazapril, lisinopril, permirolast potassium, alpha-interferon, and bioactive RGD.
20. The drug delivery system of claim 1, wherein the at least one drug is Sirolimus.
21. The drug delivery system of claim 1, wherein the at least one drug is Pacliaxel.
22. The drug delivery system of claim 1, wherein the drug delivery system is used to treat a medical condition associated with the blood vessel bifurcation, wherein the medical condition is at least one of stenosis, restenosis, blockage in an artery, thrombus in an artery, acute myocardial infarction, and arterial lesions.
23. The drug delivery system of claim 4, wherein the hydrophilic surface and the non-hydrophilic surface are coated with the plurality of nano-carriers.
24. The drug delivery system of claim 23, wherein at least one of the plurality of nano-carriers, the nano-particles of the at least one drug, the nano-particles of the at least one biological agent, and at least one excipient are deposited in a polymer matrix coated on at least one of the hydrophilic surface and the non-hydrophilic surface.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=bGDRXA2apeN8fQM396gcwg==&loc=vsnutRQWHdTHa1EUofPtPQ==

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Patent Number

269455

Indian Patent Application Number

176/MUM/2010

PG Journal Number

44/2015

Publication Date

30-Oct-2015

Grant Date

23-Oct-2015

Date of Filing

22-Jan-2010

Name of Patentee

CONCEPT MEDICAL RESEARCH PRIVATE LIMITED

Applicant Address

1-3, SILVER PALM II, NEAR SNEH MILAN GARDEN, KADAMPALLI, NANPURA, SURAT 395 001

Inventors:

#	Inventor's Name	Inventor's Address
1	DOSHI, MANISH	703-704, A. MEGHMALHAR, APARTMENT, BHATAR ROAD, SURAT(GUJARAT), INDIA-395017
2	SHERDIWALA, DIVYESH	2/280, MOTO MOHALLO, RUSTAMPURA, SURAT(GUJARAT), INDIA - 395002
3	SOJITRA, PRAKASH	92, RAJMANDIR SOCIETY, NEAR YOGI CHOWK, PUNA-SIMADA ROAD, SURAT(GUJARAT), INDIA-395006

PCT International Classification Number

A61K31/195

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA