Polymer-encapsulated drug particles

Abstract

The present invention provides polymer-encapsulated drug particles and drug-releasing coatings containing them, as well as drug-coated balloon catheters and methods for treating, preventing, or reducing the recurrence of stenosis in body lumens. [Solution] A drug-coated balloon catheter for delivering a therapeutic agent to a target site of stenosis in a body cavity includes an extended balloon. The balloon catheter includes a coating layer overlapping the outer surface of the balloon. The coating layer includes polymer-encapsulated drug particles; or a drug-release coating containing polymer-encapsulated drug particles; or a therapeutic agent and a first or second additive; or a combination thereof.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 62 / 979,980 filed on 21 February 2020 and U.S. Provisional Patent Application No. 63 / 104,965 filed on 23 October 2020, and all disclosures thereof are hereby cited and deemed to be part of this specification.

[0002] Each of the following disclosures of applications is hereby cited and deemed to be part of this specification: U.S. Patent Application No. 16 / 135,436, which is a continuation in part of PCT / US2018 / 03108, filed on 4 May 2018, claiming priority to U.S. Provisional Patent Application No. 62 / 502,212, filed on 5 May 2017. Also, U.S. Patent Application No. 16 / 135,436 is a continuation in part of U.S. Provisional Patent Application No. 15 / 568,614, filed on 23 October 2017, which is a U.S. national phase application under Section 371 of the U.S. Patent Act, derived from International Application PCT / US2016 / 028652, filed on 21 April 2016, claiming priority to U.S. Provisional Patent Application No. 62 / 152,559, filed on 24 April 2015. Furthermore, U.S. Patent Application No. 16 / 135,436 is a continuation in part of U.S. Provisional Patent Application No. 14 / 438,327, filed on April 24, 2015, which is a U.S. national phase application under Section 371 of the U.S. Patent Act, derived from International Application PCT / US2013 / 064842, filed on October 14, 2013, claiming priority from U.S. Provisional Patent Application No. 61 / 795,790, filed on October 26, 2012. U.S. Patent Application No. 16 / 135,472 is a continuation of PCT / US2018 / 03108 filed on May 4, 2018, claiming priority to U.S. Provisional Patent Application No. 62 / 502,212 filed on May 5, 2017. Furthermore, U.S. Patent Application No. 16 / 135,472 is a continuation of U.S. Provisional Patent Application No. 15 / 568,614 filed on October 23, 2017, which is a U.S. national phase application under Section 371 of the U.S. Patent Act, derived from International Application PCT / US2016 / 028652 filed on April 21, 2016, claiming priority to U.S. Provisional Patent Application No. 62 / 152,559 filed on April 24, 2015. Furthermore, U.S. Patent Application No. 16 / 135,472 is a continuation in part of U.S. Provisional Patent Application No. 14 / 438,327, filed on April 24, 2015, which is a U.S. national phase application under Section 371 of the U.S. Patent Act, derived from International Application PCT / US2013 / 064842, filed on October 14, 2013, claiming priority from U.S. Provisional Patent Application No. 61 / 795,790, filed on October 26, 2012. [Background technology]

[0003] (background) Benign prostatic hyperplasia (BPH) is a non-cancerous enlargement of the prostate gland and affects more than 50% of men over the age of 60. Early in life, the prostate is the size and shape of a walnut and weighs about 20 grams. BPH appears to be a normal process. With age, the prostate gradually increases in size to more than twice its normal size. As the prostate grows, it compresses and narrows the urethra, causing prostatic urethral compression and urinary obstruction, which makes urination difficult or impossible.

[0004] Urethral stricture occurs in a relatively high percentage of men (0.6%) in some populations. Urethral stricture appears to be more common in the elderly population. Patients with urethral stricture experience moderate to severe complications, such as lower urinary tract voiding symptoms or urinary retention, recurrent urinary tract infections, and repeated urethral procedures such as dilation, urethrotomy, or urethroplasty.

[0005] Ureteral strictures in the upper urinary tract can be either congenital or acquired. Congenital ureteral strictures are most commonly located at the renal pelvis-urinary junction. Most ureteral strictures are acquired and are usually iatrogenic. The most common etiology of ureteral stricture is injury during endoscopic, open, or laparoscopic surgery.

[0006] Bladder neck stricture (e.g., stenosis or contracture) and urethral stricture are recognized complications of all treatments for prostate cancer. Refractory bladder neck strictures are relatively rare overall; however, they are associated with a considerable morbidity and often require numerous interventions with associated complications and impact on quality of life. Bladder neck strictures and urethral strictures are complications following treatments for prostate cancer such as radical prostatectomy (RP), radiotherapy, cryotherapy, and high-intensity focused ultrasound (HIFU).

[0007] Stenosis in the internal lumen of the digestive body or gastrointestinal tract includes esophageal stricture, achalasia, biliary stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, and large intestinal stricture. The type of disease classifies the stricture as benign or malignant.

[0008] When the bile duct becomes smaller or narrower, a biliary stricture, also called a bile duct stricture, occurs. The bile duct is the tube that carries bile from the liver to the small intestine. When the bile duct narrows, it makes it difficult for food to be digested. Biliary stricture can result from any injury or swelling of the bile duct, pancreatitis, intestinal injury, and cancer in the bile duct or pancreas. Symptoms of biliary stricture include pain, chills and fever, itching, and nausea or vomiting.

[0009] Esophageal stricture is a common problem encountered in gastroenterology and can be caused by malignant or benign injuries. Dysphagia is a symptom experienced by all patients. Most of these patients require symptomatic treatment to alleviate dysphagia.

[0010] Barrett's disease, also known as Barrett's esophagus, is a condition characterized by abnormal (dysplastic) changes in the mucosal cells that line the lower part of the esophagus, from normal stratified squamous epithelium with scattered goblet-shaped cells to simple columnar epithelium, which are normally only found in the colon. These changes are associated with a high frequency of further progression to esophageal adenocarcinoma, a cancer that is often fatal, and are therefore considered a precancerous condition.

[0011] Eosinophilic esophagitis (EoE) is a chronic inflammatory disease. Symptoms of this disease include dysphagia and food impaction, often resulting from esophageal stricture. Repeated endoscopic dilation of fibrostenotic esophageal strictures in eosinophilic esophagitis using bougies and balloon catheters is used to treat such strictures.

[0012] Lower gastrointestinal strictures are narrowings of sections of the intestine that cause problems by delaying or obstructing the movement of food through that area. Strictures can be caused by recurrent inflammation, cancer, Crohn's disease, and ulcerative colitis. Strictures include esophageal strictures, achalasia strictures, strictures in stents, biliary strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, and large intestinal strictures.

[0013] Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC). Crohn's disease and ulcerative colitis-induced strictures are common complications of inflammatory bowel disease and surgery for its treatment. The rate of strictures in individuals with inflammatory bowel disease ranges from 34% to 70% over time. Some strictures are refractory or recurrent, requiring repeated endoscopic dilation for treatment.

[0014] An anastomosis is a connection or opening between two fluid-carrying body structures. A surgical anastomosis is the connection of two fluid-carrying body lumen structures via surgical techniques. Anastomotic stricture is narrowing of an anastomosis. Anastomotic stricture is a common complication of surgical anastomosis, as well as various other surgical procedures such as radical prostatectomy, bowel resection, and gastric bypass. Anastomotic stricture is usually fibrosis and can be difficult to manage and treat. Anastomotic stricture can include stricture in an anastomosis between two parts of the same body structure or between two different body structures, and the body structures may be the esophagus, bile duct, stomach, small intestine, duodenum, jejunum, ileum, colon, rectum, large intestine, urethra, urinary tract, or bladder neck. Anastomotic strictures can be colorectal strictures, strictures after gastric bypass, ileocolonic strictures, gastrointestinal strictures, J-type pouch strictures, or bladder neck strictures (e.g., stenosis). While balloon dilation has been shown to be a safe and effective non-surgical method for managing anastomotic strictures, issues remain, such as the need for repeated balloon dilation due to refractory or recurrent anastomotic strictures.

[0015] Vaginal stenosis is an abnormal condition in which the vagina becomes narrower and shorter due to the formation of fibrous tissue. Vaginal stenosis has a negative impact on sexual dysfunction and dyspareunia, and can make pelvic examinations difficult and painful. The vaginal lining may also be thinner and drier and may contain scar tissue. As a result of this condition, pain may occur during sexual intercourse or pelvic examinations. Vaginal stenosis often results from episiotomy, pelvic radiation therapy, or various types of surgery.

[0016] Chronic obstructive pulmonary disease (COPD) is a term used to classify two major airflow obstruction diseases: chronic bronchitis and emphysema. Approximately 16 million Americans have COPD, and 80-90% of them were smokers for much of their lifetime. COPD is a leading cause of death in the United States. Chronic bronchitis is inflammation of the bronchial airways. The bronchial airways connect the trachea to the lungs. When inflamed, the bronchi secrete mucus, causing a chronic cough. Emphysema is the over-inflation of the alveoli, or air sacs, in the lungs. This condition causes shortness of breath.

[0017] Asthma is a chronic respiratory disease characterized by airway inflammation, excessive mucus production, and airway hyperreactivity, as well as a condition in which narrowed airways respond excessively or too easily to stimuli. An asthma attack or outbreak causes narrowing of the airways, making breathing difficult. Asthma attacks can have a significant impact on a person's life, limiting participation in many activities. In severe cases, asthma attacks can be life-threatening. Currently, there is no known cure for asthma.

[0018] Chronic sinusitis is inflammation of the membrane lining of one or more sinuses. Chronic sinusitis typically lasts longer than three weeks, often for several months. Tissue damage is usually present in cases of chronic sinusitis. According to the Centers for Disease Control and Prevention (CDC), 37 million cases of chronic sinusitis are reported annually.

[0019] Radiation (e.g., radiotherapy) is used as one mode of treatment for localized cancer. Localized cancer is the most commonly diagnosed type of cancer. The vast majority of patients are diagnosed at an early stage that is potentially treatable. Standard localized treatment options include active surveillance, radical prostatectomy (RP) for prostate cancer, and, generally for all cancer treatments, radiotherapy (RT). Radiotherapy can be delivered via external beam radiation therapy (EBRT) or brachytherapy (BT). Side effects associated with each treatment can vary considerably. Localized cancers include prostate cancer, urethral cancer, urinary tract cancer, esophageal cancer, biliary tract cancer, gastric cancer, small intestine cancer, duodenal cancer, jejunal cancer, ileal cancer, colon cancer, rectal cancer, colorectal cancer, and lung cancer. Radiation treatments can create damage to adjacent healthy tissue, such as stenosis. Radiation-induced strictures can include urethral strictures, ureteral strictures, esophageal strictures, bile duct strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, and large intestinal strictures. Treatment of radiation-induced strictures can be complex and difficult. Due to high survival rates, the number of prostate cancer survivors in the United States has increased by 220,000 annually, reaching nearly 2.8 million in 2015, leaving a large number of men in a dangerous condition due to short-term or long-term side effects of radiation therapy for prostate cancer treatment. The progression of urethral stricture as a side effect of radiation therapy for prostate cancer treatment is particularly problematic.

[0020] Various minimally invasive methods used to treat various cancers, large colon polyps, and Barrett's esophagus are a global practice. When patients prefer to avoid surgery, these minimally invasive methods are gaining favor over surgical procedures. Several randomized controlled trials and meta-analyses have demonstrated the clinical and oncological safety and efficacy of laparoscopic gastrectomy, robot-assisted gastrectomy, EMR (endoscopic mucosal resection), and ESD (endoscopic submucosal dissection) in the treatment of cancers and Barrett's esophagus at various stages. EMR and ESD are safe and effective for the treatment of early-stage superficial cancers such as esophageal cancer, biliary tract cancer, gastric cancer, small intestine cancer, duodenal cancer, jejunal cancer, ileal cancer, colon cancer, rectal cancer, colorectal cancer, ileal cancer, and gastrointestinal cancer. EMR and ESD are safe and effective for the treatment of high-grade Barrett's esophagus. Laparoscopic gastrectomy, robot-assisted gastrectomy, EMR, and ESD are feasible procedures from a clinical and oncological safety standpoint; however, recurrence of malignant and refractory strictures has been noted in some patients. The local recurrence rate of cancer after minimally invasive procedures ranges from 2 to 20%, depending on the type and stage of cancer, as well as follow-up time. The incidence of stricture or stenosis after minimally invasive procedures is approximately 26% to 70%. Repeated endoscopic balloon dilation is necessary to treat refractory or recurrent strictures or stenosis.

[0021] Cardiac disease or atherosclerosis is characterized by hardening and narrowing of arteries due to the accumulation of fatty plaques in the arterial lumen. Over time, plaque buildup can become severe enough to block the flow of oxygen-rich blood to downstream tissues. Atherosclerosis can occur in any artery in the body. Blockage or narrowing of critical arteries such as the carotid and coronary arteries can lead to sudden death. Narrowed peripheral arteries such as the iliac, superficial femoral, popliteal, tibia, and fibula arteries may lead to the need for amputation. If the renal arteries are blocked, chronic kidney disease may develop. Stenosis is treated with current drug-coated balloons and drug-eluting stents. Long-term mortality, thrombosis rates, and the efficacy of these drug-coated devices remain insufficient. Better devices are needed to improve safety and efficacy for cardiovascular stenosis.

[0022] Renal failure is a disease that leads to the accumulation of waste in the blood. To prevent waste accumulation, patients undergo a medical procedure called chronic hemodialysis. During hemodialysis, blood is delivered through a dialysis machine to remove waste. The access point for the blood is typically located within the limb at a special vascular junction created, called an arteriovenous fistula (AVF) or arteriovenous graft (AVG). An AVF is a special type of anastomosis in which an artery is directly sutured to a vein. An AVG is a different type of anastomosis in which the connection between the artery and vein is facilitated by a synthetic or autologous tube. AVFs and AVGs often narrow, causing blood flow obstruction. When this occurs, they must be dilated or abandoned in order to create a new AVF or AVG to complete hemodialysis. Drug-coated balloons are used to dilate narrowed AVFs and AVGs, however, better devices are needed to improve safety and efficacy.

[0023] Heart valve diseases are common diseases that afflict the elderly population. It is diagnosed by listening to the heartbeat with a stethoscope during a health check. The abnormal sounds produced by the heart are called murmurs, and various murmurs can indicate specific types of heart valve diseases. Types of heart valve diseases include stenosis, regurgitation, prolapse, and atresia. Heart valve stenosis is the narrowing or hardening of the heart valve that results in it not opening or closing properly. The flaps of the valve can become thickened, hardened, or fused together. As a result, the valve cannot open fully, and then the heart has to work harder to pump blood through the valve. This can result in hypoxia or reduced oxygen supply, which can affect the whole body, local tissues, or a part of the body. Heart valve stenosis can be treated by a procedure called balloon valvuloplasty or BAV. BAV involves tracking an inflatable balloon through the vasculature to the heart valve and then expanding the heart valve annulus. Recently, the number of BAV procedures performed has increased because BAV is being used before, after, and / or during transcatheter aortic valve replacement (TAVR) procedures. The restenosis rate after BAV ranges from 40 to 80% at 5 to 9 months, indicating the need for improvements in devices and techniques. SUMMARY OF THE INVENTION

[0024] (SUMMARY OF THE INVENTION) In various embodiments, the present invention provides polymer-encapsulated (or polymer-encapsulated, or polymer-encapsulated, or polymer-encapsulated, or polymer-encapsulated: polymer encapsulated) drug particles comprising a therapeutic agent and one or more polymers. Optionally, the polymer-encapsulated drug particles comprise a first ionic or zwitterionic additive. The first ionic or zwitterionic additive (or additive: additive), when present, is within the polymer-encapsulated drug particles, coated on the surface of the polymer-encapsulated drug particles, or a combination thereof.

[0025] In various embodiments, the present invention provides a drug-release coating comprising polymer-encapsulated drug particles containing a therapeutic agent and one or more polymers. Optionally, the polymer-encapsulated drug particles include a first ionic or amphoteric additive. The first ionic or amphoteric additive, if present, is either within the polymer-encapsulated drug particles, coated on the surface of the polymer-encapsulated drug particles, or a combination thereof. The coating also includes a release matrix containing the ionic or amphoteric additive. The coating can be placed in any suitable location, such as a balloon catheter, a drug-coated catheter, a drug-eluting stent, a drug-eluting stent on a balloon, a drug-eluting stent on a drug-coated balloon, a stent on a drug-coated balloon, or a combination thereof.

[0026] In various embodiments, the present invention provides a drug-release coating comprising a therapeutic agent and polymer-encapsulated drug particles containing one or more polymers that encapsulate the therapeutic agent. The polymer-encapsulated drug particles also contain ionic or amphoteric additives. The polymer-encapsulated drug particles may be charged polymer-encapsulated drug particles.

[0027] Various embodiments provide methods for treating or preventing non-vascular or vascular stenosis or stenosis. The methods include inserting a catheter into a body lumen, the catheter comprising a balloon or stent comprising a drug coating containing polymer-encapsulated drug particles. The methods include expanding the balloon or stent to bring the coating layer into contact with the area of ​​stenosis, stenosis, or the area where stenosis or stenosis is to be prevented. If a balloon is used, the methods may include deflating the balloon. Alternatively, if a balloon is used, the methods may include removing the balloon or stent from the body lumen.

[0028] Various embodiments provide a method for producing polymer-encapsulated drug particles. The method comprises forming a suspension containing a therapeutic agent and a polymer. The method comprises treating the suspension to reduce the particle size of the suspension. The method also comprises adding an aqueous premix to the suspension to form polymer-encapsulated drug particles in the suspension. The polymer-encapsulated drug particles contain a therapeutic agent and a polymer.

[0029] Various embodiments provide methods for producing polymer-encapsulated drug particles. The method includes forming an organic premix comprising an organic solvent, one or more polymers, a therapeutic agent, and optionally a first ionic or amphoteric additive. The method also includes forming an aqueous premix comprising water and a water-soluble polymer or surfactant. The method includes adding the organic solvent to the aqueous premix. The method includes combining the aqueous premix and the organic premix. Furthermore, the method includes stirring the combined aqueous premix and organic premix to form an emulsion containing polymer-encapsulated drug particles.

[0030] In various embodiments, the present invention provides a method for preparing polymer-encapsulated drug particles comprising a therapeutic agent, one or more polymers, and optionally a first ionic or amphoteric additive. The method comprises preparing an organic premix by solubilizing and mixing one or more polymers, a therapeutic agent, and optionally a first ionic or amphoteric additive to form a premix in an organic solvent. The organic solvent may be at least partially miscible with aqueous solutions (e.g., a polar organic solvent). The method comprises preparing a second aqueous premix comprising a water-soluble polymer and adding the organic solvent used in the first premix. The method comprises mixing the organic premix with the aqueous premix so that an organic solvent in a water coacervate is created. The method comprises further adding water to the coacervate solution to displace the organic solvent from the coacervate in order to cure it into polymer-encapsulated drug particles.

[0031] Various embodiments provide a method for fabricating a balloon catheter. The method involves applying (or coating) polymer-encapsulated drug particles or a drug-release coating containing them to the outside of the balloon of the balloon catheter.

[0032] Various embodiments provide balloon catheters. The balloon catheter comprises an elongated balloon. The balloon catheter also comprises a coating layer overlapping the outer surface of the balloon. The coating layer comprises polymer-encapsulated drug particles; or a drug-release coating containing polymer-encapsulated drug particles; or a composition comprising a therapeutic agent, a first additive and a second additive; or a combination thereof. The therapeutic agent in the composition is selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogues (or analogues) and combinations thereof, and the therapeutic agent has a particle size of 0.2 to 10 microns. The first additive comprises a water-insoluble or partially water-insoluble additive containing at least one alkyl fatty group or cholesteryl group, and the first additive has a molecular weight of 50 to 750. The second additive is more hydrophilic or more water-soluble than the first additive and contains polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The second additive has a molecular weight in the range of 750 to 100,000.

[0033] In various embodiments, the present invention provides a balloon catheter for delivering a therapeutic agent to a target site in a body lumen. The balloon catheter comprises an extended balloon and a coating layer overlapping the outer surface of the balloon. The coating layer comprises polymer-encapsulated drug particles; or a drug-release coating containing polymer-encapsulated drug particles; or a composition comprising two or more additives and an initial drug load of the therapeutic agent. The therapeutic agent in the composition is selected from mTOR inhibitors, paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, their analogs, and combinations thereof. The therapeutic agent in the composition is crystalline, partially crystalline, amorphous (or amorphous, or amorphous), partially amorphous, or a combination thereof. The first additive comprises a water-insoluble or partially water-insoluble additive having a molecular weight of 50 to 750 (for example, 50 or more, or 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, less than or greater than 700, or 750 or less) and containing at least one alkylaliphatic group or cholesteryl group. The second additive is more hydrophilic or more water-soluble than the first additive and contains polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The second additive has a molecular weight in the range of 750 to 100,000 (for example, 750 or more, or 1,000, 2,000, 4,000, 6,000, 8,000, 10,000, 20,000, 40,000, 60,000, 80,000, less than, equal to, or less than, or 100,000 or less). The particle size of the therapeutic agent particles during coating is in the range of 0.2 microns to 10 microns (for example, 0.2 microns or more, or 0.3 microns, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, less than or greater than 9, 9.5, or 10 microns or less).

[0034] In various embodiments, the present invention provides a balloon catheter for delivering a therapeutic agent to a target site of stenosis or narrowing of a body cavity. The balloon catheter comprises an extended balloon and a coating layer overlapping the outer surface of the balloon. The coating layer comprises polymer-encapsulated drug particles; or a drug-release coating containing polymer-encapsulated drug particles; or a composition comprising two or more additives and an initial drug load of the therapeutic agent. The balloon comprises polyester, polyamide, nylon 12, nylon 11, polyamide 12, block copolymers of polyether and polyamide, polyether block amide, polyurethane, block copolymers of polyether and polyester, or combinations thereof. The therapeutic agent in the composition is selected from paclitaxel, docetaxel, taxol, their analogues, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, their analogues, and combinations thereof. The therapeutic agent in the composition is crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. The particle size of the therapeutic agent in the composition is in the range of 0.2 microns to 5 microns (for example, 0.2 microns or more, or 0.3 microns, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, less than or greater than 4.8, or 5 microns or less). In embodiments comprising the composition, the first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, and the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive during coating is in the range of 0.3 microns to 10 microns (e.g., 0.3 microns or more, or 0.4 microns, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or more, or 10 microns or less). In embodiments comprising the composition, the therapeutic agent is in contact with the additive (e.g., individual particles,The treatment agent encapsulated in the additive is partially or completely encapsulated so as to be partially or completely surrounded by (or as a partially or completely continuous coating). For example, 25% to 100% of the surface area of ​​the treatment agent encapsulated in the additive may be in contact with the first additive, the second additive, or a combination thereof, or 50 to 100%, 75 to 100%, or 1% or more, or less than or greater than 25%, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99%, or less than or equal to 100%. The first additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one alkylaliphatic group or cholesteryl group, and the first additive may have a molecular weight of 50 to 750. In embodiments comprising the composition, the first additive in the coating has a lower melting temperature than the first additive in its pure form, and the first additive in the coating has a lower degree of crystallinity than the first additive in its pure form. The second additive is more hydrophilic or more water-soluble than the first additive and contains polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The second additive has a molecular weight in the range of 750 to 100,000, 750 to 50,000, or 750 to 10,000. Stenosis or narrowing of internal body cavities is selected from urethral stricture, prostatic urethral stricture, ureteral stricture, esophageal stricture, sinus stricture, gastric stricture, small intestinal stricture, colonic stricture, rectal stricture, large intestinal stricture, bladder neck stricture, bile duct stricture, vaginal stricture, restenosis within a stent, coronary artery stenosis, superficial femoral artery stenosis, popliteal artery stenosis, anterior tibial artery stenosis, posterior tibial artery stenosis, and peroneal artery stenosis. The first additive containing a cholesteryl group is cholesterol, cholesteryl acetate, cholesteryl phenylacetate, cholesteryl laurate, cholesteryl palmitate, cholesteryl stearate, cholesteryl n-valerate, cholesteryl benzoate, cholesteryl heptylate, cholesteryl decylate, cholesteryl caproate, cholesteryl oleate, cholesteryl oleyl carbonate, cholesteryl linoleate, cholesteryl pelargonicate, cholesteryl erucate, cholesteryl caprylate, 5α-cholestane,Selected from 5α-cholestane-3-one and combinations thereof. The first additive, which is water-insoluble or slightly or partially water-insoluble and has an alkyl aliphatic group, is alkylglyceryl ether, monoglycerides of C8-C12 fatty acids, alkyl alcohol, alkyl ether, alkyl ester, caprylic acid, monocaprylin, capric acid, monocaprin, lauric acid, dodecylglycerol, butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, pa Selected from luminoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di-, or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha-tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobee, niosomes, their derivatives and combinations thereof. The second water-soluble additive is cholesteryl-polyethylene glycol 600 sebacate, polyoxyethanol α-tocopheryl sebacate, methylated polyethylene glycol cholesterol (mPEG cholesterol), polyethylene glycol cholesterol (PEG cholesterol), polyethylene glycol ester cholesterol (PEG cholesterol), polyethylene glycol ether cholesterol (PEG cholesterol), methylated polyethylene glycol-amide-cholesterol (mPEG cholesterol),Polyethylene glycol-amide-cholesterol (PEG cholesterol), polyethylene glycol (PEG)-cholesteryl sebacate, polyethylene glycol cholesterol, PEG amide ester cholesterol, PEG amide ether cholesterol, mPEG amide ester cholesterol, DSPE-PEG-cholesterol, PEGylated phospholipids, methylated PEGylated phospholipids, PEG caprylic / capric acid diglyceride, PEG-8 caprylic / capric acid glyceride, PEG caprylate, PEG caprate, PEG caproate, PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), PEG-20 sorbitan monooleate (Tween-80), PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG-30 glyceryl oleate, polyglyceryl fatty acid ester, polyglyceryl oleate, (Plurol Polyglyceryl-2 Dioleate (Nikkol DGDO), Polyglyceryl-10 Trioleate, Polyglyceryl Stearate, Polyglyceryl Laurate, Polyglyceryl Myristate, Polyglyceryl Palmitate, Polyglyceryl Linoleate, Polyglyceryl-10 Laurate (Nikkol Decaglyn 1L), Polyglyceryl-10 Oleate (Nikkol Decaglyn 1-O), Mono / Polyglyceryl-10 Dioleate (CaproI (Trademark) PEG) Selected from 860), polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-6 linoleate, and combinations thereof.

[0035] In various embodiments, the present invention provides a method for preventing or treating strictures in the body lumen or gastrointestinal tract. The method comprises inserting a balloon catheter into a target site in the body lumen, including a nonvascular stricture. The balloon catheter comprises an extended balloon and a coating layer overlapping the outer surface of the balloon. The coating layer comprises polymer-encapsulated drug particles; or a drug-release coating containing polymer-encapsulated drug particles; or a composition comprising two or more additives and an initial drug load of a therapeutic agent. The composition comprises a first additive comprising a water-insoluble or partially water-insoluble additive, a second additive having greater affinity or water solubility than the first additive, and an initial drug load of a therapeutic agent selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, their analogs and combinations thereof. In embodiments comprising the composition, a first additive, a second additive, or a combination thereof encapsulates a therapeutic agent, the therapeutic agent encapsulated in the additive having a larger particle size than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive during coating is in the range of 0.3 microns to 10 microns. The method comprises inflating the balloon at the target site to bring the coating layer into contact with the wall of the body lumen at the location of the nonvascular stricture until the balloon achieves the inflated balloon diameter for the inflation period. The method comprises compressing the balloon after the inflation period. The method comprises retrieving the balloon catheter from the body lumen. Stenosis in the digestive body lumen or gastrointestinal tract includes esophageal stricture, achalasia, biliary stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, ileoanal J-type sac stricture, and large intestinal stricture. Stenosis in the body lumen or gastrointestinal tract includes esophageal strictures due to eosinophilic esophagitis, radiation-induced strictures, Crohn's disease-induced strictures, ulcerative colitis-induced strictures, chronic inflammatory bowel disease (IBD)-induced strictures, surgical anastomotic strictures, or combinations thereof.

[0036] In various embodiments, the present invention provides a method for the prevention or treatment of stenosis or narrowing of a vascular body lumen. The method comprises inserting a balloon catheter into a target site of a body lumen containing vascular stenosis or narrowing. The balloon catheter comprises an extended balloon and a coating layer overlapping the outer surface of the balloon. The coating layer comprises polymer-encapsulated drug particles; or a drug-release coating containing polymer-encapsulated drug particles; or a composition comprising two or more additives and an initial drug load of a therapeutic agent. The composition comprises a first additive, a second additive, and an initial drug load of a therapeutic agent selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs and combinations thereof. In the composition, the therapeutic agent is crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. In the composition, the particle size of the therapeutic agent is in the range of 0.2 microns to 5 microns. In embodiments comprising the composition, a first additive, a second additive, or a combination thereof encapsulates a therapeutic agent, the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive during coating is in the range of 0.3 microns to 10 microns. The first additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one alkyl aliphatic group or cholesteryl group, and the first additive may have a molecular weight of 50 to 750. In embodiments comprising the composition, the first additive during coating has a lower melting temperature than the first additive in its pure form, and the first additive during coating has a lower degree of crystallinity than the first additive in its pure form. The second additive is more hydrophilic or more water-soluble than the first additive, and it contains polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The molecular weight of the second additive is in the range of 750 to 100,000. The method involves inflating the balloon at the target site to bring the coating layer into contact with the wall of the body lumen at the site of stenosis or stenosis until the balloon achieves the inflated balloon diameter for the inflation period.The method includes compressing the balloon after the inflation period. The method also includes retrieving the balloon catheter from the body lumen.

[0037] In various embodiments, the present invention provides a method for preparing a coated balloon catheter. The method comprises providing a crystalline therapeutic agent, which is selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs and combinations thereof. The method comprises processing the therapeutic agent so that the majority of the crystalline therapeutic agent has a particle size of 0.2 to 5.0 microns. The method comprises providing a fluid in which the therapeutic agent is substantially insoluble. The method comprises mixing the fluid with the therapeutic agent, a first water-insoluble additive and a second water-soluble additive, the first additive encapsulating the crystalline therapeutic agent, and the first additive having a particle size of 0.3 to 10 microns. The method comprises applying the mixture to the outer surface of a balloon catheter. The first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, and the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, with the particle size of the therapeutic agent encapsulated in the additive during coating ranging from 0.3 microns to 10 microns.

[0038] In various embodiments, the present invention provides a method for preparing a drug coating solution. The method comprises mixing water, a water-miscible solvent, a therapeutic agent, and a water-soluble additive to form a mixture. The method comprises treating the premix to reduce the particle size of the therapeutic agent. The method comprises mixing an insoluble water additive, a water-soluble additive, water, and a water-miscible solvent to form a second premix. The method comprises mixing the second premix with the first treated premix to form a coating solution. The therapeutic agent is selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs, and combinations thereof. The therapeutic agent is crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. The coating solution is an aqueous suspension of the therapeutic agent. The particle size of the therapeutic agent is in the range of 0.2 microns to 5 microns. The first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, and the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, with the particle size of the therapeutic agent encapsulated in the additive during coating ranging from 0.3 microns to 10 microns. The process is one of microfluidization, homogenization, rotator-stator milling, high or low energy bead milling, or high-power ultrasonic probe homogenization. The first additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one alkyl aliphatic group or cholesteryl group, and the first additive can have a molecular weight of 50 to 750. The first additive during coating has a lower melting temperature than the first additive in its pure form (e.g., determined by DSC-vs-DSC of the coating and the pure additive). The first additive in the coating has a lower degree of crystallinity than the first additive in its pure form (e.g., determined by the DSC of the coating versus the DSC of the pure additive).The second additive is more hydrophilic or more water-soluble than the first additive and contains polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The second additive has a molecular weight in the range of 750 to 100,000, or 750 to 50,000, or 750 to 10,000.

[0039] In various embodiments, the present invention provides a method for coating a balloon catheter. The method comprises preparing an aqueous suspension coating solution. Preparation of the aqueous suspension comprises mixing water, a water-miscible solvent, a therapeutic agent, and a water-soluble additive to form a premix. Preparation of the suspension comprises treating the premix to reduce the particle size of the therapeutic agent. Preparation of the suspension comprises mixing an insoluble water additive, a water-soluble additive, water, and a water-miscible solvent to form a second premix. Preparation of the suspension comprises mixing the second premix with the first treated premix to form a coating solution. The therapeutic agent may be an mTOR inhibitor (e.g., rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, or a combination thereof) or an analog or derivative thereof. The therapeutic agent may be crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. The coating solution is an aqueous suspension of the therapeutic agent. The particle size of the therapeutic agent is in the range of 0.2 microns to 5 microns. The first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, and the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, with the particle size of the therapeutic agent encapsulated in the additive during coating ranging from 0.3 microns to 10 microns. The first additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one alkyl aliphatic group or cholesteryl group, and the first additive may have a molecular weight of 50 to 750. The first additive during coating has a lower melting temperature than the first additive in its pure form. The first additive during coating has a lower degree of crystallinity than the first additive in its pure form. The second additive is more hydrophilic or more water-soluble than the first additive, and it contains polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The second additive has a molecular weight in the range of 750 to 100,000, or 750 to 50,000, or 750 to 10,000. The method includes preparing a balloon catheter. The preparation of the balloon catheter includes inflating the balloon catheter.The preparation of the balloon catheter includes cleaning the surface of the balloon, such as with an ethanol wipe. The preparation of the balloon catheter includes securing the balloon so that it can be mounted horizontally inside the coating machine and rotated at a fixed speed. The method includes distributing the coating solution onto the surface of the balloon while a nozzle moves laterally across the balloon. The method includes continuing to rotate the balloon to evaporate the solvent at room temperature or above room temperature. The method includes pleating and folding the balloon catheter. The method includes sterilizing the coated balloon catheter.

[0040] In various embodiments, the present invention provides minimally invasive methods for the treatment or prevention of nonvascular or vascular stenosis or stenosis. The method involves inserting a catheter having an expandable body through a body lumen containing a stenosis or stenosis such that the expandable body is inside the stenosis or stenosis. Catheters having an expandable body include balloon catheters, drug-coated catheters, drug-eluting stents, and corrugated drug-eluting stents on drug-coated balloons. The catheter includes an expandable body having a coating layer that overlaps the outer surface of the expandable body of the catheter. The coating layer includes polymer-encapsulated drug particles; or a drug-releasing coating containing polymer-encapsulated drug particles; or a composition comprising two or more additives and an initial drug load of a therapeutic agent. One or more additives are selected from water-insoluble additives, slightly or partially water-soluble additives, water-soluble additives, or a combination thereof. The method involves expanding the body to bring the coating layer into contact with the narrowed or stenotic body lumen to a certain diameter for a period of time. The method involves deflating the expanded body after that period and retrieving it from the narrowed or stenotic body lumen. In some embodiments, the method further includes performing a surgical procedure to dilate, cut, or remove tissue prior to inserting a balloon catheter into the target site.

[0041] Embodiments of the present invention provide medical device (or medical device) coating formulations comprising therapeutic agents or therapeutic drugs for the treatment of stenosis in nonvascular and vascular body lumens, and additives that enhance the absorption of the drug into the tissues of the body lumen. Some embodiments provide coatings for covering the expandable portion of a catheter, having a single layer or multiple layers comprising one or more therapeutic agents. In some embodiments, the layer in contact with the expandable portion of the catheter is free of therapeutic agents and is formulated with components that allow all or substantial portions of the coating to transfer to the stenosis or stenosis upon catheter expansion. Causes and associated diseases of body lumen stenosis may include infection and inflammation caused by pathogens such as bacteria and viruses. In some embodiments, the coating has additives having antibacterial and antiviral properties. In some embodiments, the coating layer containing the therapeutic agent has a drug that is crystalline, amorphous, or a combination thereof. In some embodiments, the coating layer containing the therapeutic agent has at least one hydrophilic component and at least one hydrophobic component. In some embodiments, the coating layer contains components that enhance the adhesion of the coating to the lumen surface of the expanded stenosis or stenosis. In some embodiments, the coating is formulated so that, upon catheter expansion, the coating transfers to the stenosis or stenosis as microparticles, aggregated microparticles, dissolved substances, or a combination thereof. In some embodiments, the size of the transferred microparticles or aggregated microparticles is small, less than 10 μm, or more preferably less than 5 μm. In some embodiments, the coating layer comprises polymer-encapsulated drug particles or a drug-releasing coating containing them.

[0042] In various embodiments, the present invention provides a catheter comprising an expandable portion of an elongated body used to dilate nonvascular and vascular stenosis or stenosis. In some embodiments, the elongated body is a cylindrical balloon. In some embodiments, the elongated body is a balloon having a shape or longitudinal profile that prevents the balloon from moving within the body lumen in which it is being expanded.

[0043] In various embodiments, the present invention provides a method for applying a coating solution to the expandable portion of a catheter by evaporating the liquid in the coating solution to leave a dry coating on the catheter.

[0044] (Brief explanation of the drawing) The drawings generally illustrate various embodiments of the present invention, without limitation. [Brief explanation of the drawing]

[0045] [Figure 1] Figure 1 is a perspective view of an embodiment of a balloon catheter according to the present invention, according to various embodiments (the balloon catheter includes a fixed wire on a wire, and details of a rapidly replaced balloon catheter are not shown in Figure 1). [Figure 2A-2C] Figures 2A-2C are cross-sectional views of different embodiments of the distal portion of the balloon catheter shown in Figure 1 along line AA, showing typical coating layers according to various embodiments. [Figure 3A] Figure 3A shows a balloon catheter having a single neck portion according to various embodiments. [Figure 3B] Figure 3B shows a balloon catheter having two neck sections according to various embodiments. [Figure 3C] Figure 3C shows a balloon catheter having three neck sections according to various embodiments. [Figure 4A-4D]Figures 4A to 4D show balloon catheters including an extended rigid member, which is a spring, according to various embodiments. [Figure 5] Figure 5 shows an extended rigid member, which is a spring, according to various embodiments. [Figure 6] Figure 6 shows examples of drug coating particle size analysis using a Beckman Coulter LS 13 320 Particle Sizing Analyzer with a Liquid Analyzer Module, according to various embodiments. (Figures, diagrams, or tables are provided.) [Figure 7A-7C] Figures 7A to 7C show SEM images of examples of sirolimus according to various embodiments, with Figure 7A showing 37x magnification, Figure 7B showing 1,600x magnification, and Figure 7C showing 7,500x magnification. [Figures 8A-8C] Figures 8A-8C show typical powder X-ray diffraction graphs obtained from crystalline sirolimus (Figure 8A), dodecylglycerol (Figure 8B), and sterile sirolimus drug coating on a balloon (Figure 8C). [Figures 9A-9C] Figures 9A-C show diagrams of DSC scans of crystalline sirolimus (Figure 9A), dodecylglycerol (Figure 9B), and a sirolimus drug-coated balloon (Figure 9C) according to various embodiments. [Figure 10] Figure 10 shows a graph of sirolimus particle size reduction obtained using high-pressure homogenizers according to various embodiments. [Figure 11] Figure 11 shows the Kaplan-Meier curves without re-intervention for esophageal and intestinal paclitaxel-coated balloon treatment under various embodiments. [Modes for carrying out the invention]

[0046] (Detailed description of the invention) Certain embodiments of the disclosed subject matter are now referenced, and examples of such embodiments will be shown in part in the accompanying drawings. The disclosed subject matter will be described together with the enumerated claims, but it will be understood that the illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0047] Throughout this document, values ​​expressed in range form should be interpreted flexibly to include not only the numerical range explicitly stated as a limit on the range, but also all individual numerical values ​​or subranges contained within that range, as if numerical values ​​and subranges were explicitly stated. For example, the range "approximately 0.1% to approximately 5%" or "approximately 0.1% to approximately 5%" should be interpreted to include not only approximately 0.1% to approximately 5%, but also the individual values ​​within that range (e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, and 3.3% to 4.4%). Unless otherwise specified, the notation "approximately X to Y" has the same meaning as "approximately X to approximately Y". Similarly, the statement "approximately X, Y, or approximately Z" has the same meaning as "approximately X, approximately Y, or approximately Z" unless otherwise specified.

[0048] Throughout this document, the terms “a,” “an,” or “that” are used to include one or more unless the context clearly indicates otherwise. The term “or” is used to mean non-exclusive “or” unless otherwise specified. The statement “at least one of A and B” is synonymous with “A, B, or A and B.” In addition, it should be understood that any usage or terminology used herein and otherwise defined is for illustrative purposes only and not for restrictive purposes. Any use of section headings is intended to aid the reading of the document and should not be interpreted as restrictive; information relating to a section heading may occur both within and outside that particular section.

[0049] In the methods described herein, the actions may be performed in any order without departing from the rules of the invention, unless otherwise explicitly stated, such as temporary or sequential operations. Furthermore, the specified actions may be performed simultaneously unless the explicit claim language states that they should be performed separately. For example, the claimed action of performing X and the claimed action of performing Y may be performed simultaneously within a single operation, and the resulting process will be within the literal scope of the claimed process.

[0050] As used herein, the term "about" includes the exact value or range, allowing for a degree of variability within a value or range, for example, within 10%, 5%, or 1% of the mentioned limit of the value or range mentioned.

[0051] As used herein, the term “substantially” means at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or a large majority such as 100%.

[0052] Polymer-encapsulated drug particles Various embodiments provide polymer-encapsulated drug particles. The polymer-encapsulated drug particles comprise a therapeutic agent and one or more polymers that encapsulate the therapeutic agent. Optionally, the polymer-encapsulated drug particles include a first ionic or amphoteric additive. The first ionic or amphoteric additive, if present, is present on the polymer-encapsulated drug particles (e.g., encapsulated by the encapsulation polymer), coated on the surface of the polymer-encapsulated drug particles (e.g., on the outer surface of the encapsulation polymer), or a combination thereof. In some embodiments, the polymer-encapsulated drug particles include a first ionic or amphoteric additive. In other embodiments, the polymer-encapsulated drug particles do not include a first ionic or amphoteric additive.

[0053] The therapeutic agent can be any appropriate therapeutic agent. The therapeutic agent can be selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs and combinations thereof. The therapeutic agent can be crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. The therapeutic agent may be crystalline and / or partially crystalline. The therapeutic agent may have any appropriate maximum dimensions (e.g., diameter), e.g., 0.1–29.9 microns, 0.5–15 microns, 1–10 microns, or 29.9 microns or less and 0.1 microns or more, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 29 microns. The therapeutic agent can form polymer-encapsulated drug particles in appropriate proportions, for example, 5-45% by weight, 25-35% by weight, or 45% by weight or less, and 5, 10, 15, 20, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 40% by weight or more.

[0054] The polymer encapsulating the therapeutic agent in polymer-encapsulated drug particles can be one or more suitable polymers. The polymer can be at least one selected from polylactic acid (PL), polyglycolic acid (GA), polylactic acid / polyglycolic acid copolymer (PLGA), polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycans, and their copolymers. PLGA copolymers can be ester-capped or have carboxylic acid terminal groups. PLGA copolymers can have a lactic acid-to-glycolic acid weight ratio of 50:50, 65:35, 75:25, or 85:15. The molecular weight of PLGA copolymers can range from 20,000 g / mol to 300,000 g / mol. One or more polymers can form any appropriate proportion of polymer-encapsulated drug particles, for example, 30–80% by weight, 50–75% by weight, or 80% by weight or less, or 30, 35, 40, 45, 50, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, or 75% by weight or more. The polymers can be neutral polymers. The polymers can be anionic, cationic, or amphoteric polymers, for example, any of the polymers described herein that are suitable for use as a first ionic or amphoteric additive to a second ionic or amphoteric additive.

[0055] In polymer-encapsulated drug particles, the polymer encapsulates the therapeutic agent. The polymer-encapsulated drug particles have a larger diameter than the therapeutic agent particles placed in the capsule. As used herein, “encapsulate” can mean 50–100% surface coverage of the material (i.e., the therapeutic agent and the desired first ionic or amphoteric additive) encapsulated by the encapsulant (e.g., the polymer described herein, a first ionic or amphoteric additive and / or first and second additives), or 60–100%, 75–100%, 90–100%, or 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 94%, 96%, 98%, 99%, 99.5%, or 99.9% or more.

[0056] Polymer-encapsulated drug particles may contain a first ionic or amphoteric additive. The first ionic or amphoteric additive may be present on the polymer-encapsulated drug particles or in combination thereof, coated on the surface of the polymer-encapsulated drug particles. The first ionic or amphoteric additive may be homogeneously distributed within the particles (e.g., in the therapeutic agent within the encapsulating polymer), outside the particles (e.g., on the encapsulating polymer), or in combination thereof. The first ionic or amphoteric additive may be a coating on the surface of the polymer-encapsulated drug particles. The coating of the first ionic or amphoteric additive may be part of the polymer-encapsulated drug particles so that the coating of the first ionic or amphoteric additive can be taken into account in the particle dimensions when determining the maximum dimensions of the polymer-encapsulated drug particles. The polymer-encapsulated drug particles may contain one, two, three, or four or more first ionic or amphoteric additives, for example, one or two first ionic or amphoteric additives, for example, one first ionic or amphoteric additive. One or more first ionic or amphoteric additives may form an appropriate proportion of any of the polymer-encapsulated drug particles, 0.5 to 20% by weight, 1 to 10% by weight or 20% by weight or less, and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, or 18% by weight or more.

[0057] The first ionic or amphoteric additive may include cationic molecules, anionic additives, or amphoteric additives. The first ionic or amphoteric additive can increase the zeta potential (i.e., make the zeta potential more positive) of the polymer-encapsulated drug particles. A positive zeta potential of polymer-encapsulated drug particles can provide better adhesion to tissues and / or better drug delivery to tissues. For example, a positive zeta potential of polymer-encapsulated drug particles can attract amino groups in peptides or proteins and / or negatively charged lipids in the lipid bilayer of cell membranes (e.g., anions on the surface of cell membranes), resulting in better adhesion. Increased adhesion can extend the stay (or retention) of polymer-encapsulated drug particles on the walls of body lumens, leading to higher drug doses and / or a greater percentage of drug delivery to tissues. The first ionic or amphoteric additive may include charged polymers, charged lipids, phospholipids, phosphocholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and combinations thereof.

[0058] Two acyl groups in a charged lipid or two acyl groups in a charged phospholipid (e.g., an ester bonded to a triglyceride backbone) may include mismatched acyl groups that differ in one or more properties or characteristics. Mismatched acyl groups can differ in length, degree of saturation, substituents, substitution pattern, or combinations thereof. For example, both acyl groups may be saturated, one may be saturated and the other unsaturated, or both may be unsaturated. For example, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) has two unsaturated acyl chains, and 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine has an acyl group where one is saturated and the other is unsaturated. In embodiments including two unsaturated acyl groups, the unsaturated acyl groups may have double bonds at the same or different carbon positions, or may have multiple double bonds along the carbon chain at the same or different positions. Mismatched or matched acyl groups with different lengths, saturation levels, substituents, and substitution patterns can have different phase transition or softening temperatures. The phase transition or softening temperature of charged lipids can affect the properties of the coating, e.g., coating integrity, drying durability, rate of drug release from the coating, rate and / or degree of uptake into tissue, or a combination thereof. Lipids and phospholipids with high phase transition temperatures can lead to brittle coatings that crack and peel, potentially resulting in inconsistent drug dosing. Lipids and phospholipids with low phase transition temperatures can be difficult to handle, as they are wet and sticky, potentially leading to inconsistent drug dosing. The phase transition temperatures of charged lipids and phospholipids can be in the range of -70°C to 80°C. A preferred range for phase transition temperatures is -30°C to 50°C. The most preferred range for phase transition temperatures is -20°C to 40°C. In some embodiments, the coating is The coating may have a mixture of lipids and / or phospholipids that allows the phase transition temperature to be within a desirable range with desirable mechanical properties (dry and flexible, not viscous and not brittle).

[0059] The mismatched acyl groups of charged lipids or charged phospholipids can have lengths of C6–C34, for example, C6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34. In some embodiments, identical or different lengths of acyl groups having chain lengths of C6–C34 can create confusion, irregularity, and / or bends in the lipid bilayer of cell membranes to enhance drug penetration into tissues. In embodiments comprising charged lipids or phospholipids having mismatched acrylic groups of different lengths, the lengths of the two acyl groups may vary by the length of C1-C28, C1-C10, or C1-C8, or C1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or more, or C28. For example, two acyl groups of different lengths can have lengths such as C12 / C14, C12 / C16, C12 / C18, C12 / C20, C12 / C22, C12 / C24, C12 / C26, C14 / C16, C14 / C18, C14 / C20, C14 / C22, C14 / C24, C14 / C26, C16 / C18, C16 / C20, C16 / C22, C16 / C24, C16 / C26, C18 / C20, C18 / C22, C18 / C24, C18 / C26, C20 / C22, C20 / C24, C20 / C26, C22 / C24, C22 / C26, or C24 / C26.

[0060] Charged polymers include polycation-containing cyclodextrins, aminocyclodextrins or their derivatives, aminodextrans, histones, protamines, cationized human serum albumin, aminopolysaccharides, chitosan, peptides, poly-L-lysine, poly-L-ornithine, poly(4-hydroxy-L-proline ester), polyethyleneimine, polyallylamine, polypropyleneimine, polyamidoamine dendrimers, cationic polyoxazolines, poly(beta-aminoesters), PEG-PEI copolymers, PLGA-PEI copolymers, and positively charged gelatin (e.g., base-treated...). You can choose from processed gelatin, hydroxy-terminated poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), stearic acid-modified branched polyethyleneimine, branched PEI-g-PEG, poly(1-vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate, poly(1-vinylpyrrolidone)-graft-(1-triacontene), polylysine, polyarginine, poly(N,N-dimethylaminoethyl methacrylate), cationic copolymers of dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate (e.g., Eudragit E), anionic copolymers of methacrylic acid / methyl methacrylate (e.g., Eudragit L and / or Eudragit S), copolymers of ethyl acrylate / methyl methacrylate / methacrylic acid esters with quaternary ammonium groups (e.g., Eudragit RS and / or SR), and combinations thereof. An example of a methacrylate ester containing a quaternary ammonium group is trimethylammoniumethyl methacrylate chloride.

[0061] Charged lipids include 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (chloride salt), 1,2-distearoyl-sn-glycero-3-ethylphosphocholine (chloride salt), cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, 1,2-dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt, 1,2-dihexanoyl-sn-glycero-3-phosphocholine, and 1,2-dihepta Noyl-sn-glycero-3-phosphocholine, 1,2-dioctanoyl-sn-glycero-3-phosphocholine, 1,2-dinonanoyl-sn-glycero-3-phosphocholine, 1,2-decanoyl-sn-glycero-3-phosphocholine, 1,2-diundecanoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine Phosphorus, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine Choline (DOPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, diecosenoyl Phosphatidylcholine (1,2-diecosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonylphosphatidylcholine (1,2-diarachidonyl-sn-glycero-3-phosphocholine, C20:0 PC), diecoylphosphatidylcholine (1,2-diecoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-Didocosahexaenoyl-sn-glycero-3-phosphocholine (C22:6 PC), henocosenoyl phosphatidylcholine (1,2-henocosenoyl-sn-glycero-3-phosphocholine (C21:1 PC)), and dinerbonyl phosphatidylcholine (1,2-dinerbonoyl-sn-glycero-3-phosphocholine (C24:1 PC), or combinations thereof can be selected.)

[0062] The first ionic or amphoteric additive is 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (chloride salt), 1,2-distearoyl-sn-glycero-3-ethylphosphocholine (chloride salt), cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, 1,2-dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt, 1,2-dihexanoyl-sn-glycero-3-phosphocholine, 1,2-Diheptanoyl-sn-glycero-3-phosphocholine, 1,2-Dioctanoyl-sn-glycero-3-phosphocholine, 1,2-Dinonanoyl-sn-glycero-3-phosphocholine, 1,2-Decanoyl-sn-glycero-3-phosphocholine, 1,2-Diundecanoyl-sn-glycero-3-phosphocholine, 1,2-Dilauroyl-sn-glycero-3-phosphocholine, 1,2-Dimiristoyl-sn-glycero-3-phosphocholine Phosphorus, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOP C) The following can be selected: 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, and combinations thereof.

[0063] The first ionic or amphoteric additive may include or be a water-insoluble or slightly or partially water-insoluble additive containing at least one acyl group. The first ionic or amphoteric additive may have a molecular weight of 50 to 750, 750 to 100,000, or 750 to 50,000, or 750 to 10,000. The first ionic or amphoteric additive may have a lower melting temperature than the additive in its pure form. The first ionic or amphoteric additive may have a lower degree of crystallinity than that of the additive in its pure form.

[0064] Polymer-encapsulated drug particles can have either a suitable zeta potential, such as a negative zeta potential or a positive zeta potential. The zeta potential is the potential of the slip plane (i.e., at the interface that separates the mobile fluid from the fluid adhering to the particle's surface). The zeta potential of polymer-encapsulated drug particles can be measured by any suitable method, such as using electrophoretic light scattering (ELS) or electroacoustic measurements. Polymer-encapsulated drug particles can have positive zeta potentials such as greater than zero (0), 1 to 50, or 2 to 40, or less than or equal to 50, and greater than or equal to 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, or 45. Polymer-encapsulated drug particles can have negative zeta potentials, such as zeta potentials less than zero (0), or between -1 and -50, or between -2 and -40, or more positive than -50, or equal to -50, and more positive than or equal to -45, -40, -35, -30, -25, -20, -18, -16, -14, -12, -10, -8, -6, -5, -4, -3, -2, -1, or -0.5. A positive zeta potential of polymer-encapsulated drug particles can provide better adhesion to tissues and / or better drug transfer to tissues. For example, a positive zeta potential of polymer-encapsulated drug particles can attract amino groups in peptides or proteins and / or negatively charged lipids in the lipid bilayer in cell membranes (e.g., anions on the surface of cell membranes), resulting in better adhesion. Increased adhesion can extend the stay (or retention) of polymer-encapsulated drug particles on the walls of body lumens, leading to higher drug doses and / or a greater percentage of drug delivery to tissues. In embodiments of polymer-encapsulated drug particles containing a first ionic or amphoteric additive on or within them, the zeta potential of the polymer-encapsulated drug particles can be higher (i.e., more positive) than that of corresponding polymer-encapsulated drug particles that do not contain the first ionic or amphoteric additive. Polymer-encapsulated drug particles that are CPDEPs are polymer-encapsulated drug particles having a non-zero (0) zeta potential due to the presence of a first ionic or amphoteric additive, for example, inside the particle, on the particle surface, or a combination thereof, and / or the use of one or more charged polymers as the encapsulating polymer. The ionic or amphoteric additive in the CPDEP particles can migrate to the surface of the CPDEP and / or be applied to the surface of the CPDEP particles. The charged head of the ionic or amphoteric additive can be oriented away from the particle so that the zeta potential of the polymer-encapsulated drug particles is higher, and the hydrophobic tail can be oriented in the direction of the particle.

[0065] Polymer-encapsulated drug particles can have any suitable dimensions. A first ionic or amphoteric additive, if present, can be used in combination with the polymer to measure the particle size. Polymer-encapsulated drug particles can have a maximum dimension of 0.2 to 30 microns, or 0.5 to 5 microns, or 0.8 to 3 microns, 0.2 microns, 0.5, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, or 28 microns or larger.

[0066] Polymer-encapsulated drug particles can be polymer-encapsulated drug particles (PEDPs), charged polymer-encapsulated drug particles (CPEDPs), or a combination thereof. The positive charge density or zeta potential of CPEDPs can be higher (i.e., more positive) than that of PEDPs. The positive charge density or zeta potential of CPEDPs can be higher than that of the therapeutic agent in the absence of the polymer encapsulant. For polymer-encapsulated drug particles that are CPEDPs containing a first ionic or amphoteric additive, the positive charge density or zeta potential of the CPEDPs can be higher than that of the therapeutic agent in the absence of the first ionic or amphoteric additive.

[0067] Polymer-encapsulated drug particles may contain one or more antioxidants, such as BHT. One or more antioxidants may be mixed with the therapeutic agent during particle formation. One or more antioxidants may be in any appropriate proportion of the polymer-encapsulated drug particles, for example, 0.5 to 20% by weight, 1 to 10% by weight, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% or more by weight, but less than 20% by weight.

[0068] Polymer-encapsulated drug particles can be on any suitable surface intended for drug delivery to a target site, for example, on a medical device such as a balloon catheter, drug-coated catheter, drug-eluting stent, drug-eluting stent on a balloon, drug-eluting stent on a drug-coated balloon, stent on a drug-coated balloon, or a combination thereof. Polymer-encapsulated drug particles can be part of a coating on the medical device, and the coating is a drug-release coating.

[0069] Drug-releasing coating containing polymer-encapsulated drug particles Various embodiments of the present invention provide drug-releasing coatings. The drug-releasing coating comprises a therapeutic agent and polymer-encapsulated drug particles containing one or more polymers that encapsulate the therapeutic agent. Optionally, the polymer-encapsulated drug particles include a first ionic or amphoteric additive. The first ionic or amphoteric additive, if present, is present on the polymer-encapsulated drug particles or a combination thereof, coated on the surface of the polymer-encapsulated drug particles. In some embodiments, the polymer-encapsulated drug particles include a first ionic or amphoteric additive. In other embodiments, the polymer-encapsulated drug particles do not include a first ionic or amphoteric additive. The drug-releasing coating also includes a release matrix containing a second ionic or amphoteric additive. Any coating containing a drug referenced herein (e.g., a drug coating or drug coating layer) may be or contain polymer-encapsulated drug particles.

[0070] Polymer-encapsulated drug particles can be homogeneously dispersed in a release matrix. Polymer-encapsulated drug particles can be formed in appropriate proportions of any of the drug release coatings, for example, 10% to 90% by weight, 10% to 80% by weight, 25% to 70% by weight, 40% to 60% by weight, or 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% by weight or more, up to 90% by weight.

[0071] The release matrix may include therapeutic particles that are not encapsulated by polymers (i.e., polymers of polymer-encapsulated drug particles), such as crystalline particles of the therapeutic. In other embodiments, the release matrix may be substantially free of therapeutic particles that are not encapsulated by polymers. The therapeutic particles that are not encapsulated by polymers may form an appropriate proportion of any of the drug-release coatings, 0.001% to 50% by weight, or 1% to 20% by weight, or 1% to 10% by weight, 0.001% or more, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, or 45% or more by weight. The therapeutic particles that are not encapsulated by polymers may be homogeneously distributed (or dispersed) in the release matrix.

[0072] The second ionic or amphoteric additive may have the same molecular structure as the first ionic or amphoteric additive, or it may have a different molecular structure from the first ionic or amphoteric additive. The drug-release coating may contain one, two, three, or four or more second ionic or amphoteric additives, for example, one or two second ionic or amphoteric additives, for example, two second ionic or amphoteric additives. One or more second ionic or amphoteric additives may form an appropriate proportion of any of the drug-release coatings, for example, 10-80% by weight, 40-60% by weight, or 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75% by weight or less.

[0073] The second ionic or amphoteric additive may include cationic molecules, anionic additives, or amphoteric additives. The second ionic or amphoteric additive may increase the zeta potential of the drug-release coating (i.e., make it more positive), which can increase the adhesion of the drug-release coating to tissues and / or increase the rate of drug transfer from the coating to the tissues. For example, a positive zeta potential of the drug-release coating can attract amino groups in peptides or proteins and / or negatively charged lipids in the lipid bilayer in cell membranes (e.g., anions on the surface of the cell membrane), resulting in better adhesion. Increased adhesion can extend the stay of the drug-release coating on the walls of body lumens, leading to higher drug doses and / or a greater rate of drug delivery to tissues. The second ionic or amphoteric additive may include charged polymers, charged lipids, phospholipids, phosphocholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and combinations thereof. A second ionic or amphoteric additive can migrate to the surface of the drug-releasing coating. The charged head of the ionic or amphoteric additive can be oriented away from the coating so that the zeta potential of the coating is higher, and the hydrophobic tail is oriented in the direction of the coating.

[0074] Two acyl groups in a charged lipid or two acyl groups in a charged phospholipid (e.g., an ester bonded to a triglyceride backbone) may include mismatched acyl groups that differ in one or more properties or characteristics. Mismatched acyl groups can differ in length, degree of saturation, substituents, substitution patterns, or combinations thereof. For example, both acyl groups may be saturated, one may be saturated and the other unsaturated, or both may be unsaturated. For example, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) has two unsaturated acyl chains, and 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine has an acyl group where one is saturated and the other is unsaturated. In embodiments including two unsaturated acyl groups, the unsaturated acyl groups may have double bonds at the same or different carbon positions, or may have multiple double bonds along the carbon chain at the same or different positions. Mismatched or matched acyl groups with different lengths, saturation levels, substituents, and substitution patterns can have different phase transition or softening temperatures. The phase transition or softening temperature of charged lipids can affect the properties of the coating, e.g., coating integrity, drying durability, rate of drug release from the coating, rate and / or degree of uptake into tissue, or a combination thereof. Lipids and phospholipids with high phase transition temperatures can lead to brittle coatings that crack and peel, potentially resulting in inconsistent drug dosing. Lipids and phospholipids with low phase transition temperatures can be difficult to handle, as they are wet and sticky, potentially leading to inconsistent drug dosing. The phase transition temperatures of charged lipids and phospholipids can be in the range of -70°C to 80°C. A preferred range for phase transition temperatures is -30°C to 50°C. The most preferred range for phase transition temperatures is -20°C to 40°C. In some embodiments, the coating is The coating may have a mixture of lipids and / or phospholipids that allows the phase transition temperature to be within a desirable range with desirable mechanical properties (dry and flexible, not viscous and not brittle).

[0075] The mismatched acyl groups of charged lipids or charged phospholipids can have lengths of C6–C34, for example, C6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34. In some embodiments, identical or different lengths of acyl groups having chain lengths of C6–C34 can create confusion, irregularity, and / or bends in the lipid bilayer of cell membranes to enhance drug penetration into tissues. In embodiments comprising charged lipids or phospholipids having mismatched acrylic groups of different lengths, the lengths of the two acyl groups may vary by the length of C1-C28, C1-C10, or C1-C8, or C1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or more, or C28. For example, two acyl groups of different lengths can have lengths such as C12 / C14, C12 / C16, C12 / C18, C12 / C20, C12 / C22, C12 / C24, C12 / C26, C14 / C16, C14 / C18, C14 / C20, C14 / C22, C14 / C24, C14 / C26, C16 / C18, C16 / C20, C16 / C22, C16 / C24, C16 / C26, C18 / C20, C18 / C22, C18 / C24, C18 / C26, C20 / C22, C20 / C24, C20 / C26, C22 / C24, C22 / C26, or C24 / C26.

[0076] Charged polymers include polycation-containing cyclodextrins, aminocyclodextrins or their derivatives, aminodextrans, histones, protamines, cationized human serum albumin, aminopolysaccharides, chitosan, peptides, poly-L-lysine, poly-L-ornithine, poly(4-hydroxy-L-proline ester), polyethyleneimine, polyallylamine, polypropyleneimine, polyamidoamine dendrimers, cationic polyoxazolines, poly(beta-aminoesters), PEG-PEI copolymers, PLGA-PEI copolymers, and positively charged gelatin (e.g., base-treated...). You can choose from processed gelatin, hydroxy-terminated poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), stearic acid-modified branched polyethyleneimine, branched PEI-g-PEG, poly(1-vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate, poly(1-vinylpyrrolidone)-graft-(1-triacontene), polylysine, polyarginine, poly(N,N-dimethylaminoethyl methacrylate), cationic copolymers of dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate (e.g., Eudragit E), anionic copolymers of methacrylic acid / methyl methacrylate (e.g., Eudragit L and / or Eudragit S), copolymers of ethyl acrylate / methyl methacrylate / methacrylic acid esters with quaternary ammonium groups (e.g., Eudragit RS and / or SR), and combinations thereof. An example of a methacrylate ester containing a quaternary ammonium group is trimethylammoniumethyl methacrylate chloride.

[0077] Charged lipids include 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (chloride salt), 1,2-distearoyl-sn-glycero-3-ethylphosphocholine (chloride salt), cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, 1,2-dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt, 1,2-dihexanoyl-sn-glycero-3-phosphocholine, and 1,2-dihepta Noyl-sn-glycero-3-phosphocholine, 1,2-dioctanoyl-sn-glycero-3-phosphocholine, 1,2-dinonanoyl-sn-glycero-3-phosphocholine, 1,2-decanoyl-sn-glycero-3-phosphocholine, 1,2-diundecanoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine Phosphorus, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine Choline (DOPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, diecosenoyl Phosphatidylcholine (1,2-diecosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonylphosphatidylcholine (1,2-diarachidonyl-sn-glycero-3-phosphocholine, C20:0 PC), diecoylphosphatidylcholine (1,2-diecoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-Didocosahexaenoyl-sn-glycero-3-phosphocholine (C22:6 PC), henocosenoyl phosphatidylcholine (1,2-henocosenoyl-sn-glycero-3-phosphocholine (C21:1 PC)), and dinerbonyl phosphatidylcholine (1,2-dinerbonoyl-sn-glycero-3-phosphocholine (C24:1 PC), or combinations thereof can be selected.)

[0078] The second ionic or amphoteric additive is 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (chloride salt), 1,2-distearoyl-sn-glycero-3-ethylphosphocholine (chloride salt), cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, 1,2-dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt, 1,2-dihexanoyl-sn-glycero-3-phosphocholine, 1,2-Diheptanoyl-sn-glycero-3-phosphocholine, 1,2-Dioctanoyl-sn-glycero-3-phosphocholine, 1,2-Dinonanoyl-sn-glycero-3-phosphocholine, 1,2-Decanoyl-sn-glycero-3-phosphocholine, 1,2-Diundecanoyl-sn-glycero-3-phosphocholine, 1,2-Dilauroyl-sn-glycero-3-phosphocholine, 1,2-Dimiristoyl-sn-glycero-3-phosphocholine Phosphorus, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOP C) The following can be selected: 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, and combinations thereof.

[0079] The second ionic or amphoteric additive may include or be a water-insoluble or slightly or partially water-insoluble additive containing at least one acyl group. The second ionic or amphoteric additive may have a molecular weight of 50-750, 750-100,000, 750-50,000, or 750-10,000. The second ionic or amphoteric additive may have a lower melting temperature than that of the pure form of the additive. The second ionic or amphoteric additive may have a lower degree of crystallinity than that of the pure form of the additive.

[0080] The drug-release coating can be on any suitable surface intended for drug delivery to a target site, for example, on a medical device such as a balloon catheter, drug-coated catheter, drug-eluting stent, drug-eluting stent on a balloon, drug-eluting stent on a drug-coated balloon, stent on a drug-coated balloon, or a combination thereof.

[0081] A method for treating or preventing non-vascular or vascular stenosis or stenosis, comprising using a medical device containing polymer-encapsulated drug particles. Various embodiments provide methods for treating or preventing nonvascular or vascular stenosis or stenosis. The methods include inserting a catheter containing a balloon or stent into a body lumen, wherein the balloon or stent includes a drug-releasing coating containing polymer-encapsulated drug particles containing a therapeutic agent and one or more polymers encapsulating the therapeutic agent, or polymer-encapsulated drug particles. The methods may include inflating the balloon or stent to bring the coating layer into contact with the area of ​​stenosis, stenosis, or the area where stenosis or stenosis is to be prevented. If a balloon is used, the methods may include compressing the balloon or stent. Also, if a balloon is used, the methods may include removing the balloon from the body lumen. If a stent is used, it may be either a self-expanding or balloon-expandable stent.

[0082] Method for preparing polymer-encapsulated drug particles and / or drug-release coatings. Various embodiments provide a method for producing polymer-encapsulated drug particles comprising a therapeutic agent and one or more polymers that encapsulate the therapeutic agent. The method comprises forming a suspension comprising the therapeutic agent and polymers. The suspension may contain insoluble solid therapeutic agent particles. The method comprises treating the suspension to reduce its particle size. The method also comprises adding an aqueous premix to the suspension to form polymer-encapsulated drug particles in the suspension. The polymer-encapsulated drug particles may be the final product or may be an intermediate in further steps taken to achieve a particular embodiment of the polymer-encapsulated drug particles of the present invention.

[0083] The treatment may be any suitable treatment that reduces the particle size of the suspension. The treatment may include sonication. The method may further include adding a first ionic or amphoteric additive to the suspension or the formed polymer-encapsulated drug particles to coat the particles thereon. The method may further include forming a suspension comprising a therapeutic agent, a polymer and a first ionic or amphoteric additive such that the formed polymer-encapsulated drug particles contain the first ionic or amphoteric additive in, on, or in combination with the first ionic or amphoteric additive.

[0084] The method may be a method for forming a drug-release coating comprising polymer-encapsulated drug particles and a release matrix. The method may further include adding a second ionic or amphoteric additive to the suspension, optionally stirring the suspension to homogeneously distribute the polymer-encapsulated drug particles, and drying the suspension to form a drug-release coating.

[0085] A method for preparing polymer-encapsulated drug particles may include forming an organic premix comprising an organic solvent, one or more polymers, a therapeutic agent, and optionally a first ionic or amphoteric additive. The method may also include forming an aqueous premix comprising water and a water-soluble polymer or surfactant. The method may also include adding an organic solvent to the aqueous premix. In some embodiments, the organic solvent in the organic premix and the organic solvent added to the aqueous premix are the same organic solvent. The organic solvent in the organic premix and the organic solvent added to the aqueous premix may be polar organic solvents. The method may also include combining the aqueous premix and the organic premix. The method may also include stirring the combined aqueous premix and organic premix to form an emulsion containing polymer-encapsulated drug particles. The method may also include adding water to the emulsion containing the polymer-encapsulated drug particles to cure the formed polymer-encapsulated drug particles. The method may also include separating the polymer-encapsulated drug particles from the combined aqueous premix and organic premix. The method may also include washing the polymer-encapsulated drug particles with an aqueous liquid, drying the polymer-encapsulated drug particles, or a combination thereof. The aqueous liquid used for cleaning may optionally contain one or more water-soluble additives, such as any of the water-soluble additives described herein or ionic or amphoteric additives, which can coat polymer-encapsulated drug particles during cleaning. Coating of polymer-encapsulated drug particles during cleaning can alter the zeta potential of the polymer-encapsulated drug particles.

[0086] The organic solvents in the organic premix and the organic solvents added to the aqueous premix may independently be: (a) alkanes such as hexane, octane, cyclohexane, and heptane; (c) aromatic solvents such as benzene, toluene, and xylene; (d) alcohols such as ethanol, propanol, isopropanol, diethylamide, ethylene glycol monoethyl ether, transktol, and benzyl alcohol; (f) esters / acetates such as ethyl acetate and isobutyl acetate; (e) ethers such as dioxane, dimethyl ether, and tetrahydrofuran; (g) ketones such as acetone, acetonitrile, diethyl ketone, and methyl ethyl ketone; and (h) chlorinated solvents such as chloroform or methylene chloride.

[0087] The water-soluble polymer or surfactant of the aqueous premix may be any suitable water-soluble polymer or surfactant, such as any of the water-soluble polymers or surfactants disclosed herein, such as polyvinyl alcohol, polyethylene glycol, phosphatidylcholine or a combination thereof. The water-soluble polymer or surfactant may be N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-amino-propyl)amino]butylcarboxyamide)ethyl]-3,4-di[oleyloxy]-benzamide, 1,2-di-O-octadekenyl-3-trimethylammonium propane (chloride salt)), 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dioleoyl-3-trimethylammonium-propane (chloride salt), N 4These can be -cholesteryl-spermine HCl salt, 1,2-dioleyloxy-3-dimethylaminopropane, calcidiol, cholecalciferol, 1α and 25-dihydroxyvitamin D3, poly(1-vinylpyrrolidone)-graft-(1-triaconten), poly(1-vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate), poly2-dimethylaminoethyl methacrylate, branched PEI-g-PEG, stearic acid-modified branched polyethyleneimine, poly(2-ethyl-2-oxazoline), hydroxy-terminated poly(2-methyl-2-oxazoline), 1-stearoyl-sn-glycero-3-phosphocholine, poly(2-(dimethylamino)ethyl methacrylate), iodide acetylcholine, acetylcholine chloride, or combinations thereof.

[0088] The emulsion formed from a combination of organic and aqueous premixes can be a coacervate of organic solvent and water, with the dispersed phase being the organic solvent. Adding water to the coacervate solution can cure the polymer-encapsulated drug particles and drive the organic solvent out of the continuous aqueous phase. The mixing used to form the emulsion can be any suitable agitation, e.g., an ultrasonic bath or probe, a rotor starter, flow through a packed bed, a stirring rod, an eductor funnel, a mill type, a homogenizer, or an overhead impeller type. Collection of the polymer-encapsulated drug particles can include any suitable recovery method, such as filtration or centrifugation. During collection, the particles can be washed with an aqueous liquid. The aqueous washing solution may optionally contain one water-soluble additive, e.g., any water-soluble additive described herein or an ionic or amphoteric additive, which can coat the polymer-encapsulated drug particles during washing. Coating of the polymer-encapsulated drug particles during washing can alter the zeta potential of the polymer-encapsulated drug particles. Drying of the particles can include spray drying, vacuum drying, sublimation, or evaporation. The formed polymer-encapsulated drug particles can be optionally used to prepare drug coating solutions for the formation of drug-releasing coatings.

[0089] A method for forming a drug-release coating may include forming a first mixture comprising polymer-encapsulated drug particles and an organic solvent. The first mixture may be a dispersion of polymer-encapsulated drug particles in an organic solvent, which is prepared, for example, via a suitable mixing method, such as sonic probe mixing, stirring rod, vortexer, overhead stirrer, or rotor stirrer. The method may also include forming a second mixture comprising a second ionic or amphoteric additive and an organic solvent. The method may also include combining the first and second mixtures. In some embodiments, the organic solvents of the first and second mixtures are nonpolar organic solvents such as hexane, cyclohexane, heptane, or pentane. In some embodiments, the organic solvents of the first and second mixtures are the same organic solvent. The method may also include drying the combination of the first and second mixtures to form a drug-release coating. Prior to drying, the combination of the first and second mixtures may be stirred to homogeneously disperse the polymer-encapsulated drug particles therein.

[0090] The second ionic or amphoteric additive used to form the drug-releasing coating is any suitable material described herein, e.g., phospholipids, e.g., 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (chloride salt), 1,2-distearoyl-sn-glycero-3-ethylphosphocholine (chloride salt), cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid in a nonpolar solvent such as hexane, cyclohexane, heptane, or pentane. , 1,2-dilauroyl-sn-glycero-3-phosphoglycerol (sodium salt), 1,2-dihexanoyl-sn-glycero-3-phosphocholine, 1,2-dheptanoyl-sn-glycero-3-phosphocholine, 1,2-dioctanoyl-sn-glycero-3-phosphocholine, 1,2-dinonanoyl-sn-glycero-3-phosphocholine, 1,2-decanoyl-sn-glycero-3-phosphocholine, 1,2-diundecanoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl Royl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-diol The phospholipids may be oleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, or combinations thereof. The second premix may be heated to ensure that the phospholipids are completely dissolved. The second premix may then be allowed to cool once it has been heated, and then it may be added to the first premix.The final mixture of the two mixtures can be thoroughly mixed by any suitable mixing method, such as sonic probe mixing, stirring rods, vortex stirrers, overhead stirrers, or rotor starters.

[0091] Method for preparing a balloon catheter containing polymer-encapsulated drug particles Various embodiments of the present invention provide a method for preparing a balloon catheter. The method includes applying polymer-encapsulated drug particles, which contain a therapeutic agent and one or more polymers that encapsulate a therapeutic agent or drug-release coating containing the same substance to the outside of the balloon of the balloon catheter.

[0092] Drug-coated balloon catheter The balloon catheters described throughout this application may include a coating layer containing a therapeutic agent and polymer-encapsulated drug particles comprising one or more polymers that encapsulate the therapeutic agent; or a drug-release coating containing polymer-encapsulated drug particles; or a composition; or a combination thereof. The composition may include a therapeutic agent; or a first additive; or a second additive; or a combination thereof. The therapeutic agent may be selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs, and combinations thereof. The therapeutic agent may have a particle size of 0.2 to 10 microns. The first additive may include a water-insoluble or partially water-insoluble additive containing at least one alkylaliphatic group or cholesteryl group. The first additive may have a molecular weight of 50 to 750. The second additive may be more hydrophilic or more water-soluble than the first additive and may contain polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The second additive may have a molecular weight in the range of 750 to 100,000.

[0093] The balloon catheter may be any suitable balloon catheter described herein. The balloon of the balloon catheter may include polyester, polyamide, nylon 12, nylon 11, polyamide 12, polyether and polyamide block copolymers, polyether block amide, polyurethane, polyether and polyester block copolymers, or combinations thereof.

[0094] Balloon catheters can be used to deliver therapeutic agents to stenoses or narrowings of body lumens, which are selected from urethral stenosis, prostatic urethral stenosis, ureteral stenosis, esophageal stenosis, sinus stenosis, gastric stenosis, small bowel stenosis, colon stenosis, rectal stenosis, large bowel stenosis, bladder neck stenosis, biliary stenosis, vaginal stenosis, in-stent restenosis, coronary artery stenosis, superficial femoral artery stenosis, popliteal artery stenosis, anterior tibial artery stenosis, posterior tibial artery stenosis, and peroneal artery stenosis.

[0095] Balloon catheters can be used to deliver therapeutic agents to target sites in the body lumen, which are selected from urethral strictures, prostatic urethral strictures, ureteral strictures, esophageal strictures, sinus strictures, gastric strictures, small bowel strictures, colon strictures, rectal strictures, large bowel strictures, bladder neck strictures, bile duct strictures, vaginal strictures, in-stent restenosis, coronary artery strictures, superficial femoral artery strictures, popliteal artery strictures, anterior tibial artery strictures, posterior tibial artery strictures, and peroneal artery strictures.

[0096] In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a target site of stenosis or narrowing of a body cavity, wherein the balloon comprises polyester, polyamide, nylon 12, nylon 11, polyamide 12, polyether and polyamide block copolymers, polyether block amide, polyurethane, polyether and polyester block copolymers, or combinations thereof. In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a target site of stenosis of a body cavity, wherein the balloon catheter comprises a drug coating overlapping the outer surface of the balloon. The coating may include polymer-encapsulated drug particles containing the therapeutic agent and one or more polymers that encapsulate the therapeutic agent; or a drug-release coating containing polymer-encapsulated drug particles; or a composition containing the therapeutic agent and one or more additives; or combinations thereof. The composition may include an initial drug load of the therapeutic agent and one or more water-insoluble or slightly or partially water-insoluble additives and one more water-soluble additive. The therapeutic agent can be selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs, and combinations thereof. The therapeutic agent can be crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. The particle size of the therapeutic agent can be in the range of 0.2 to 10 μm, or preferably 0.2 to 5 μm. The first additive, the second additive, or a combination thereof can encapsulate the therapeutic agent, and the therapeutic agent encapsulated in the additive can have a larger particle size than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive during coating can be in the range of 0.3 microns to 10 microns. The first additive may include a water-insoluble or slightly or partially water-insoluble additive containing at least one alkylaliphatic group or cholesteryl group. The first additive may have a molecular weight of 50 to 750. Water-insoluble additives in coatings may have a lower melting temperature than their pure form. Water-insoluble additives in coatings may have a lower degree of crystallinity than their pure form.Water-soluble additives can be more hydrophilic or more water-soluble than water-insoluble or slightly or partially water-insoluble additives. Water-soluble additives may contain polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. Second additives may have molecular weights in the range of 750 to 100,000, or 750 to 50,000, or 750 to 10,000.

[0097] Water-insoluble or slightly or partially water-insoluble additives can be selected from cholesteryl acetate, cholesteryl phenylacetate, cholesteryl laurate, cholesteryl palmitate, cholesteryl stearate, cholesteryl n-valerate, cholesteryl benzoate, cholesteryl heptylate, cholesteryl decylate, cholesteryl caproate, cholesteryl oleate, cholesteryl oleyl carbonate, cholesteryl linoleate, cholesteryl pelargonate, cholesteryl erucate, cholesteryl caprylate, 5α-cholestane, and 5α-cholestane-3-one. The first additive, which is water-insoluble or slightly or partially water-insoluble and has an alkyl aliphatic group, can be selected from alkyl glyceryl ethers, monoglycerides of C8-C12 fatty acids, alkyl alcohols, alkyl ethers, alkyl esters, caprylic acid, monocaprylin, capric acid, monocaprin, lauric acid, dodecylglycerol, butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid You can choose from phospholipids, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di-, or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha-tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobi and their derivatives and combinations thereof.

[0098] The second water-soluble additive is polyoxyethanol α-tocopheryl sebacate, methylated polyethylene glycol cholesterol (mPEG cholesterol), PEG amide ether cholesterol, PEG amide ester cholesterol, mPEG amide ether cholesterol, mPEG amide ester cholesterol, DSPE-PEG-cholesterol, PEG-modified phospholipids, methylated PEG-modified phospholipids, PEG-caprylic acid / capric acid diglyceride, PEG-8-caprylic acid / capric acid glyceride, and caprylic acid P. EG, PEG caprate, PEG caproate, PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), PEG-20 sorbitan monooleate (Tween-80), PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG-30 glyceryl oleate, polyglyceryl fatty acid ester, polyglyceryl oleate, (Plurol Polyglyceryl-2 Dioleate (Nikkol DGDO), Polyglyceryl-10 Trioleate, Polyglyceryl Stearate, Polyglyceryl Laurate, Polyglyceryl Myristate, Polyglyceryl Palmitate, Polyglyceryl Linoleate, Polyglyceryl-10 Laurate, Polyglyceryl-10 Oleate, Mono / Polyglyceryl-10 Dioleate (CaproI (Trademark) PEG) 860), Polyglyceryl-10 stearate, Polyglyceryl-10 laurate, Polyglyceryl-10 myristate, Polyglyceryl-10 palmitate, Polyglyceryl-10 linoleate, Polyglyceryl-6 stearate, Polyglyceryl-6 laurate, Polyglyceryl-6 myristate, Polyglyceryl-6 palmitate, Polyglyceryl-6 linoleate, Polyethylene glycol (PEG)-cholesteryl sebacate (disebacate diester bond, cholesterol, water-soluble, CAS 69068-97-9):

[0099] [ka]

[0100] Polyethylene glycol cholesterol (ether bond, cholesterol-(polyethylene glycol-600):

[0101] [ka]

[0102] PEG amide ester cholesterol (ester amide bond, hydroxyl-terminated PEG cholesterol, various molecular weights):

[0103] [ka]

[0104] PEG amide ether cholesterol (methyl-terminated, amide ether bond, MW=550, 1K, 2K, 5K, 10K, 20K, 30K, 40K):

[0105] [ka]

[0106] mPEG amide ester cholesterol (methyl-terminated, amide ester bond, MW=550, 1K, 2K, 5K, 10K, 20K, 30K, 40K):

[0107] [ka]

[0108] DSPE-PEG-cholesterol:

[0109] [ka]

[0110] Or a combination of those may be included.

[0111] In one embodiment, the concentration density of at least one therapeutic agent applied to the surface of a medical device is approximately 1 to 20 μg / mm³. 2 , or approximately 2-6 μg / mm³ 2 , or approximately 0.5 micrograms / mm³ 2 , or less or greater than approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, or approximately 20 micrograms / mm³ 2 That concludes the explanation. If the medical device is a balloon, these measurements are calculated using the nominal diameter. In embodiments of the present invention, the weight-to-additive-to-drug ratio in the coating layer can be about 20:0.05, about 10:0.1, or about 6:0.15.

[0112] The weight ratio of the therapeutic agent in the coating layer to the total weight of one or more additives in the coating layer may be approximately 0.05 to approximately 20, approximately 0.1 to approximately 10, approximately 0.1 to approximately 5, approximately 0.5 to approximately 8, approximately 0.5 to approximately 3, approximately 2 to approximately 6 or approximately 0.05 or less, or less or greater than approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or approximately 20 or more.

[0113] The present invention provides novel drug-coated balloon catheters and their uses. The novel method opens the lumen and prevents, reduces, or minimizes restenosis and recurrent non-vascular or vascular stenosis. The lumen of the tube includes any lumen containing arteries, veins, or blood. Non-vascular lumens include those lumens that do not contain blood. The method involves using a medical device in the lumen that includes a drug coating. The coating may include polymer-encapsulated drug particles containing a therapeutic agent and one or more polymers that encapsulate the therapeutic agent; or a drug-releasing coating containing polymer-encapsulated drug particles; or a composition containing a therapeutic agent and one or more additives; or a combination thereof. The drug coating may have more than one layer and may contain an effective amount of therapeutic agent (e.g., paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, umilolimus, mTOR inhibitors, or their analogues) for delivery to stenosis or narrowing of body cavities, one or more water-soluble additives, and one or more water-insoluble or partially water-soluble additives. The treatment is intended for a variety of animals, from premature neonates to human adults.

[0114] Unless otherwise specified, the stretch ratio is defined herein as the ratio of the nominal diameter of the balloon to the diameter of the body lumen within the area treated by the balloon catheter. The nominal diameter of the balloon is the diameter achieved by the balloon in an unrestricted environment at nominal pressure. The lumen diameter is the average diameter of the stenosis or stenosis, or lesion of the lumen. For the urinary tract, for example, in the urethra and prostatic urethra, the body lumen diameter would be the average diameter of the urethra from which the obstructed body lumen is excreted. The inflated balloon diameter may be the actual diameter of the balloon after inflation, which in some embodiments may be equal to, less than, or greater than, the nominal diameter of the balloon. In various embodiments, the stretch ratio of the balloon catheter of the present invention makes it more effective than other catheters for treating non-vascular lumens. During the performance of the method of the present invention, the stretch ratio may be selected to be any suitable ratio to achieve the desired ratio of the actual inflated balloon diameter to the lumen diameter within the range of pressures used in the method.In various embodiments, the balloon's extension ratio is approximately 1.0-40, 1.1-40, 1.2-40, 1.3-40, or 1.4-40 (for example, 1 or 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 1 The expansion ratio can be greater than or less than 2, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or less than or equal to 40 or any value in between; as a result of such an expansion ratio, the desired ratio of the expanded balloon diameter to the lumen diameter at the pressure used during the expansion period can be the same, similar, or different from the expansion ratio, for example, about 1.0~40, 1.1~40, 1.2~40, 1.3~40 or 1.4~40 (for example, 1 or 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3. It can result in values ​​greater than or less than 5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 or less, or any value in between.

[0115] Various embodiments of the present invention relate to coated medical devices. The devices include one of the following: balloon catheters, fixed wire balloon catheters, wire balloon catheters, rapid replacement balloon catheters, perfusion balloon catheters, double-spaced balloons, cut balloon catheters, scoring balloon catheters, or infusion catheters (e.g., distally perforated drug infusion tubes arranged at regular intervals, perforated balloons, double-spaced balloons, porous balloons, or weeping balloons). In one embodiment, as shown in Figure 1, the medical device is a balloon catheter. The balloon catheter can be any suitable catheter for any desired use, including a conventional cylindrical balloon catheter known to those skilled in the art. For example, the balloon catheter 10 may include an expandable and inflatable balloon 12 at the distal end of the catheter 10, a handle assembly 16 at the proximal end of the catheter 10, and an extendable flexible member 14 extending between the proximal and distal ends. The handle assembly 16 can connect to and / or receive one or more suitable medical devices, e.g., an inflation medium (e.g., air, Seline, or contrast agent). The flexible member 14 may be a tube made of a suitable biocompatible material and having one or more lumens therein. At least one lumen is configured to receive an inflation medium for its expansion and to pass such medium to the balloon 12. The balloon catheter may be a rapid-replacement or over-the-wire catheter and may be made of any suitable biocompatible material. The material of the balloon 12 may include one or more of polyester, polyamide, nylon 12, nylon 11, polyamide 12, polyether and polyamide block copolymers, PEBAX®, polyurethane and polyether and polyester block copolymers.The balloon catheter shaft can be constructed from any other semi-compliant or non-compliant polymer, including polyetheramide block copolymers, polyamides, nylon, polyester, polyethylene terephthalate, or blends thereof. Alternatively, the balloon catheter shaft can be constructed using rigid materials such as stainless steel, polycarbonate, titanium, PEEK (polyetheretherketone), or other rigid, biocompatible materials.

[0116] In some embodiments, the balloon may include one neck portion and not the other, such that the balloon includes two main parts separated by one neck portion. The one neck portion may have any suitable position on the balloon, such as being approximately in the center with respect to the balloon or being off-center with respect to the balloon. The one neck portion may be off-center with respect to the length of the balloon and may be at the distal end of the balloon. An embodiment of a balloon including one neck portion off-center with respect to the length of the balloon is shown in Figure 3A.

[0117] In some embodiments, the balloon may have two neck sections, with no other, such that the balloon contains three rounded lobes separated by the two neck sections. The two neck sections may have approximately the same diameter, or one neck section may have a smaller diameter than the other. The two neck sections may be positioned symmetrically or asymmetrically with respect to the center of the balloon's length. The three lobes may have approximately equal lengths, or they may have different lengths. Figure 3B shows an embodiment of a balloon catheter having two neck sections with three lobes, where the neck sections are positioned symmetrically with respect to the center of the balloon's length, and the three lobes of the balloon are approximately the same length. During use, the distal neck section (e.g., the distal end of the balloon catheter initially inserted into the body) may be positioned to tether the balloon to the bladder neck, while the proximal neck section may be positioned in the prostatic urethra. The distal neck portion of the balloon catheter, which is initially inserted into the body, can be located by tethering the balloon to the bladder neck. The proximal neck portion, on the other hand, can be positioned in the prostatic urethra. In some embodiments, the distal main portion of the balloon catheter may be devoid of the therapeutic agent.

[0118] In some embodiments, the balloon may include three necks and not include other neck sections, such that the balloon comprises four sections separated by the three necks. The three neck sections may be arranged in any suitable way along the length of the balloon. The four main sections formed by the three neck sections may have equal or different lengths. The three neck sections may have equal or different diameters. In some embodiments, two of the neck sections have equal diameters smaller than the diameters of the other neck sections. Figure 3C shows an embodiment of a balloon catheter having three neck sections with four main sections, each having approximately equal length, where two of the neck sections have equal diameters smaller than the diameters of the other neck sections.

[0119] In various embodiments, the present invention provides a balloon catheter for delivering a therapeutic agent to a target site in a body lumen. The balloon catheter may include an elongated balloon having a plurality of main or body, parts and at least one neck portion having a diameter smaller than the main part. The balloon catheter may include an elongated balloon having a main diameter, or a plurality of main portions having an average diameter equal to the main diameter. A segmented balloon with smaller diameter neck portions mechanically tethers the balloon within a body lumen; thus, it can prevent the balloon from slipping within the body lumen. If the balloon slips away from the targeted diseased site, it can be missed, potentially damaging a healthy lumen. The balloon catheter may include at least one neck portion on the balloon having a diameter smaller than the main diameter. The balloon catheter may also include a coating layer overlapping the outer surface of the balloon. The coating may include a therapeutic agent and polymer-encapsulated drug particles containing one or more polymers that encapsulate the therapeutic agent; or a drug-release coating containing polymer-encapsulated drug particles; or a composition containing a therapeutic agent and one or more additives; or a combination thereof. The coating layer may contain one or more water-soluble additives and one or more water-insoluble or partially water-soluble additives, and an initial drug load of therapeutic agents (e.g., paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, their analogs and combinations thereof).In a method using a balloon catheter, features (a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or (a), (b), and (c) may exist: (a) the ratio of the inflated balloon diameter to the lumen diameter of the stenosis or stenosis at the target site is approximately 1.0 to approximately 40; or (b) inflation involves inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the elongation ratio of the nominal diameter of the balloon catheter to the lumen diameter of the stenosis or stenosis at the target site is approximately 1.0 to approximately 40; or (c) inflation involves inflating to a pressure greater than the nominal pressure of the balloon catheter, and the nominal diameter of the balloon catheter is less than the inflated balloon diameter; or (d) a combination of (a), (b), and (c).

[0120] When a balloon is inflated, the primary diameter of the balloon may be the diameter of the main part of the balloon. In some embodiments, the inflated pressure used to determine the primary diameter may be any pressure that removes any folded or crimped areas of the balloon and achieves tension in the balloon. The inflated pressure used to determine the primary diameter is the pressure at which the inflated balloon has a shape and size corresponding to the desired shape and size of the balloon during the intended procedure in a body lumen. The inflated pressure used to determine the primary diameter may be the nominal pressure of the balloon at which the nominal diameter of the balloon catheter is equal to the primary diameter of the balloon.

[0121] In one embodiment, a drug-coated balloon includes two main sections at both ends having the same diameter, one neck section with a smaller diameter between the two main sections, and two cones in the proximal and distal balloon body. A balloon catheter includes at least one neck section on the balloon having a diameter smaller than the balloon diameter of the main sections. A balloon catheter may include an elongated cylindrical balloon having a plurality of compartments with varying diameters. Features (a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or (a) and (b) and (c), may exist: (a) the ratio of the inflated balloon diameter to the body lumen diameter of the target site is about 1.0 to about 40; or (b) inflation involves inflating the balloon to a pressure greater than or equal to the nominal pressure of the balloon catheter, and the elongation ratio of the nominal diameter of the balloon catheter to the body lumen diameter of the target site is about 1.0 to about 40; or (c) inflation involves inflating to a pressure greater than the nominal pressure of the balloon catheter, and the nominal diameter of the balloon catheter is less than the inflated balloon diameter; or (d) a combination of (a), (b), and (c). Multiple segmented balloons with smaller necks can increase friction between the balloon and the body lumen; therefore, it can prevent the balloon from slipping within the body lumen.

[0122] In some embodiments, the catheter shaft may include an elongated rigid component, such as a rod, mandrel, or wire, aligned longitudinally with the catheter shaft. Figures 4A–4D show balloon catheters including an elongated rigid component or core wire 505. Figure 4A shows an embodiment including an inflated balloon, and Figure 4B shows the balloon in an uninflated state. At the proximal end of the shaft, the core wire 505 is attached to the catheter shaft 501 under load relief 508. The core wire 505 extends distally to the catheter shaft 501. In some embodiments, the catheter shaft is made from 72D PEBA polymer. The shaft 501 is made from a material that exhibits a certain amount of elasticity under tension. Under the balloon 503, the core wire 505 is covered by a hypotube 510. The hypotube 510 provides lateral strength to the core wire 505 so that it does not buckle when the balloon 503 is inflated. Near the distal end of the catheter, the hypotube 510 and core wire 505 are coupled to the tip 502. The tip extruder 506 connects the tip 502 to the hypotube 510 and core wire 505. The space between the shaft 501 and core wire 505 is the inflation lumen for the balloon 503, and the inside of the balloon 503 is in fluid communication with the Luer hub 507. This embodiment can be used with any suitable balloon of the present invention, but Figures 4A and 4B show a balloon 510 503 with one neck, and polyethylene fiber 504 is used to reinforce the neck.

[0123] The elongated rigid component may be cylindrical, tapered, rectangular, hexagonal, or another shape, and may have a cross-sectional profile that can be made from relatively incompressible metallic or non-metallic material. The elongated component may extend from the proximal to the distal end of the balloon, or from a position near the proximal end of the balloon to the distal end. The elongated component may float freely within the central lumen of the catheter shaft, or be positioned in a dedicated lumen within a multilumen catheter shaft, or run longitudinally outside the main catheter shaft. The elongated component may be anchored along the catheter shaft at a single point, two points, or two or more points. The elongated component may be anchored to the catheter shaft by thermal fusion, adhesive or chemical bonding, bending with a mold, or by swaging or crimping, overforming, or any other suitable method to one or more portions of the catheter. The elongated component can be reinforced along its entire length or along a portion thereof, such as under a balloon to prevent buckling; for example, the elongated metallic component can be a reinforced wire. The reinforcement can be constructed using any rigid material such as stainless steel, nitinol (i.e., nickel-titanium alloy), steel, tungsten, iridium; superalloys containing elements including nickel (Ni), chromium (Cr), aluminum (Al), titanium (Ti), tungsten (W), niobium (Nb), tantalum (Ta), and cobalt (Co); or polyetheretherketone (PEEK), and can have any suitable cross-sectional shape. In some embodiments, the reinforcement is a tube having a cylindrical, rectangular, hexagonal, or any suitable external profile. The elongated component can be positioned inside the reinforcement tube or along the outside of the reinforcement tube, as shown in Figure 4C.

[0124] As shown in Figures 4A and 4B, the catheter may include a balloon length control mechanism that stretches and extends the balloon when it is in a compressed (or deflated) state, giving the balloon a smaller cross-section for tracking through the body lumen and for post-procedure removal. When the balloon is inflated, the length control mechanism may allow the balloon to shorten in length and inflate to a predetermined inflated diameter and length (e.g., created during a molding or forming method) for the balloon. In one embodiment, the force generated from balloon inflation could be transferred from the distal end of the balloon, for example, via the balloon coupling to an elongated metal component, or via the connection between the catheter tip and the elongated metal component, or via the return of the catheter shaft by the elongated rigid metal component, to the proximal end of the balloon, for example, or proximal to the proximal end of the balloon, via the connection between the elongated metal component and the catheter shaft. This transfer of force to the catheter shaft would allow the catheter shaft material to act as a spring, while acting in the elastic region of the stress-strain curve of the catheter shaft material. Energy can be stored in the catheter shaft material during balloon inflation when the catheter shaft is stretched under tension by balloon inflation, and can be released by the catheter shaft to push the stretched metal component during deflation to extend the balloon. In some embodiments, a spring oriented longitudinally along the catheter shaft can be used to store and release force for the balloon length control mechanism. Figure 5 shows an embodiment of the spring 600, which can be used in place of the core wire 505 shown in Figures 4A and 4D. Referring to Figure 5, the spring 600 has a spring portion 601 and a wire portion 602. In some embodiments, the spring portion 601 may be located at the proximal end of the catheter shaft. The spring may be located within the lumen of the catheter shaft, outside the lumen but inside the catheter shaft, or outside the catheter shaft.The spring may be located inside the balloon, or separately from the balloon, such as at the proximal end of the balloon, or a combination thereof. Compared to the length of the inflated balloon, the stretched length of the compressed balloon can be about 0.1 mm longer to about 100 mm longer, about 0.1 mm longer, 0.2, 0.4, 0.6, 0.8, 1, 1.5, 1, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 mm longer or longer, or about 100 mm or longer. The catheter shaft may contain various materials to achieve the desired amount of force to stretch the balloon, such as polyamide, nylon (e.g., nylon 6,6, or nylon 12), polyether block amide (PEBA) (e.g., 35D PEBA, 55D PEBA, or 72D PEBA), polyurethane, silicone, rubber, another thermoplastic polymer, or a combination thereof. The catheter shaft can be uniform in composition, or it can include a combination of materials distributed along one or more portions of the catheter shaft to create a desired stretching force. Different materials can result in different elastic strains and different forces applied to the stretched rigid metal component for balloon extension. The catheter shaft can be an extruded catheter shaft.

[0125] Drug-coated balloon catheters can be medical devices for the treatment of benign prostatic hyperplasia (BPH). The balloon catheter can dilate the proximal urethra and may include a catheter shaft for insertion into the urethra and an adaptive, semi-adaptive, or non-adaptive balloon for inflation in the prostatic urethra. The balloon may be coated with a coating containing a therapeutic agent delivered to the prostatic tissue and prostatic urethra upon balloon inflation. The balloon can be positioned within the prostate using any suitable method, for example, separate position balloons in the bladder, a bulbous position balloon in the urethra, or via a marker band under the balloon visible by fluoroscopy, or the catheter shaft may allow positioning via direct visualization, being scope-(cystoscope-) compatible, and the catheter may be aligned with the scope. For example, several possible catheter designs allow for direct visualization of the balloon during positioning and inflation.

[0126] In some embodiments, when treating the prostate, the balloon catheter may be sized such that the body of the catheter is located between the bladder neck sphincter (at the bladder outlet) and the external sphincter. In other embodiments, the body of the catheter is located over the external sphincter, which is positioned through the prostate, and one or more body portions pass through the bladder neck sphincter to be positioned in the bladder. In these embodiments, preferably, the neck region of the balloon catheter is aligned with the bladder neck. As referred to herein, a scope equipped with visualization can be used to appropriately size, classify, and position the balloon catheter.

[0127] In some embodiments, the balloon catheter includes a flexible tip, such as a Coude tip, which can be used to assist in device insertion and tracking through the urethra. In other embodiments, the balloon catheter includes a lumen or channel designed to allow insertion and tracking into a target site or prostate through the urethra.

[0128] Achalasia is a rare obstruction that makes it difficult for food and liquids to pass from the esophagus to the stomach. In some embodiments, when treating achalasia, a balloon catheter, as shown in Figure 3A, should be sized such that the proximal body portion of the catheter is in the achalasia and over the lower esophageal sphincter. In these embodiments, the neck region of the balloon catheter can be aligned with the lower esophageal sphincter neck. As referred to herein, a scope equipped with visualization can be used to properly size and position the balloon catheter. In embodiments in which the balloon catheter includes a flexible tip, the tip can be inserted into the sphincter (e.g., the lower esophageal sphincter) or stomach to assist in positioning the balloon catheter in the desired location.

[0129] Balloon catheters can alleviate lower urinary tract signs (LUTS) through BPH via direct dilation of prostatic tissue. Dilation of the prostate with a balloon having a ratio of inflated balloon diameter to body lumen diameter at the target site of 1.0–40, or a balloon having an elongation ratio of nominal balloon diameter to body lumen diameter at the target site of 1.0–40, can create a commissure in a natural plane that separates the lateral sections of the prostatic metastatic area. Simultaneously, drugs can be released from the coating on the prostatic tissue, which can prevent, for example, the re-narrowing of the prostatic dilation and newly formed opening.

[0130] In various embodiments, during inflation of the balloon in a body lumen (e.g., during performance of the method of the present invention), the nominal balloon diameter of the catheter (e.g., the diameter typically achieved at nominal pressure) can be such that the ratio of the nominal balloon diameter to the diameter of the body lumen at the treatment site is any appropriate ratio, e.g., about 1.01 to about 40, about 1.01 to about 15, or about 1.2 to about 10, or about 1.31 to about 8, or less or greater than about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 40 or greater. In some embodiments, the inflated diameter of the balloon at the target site during inflation to nominal pressure is equal to the nominal diameter; however, during actual use, some stenosis may prevent the achievement of the nominal diameter or may restrict the inflated balloon to form a "dogbone" shape. The nominal balloon diameter at a given pressure (e.g., 2 atmospheres, 3 atmospheres, 6 atmospheres, or 9 atmospheres) can vary for different balloon diameters for various diseases. For example, the nominal diameter of a urethral stricture balloon can be 6 mm, 8 mm, 10 mm, 12 mm, and 14 mm for balloon catheters with balloon lengths of 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, and 50 mm for balloon catheters with balloon lengths of 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, and 50 mm for balloon catheters with balloon diameters of 6 mm, 8 mm, 10 mm, 12 mm, and 1414 mm, 10 mm, 12 mm, and 14 mm for balloon catheters with balloon diameters of 14 mm, 10 The nominal diameter of a BPH stenosis balloon can be 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, and 60 mm in balloon catheter lengths, with balloon lengths of 25 mm, 30 mm, 35 mm, 40 mm, and 45 mm in balloon catheter lengths of 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, and 60 mm in nominal pressures of 2 atmospheres, 3 atmospheres, 4 atmospheres, 6 atmospheres, or 9 atmospheres. Table 1 shows examples of nominal balloon size, nominal pressure, and minimum balloon diameter to lumen diameter ratio for use in treating stenosis in various diseases. Nominal pressure is the pressure required to bring the balloon to its labeled nominal diameter in an unconstrained pressure ramp test.The nominal diameter is the desired diameter to which the product is labeled. All physicians purchase balloons and select them for use based on their nominal diameter. The evaluated burst pressure is the maximum pressure at which the balloon can be inflated and at which there is a very high degree of confidence that it will not burst, and is a labeling requirement for balloon catheters calculated from a statistical analysis of the pressures observed when the balloon bursts in a free pressure gradient test.

[0131] [Table 1]

[0132] In various embodiments, the balloon catheter can be sufficient at a predetermined pressure (e.g., nominal pressure), for example, at a pressure of about 1 atmosphere (304 kPa) to about 30 atmospheres (3040 kPa) (e.g., less than or equal to about 1 atmosphere, or less or greater than or equal to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28 atmospheres, or about 30 atmospheres or more), so that the balloon can have an appropriate ratio of the diameter of the inflated balloon catheter to the diameter of the body lumen at the treatment site.

[0133] The inflated diameter of the balloon can be any suitable diameter achieved during or within the inflation period such that a desired ratio of the inflated balloon diameter to the diameter of the body lumen is achieved. The inflated diameter of the balloon can correspond to the pressure used to inflate the balloon during the inflation period. The swelling pressure can be in the range of nominal swelling pressure to evaluated burst pressure. The nominal pressure is the pressure at the nominal diameter of the inflated balloon catheter. The nominal diameter is the diameter of the balloon catheter at the nominal pressure and is specified with respect to product labeling. In some embodiments, the inflated pressure can be the nominal pressure for the balloon, and the inflated diameter of the balloon can be approximately equal to the nominal diameter of the balloon or less than the nominal diameter of the balloon due to limitations from stenosis. In some embodiments, the inflated pressure of the balloon during the inflation period can be above or below the nominal pressure, and the inflated diameter of the balloon can, correspondingly, be above or below the nominal diameter of the balloon.

[0134] In various embodiments, the balloon catheter of the present invention is compatible with a range of flexible (or pliable) or rigid characteristics that allow visualization of the treatment zone, enabling more accurate and efficient placement than other balloon catheters. The scope can be a gastroscopy, small bowel endoscope, duodenoscope, colonoscope, sigmoidoscope, rectoscope, anoscope, nasal endoscope, bronchoscope, or cystoscope. In various embodiments, the balloon catheter of the present invention is self-serving in that the neck of the balloon catheter directs the balloon catheter to the appropriate position during inflation (for example, at the neck of the balloon catheter, such as the majority of the distal neck at the bladder neck), even if the balloon catheter is slightly off-position at the start of inflation.

[0135] In various embodiments, the balloon catheter has one or more neck portions separating one or more main portions, and at least one neck portion, or arrangement of one or more neck portions, which allows the balloon catheter to remain in place more consistently and effectively to dilate a stenosis and deliver a drug compared to other balloon catheters lacking such neck portions or arrangement.

[0136] A drug-coated balloon catheter may include an elongated balloon body having multiple main sections, two cones at the distal and proximal ends of the balloon body, an inflatable lumen, and a wire lumen, wherein the balloon body includes at least two main sections with a larger diameter and at least one neck section with a smaller diameter, and the main sections and neck sections with the larger diameters are aligned either alternately or adjacently. The elongated balloon may have a substantially cylindrical shape, except for any neck section on the balloon, any tapered section (e.g., a cone) between the neck section and the main sections having the main diameters, and any tapered or shaped section at the longitudinal end of the balloon. The elongated balloon may have any suitable profile obtained perpendicular to the longitudinal direction of the balloon, for example, circular (e.g., cylindrical balloon), elliptical, or polygonal (e.g., pentagon, hexagon, heptagon, octagon, etc.) or a combination thereof. The diameter of a non-cylindrical balloon may be the maximum or minimum size perpendicular to the longitudinal direction.

[0137] The balloon can have any appropriate size. The balloon can be designed to fit within the prostatic urethra, with the distal end of the balloon positioned in the bladder. The main diameter and nominal balloon diameter can be in the range of approximately 5 mm to approximately 50 mm, 25 mm to 45 mm, at least 10 mm, at least 15 mm, at least 20 mm, at least 30 mm, for example, less than or equal to approximately 5 mm, or less than or equal to approximately 6 mm, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 36, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48 mm or more, or about 50 mm or more; the main diameter can independently be in any of these ranges or any of the specific sizes. The balloon length can be approximately 20mm to 160mm, 40mm to 80mm, or less than 20mm, or less than or greater than approximately 22mm, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, or 78mm, or about 80mm or greater. The balloon length and diameter can be selected based on the patient's unique prostate anatomy.

[0138] The neck portion may be a rigid or semi-rigid neck portion whose diameter (e.g., a portion of the neck portion having a neck diameter) remains substantially static during balloon inflation. The neck portion may include an inelastic material circulated around the neck portion, for example, stitches or monofilaments or multifilaments of such material, such as nylon, polyamide, aromatic polyamide, ultra-high molecular weight polyethylene (UHMWPE), polyester, aromatic polyester, polyethylene terephthalate (PET), or a combination thereof.

[0139] Catheter shafts, balloons, or combinations thereof may include one or more markings along their length to assist in positioning and alignment with certain anatomical structures. The markings may have either an appropriate orientation, e.g., circumferential or longitudinal along the catheter shaft or balloon. Markings on the catheter shaft or balloon can be used to assist in positioning the balloon in the treatment area, to indicate that the balloon is fully recovered in the sheath, or to position the device within the patient's anatomy. Markings on the catheter shaft can be visualized using an endoscope, cystoscope, or the naked eye, or the markings may include radiometrically identifiable components such as radiopaque material. Markings can be created by thermally bonding a polymer to the surface of the catheter shaft having an identifiable color via pad printing, laser marking, or any other method. Figures 4A and 4B show embodiments of balloon recapture marks 509 and positioning marks 511. Balloon recapture marks 509 can be used when the balloon catheter includes a sheath covering the balloon. If the sheath covers the balloon, mark 509 can be positioned just proximal to the proximal end of the sheath. After the user has advanced the catheter to the desired position, removed the sheath, and inflated the balloon, the user may want to advance the sheath backward so that the balloon is covered for removal. In this case, after compression, the user will advance the sheath distally until the recapture mark 509 is visible. Positioning mark 511 can be used to assist the user in positioning the catheter within the body lumen. For example, when using a single neck balloon for BPH treatment as shown in Figures 4A and 4B, the positioning mark, which can be positioned just proximal to the proximal end of the balloon, can be positioned just proximal to the external sphincter. In various embodiments, the user can see mark 511 through the scope and, if the mark is just proximal to the external sphincter, the user can be confident that the balloon is properly positioned.

[0140] A balloon catheter may include a catheter tip at the distal end, which is the first to be inserted into the body. The catheter tip can facilitate the passage of the balloon through the body lumen. The tip may be a non-traumatic tip that helps prevent damage to the body lumen during insertion within it. The tip may be a non-traumatic Coude tip. A non-traumatic Coude tip is designed to facilitate the passage of the catheter through bends in the body lumen while preventing damage to the body lumen wall during tracking. It may be a low-durometer, biocompatible material that is overmolded onto the catheter shaft or adhesively bonded onto the shaft. For example, a Coude tip may be formed from PEBAX® or liquid silicone rubber.

[0141] In some embodiments, the catheter may include an insertion sheath that covers the balloon (e.g., a covered and folded / pleated balloon) during insertion and can be completely removed from the body during the procedure. The sheath may be designed to be connected to an occlusion or dilator to facilitate reinsertion of the sheath into the body lumen. The sheath may contain one or more materials. The sheath may have a laminated construction in which several different layers of material are combined to create the sheath, or which can be constructed using simple extrusion or co-extrusion. In one embodiment, the sheath includes an inner layer containing a fluoropolymer such as PTFE or FEP, a central reinforcing layer containing braided or wound wire filaments such as stainless steel, Nitinol, PEEK or other material, and an outer layer containing a polymer such as PEBAX®, nylon, polyurethane or another thermoplastic material. The durometer of the outer sheath material and the pitch of the braided or wound reinforcing material may be uniform or may vary along the length of the sheath. The occlusion device may be an extruded tube or molded into a specific geometry and may include a wide range of materials, such as LDPE, HDPE, PE, PEBA, nylon, silicone, polyurethane, or other biocompatible materials. The distal tip of the occlusion device (inserted into the body) may include a taper, radius, or some combination thereof to facilitate passage through the body lumen. The sheath and occlusion device may have overmolded, swaged, crimped, or adhesively bonded hub connections that allow them to connect together. Alternatingly, the occlusion device may be flared proximally to create a grasping feature and an interference connection with the sheath. After the procedure, the occlusion device and sheath can be inserted proximally into the balloon through the body lumen. Once in position, the occlusion device can be separated from the sheath, and the sheath can be replaced on the compressed balloon to facilitate the removal of the balloon catheter.

[0142] Figure 4 shows an embodiment of a balloon catheter used for treating BPH, including the catheter shaft, catheter tip, and Tuohy Borst adapter / stopcock assembly.

[0143] The main sections of the balloon can be formed with the same or similar diameters. In some embodiments, when measured at the nominal balloon diameter, the diameters of the various main sections can differ from each other by approximately 30%. In Figures 3A, 3B, 3C, and 4, the main sections of the balloon are shown with equal diameters, and the diameter of each main section is constant. In practice, at higher pressures, the diameter of the main sections will bow out slightly, in that the diameter of the central part of the main section may be slightly larger than the diameter of the edges of the main section near the balloon cone and / or near the neck.

[0144] In embodiments where the balloon shown in Figures 3A, 3B, 3C, and 4 has a neck and a main section, and in embodiments where the balloon shown in Figure 1 does not have a neck section after the balloon catheter is assembled, the balloon can be coated with at least one water-soluble additive and drug as referred to herein. In some embodiments where the balloon has multiple main sections, the distal main section may not be coated. The balloon can be coated according to the process discussed herein. If a sheath is used, it can be placed on the balloon after it has been coated. The catheter is then packaged, sterilized, and labeled as known in the art.

[0145] In Figure 3A, one embodiment shows a balloon having one neck section. The balloon 100 has a waist 101, a cone 102, a first body section 103, a neck 104, a second body section 105, a cone 106, and a waist 107. As is known in the art, when assembled into a balloon catheter, the waists 101 and 107 would be attached to (or joined to) the catheter shaft, etc. (not shown). During inflation, the waists 101 and 107 do not expand because they are attached to the catheter shaft. Sections 102, 103, 104, 105, and 106 can all expand simultaneously by a single inflation point in communication with the catheter shaft and an external Luer hub. In Figure 3B, one embodiment shows a balloon having two neck sections. The balloon 120 has a waist 121, a cone 122, a first body 123, a first neck 124, a second body 125, a second neck 126, a third body 127, a cone 128, and a waist 129. As is known in the art, when assembled into a balloon catheter, the waists 121 and 129 will be attached to or coupled to the catheter shaft. During swelling, the waists 121 and 129 do not expand because they are attached to the catheter shaft. The portions 122, 123, 124, 125, 126, 127, and 128 can all expand simultaneously via a single swelling point in communication with the catheter shaft and an external Luer hub. Although the neck portions 124 and 126 are shown as having the same diameter in their current state of swelling, they can be the same or different diameters with the same or different compliance. In one embodiment, a balloon with three neck portions is shown in Figure 3C. It has a balloon 140, a waist 141, a cone 142, a first torso 143, a first neck 144, a second torso 145, a second neck 146, a third torso 147, a third neck 148, a fourth torso 149, a cone 150, and a waist 151.As is known in the art, when assembled into a balloon catheter, waists 141 and 151 will be attached to or coupled to the catheter shaft. During swelling, waists 141 and 151 do not expand because they are attached to the catheter shaft. Sections 142, 143, 144, 145, 146, 147, 148, 149 and 150 can all expand simultaneously by a single swelling point in communication with the catheter shaft and the external Luer hub. Although neck sections 144, 146 and 148 are shown with different diameters in their current state of swelling, they can be the same and identical or different diameters with different compliances.

[0146] In various embodiments, the balloon catheter can be assembled with a sheath. The catheter assembly and scope (e.g., cystoscope) are inserted transurethrally into the prostatic urethra, and they are positioned side by side near the external sphincter. The external sphincter can be positioned using a live video feed from the scope. The balloon can be positioned adjacent to the external sphincter and within the prostatic urethra. Balloon expansion, drug release, and balloon deflation can be visualized by the scope.

[0147] Coating design and formulation In one embodiment, the present invention provides a balloon catheter for delivering a therapeutic agent to tissue such as vascular or non-vascular tissue. The device may include a coating applied to the outer surface of the balloon catheter. The coating may include polymer-encapsulated drug particles containing a therapeutic agent and one or more polymers that encapsulate the therapeutic agent; or a drug-releasing coating containing polymer-encapsulated drug particles; or a composition containing a therapeutic agent and one or more additives; or a combination thereof. The layer may include a composition containing a therapeutic agent and one or more additives. The additive may be any suitable additive. The layer may contain one additive, or the layer may contain more than one additive, such as a first water-soluble additive and a second water-soluble additive. For example, as shown in the embodiment depicted in Figure 2A, the balloon 12 is coated with a layer 20 containing a therapeutic agent and polymer-encapsulated drug particles containing one or more polymers that encapsulate the therapeutic agent; or a drug-releasing coating containing polymer-encapsulated drug particles; or a composition containing a therapeutic agent and one or more additives; or a combination thereof. In some embodiments, the layer is substantially composed of a therapeutic agent and an additive, for example, the layer contains only the therapeutic agent and the additive without other materially substantial components. In some embodiments, the device may optionally include an adhesion layer. For example, as shown in the embodiment depicted in Figure 2B, the balloon 12 is coated with an adhesion layer 22. Layer 24 may overlap the adhesion layer and may contain a therapeutic agent and polymer-encapsulated drug particles containing one or more polymers that encapsulate the therapeutic agent; or a drug-release coating containing polymer-encapsulated drug particles; or a composition containing a therapeutic agent and one or more additives; or a combination thereof. The adhesion layer, which is another layer underlying the drug coating layer, improves the adhesion of the drug coating layer to the outer surface of the medical device and protects the coating integrity. For example, if the drug and additive differ in their adhesion to the medical device, the adhesion layer can prevent differential loss of components and maintain the drug-to-additive ratio in the coating during passage to the target site for therapeutic intervention.Furthermore, the adhesion layer can function to facilitate the rapid release of coating layer components from the device surface upon contact with tissue at the target site. In other embodiments, the device may include a top layer. For example, as shown in the embodiment depicted in Figure 2C, the balloon 12 is covered with an adhesion layer 22, a coating layer 26 containing the therapeutic agent and overlapping the adhesion layer, and a top layer 28. For example, before the coating layer 20 is pressed into direct contact with the target tissue, the top layer can reduce the loss of the drug layer during the passage of the balloon 12 to the site of intervention or during the first moment of inflation of the balloon 12, before it is brought into contact with the target tissue.

[0148] In various embodiments, the coating covering the balloon portion of the catheter has one or more layers containing one or more therapeutic agents. In some embodiments, the layer in contact with the inflatable portion of the catheter does not contain therapeutic agents and is formulated (or prescribed) with a component that allows all or substantial of the coating to transfer to stenosis or stenosis as the balloon catheter inflates. In some embodiments, the layer in contact with the balloon portion of the catheter does not contain therapeutic agents and is formulated with a component that allows the coating to adhere to the balloon.

[0149] Embodiments of the present invention relate to balloon catheters having a rapid drug-release coating and methods for preparing such coated devices. The drug-release coating may include polymer-encapsulated drug particles containing a therapeutic agent and one or more polymers encapsulating the therapeutic agent; or a drug-release coating containing polymer-encapsulated drug particles; or a composition containing a therapeutic agent and one or more additives; or a combination thereof. The therapeutic agent according to embodiments of the present invention does not require delayed or prolonged release; instead, the therapeutic agent is released over a very short period of time to provide a therapeutic effect, for example, upon contact with tissue. An object of embodiments of the present invention is to facilitate rapid and efficient uptake of the drug by target tissue during transient device placement at a target site. Other embodiments of the present invention relate to balloon catheters having a drug coating containing therapeutic agent particles encapsulated in additives or by one or more polymers. After inflation of the drug-coated balloon, the therapeutic agent particles are embedded in the lumen wall, providing prolonged drug delivery.

[0150] In one embodiment, the present invention provides a balloon catheter for delivering a therapeutic agent to a tissue such as a vascular tissue or a non-vascular tissue. The device includes a layer applied to the outer surface of the balloon catheter. The layer includes polymer-encapsulated drug particles comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent; or a drug-release coating comprising polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or a combination thereof. The additive can be any suitable additive. The layer can include one additive, or the layer can include more than one additive such as a water-soluble first additive and a water-soluble second additive. Also, the layer can include a water-insoluble or partially water-soluble additive, or the layer can include more than one water-insoluble or partially water-soluble additive. In some embodiments, the therapeutic agent and excipient are dispersed in one of the coating layers. The range of dispersion can vary from molecular dispersion to dispersion having drug particles with a size of dozens of microns. In one embodiment, the therapeutic agent has a size of less than 10 μm, and in another embodiment, the therapeutic agent is 5 μm or less. In another embodiment, the therapeutic agent is at least 75% crystalline, or more preferably at least 90% crystalline. In another embodiment, the drug is amorphous without molecular orientation. Techniques for determining whether a drug is crystalline or amorphous include powder X-ray diffraction (pXRD), modulated differential scanning calorimetry (mDSC), or confocal Raman spectroscopy.

[0151] In one embodiment, the concentration density of at least one therapeutic agent applied to the surface of the medical device is about 1 to 20 μg / mm 2 , or about 2 to 6 μg / mm 2 , or about 0.5 micrograms / mm 2 , or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18 less than or more than, or about 20 micrograms / mm 2That concludes the explanation. If the medical device is a balloon, these measurements are calculated using the nominal diameter. In embodiments of the present invention, the weight-to-additive-to-drug ratio in the coating layer can be about 20:0.05, about 10:0.1, or about 6:0.15.

[0152] The weight ratio of the therapeutic agent in the coating layer to the total weight of one or more additives in the coating layer may be approximately 0.05 to approximately 20, approximately 0.1 to approximately 10, approximately 0.1 to approximately 5, approximately 0.5 to approximately 8, approximately 0.5 to approximately 3, approximately 2 to approximately 6 or approximately 0.05 or less, or less or greater than approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or approximately 20 or more.

[0153] The drug coating can cover an appropriate percentage of any of the outer surfaces of the balloon (e.g., the percentage of the balloon surface that gives the main diameter during inflation relative to the nominal pressure, excluding the neck and end cones) from about 1% to about 100%, or about 50% to about 100%, about 80% to about 100%, or less than or equal to about 10%, or less than or equal to 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or about 100% or more.

[0154] The balloon may have a residual amount of drug on it after retrieval. Any appropriate residual amount of drug, for example, about 70% by weight, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5% by weight or more, or about 0% by weight, may remain after retrieval.

[0155] In some embodiments, one or more additives or one or more polymers, or a first and / or second ionic or amphoteric additive can facilitate the rapid release of the therapeutic agent from the balloon, thereby including the residual amount of therapeutic agent remaining on the balloon after it has been inflated at a target site in a nonvascular body lumen for an inflation period of about 0.1 to 10 minutes, and subsequently withdrawn from the nonvascular lumen.

[0156] The coating layer that overlaps the outside of the medical device may contain one or more water-soluble additives (e.g., a first water-soluble additive, a second water-soluble additive, and a third water-soluble additive).

[0157] The water-soluble additive may include a first water-soluble additive, which is a surfactant such as PEG-sorbitan monolaurate, PEG-sorbitan monooleate, or a combination thereof. The water-soluble additive may also include a second water-soluble additive, which is a compound having one or more groups that are hydroxyl, amine, carbonyl, carboxyl, or ester, such as sorbitol, sorbitan, xylitol, gluconolactone, or a combination thereof. The drug coating may contain both the first and second water-soluble additives. In some embodiments, the distal end of the balloon may be devoid of the therapeutic agent.

[0158] In some embodiments, the additive is at least one surfactant and a chemical compound. The coating layer that overlaps the outside of the medical device may include one or more water-soluble additives and one or more water-insoluble or partially water-soluble additives. The water-soluble additives may be neutral, anionic, cationic, or amphoteric. The water-insoluble additives may be neutral, anionic, cationic, or amphoteric.

[0159] In some embodiments, the coating containing the therapeutic agent is released from the balloon into an aqueous solvent in less than 30 seconds without aggregated particles or individual particles larger than 20 μm. In some embodiments, the released coating has particles or aggregated particles smaller than 10 μm, or preferably smaller than 5 μm.

[0160] The device can release the therapeutic agent and deliver it to the tissue in approximately 0.1 to 10 minutes.

[0161] In some embodiments, the additive can enhance the release of the therapeutic agent from the balloon. The additive can enhance the penetration and absorption of the therapeutic agent into the tissue. The additive may have a solubility of at least 1 mg / mL of water and ethanol. The therapeutic agent may also be water-insoluble.

[0162] In some embodiments, the layer overlapping the outer surface of the medical device may include a therapeutic agent and at least two additives, each additive comprising a hydrophilic portion and a drug-affinity portion, the drug-affinity portion being at least one of a hydrophobic portion, a portion having affinity to the therapeutic agent by hydrogen bonding, and a portion having affinity to the therapeutic agent by van der Waals interactions, and each additive being soluble in polar organic solvents and soluble in water. In one embodiment of this embodiment, the polar organic solvent is selected from methanol, ethanol, isopropanol, acetone, dimethylformide, tetrahydrofuran, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, ethyl acetate, and chloroform, as well as mixtures of these polar organic solvents with water. In another embodiment of this embodiment, the device further includes a top layer overlapping the surface of the layer overlapping the outer surface of the medical device to reduce drug loss during passage through the body to target tissue.

[0163] Methods for treating stenosis and stenosis. The present invention provides a novel method for treating luminal stenosis of the body to have a long-lasting and sustained effect. The novel method opens the lumen and prevents, reduces, or minimizes restenosis and recurrent nonvascular or vascular stenosis. Lumens of blood vessels (or vascular ducts) include arteries, veins, or any of these lumens containing blood. Nonvascular lumens include those lumens that do not contain blood. The method includes the delivery of a drug coating comprising a therapeutic agent and polymer-encapsulated drug particles containing one or more polymers that encapsulate the therapeutic agent; or a drug-release coating comprising polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or a combination thereof. The drug coating may have one or more layers and contain an effective amount of the therapeutic agent, for example, an anti-inflammatory and antiproliferative drug (e.g., from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs and combinations thereof). The coating may contain one or more water-soluble additives and one or more water-insoluble or partially water-soluble additives for stenosis or stenosis. The treatment is intended for a variety of animals, from premature neonates to human adults.

[0164] In various embodiments, the present invention provides minimally invasive methods for treating or preventing nonvascular strictures of the upper and lower urinary tract. These urinary tract strictures may include trauma-induced urethral strictures, iatrogenic strictures, idiopathic urethral strictures, ureteral strictures, bladder neck contractures induced by treatment or stricturotomy for prostate cancer, and benign prostatic hyperplasia (BPH) due to lateral lobe obstruction and / or middle lobe obstruction. The method comprises inserting a balloon catheter and tracking it to the urinary tract stricture. The balloon catheter comprises an extended balloon and a drug coating. The method comprises inflating the balloon to bring the urinary tract stricture tissue and the coating layer into contact until the balloon achieves an inflated balloon diameter for the inflation period. The method comprises deflating the balloon after the inflation period and withdrawing it from the urethra. In some embodiments, the method further includes performing a surgical procedure such as prostate cancer treatment, BPH treatment, or stenosis incision prior to the insertion of a balloon catheter into the target site. In some embodiments, prostate cancer treatment includes radical prostatectomy (RP), radiotherapy, cryotherapy, or high-intensity focused ultrasound (HIFU). In some embodiments, BPH surgery includes transurethral resection of the prostate, photoselective laser vaporization of the prostate, or holmium laser enucleation of the prostate. In some embodiments, stenosis incision includes heated or cooled knife urethral incision or direct intravisual urethral incision (DVIU).

[0165] In various embodiments, the present invention provides a method for the treatment of benign prostatic hyperplasia. The method comprises 1) inserting a rigid cystoscope (including optics and a bridge with irrigation capability) in a sheath into the urethra and tracking the cystoscope tip into the bladder. The method comprises 2) removing the bridge and optics, inserting a drug-coated balloon catheter through the length of the cystoscope, and then removing the cystoscope while leaving the drug-coated balloon in the bladder. The method comprises 3) reinserting the reassembled cystoscope, with the optics and irrigation-capable bridge, along with the drug-coated balloon catheter, hydrating the coating in the irrigation fluid until the coating is immersed, and aligning the tip of the scope and the proximal end edge of the balloon near the external sphincter. The method comprises 3) inflating to an initial pressure (e.g., 0.5 atmospheres, 1 atmosphere, or 1.5 atmospheres) and maintaining the initial pressure until the pressure no longer drops for 1-2 minutes. The method includes 4) inflating to the next higher pressure, including an increase of 0.5, 1 or 1.5 atmospheres from the previous pressure, and maintaining the higher pressure until the pressure no longer drops for 1 to 2 minutes. The method includes 5) repeating step 4) until the prostate tissue yields and a commissure is formed. The method includes 6) keeping the balloon inflated for 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to release the drug into the tissue and prevent bleeding. The method includes 7) compressing the balloon catheter. The method includes 8) retrieving the scope and balloon catheter assembly from the body cavity.Features (a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or (a) and (b) and (c), may exist: (a) the ratio of the inflated balloon diameter to the body lumen diameter of the target site is approximately 1.0 to approximately 40; or (b) inflation involves inflating the balloon to a pressure greater than or equal to the nominal pressure of the balloon catheter, and the elongation ratio of the nominal diameter of the balloon catheter to the body lumen diameter of the target site is approximately 1.0 to approximately 40; or (c) inflation involves inflating to a pressure greater than the nominal pressure of the balloon catheter, and the nominal diameter of the balloon catheter is less than the inflated balloon diameter; or (d) a combination of (a), (b), and (c).

[0166] In some embodiments, when treating the prostate, it is preferable to position the proximal balloon waist in relation to the external sphincter so that the external sphincter is not dilated. It is also preferable to classify the balloon, and if the balloon waist is in relation to the external sphincter, it is preferable to size the balloon so that the balloon neck (e.g., the most distal balloon neck) aligns with the bladder neck. This arrangement provides holding forces to prevent the balloon from slipping during expansion. If the balloon neck cannot be aligned with the bladder neck, it may be preferable to inflate the balloon slowly so that the prostate can yield as the balloon expands.

[0167] Once properly positioned, the balloon is inflated using an inflation device, such as one containing a pressure gauge. The balloon can be inflated slowly, allowing the prostatic tissue to flex and reducing the tendency for the balloon to slip proximally into the bladder and distally posteriorly. The shape of the balloon with one or more necks can prevent balloon migration by aligning the distal neck with the bladder neck in some abnormal conditions, such as in the dilated middle lobe (e.g., in about 10-15% of cases). However, the balloon necks may not stay aligned with the bladder neck during inflation, and further techniques may be useful in preventing balloon migration. In some cases, inflation at a rate of about 0.5-1 atmosphere / minute can prevent balloon migration. As the tissue flexes, the balloon pressure decreases accordingly, allowing further fluid to be injected into the balloon without increasing the pressure. Once the pressure is stable for about 1-2 minutes, the pressure can be increased and maintained in 0.5 or 1 atmosphere increments in a similar manner. The pressure can be increased continuously, and this method of increasing the pressure is followed by stabilizing the pressure after a pressure drop, and the pressure continues to increase until a commissure or split (or rupture) is achieved. Alternatively, very slow inflation can prevent balloon movement to achieve a commissure or prostatic split. Once a commissure or split of the prostatic urethra and prostate is observed and confirmed by a video feeder from the scope, mechanical decompression can be achieved. The balloon can be left inflated for approximately 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to allow the drug in the coating to migrate into the tissue. Once the procedure is complete, the balloon can be deflated, and the catheter and scope can be removed from the patient's body cavity.

[0168] In some embodiments, when treating the prostate, it may be desirable to pre-dilate the stenosis. In this embodiment, the pre-dilation catheter may be shorter and / or have a smaller diameter than the drug-coated balloon treatment catheter. In this scenario, the pre-dilation catheter is positioned at the proximal waist of the balloon in the neck region aligned with the external sphincter and the bladder neck. The balloon is slowly inflated as described herein to assist in flexing the prostate while protecting against balloon slippage. Once inflated, the pre-dilation balloon is compressed and removed, and the drug-coated treatment balloon is inserted. The proximal waist of the treatment balloon is aligned with the external sphincter. Aligning the balloon neck with the bladder neck is not necessary so that the balloon does not slip to the same extent, as if the prostate is properly pre-dilated, it would be a non-pre-dilated body lumen.

[0169] In one embodiment, the present invention relates to a method for treating at least one of benign prostatic hyperplasia and prostate cancer, the method comprising: rinsing (or washing, or flushing) the prostate with water, Saline solution, or an aqueous solution containing at least one water-soluble additive; inserting a balloon catheter into a target site of the prostate, the balloon catheter comprising a balloon and a coating layer overlapping the outer surface of the balloon; the coating layer may include a therapeutic agent and polymer-encapsulated drug particles containing one or more polymers that encapsulate the therapeutic agent; or a drug-releasing coating containing polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or a combination thereof. The method may include inflating the balloon until the coating layer is in contact with the wall of the benign prostatic hyperplasia or prostate cancer at the target site and the balloon achieves an inflated balloon diameter during inflation, the inflation period being 0.1 to 10 minutes; compressing the balloon after the inflation period; and retrieving the balloon catheter from the prostate. The ratio of the inflated balloon diameter to the diameter of the body lumen stenosis can be approximately 1.0–40, 1.1–40, 1.2–40, 1.3–40, or 1.4–40 (for example, 1 or any value greater than or less than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or less than or equal to 40, or any value in between). If desired, inflation may include inflating to a pressure equal to or exceeding the nominal pressure of the balloon catheter.

[0170] In one embodiment, the present invention relates to a method for treating a urethral stricture, the method comprising: rinsing the urethral stricture with water, Seline solution, or an aqueous solution containing at least one water-soluble additive so as to immerse or wet a drug coating; inserting a balloon catheter into a target site of the urethral stricture, the balloon catheter comprising a balloon and a coating layer overlapping the outer surface of the balloon. The coating layer may include a therapeutic agent and polymer-encapsulated drug particles containing one or more polymers that encapsulate the therapeutic agent; or a drug-releasing coating containing polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or a combination thereof. The weight ratio of the therapeutic agent in the coating layer to the total weight of one or more water-insoluble or slightly or partially water-insoluble and one or more water-soluble additives may be about 0.05 to 20. The method may include inflating the balloon until the coating layer is in contact with the wall of the urethral stricture at the target site and an inflated balloon diameter is achieved for an inflation period; deflating the balloon after the inflation period, the inflation period being 0.1 to 10 minutes; and retrieving the balloon catheter from the urethral stricture. The ratio of the inflated balloon diameter to the urethral diameter at the site of the stricture can be approximately 1.0 to approximately 40, approximately 1.01 to approximately 15, or approximately 1.01 or less, or approximately 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18 or less, or approximately 40 or more. After dilation, the diameter of the urethral stricture can be 6.7 mm or more, for example, approximately 6.7 mm to approximately 20 mm, or approximately 6.7 mm to approximately 15 mm, or approximately 6.7, 6.8, 6.9, 7.0, 7.2, 7.4, 7.6, 7.8, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14 or less, or 15 mm or more. If desired, inflation may include inflating to a pressure equal to or exceeding the nominal pressure of the balloon catheter.

[0171] In various embodiments, the present invention provides minimally invasive methods for treating or preventing strictures in the gastrointestinal tract or the lumen of the digestive body. Gastrointestinal strictures include esophageal strictures, achalasia strictures, biliary strictures, gastric strictures, gastrectomy-induced gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, ileoanal J-type pouch strictures, and large intestinal strictures. Stricures include esophageal strictures due to eosinophilic esophagitis or Barrett's esophagus, radiation-induced strictures, Crohn's disease-induced strictures, ulcerative colitis-induced strictures, chronic inflammatory bowel disease (IBD)-induced strictures, and anastomotic strictures of any part of the gastrointestinal tract. The method comprises inserting a balloon catheter into the gastrointestinal stricture, the balloon catheter comprising an extended balloon and a drug coating. The method comprises rinsing the gastrointestinal stricture with water, Seline solution, or an aqueous solution containing at least one water-soluble additive to immerse or wet the drug coating. The method includes inflating the balloon at the target site to bring the coating layer into contact with the wall of the body lumen at the site of the gastrointestinal lumen stenosis until the balloon achieves the inflated balloon diameter for the inflation period. The method also includes retrieving the balloon catheter from the body lumen. In some embodiments, the method further includes performing a surgical procedure, such as stenotomy or resection, prior to insertion of the balloon catheter into the target site. In some embodiments, the stenotomy or resection includes needle knife electroincision, endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD).

[0172] In various embodiments, the present invention provides a method for treating or preventing inflammatory disease-induced (IBD) nonvascular strictures. IBD may include Crohn's disease and ulcerative colitis. In some embodiments, the stricture is a small bowel stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, large intestine stricture, colorectal stricture, ileocolonic stricture, or gastrointestinal stricture. The method comprises inserting a balloon catheter into a target site in a body lumen containing an inflammatory disease-induced nonvascular stricture, the balloon catheter comprising an extended balloon and a drug coating. The method may include rinsing the inflammatory disease-induced nonvascular stricture with water, Seline solution, or an aqueous solution containing at least one water-soluble additive to immerse or wet the drug coating. The method may include inflating the balloon at the target site to bring the coating layer into contact with the wall of the body lumen at the location of the inflammatory disease-induced nonvascular stricture until the balloon achieves an inflated balloon diameter for an inflation period. The method may include deflating the balloon after the inflation period. The method involves retrieving the balloon catheter from a body lumen.

[0173] In one embodiment, the present invention relates to a method for treating esophageal strictures, including achalasia, the method comprising, optionally, rinsing the esophageal stricture with water, Saline solution, or an aqueous solution containing at least one water-soluble additive, during or after the insertion of a balloon catheter; and inserting the balloon catheter into a target site in the esophageal stricture, the balloon catheter comprising a balloon and a drug coating. The drug-coated balloon catheter can be delivered to the esophageal stricture in a minimally invasive manner by positioning an endoscope in the mouth or nose to access the esophagus. The drug-coated balloon can then be positioned through the working channel of the scope or tracked with respect to a previously positioned guidewire so that the working portion of the balloon is centered in the stricture. The scope used may be a gastroscopy, colonoscopy, bowel endoscope, nasal endoscope, or other endoscope suitable for tracking to the esophageal stricture treatment site. The method may include rinsing the esophageal stricture with water, Saline solution, or an aqueous solution containing at least one water-soluble additive to immerse or moisten the drug coating. The procedure may include inflating the balloon until the coating layer contacts the wall of the esophageal stricture at the target site and the balloon achieves the inflated balloon diameter for the inflation period; deflating the balloon after the inflation period, which is 0.1 to 10 minutes; and retrieving the balloon catheter from the esophageal stricture. The ratio of the inflated balloon diameter to the esophageal diameter at the site of stenosis can be approximately 1.0–40, 1.1–40, 1.2–40, 1.3–40, or 1.4–40 (for example, 1, or any value above or below 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 or less, or any value in between). In some embodiments, the balloon catheter characteristics are equal to or similar to those given in Table 2, and have a growth rate that slows down at higher pressures.Compliance is the percentage change in balloon diameter from the nominal diameter to the evaluated burst pressure (RBP) diameter, calculated as (Diameter @ RBP - Nominal pressure at Diameter @) / (Nominal pressure at Diameter @) × 100%. Optionally, inflation may include inflating to a pressure equal to or exceeding the nominal pressure of the balloon catheter.

[0174] [Table 2]

[0175] In some embodiments, the balloon catheter characteristics are equal to or similar to those given in Table 3, and the single balloon catheter has the ability to achieve a wide range of balloon diameters at relatively high operating pressures compared to conventional compliant balloons. The balloons in Table 3 have the unique feature of having three increasing balloon diameters for each of the three increasing inflation pressure stages. The nominal swelling diameter is the diameter at stage I. The diameter increases by 0.5 to 4 mm, preferably 0.75 to 3 mm, and most preferably 0.9 to 2 mm for each stage of pressure increase. For example, a balloon with a diameter of 15 mm at pressure I (3 atm) has a diameter of 16.5 mm at pressure II (4.5 atm) and a diameter of 18 mm at pressure III (7 atm).

[0176] [Table 3]

[0177] In various embodiments, the present invention provides a minimally invasive method for the treatment or prevention of vaginal stenosis or stricture. The method comprises inserting a balloon catheter into the vagina and tracking it to the site of stenosis. The balloon catheter comprises an elongated balloon, a coating layer, or one or more drug coating layers overlapping the outer surface of the balloon. The method comprises inflating the balloon to bring the coating layer into contact with the vaginal wall until the balloon achieves an inflated balloon diameter for the inflation period. The method comprises deflating the balloon after the inflation period and retrieving it from the vagina.

[0178] In various embodiments, the present invention provides a minimally invasive method for treating cancer treatment-induced nonvascular stenosis. The method comprises inserting a balloon catheter into a target site in a body lumen containing the cancer treatment-induced nonvascular stenosis, the balloon catheter comprising an extended balloon and a drug coating layer overlapping the outer surface of the balloon. The method comprises inflating the balloon at the target site to bring the balloon into contact with the wall of the body lumen and the coating layer at the site of the cancer treatment-induced nonvascular stenosis until the balloon achieves an inflated balloon diameter for the inflation period. The method comprises deflating the balloon after the inflation period. The method comprises retrieving the balloon catheter from the body lumen. In some embodiments, the cancer treatment is radiotherapy, EMR, or ESD of the prostate.

[0179] In various embodiments, the present invention provides a minimally invasive method for reducing or preventing cancer recurrence. The method comprises inserting a balloon catheter into a target site in a body lumen, the target site being the site of a cancer treatment performed, or adjacent, proximal, or distal thereto, and the balloon catheter comprising an extended balloon and a drug coating. The method comprises inflating the balloon at the target site to bring the coating layer into contact with the wall of the body lumen at the target site until the balloon achieves an inflated balloon diameter for the inflation period. The method comprises deflating the balloon after the inflation period. The method comprises retrieving the balloon catheter from the body lumen. In some embodiments, the method further comprises performing a cancer treatment of an adjacent, proximal, or distal body lumen at the target site prior to insertion of the balloon catheter into the target site. In some embodiments, the cancer treatment performed is radiotherapy of the prostate, transurethral resection of the prostate, or EMR or ESD of the gastrointestinal tract.

[0180] In various embodiments, the present invention provides a method for treating or reducing the occurrence of surgical anastomosis-induced nonvascular stenosis, including treatment of the anastomosis at the time of anastomosis formation and / or before stenosis forms. The method includes inserting a balloon catheter into a target site in a body lumen containing a surgical anastomosis-induced nonvascular stenosis, the balloon catheter comprising an extended balloon and a drug coating. The method may include rinsing the anastomosis site with water, Seline solution, or an aqueous solution containing at least one water-soluble additive to immerse or wet the drug coating. The method includes inflating the balloon at the target site to bring the coating layer into contact with the wall of the body lumen at the location of the surgical anastomosis-induced nonvascular stenosis until the balloon achieves an inflated balloon diameter for an inflation period. The method includes compressing the balloon after the inflation period. The method includes retrieving the balloon catheter from the body lumen. In some embodiments, the stenosis is a fibrotic stenosis. In some embodiments, the stricture is an esophageal stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, large intestine stricture, colororectal stricture, stricture resulting from gastric bypass, ileocolonic stricture, gastrointestinal stricture, urethral stricture, ureteral stricture, vaginal stricture or stenosis, J-type sac stricture, or bladder neck stricture. If the anastomosis involves two or more body structures joined together, one or more body structures may originate from an autologous source (i.e., the same individual, e.g., bowel resection, arteriovenous fistula), an allogeneic source (i.e., another individual, e.g., in organ transplantation), or a xenogeneic source (i.e., a different species, e.g., decellularized transplantation).

[0181] In various embodiments, the present invention provides a method for treating or preventing surgically induced strictures. Surgical procedures that may induce nonvascular strictures include needle-knife electrotomy, episiotomy, urethrotomy, direct intravisual urethrotomy (DVIU), endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD). The method comprises inserting a balloon catheter into a target site in a body lumen, including a nonvascular stricture induced by needle-knife electrotomy, urethrotomy, direct intravisual urethrotomy (DVIU), endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD), wherein the balloon catheter comprises an extended balloon and a drug coating. The method may include rinsing the surgical site with water, Seline solution, or an aqueous solution containing at least one water-soluble additive to immerse or moisten the drug coating. The method includes inflating the balloon at the surgical site to bring the coating layer into contact with the wall of the body lumen at the surgical site until the balloon achieves the inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method includes retrieving the balloon catheter from the body lumen.

[0182] Various embodiments of the present invention relate to a method for treating non-vascular body lumen strictures using an endoscope to visualize the stricture. The endoscope may be a gastroscopy, small bowel endoscope (or enteroscope), duodenoscopy, colonoscopy, sigmoidoscope, rectoscope, anoscope, nasal endoscope, bronchoscope, or cystoscopy. The scope can be used to ensure that the balloon catheter is properly positioned within the targeted lumen. The method involves inserting the endoscope into a body lumen, which may be any opening (or orifice) of the body such as the mouth, nose, anus, external auditory canal, vagina, or urethra, and traversing to the stricture site to visualize the stricture. A guidewire may be delivered to the endoscope via a working channel, and so it passes through the stricture before inserting the balloon catheter. The method involves inserting the balloon catheter shown in Figure 1 or 4B into the target site of the body lumen. The method may include inserting the guidewire and the balloon catheter on the endoscope side by side or through the working channel of the endoscope into the target site of the body lumen. The method may include rinsing the body lumen with water, Seline solution, or an aqueous solution containing at least one water-soluble additive prior to, during, or after, the insertion of the balloon into the target site. The method may also include inflating the balloon until the coating layer comes into contact with the wall of the stenosis in the body lumen at the target site and the balloon achieves the inflated balloon diameter for the inflation period. Features (a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or (a) and (b) and (c), may exist: (a) the ratio of the inflated balloon diameter to the diameter of the stenosis in the body lumen of the target site is approximately 1.0 to approximately 40; or (b) inflation involves inflating the balloon to a pressure greater than or equal to the nominal pressure of the balloon catheter, and the stretch ratio of the nominal diameter of the balloon catheter to the diameter of the stenosis in the body lumen of the target site is approximately 1.0 to approximately 40; or (c) inflation involves inflating to a pressure greater than the nominal pressure of the balloon catheter, and the nominal diameter of the balloon catheter is less than the inflated balloon diameter; or (d) a combination of (a), (b), and (c).The method also includes retrieving the balloon catheter from the stenosis and endoscope, and retrieving the endoscope from the body lumen.

[0183] In various embodiments, the present invention provides a method for treating or preventing vascular stenosis. Vascular stenosis can be coronary artery stenosis, carotid artery stenosis, brachial artery stenosis, radial artery stenosis, renal artery stenosis, iliac artery stenosis, superficial femoral artery stenosis, popliteal artery stenosis, anterior tibial artery, posterior tibial artery, peroneal artery, and one of the other arteries of the foot. The method comprises inserting a balloon catheter into a target site in the blood vessel, the balloon catheter comprising a balloon and / or stent including an expanded balloon and a drug coating. The method comprises bringing the coating layer into contact with the inner lumen wall until the balloon achieves an expanded balloon diameter for an inflation period or the stent achieves an expanded diameter, inflating the balloon to expand the stenosis and / or extending the stent at the target site. The method may include deflating the balloon after the inflation period. The method may include retrieving the balloon catheter from the body lumen. In various embodiments, a sheath covering a covered balloon and / or covered stent can be used to prevent the drug from being washed away while the balloon catheter or stent is being advanced to a target site in a blood vessel.

[0184] In some embodiments, when treating a narrowed artery, it may be preferable to pre-dilate the stenosis with an uncoated pre-dilation balloon catheter before treating it with a drug-coated balloon. In some embodiments, the pre-dilation balloon catheter has a cutting or scoring element on the balloon used to break up calcified plaque. In some embodiments, the pre-dilation catheter may be shorter and / or smaller in diameter than the drug-coated balloon treatment catheter. In this scenario, the pre-dilation catheter is positioned so that the center of the balloon body aligns with the center of the stenosis. Once inflated, the pre-dilation balloon is compressed and removed, and the drug-coated treatment balloon is inserted. The size of the drug-coated balloon is selected to be larger than that of the pre-dilation balloon catheter in terms of balloon diameter and balloon length to ensure that the drug coating contacts the entire lumen wall of the pre-dilated stenosis.

[0185] In some embodiments, when treating a narrowed artery, it may be preferable to reduce or remove tissue from the stenosis with an atherectomy device prior to treating it with a drug-coated balloon. Any suitable type of atherectomy device, such as laser, directional, rotational, or jet, can be used. After the atherectomy is performed, angiography can be obtained to select the size of the drug-coated balloon such that the balloon diameter and balloon length are large enough to ensure that the drug coating contacts the entire lumen wall of the reduced stenosis.

[0186] In various embodiments, the present invention provides a method for treating or preventing in-stent restenosis, including, but not limited to, coronary artery stenosis, superficial femoral artery stenosis, popliteal artery stenosis, anterior tibial artery, posterior tibial artery, peroneal artery, and other arteries of the foot. The method comprises inserting a balloon catheter into a target site of in-stent restenosis, the balloon catheter comprising an extended balloon and a drug coating. The method comprises bringing the coating layer into contact with the wall of the inner lumen and inflating the balloon at the target site to dilate the stenosis until the balloon achieves an inflated balloon diameter for the inflation period. The method comprises deflating the balloon after the inflation period. The method comprises retrieving the balloon catheter from the body lumen.

[0187] In various embodiments, the present invention provides a method for treating or preventing fistulas (or stenotic arteries and veins). The method comprises inserting a balloon catheter into a target site in a blood vessel, the balloon catheter comprising an extended balloon and a drug coating. The method comprises bringing the coating layer into contact with the wall of the inner lumen and inflating the balloon at the target site to dilate the stenosis until the balloon achieves an inflated balloon diameter for the inflation period. The method comprises deflating the balloon after the inflation period. The method comprises retrieving the balloon catheter from the body lumen.

[0188] In various embodiments, the present invention provides a method for treating or preventing stenosis of a heart valve. The method comprises inserting a balloon catheter into a target site within the heart valve, the balloon catheter comprising an extended balloon and a drug coating. The method comprises bringing the coating layer into contact with the wall of the inner lumen and inflating the balloon at the target site to dilate the stenosis of the heart valve until the balloon achieves an inflated balloon diameter for the inflation period. The method comprises deflating the balloon after the inflation period. The method comprises retrieving the balloon catheter from the body lumen.

[0189] In various embodiments, the present invention provides a method for treating a body lumen, comprising inserting a balloon catheter, such as one of the balloon catheters described herein, into a target site in the body lumen. In some embodiments, the balloon is inflated until the drug-coated layer contacts the wall of the stenosis and the stenosis is expanded with the simultaneous transfer of the drug to the stenosis. In some embodiments, the balloon is inflated until the drug-coated layer contacts the wall of the stenosis and the balloon expands the stenosis to increase its diameter, so that the contact with the stenosis provides sufficient peripheral transfer of the drug to the wall of the stenosis. In some embodiments, a portion of the balloon containing the drug (e.g., an embodiment including less than 100% of the drug-covered surface area) can make uniform contact with the stenosis. In other embodiments, the contact between the stenosis and various portions of the balloon surface is non-uniform.

[0190] In various embodiments, the method includes measuring the stenosis of the body cavity to be treated. The distal and proximal healthy tissue diameters and the length of the stenosis can be evaluated to select the drug-coated balloon to be used. The physician will select the balloon based on the diameter of the body cavity stenosis, achieving an expansion ratio of the balloon's nominal diameter to the diameter of the body cavity stenosis of 1.0 to 40. The physician can then inflate the balloon to at least the nominal pressure, and in some cases, beyond the nominal pressure, up to the evaluated burst pressure of the balloon. The range of pressure used during the inflation period can be called the working pressure of the drug-coated balloon. In some cases, the method can include exceeding the evaluated burst pressure of the balloon. Since the nominal diameter of the balloon is determined without compression, the inflated diameter of the balloon during treatment will be approximately the same as, smaller than, or larger than the nominal diameter, even in a stenosis. At or above the burst pressure, the inflated diameter of the balloon may be less than the nominal diameter, equal to the nominal diameter, or exceed the nominal diameter. For example, a stenosis of a body cavity can be measured to have a diameter of 10 mm. The physician may select a drug-coated balloon with a nominal diameter of 14 mm, having a nominal pressure of 6 atmospheres and an evaluated burst pressure of 10 atmospheres. The elongation ratio is 1.4. The physician inflates the balloon to at least 6 atmospheres, in some cases to 8 or 10 atmospheres, and in some cases to more than 10 atmospheres to achieve the desired inflated balloon diameter during the procedure.

[0191] Various embodiments provide methods for treating benign prostatic hyperplasia (BPH) strictures, urethral strictures, ureteral strictures, vaginal strictures or strictures, prostate cancer, esophageal strictures, biliary strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, large intestine strictures, colororectal strictures, strictures after gastric bypass, ileocolonic strictures, gastrointestinal strictures, J-type pouch strictures, bladder neck strictures (e.g., stenosis), fibrostenotic strictures of eosinophilic esophagitis, Crohn's disease (CD)- and ulcerative colitis (UC)-induced strictures, radiation-induced strictures, endoscopic resection (EMR and ESD)-induced strictures, surgery-related anastomotic strictures, achalasia strictures, gastrectomy-induced strictures, asthma, or chronic obstructive pulmonary disease (COPD). The method is for treating strictures in body lumens such as urethral stricture, benign prostatic hyperplasia (BPH) stricture, ureteral stricture, esophageal stricture, sinus stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, large intestinal stricture, and biliary stricture. The stricture in body lumen can be benign prostatic hyperplasia (BPH) stricture, urethral stricture, or esophageal stricture. The method can be for treating benign prostatic hyperplasia, prostate cancer, or a combination thereof, and the body lumen is the prostate.

[0192] The body cavity may be the prostate gland, and the insertion of the balloon catheter involves positioning the balloon catheter within the prostate gland using a scope (e.g., a flexible or rigid cystoscope). The balloon catheter may include a scope, and the method may include using a video feeder from the scope to locate the target site. The method may include using a video feeder from the scope to position the balloon catheter at the target site.

[0193] The body cavity may be the prostate gland, and the balloon may have multiple main parts divided by one or more necks. The insertion of the balloon catheter may include positioning one of the main parts of the balloon catheter in the prostate gland and positioning a second main part of the balloon catheter in the bladder.

[0194] Insertion may include positioning at least one neck portion of the balloon in the bladder neck. At least one neck portion of the balloon catheter may be a distal neck portion, and insertion may include positioning the distal neck portion in the bladder neck. The balloon catheter may include a proximal neck portion, and insertion may include positioning the proximal neck portion in the prostatic urethra.

[0195] The swelling period may be any appropriate swelling period, for example, 0.1 minutes to about 10 minutes, about 0.5 minutes to about 2 minutes, or about 0.1 minutes or less, or about 0.2 minutes, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 minutes, or about 10 minutes or more.

[0196] Inflation can include increasing the pressure inside the balloon by any appropriate percentage (for example, the period during which pressure drops due to yielding and pressure can be maintained during these times can be excluded), for example, about 0.1 atmospheres / min to about 10 atmospheres / min or about 0.5 to about 1.5 atmospheres / min or less than about 0.1 atmospheres / min or less than or greater than about 0.2 atmospheres / min, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 atmospheres / min or more than or less than about 10 atmospheres / min).

[0197] Embodiments of the present invention are directed toward the treatment of strictures in body lumens by delivery of an effective amount of a therapeutic agent such as an anti-inflammatory and antiproliferative drug (e.g., rapamycin, paclitaxel, or their analogues). Stricures in body lumens include vascular strictures, urethral strictures, ureteral strictures, vaginal strictures, stenosis, esophageal strictures, achalasia strictures, strictures in stents, sinus strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, large intestinal strictures, and biliary strictures. Embodiments of the present invention are directed toward methods for treating at least one of the following conditions: vascular stenosis, benign prostatic hyperplasia (BPH), urethral problems, prostate cancer, colorectal stenosis, stenosis after gastric bypass, ileocolonic stenosis, gastrointestinal stenosis, J-type sac stenosis, bladder neck stenosis (e.g., stenosis), fibrotic stenosis, eosinophilic esophagitis stenosis, Crohn's disease (CD)- and ulcerative colitis (UC)-induced stenosis, radiation-induced stenosis, endoscopic resection (EMR and ESD)-induced stenosis, surgery-related anastomotic stenosis, achalasia stenosis, gastrectomy-induced stenosis, asthma, and chronic obstructive pulmonary disease (COPD). According to one embodiment, the method includes inflating a balloon catheter to release the drug into the wall of the stenosis, compressing the balloon, and retrieving the balloon catheter, wherein the residual drug may be about 1-70% of the total loaded drug on the balloon catheter, and the drug in the wall of the body lumen may be about 0.1-25% of the total loaded drug on the balloon catheter. In one embodiment of this embodiment, an additive enhances the absorption of the drug into the tissue of the stenosis in the body lumen.

[0198] A therapeutic agent. The therapeutic agents that can be used in embodiments of the present invention may be any drug or biologically active substance. The therapeutic agents may be hydrophobic therapeutic agents, antiproliferative therapeutic agents, anti-inflammatory agents, or combinations thereof. The drugs may be in various physical states, such as molecular distribution, crystalline form, or cluster form. Examples of drugs particularly useful in embodiments of the present invention are substantially water-insoluble drugs with lipophilicity, such as paclitaxel, docetaxel, taxol, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, their analogs, and combinations thereof, daunorubicin, doxorubicin, lapacone, vitamin D2 and / or D3, their analogs or derivatives, or combinations thereof. Therapeutic agents such as paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, umirolimus, everolimus, mTOR inhibitors (i.e., a class of drugs that inhibit the mechanistic target of rapamycin), or their analogues, or other antiproliferative drugs, can be delivered to the walls of body lumens to treat narrowing or stenosis.

[0199] Other drugs that may be useful in embodiments of the present invention include, without limitation, glucocorticoids (e.g., dexamethasone, betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisense agents, anticancer agents, antiproliferative agents, oligonucleotides, and more generally, antiplatelet agents, anticoagulants, antifibrillating agents, antioxidants, antimetabolite agents, antichemotactic agents, anti-inflammatory agents, and combinations thereof.

[0200] Some drugs that can be useful in various embodiments, such as for application to the urethra as well as the airways, nasal cavity and other nasal lumens, are corticosteroids, such as budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cortisone, betamethasone, triamcinolone acetonide, etc. Some other suitable drugs are terbutaline, albuterol, ipratropium, pirbuterol, epinephrine, salmeterol, levalbuterol, formoterol, etc.; the drugs can be bronchodilators or vasoconstrictors.

[0201] Furthermore, useful in embodiments of the present invention are, for example, polynucleotides, antisense, RNAi, or siRNAs that suppress inflammation and / or the proliferation of smooth muscle cells or fibroblasts.

[0202] Antiplatelet agents may include drugs such as aspirin and dipyridamole. Aspirin is classified as an analgesic, antipyretic, anti-inflammatory, and antiplatelet drug. Dipyridamole is a drug similar to aspirin in that it has antiplatelet properties. Dipyridamole is also classified as a coronary vasodilator. Anticoagulant agents used in embodiments of the present invention may include drugs such as heparin, protamine, hirudin, and mite anticoagulant proteins. Antioxidants may include probucol. Antiproliferative agents may include drugs such as amlodipine and doxazosin. Anti-fibrillation agents and anti-metabolite agents that can be used in embodiments of the present invention include drugs such as methotrexate, azathioprine, vincristine, vinblastine, 5-fluorouracil, adriamycin, and mutamycin. Antibiotics used in embodiments of the present invention include penicillin, cefoxitine, oxacillin, tobramycin, and gentamicin. A suitable antioxidant used in embodiments of the present invention includes probucol. In addition, genes, nucleic acids, or portions thereof can be used as therapeutic agents in these embodiments of the present invention. Furthermore, collagen synthesis inhibitors such as tranilast can be used as therapeutic agents in these embodiments of the present invention.

[0203] Furthermore, photosensitizing agents for photodynamic or radiotherapy, including various porphyrin compounds such as porfimers, are useful as drugs in embodiments of the present invention. Furthermore, the drugs used in embodiments of the present invention include everolimus, somatostatin, tacrolimus, roxithromycin, duramycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandmycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, and vincris. Tin, vindesine, vinorelbine, etoposide, teniposide, nimustine, calmastine, lomustine, cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan, ifosfamide, trophosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, temozolomide, thiotepa, daunorubicin, doxorubicin, acralubicin, epirubicin, mitoxantrone, idarubicin, bleoma Icin, Mitomycin, Dactinomycin, Methotrexate, Fludarabine, Fludarabine-5'-Hydrogen Diphosphate, Cladribine, Mercaptopurine, Thioguanine, Cytarabine, Fluorouracil, Gemcitabine, Capecitabine, Docetaxel, Carboplatin, Cisplatin, Oxaliplatin, Amsacrin, Irinotecan, Topotecan, Hydroxycarbamide, Miltefosine, Pentostatin, Aldesleukin, Tretinoin, Asparaginase, Pegasparagase, Anastrozole, exemestane, letrozole, formestan, aminoglutethimide, adriamycin, azithromycin, spiramycin, cepharanthine, smc proliferation inhibitor-2w, epotilon A and B, mitoxantrone, azathioprine, mycophenolate mofetil, c-myc-antisense, b-myc-antisense, betulinic acid, camptothecin, lapachol, beta-lapacon, podophyllotoxin, betulin, podophyllic acid 2-ethylhydrazide, morglamostim (rhuGM-CSF), pegylated interferon a-2b, lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab, daclizumab, selectin (cytokine antagonist),CETP inhibitors, cadherins, cytokinin inhibitors, COX-2 inhibitors, NFκB, angiopeptin, ciprofloxacin, camptothecin, fluoroblastin, monoclonal antibodies (these inhibit muscle cell proliferation), bFGF antagonists, probucol, prostaglandins, 1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one, scopoletin, colchicine, NO donors such as pentaerythritol tetranitrate and syndnoeimines, S-nitroso derivatives, ta Moxifen, staurosporine, beta-estradiol, α-estradiol, estriol, estrone, ethinylestradiol, phosphestrol, medroxyprogesterone, estradiol cypionate, estradiol benzoate, tranilast, kamebauculin and other terpenoids, which are used in cancer treatment, verapamil, tyrosine kinase inhibitors (tilphostines), cyclosporine A, 6-α-hydroxypaclitaxel, baccatin, taxotere and macrocyclic oligosaccharides of carbon monoxide (MCS) Mer and their derivatives, mofebutazone, acemetacin, diclofenac, lonazolac, dapthone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurantiomalate, oxaseprole, celecoxib, β-sitosterin, ademethionine, miltecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, elliptic Syn, D-24851 (Calbiochem), Colsemid, Cytochalasin AE, Indanosine, Nocodazole, S-100 Protein, Bacitracin, Vitronectin Receptor Antagonist, Azelastine, Guanidyl Cyclase Stimulator Tissue Inhibitors for Metalloproteinase-1 and -2, Free Nucleic Acids, Nucleic Acids Incorporated into Viral Mediators, DNA and RNA Fragments, Plasminogen Activator Inhibitor-1, Plasminogen Activator Inhibitor-2, Antisense Oligonucleotides, VEGF Inhibitors, IGF-1,Activators from the group of antibiotics such as cefadroxil, activators from the group of antibiotics such as cefadroxil, cefazolin, cefaclor, cefotaxime, tobramycin, gentamicin, penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotics such as argatroban, aspirin, absiximab, synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulfated and N-reacetylated heparin, tissue plasminogen activator, GpIIb / IIIa platelet membrane receptor, factors Xa inhibitor antibodies, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, e.g., dipyramidol, trapidil, nitroprusside, PDGF antagonists, e.g., triazolopyrimidine and seramin, ACE inhibitors, e.g., captopril, cilazapril, lisinopril, enalapril, losartan, thiol protease inhibitors, prostacyclin, bapiprost, interferon α, β and γ, histamine antagonists, serotonin blockers, cell death inhibitors, cell death regulators, p65 NF-κB or BcI-xL antisense oligonucleotides, halofginone, nifedipine, tranilast, morcidomin, tea polyphenols, epicatechin gallate, epigallocatechin gallate, boswellic acid and their derivatives, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone, mutamycin, procainamide, retinoic acid, quinidine, disopyramide, flecamide, propafate Non, sotalol, amidol, naturally and synthetically obtained steroids, e.g., briophylline A, inotodiol, macilloside A, galakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal anti-steroids (NSAIDs), e.g., fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, and antiviral agents, e.g., acyclovir.Ganciclovir and zidovudine, antifungal agents such as clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprotozoal agents such as chloroquine, mefloquine, quinine, and further natural terpenoids such as hippocaesculin, valintogenol-C21-angelate, 14-dehydroagrostistachin, agroskelin, agrostistachin, 17-hydroxyagrostistachin, and ovatodiolides. lids), 4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7, tubeimoside, bruceanol A, B and C, bruceantinoside C, yadandiol N and P, isodeoxyelephantopine, tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hyptatic acid acid) A, zeolin, iso-ylide germanal, maytenfoliol, fsantin A, excisanin A and B, longicaulin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-α-senesioyloxychaparrin, taxamairin A and B, regenilol, triptolide, further simarin, apocymarin, aristolochinic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburin chloride chloride, cictoxin, synococlin, bombrestatin A and B, cudraisoflavonei A,Curcumin, dihydronitidine, nitidine chloride, 12-beta-hydroxypregnadiene-3,20-dione, bilobol, ginkgol, ginkgolic acid, helenaline, indisine, indisine-N-oxide, lasiocarpine, inotodiol, glycoside 1a, podophyllotoxin, justicidine A and B, larreatin, malloterin, mallotochromanol, isobutyrylmalotochromanol Chromanol), macilloside A, marchantin A, meitansine, lycoridicin, margetine, pancratistatin, liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-AII, bisparthenolidine, periplocoside A, galaquinoside, ursolic acid, Deoxypsorospermin (psychorubin), lysine A, sanguinaline, manwu wheat acid, methylsorbifolin, sphatheliachromen, stizophyllin, mansonin, strebreside, akagerin, dihydrosanvalencin, hydroxysanbasin, strychnophylline, usambarine ( usambarine, usambarensine, berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferone, afromoson, acetylvismione B,It contains desacetylvismione A, and vismione A and B.

[0204] Furthermore, drug combinations can be used in embodiments of the present invention. Some combinations have an additive effect because they have different mechanisms, for example, paclitaxel and rapamycin, paclitaxel and active vitamin D, paclitaxel and rapacon, rapamycin and active vitamin D, rapamycin and rapacon. Due to the additive effect, the drug dose can be similarly reduced. These combinations can reduce complications from using high doses of drugs.

[0205] Some drugs used in various embodiments that are considered particularly suitable for the airways, nasal cavity and other nasal lumens include corticosteroids, such as budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cortisone, betamethasone, and triamcinolone acetonide.

[0206] In one embodiment of the balloon catheter, the ratio by weight of therapeutic (e.g., hydrophobic) agents in the coating layer to the total weight of one or more additives in the coating layer may be about 0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about 3, about 2 to about 6 or less than or equal to about 0.05, or less or greater than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 or more. In one embodiment of the balloon catheter, the ratio of the weight of the therapeutic agent in the coating layer to the total weight of one or more additives in the coating layer (e.g., the first and second additives in the coating layer, or the total weight of the first, second and third additives) can be about 0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about 3, about 2 to about 6 or less than or equal to about 0.05, or less than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or about 20 or more.

[0207] Additives. Additives according to embodiments of the present invention can promote rapid drug dissolution and superior penetration of drugs into tissue at disease sites. Thus, coatings according to embodiments of the present invention provide an enhanced rate and / or range of absorption of antiproliferative therapeutic agents in nonvascular lesion tissue or nonvascular body lumens. In embodiments of the present invention, coated devices deliver antiproliferative therapeutic agents to nonvascular tissue for very short placement times of less than 10 minutes and less than 2 minutes, reducing re-narrowing and recurrence of nonvascular body lumen stenosis.

[0208] In some embodiments, the additive reduces the crystal size and number of the therapeutic agent particles, the additive is water-soluble, and the therapeutic agent is not water-soluble. The additive may have fatty chains of acids, esters, ethers, or alcohols, and the fatty chains may be directly inserted into the lipid membrane structure of tissues. The additive may penetrate and rearrange the lipid membrane structure of tissues. The additive may have one or more functional groups that have affinity for the drug through hydrogen bonding and / or van der Waals interactions. In some embodiments, the additive may be at least one surfactant and a compound, and the additive has a molecular weight of 50 to 750 g / mol (e.g., 50 g / mol or more, or 75 g / mol, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725 g / mol or less, or 750 g / mol or less). The compound may have more than four hydroxyls. In some embodiments, the compound having more than four hydroxyls has a melting point of 120°C or less, and the compound is an alcohol or an ester. In some embodiments, the therapeutic agent is not water-soluble or is only slightly water-soluble.

[0209] In one embodiment of this embodiment, the additive enhances the absorption of a drug into non-vascular and vascular tissues within the body lumen. In another embodiment of this embodiment, the additive comprises a hydrophilic moiety and a drug affinity moiety, the drug affinity moiety being at least one of a hydrophobic moiety, a moiety having affinity for the therapeutic agent by hydrogen bonding, and a moiety having affinity for the therapeutic agent by van der Waals interactions. The drug affinity moiety of the additive can bind lipophilic drugs such as rapamycin, paclitaxel, or their analogues. The hydrophilic moiety accelerates the diffusion and increased penetration of the drug into the tissue. It can facilitate the rapid movement of the drug from the medical device during placement at the target moiety by preventing hydrophobic drug molecules from agglomerating with each other and with the device, increasing drug solubility in the gaps, and / or accelerating the drug lumen via polar head groups to the lipid bilayer of the cell membrane of the target tissue. The additives of various embodiments of the present invention may have two parts that work together to promote the rapid release of the drug from the device surface during placement (by accelerating drug contact with tissues to which the drug has high affinity) and uptake by the target tissue, while preventing premature release of the drug from the device surface prior to device placement at the target site.

[0210] In embodiments of the present invention, the therapeutic agent is rapidly released after the medical device comes into contact with tissue and is readily absorbed. For example, certain embodiments of the device of the present invention include a drug-coated balloon catheter that delivers a therapeutic agent, such as a lipophilic antiproliferative drug (e.g., paclitaxel or rapamycin), to nonvascular tissue via brief, direct pressure contact with a high concentration of the drug during balloon inflation. For example, the lipophilic drug is retained in the target tissue at the delivery site, which inhibits hyperplasia and allows restenosis to still be epithelialized. In these embodiments, the coating formulation of the present invention not only facilitates the rapid release of the drug from the balloon surface and the transfer of the drug to the target tissue during placement, but also prevents the drug coating from diffusing away from the device during transfer via a tortuous anatomy and from moving away from the device during the initial phase of balloon inflation, prior to reaching the target site before being pressed into direct contact with the surface of the body lumen.

[0211] Additives according to certain embodiments have a drug-affinity moiety and a hydrophilic moiety. The drug-affinity moiety is a hydrophobic moiety and / or has affinity for the therapeutic agent by hydrogen bonding and / or van der Waals interactions. The drug-affinity moiety may particularly include aliphatic and aromatic organic hydrocarbon compounds such as benzene, toluene, and alkanes. These moieties are not water-soluble. They can bind to both hydrophobic drugs (they share structural similarities) and lipids of cell membranes. The drug-affinity moiety may contain functional groups that can form hydrogen bonds with the drug and itself. The hydrophilic moiety may particularly include hydroxyl groups, amine groups, amide groups, carbonyl groups, carboxylic acids and anhydrides, ethyl oxide, ethyl glycol, polyethylene glycol, ascorbic acid, amino acids, amino alcohols, glucose, sucrose, sorbitan, glycerin, polyhydric alcohols, phosphates, sulfates, organic salts, and their substituted molecules. One or more hydroxyl, carboxyl, acid, amide, or amine groups may be advantageous, for example, because they readily replace water molecules that hydrogenate to the polar head groups and surface proteins of the cell membrane and can function to remove this barrier between the hydrophobic drug and the cell membrane lipids. These parts can be soluble in water and polar solvents. The additives of embodiments of the present invention have components for binding the drug and facilitating its rapid movement from the medical device to the target tissue during placement.

[0212] The additives in embodiments of the present invention may be surfactants and / or compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties. Surfactants include ionic, nonionic, aliphatic, and aromatic surfactants. Compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties are selected from amino alcohols, hydroxyl carboxylic acids and anhydrides, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyhydric alcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, and their substituted molecules.

[0213] The terms "hydrophilic" and "hydrophobic" are relative terms. In order to function as an additive in various embodiments of the present invention, the compound comprises a polar or charged hydrophilic portion and a nonpolar hydrophobic (lipophilic) portion.

[0214] A commonly used empirical parameter in medicinal chemistry to characterize the relative hydrophilicity and hydrophobicity of a pharmaceutical compound is the partition coefficient P, which is the ratio of the concentrations of the non-ionized compound in two phases of a mixture of two immiscible solvents, usually octanol and water, where P = ([solute]octanol / [solute]water). Compounds with higher log P are more hydrophobic, while compounds with lower log P are more hydrophilic. Lipinski's rule states that pharmaceutical compounds with log P < 5 can be more permeable membranes. For the purposes of certain embodiments of the present invention, for example, the additive has a log P less than the log P of the prescribed drug (for example, the log P of paclitaxel is 7.4). A larger log P difference between the drug and the additive can facilitate drug phase separation. For example, if the log P of the additive is much lower than the log P of the drug, the additive can accelerate the release of the drug into an aqueous environment from the surface of a device to which the drug could otherwise adhere firmly, thereby accelerating drug delivery to tissue during easy placement at the site of interposition. In certain embodiments of the present invention, the log P of the additive is negative. In other embodiments, the log P of the additive is less than the log P of the drug. While the octanol-water partition coefficient P or log P of a compound is useful as a measure of relative hydrophilicity and hydrophobicity, it is merely a rough guide that can be useful in defining a suitable additive to be used in embodiments of the present invention.

[0215] Suitable additives that can be used in embodiments of the present invention include, without limitation, organic and inorganic pharmaceutical additives, their natural products and derivatives (e.g., sugars, vitamins, amino acids, peptides, proteins, and fatty acids), low molecular weight oligomers, surfactants (anionic, cationic, nonionic, and ionic), and mixtures thereof. The additives described herein as useful for the present invention are provided only for typical purposes and are not intended to be comprehensive. Numerous other additives may be useful for the purposes of the present invention. Additives may include a first ionic or amphoteric additive, a second ionic or amphoteric additive, or a combination thereof.

[0216] Surfactants. In embodiments including a surfactant, the surfactant can be any surfactant suitable for use in a pharmaceutical composition. Such surfactants can be anionic, cationic, amphoteric, or nonionic. Furthermore, mixtures of surfactants are combinations of surfactants and other additives, as these fall within the scope of various embodiments of the present invention. Surfactants often have one or more long aliphatic chains, such as fatty acids, that can be directly inserted into the lipid bilayer of cell membranes to form part of the lipid structure, while other components of the surfactant loosen the lipid structure to enhance drug penetration and absorption. The contrast agent iopromide does not possess these properties.

[0217] A commonly used empirical parameter to characterize the relative hydrophilicity and hydrophobicity of surfactants is the hydrophilic-hydrophobic balance ("HLB" value). Surfactants with lower HLB values ​​are more hydrophobic and have greater solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Using HLB values ​​as a rough guide, hydrophilic surfactants are generally considered to be compounds with HLB values ​​greater than about 10, as well as anionic, cationic, or amphoteric compounds to which the HLB scale is not generally applicable. Similarly, hydrophobic surfactants are compounds with HLB values ​​less than about 10. In certain embodiments of the present invention, higher HLB values ​​are utilized because increased hydrophilicity can facilitate the release of hydrophobic drugs from the surface of a device. In one embodiment, the HLB of the surfactant additive is greater than 10. The additional HLB can be greater than 14. Alternatively, surfactants with lower HLB can be used, for example, to prevent drug loss prior to device placement at the target site in a top coat on a drug layer with a highly hydrophilic additive.

[0218] For example, the HLB value of a surfactant is a rough guide commonly used to enable the formulation of emulsions for industrial, pharmaceutical, and cosmetic purposes, for instance. For numerous important surfactants, including some polyethoxylated surfactants, it has been reported that the HLB value can vary by approximately 8 HLB units, depending on the empirical method chosen to determine the HLB value (Schott (J)) (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Keeping these inherent difficulties in mind, the HLB value can be used as a guide to identify suitable hydrophilic or hydrophobic surfactants for use in embodiments of the present invention as described herein.

[0219] PEG fatty acids and PEG fatty acid mono and diesters. Although polyethylene glycol (PEG) itself does not function as a surfactant, various PEG fatty acid esters possess useful surfactant properties. Among PEG fatty acid monoesters, esters of lauric acid, oleic acid, and stearic acid are most useful in embodiments of the present invention. Examples of hydrophilic surfactants include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, and PEG-20 oleate. Their HLB values ​​are in the range of 4 to 20.

[0220] Furthermore, polyethylene glycol fatty acid diesters are suitable for use as surfactants in the compositions of the embodiments of the present invention. Hydrophilic surfactants include PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, and PEG-32 dioleate. Their HLB values ​​are in the range of 5 to 15.

[0221] Furthermore, generally, mixtures of surfactants are useful in embodiments of the present invention, including mixtures of two or more surfactants, as well as mixtures of surfactants with another or more additives. Several PEG fatty acid esters are commercially available as mixtures or as mono- and diesters.

[0222] Polyethylene glycol glycerin fatty acid ester. Hydrophilic surfactants may include PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate.

[0223] Alcohol-oil transesterification reaction product. Numerous surfactants with varying degrees of hydrophobicity or hydrophilicity can be prepared by reacting various natural and / or hydrogenated oils with alcohols or polyhydric alcohols. Most commonly used oils are castor oil or hydrogenated castor oil, or edible vegetable oils such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or tonsil oil. Alcohols include glycerin, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, and pentaerythritol. Among these alcohol-oil transesterification surfactants, the hydrophilic surfactants are PEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT® TO), PEG-60 corn glyceride (Crovo I M70), PEG-60 tonsil oil (Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C-50), and PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic / capric acid glyceride (Labrasol), and PEG-6 caprylic / capric acid glyceride (Softigen 767). For example, hydrophobic surfactants in this class include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil® M 2125 CS), PEG-6 tonsil oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil (Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6 peanut oil (Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil (Labrafil® M 2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS), PEG-6 triolein (Labrafil® b M 2735 CS), and PEG-8 corn oil (Labrafil® WL 2609 CS). These are BS, PEG-20 corn glyceride (Crovol M40), and PEG-20 almond glyceride (Crovol A40).

[0224] Polyglyceryl fatty acids. Furthermore, polyglyceryl esters of fatty acids are suitable surfactants used in embodiments of the present invention. Among the polyglyceryl fatty acid esters, hydrophobic surfactants include polyglyceryl oleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO), polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate, polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryl linoleate. Hydrophilic surfactants include polyglyceryl-10 laurate (Nikkol Decaglyn 1L), polyglyceryl-10 oleate (Nikkol Decaglyn 1-O), and polyglyceryl-10 mono, as well as Dioleart (Capro I® PEG 860), polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate. Polyglyceryl polyricinoleate (Polymuls) is also a surfactant.

[0225] Propylene glycol fatty acid ester. Propylene glycol and fatty acid esters are suitable surfactants for use in embodiments of the present invention. In this class of surfactants, hydrophobic surfactants include propylene glycol monolaurate (Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propylene glycol monooleate (Myverol P-06), propylene glycol dicaprylate / dicaprate (Captex® 200), and propylene glycol dioctanoate (Captex® 800).

[0226] Sterols and sterol derivatives. Sterols and sterol derivatives are suitable surfactants for use in embodiments of the present invention. Derivatives include polyethylene glycol derivatives. A surfactant in this class is PEG-24 cholesterol ether (Solulan C-24).

[0227] Polyethylene glycol sorbitan fatty acid ester. Various PEG-sorbitan fatty acid esters are available and suitable for use as surfactants in embodiments of the present invention. Among the PEG-sorbitan fatty acid esters, surfactants include PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitan monooleate (Tween-80). In some embodiments, laurate esters are used because they have shorter lipid chains compared to oleic acid esters and increase drug absorption.

[0228] Sugars and their derivatives. Sugar derivatives are suitable surfactants used in embodiments of the present invention. Surfactants in this class include sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, and octyl-β-D-thioglucopyranoside.

[0229] Polyethylene glycol alkylphenol. Several PEG alkylphenol surfactants are available and suitable for use in embodiments of the present invention, such as PEG-10-100 nonylphenol and PEG-15-100 octylphenol ether, tyroxapole, octoxynol, octoxynol-9, and nonoxynol.

[0230] Polyoxyethylene-polyoxypropylene (POE-POP) block copolymer. POE-POP block copolymers are a unique class of polymeric surfactants. The unique structure of these surfactants, possessing well-defined ratios and positions of hydrophilic POE and hydrophobic POP moieties, provides a wide variety of surfactants suitable for use in embodiments of the present invention. These surfactants are available under various trade names, including Synperonic PE series (ICI); Pluronic® series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The collective term for these polymers is "poloxamer" (CAS 9003-11-6). These polymers share the formula: HO(C2H4O) a (C3H6O) b (C2H4O) a In the formula, "a" and "b" represent the number of polyoxyethylene and polyoxypropylene units, respectively.

[0231] This class of hydrophilic surfactants includes Poloxamer 108, 188, 217, 238, 288, 338, and 407. This class of hydrophobic surfactants includes Poloxamer 124, 182, 183, 212, 331, and 335.

[0232] Sorbitan fatty acid ester. Sorbitan esters of fatty acids are suitable surfactants for use in embodiments of the present invention. Among these esters, hydrophobic surfactants include sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate (Span-80), and sorbitan monostearate.

[0233] The amphiphilic derivative of vitamin C, sorbitan monopalmitate (which possesses vitamin C activity), can exhibit two important functions in solubilization systems. Firstly, it possesses effective polar groups that can modulate the microenvironment. These polar groups are the same groups that make vitamin C itself (ascorbic acid) one of the most water-soluble organic solid compounds available: ascorbic acid is soluble in water at approximately 30 wt / wt% (very close to the solubility of sodium chloride, for example). Secondly, it can be used when increasing the pH to convert the ratio of ascorbic acid palmitate to more soluble salts such as sodium ascorbyl palmitate.

[0234] Ionic surfactant. Ionic surfactants, including cationic, anionic, and amphoteric surfactants, are suitable hydrophilic surfactants for use in embodiments of the present invention. Ionic surfactants include quaternary ammonium salts, fatty acid salts, and bile salts. Specifically, ionic surfactants include benzalkonium chloride, benzethonium chloride, cetylpyridium chloride, dodecyltrimethylammonium bromide, cetyltrimethylammonium chloride, trimethyltetradecylammonium chloride, trimethyloctylammonium chloride, lauryltriethylammonium chloride, DOTAP-1,2-dioleoyl-3-trimethylammonium-propane (chloride salt or methyl sulfate salt), DOTMA-1,2-di-O-octadecenyl-3-trimethylammoniumpropane, DC-cholesterol-3β-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride, DODMA-1,2-dioleyloxy-3-dimethyl The compounds include minopropane, GL67-N4-cholesteryl-spermine HCl salt, DDAB-dimethyldioctadecylammonium (bromide salt), MVL5-N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-amino-propyl)amino]butylcarboxamide)ethyl]-3,4-di[oleyloxy]-benzamide, EPC-1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (chloride salt), sodium docecyl sulfate, dialkylmethylbenzylammonium chloride, edrophonium chloride, domiphene bromide, dialkyl ester of sodium sulfosuccinate, sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate. They are soluble in both organic solvents (e.g., ethanol, acetone, and toluene) and water. This makes them particularly useful for medical device coatings because they simplify the preparation and coating processes and have good adhesive properties. Water-insoluble drugs are generally soluble in organic solvents.

[0235] Some of the surfactants described herein are highly stable under heating. They remain from the ethylene oxide sterilization process. They do not react with drugs such as paclitaxel or rapamycin under the sterilization process. Hydroxyl, ester, and amide groups do not appear to react with drugs, but amine and acid groups often react with paclitaxel or rapamycin during sterilization, hence the use of hydroxyl, ester, and amide groups. Furthermore, surfactant additives improve the integrity and quality of the coating layer, resulting in no particle reduction during handling. When the surfactants described herein are formulated with paclitaxel, experimentally, it can protect the drug from premature release during the device delivery process while promoting the rapid release and elution of paclitaxel during a very short placement time of 0.2–10 minutes at the target site. Drug absorption by the tissue at the target site can be experimentally determined to be high.

[0236] A compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties. Compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties include creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerol ethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5, 12-crown-4, N-A Cetylglucosamine, N-octyl-D-gluconamide, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin, galaclocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N-oleoyl-D - Contains sphingosine, PEG caprylic / capric diglyceride, PEG-8 caprylic / capric diglyceride, PEG caprylate, PEG-8 caprylate (e.g., Labrasol®), PEG caprate, PEG caproate, glyceryl monocaprylate, glyceryl monocaprate and glyceryl monocaproate, monolaurin, monocaprin, monocaprylin, monomyristate, monopalmitorein and monoolein.

[0237] Compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties include amino alcohols, hydroxyl carboxylic acids, esters, anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyhydric alcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids, and their substituted molecules. Hydrophilic compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties with a molecular weight of 5,000 to less than 10,000 are used in certain embodiments. In other embodiments, the molecular weight of the additive having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties is 1,000 to less than 5,000, 750 to less than 1,000, or less than 750. In these embodiments, the molecular weight of the additive is less than that of the drug being delivered. Furthermore, the molecular weight of the additive should be greater than 80, because molecules with a molecular weight of less than 80 evaporate very easily and do not remain on the coating of the medical device. Smaller molecules can diffuse quickly. They can accelerate drug release and easily release themselves from the delivery balloon, and if the drug binds to the tissues in the body lumen, they can diffuse away from the drug.

[0238] In certain embodiments, additives with more than four hydroxyls are utilized, for example, in the case of high molecular weight additives. Large molecules diffuse slowly. If the molecular weight of the additive or compound is high, for example, if the molecular weight is greater than 800, 1000, 1200, 1500, or 2000; the large molecules elute too slowly away from the surface of the medical device, making it impossible to release the drug in less than two minutes. If these large molecules contain more than four hydroxyls, they increase hydrophilicity, which is necessary for relatively large molecules to release the drug rapidly. Increased hydrophilicity can help elute the coating from the balloon, accelerate drug release, and improve and / or promote drug movement through the water barrier and polar head groups of the lipid bilayer as it penetrates the tissue. In one embodiment, the hydroxyl is utilized as a hydrophilic part so that it does not react with water-insoluble drugs such as paclitaxel or rapamycin. In some embodiments, compounds with more than four hydroxyls have a melting point of 120°C or less. In some embodiments, compounds having more than four hydroxyls have three adjacent hydroxyls, all located on one side of the molecule, in their stereoconfiguration. For example, sorbitol and xylitol have three adjacent hydroxyl groups, all located on one side of the molecule, in their stereoconfiguration, while galactitol does not. The difference impacts the physical properties of the isomers, such as their melting temperatures. The stereoconfiguration of three adjacent hydroxyls can enhance drug binding. This will lead to improved compatibility of water-insoluble drugs and hydrophilic additives, resulting in improved tissue uptake and absorption of the drug.

[0239] Some of the compounds described herein that have one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties are very stable under heating. They survive the ethylene oxide sterilization process and do not react with water-insoluble drugs such as paclitaxel or rapamycin during sterilization. On the other hand, L-ascorbic acid and its salts and diethanolamine do not necessarily survive such sterilization processes, and they react with paclitaxel. Therefore, different sterilization methods are used for L-ascorbic acid and diethanolamine. For example, hydroxyl, ester, and amide groups are used because they do not appear to react with therapeutic agents such as paclitaxel or rapamycin. Sometimes, amine and acid groups do not react with paclitaxel; for example, experimentally, benzoic acid, gentisic acid, diethanolamine, and ascorbic acid were not stable under ethylene oxide sterilization, heating, and the aging process, and reacted with paclitaxel. When the compounds described herein are formulated with paclitaxel, the top coating layer can be advantageous in preventing premature drug loss during the device delivery process before placement at the target site, as hydrophilic small molecules sometimes release too readily. Small molecules, sometimes release the drug, also easily. The compounds herein can rapidly elute the drug from the balloon during placement at the target site. Surprisingly, experimentally, drug absorption by tissue is high, with the coating containing these additives, such as ribonyl lactone and gluconolactone, after only 0.2–10 minutes of placement, even though some drug may be lost during the device's passage to the target site.

[0240] Fat-soluble vitamins and their salts. Vitamins A, D, E, and K in numerous various forms and provitamin forms are considered fat-soluble vitamins, and these, along with several other vitamins and vitamin sources or closely related substances, are fat-soluble, polar groups, and have a relatively high octanol-water partition coefficient. Clearly, such compounds of a general class have a history of safe use and high benefits relative to the risk ratio, making them useful as additives in embodiments of the present invention.

[0241] Furthermore, the following examples of fat-soluble vitamin derivatives and / or sources are useful as additives: alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, tocopherol acetate, ergosterol, 1-alpha-hydroxycholecalciferol, vitamin D2, vitamin D3, alpha-carotene, beta-carotene, gamma-carotene, vitamin A, fursultiamine, methylol-riboflavin, octotiamine, prosultiamine, riboflavin, vinthiamol, dihydrovitamin K1, menadiol diacetic acid, menadiol dibutyrate, menadiol disulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamin K2, and vitamin K-S(II). Folic acid is also of this type, and although it is water-soluble at physiological pH, it can be formulated in free acid form. Other derivatives of fat-soluble vitamins useful in embodiments of the present invention can be readily obtained through well-known chemical reactions with hydrophilic molecules.

[0242] Water-soluble vitamins and their amphiphilic derivatives. Some menadione-related vitamins / provitamins, including vitamins B, C, U, pantothenic acid, folic acid, and many of their various forms, are considered water-soluble vitamins. Furthermore, they can bind or complex (or combine) with hydrophobic moieties or polyvalent ions into amphiphilic forms with relatively high octanol-water partition coefficients and polar groups. Again, such compounds can have low toxicity and a high benefit-to-risk ratio, making them useful as additives in embodiments of the present invention. Their salts can also be useful as additives in the present invention. Examples of water-soluble vitamins and derivatives include, without limitation, acetylamine, benfotiamine, pantothenic acid, cetotiamine, cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate, ascorbic acid nicotinamide, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U. Furthermore, as mentioned above, folic acid is water-soluble as a salt over a wide pH range, including physiological pH.

[0243] Compounds containing amino or other basic groups can be readily modified by simple acid-base reactions with hydrophobic acids, such as fatty acids (especially lauric acid, oleic acid, myristic acid, palmitin, stearic acid, or 2-ethylhexanoic acid), low-solubility amino acids, benzoic acid, salicylic acid, or acidic fat-soluble vitamins (e.g., riboflavin). Other compounds can also be obtained by reacting such acids with another group on the vitamin, such as a hydroxyl group, to form bonds such as ester bonds. Derivatives of water-soluble vitamins containing acidic groups can be produced, for example, in reactions with hydrophobic reactants such as stearylamine or riboflavin to create compounds useful in embodiments of the present invention. The attachment of a palmitic acid chain to vitamin C results in ascorbic acid palmitate.

[0244] Amino acids and their salts. Alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, histidine, proline, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, and their derivatives are other useful additives in embodiments of the invention.

[0245] Certain amino acids, in their zwitterionic and / or monovalent or polyvalent salt forms, possess polar groups, relatively high octanol-water partition coefficients, and are useful in embodiments of the present invention. In the context of this disclosure, the applicants take the term “lowly soluble amino acids” to mean amino acids having solubility in unbuffered water of less than about 4% (40 mg / mL). These include cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine.

[0246] Furthermore, amino acid dimers, sugar conjugations, and other derivatives are useful. To make further additives useful in embodiments of the present invention, hydrophilic molecules can be linked to hydrophobic amino acids, or hydrophobic molecules to hydrophilic amino acids, via simple reactions well known in the art.

[0247] Furthermore, catecholamines such as dopamine, levodopa, carbidopa, and DOPA are useful as additives.

[0248] Oligopeptides, peptides, and proteins. Oligopeptides and peptides are useful as additives because hydrophobic and hydrophilic amino acids can be easily linked, and various amino acid sequences can be tested to maximize drug penetration into tissues.

[0249] Furthermore, proteins are useful as additives in various embodiments of the present invention. For example, serum albumin is a useful additive because it is water-soluble and contains a considerable hydrophobic moiety for drug binding: paclitaxel has 89%–98% protein binding after intravenous injection in humans, and rapamycin has 92% protein binding to albumin, mainly (97%). Moreover, the solubility of paclitaxel in PBS increases more than 20-fold with the addition of BSA. Albumin is naturally present in serum at high concentrations and is therefore very safe for human use.

[0250] Other useful proteins include, without limitation, other albumins, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobulins, α-2-macroglobulins, fibronectin, vitronectin, fibrinogen, lipases, and other similar proteins.

[0251] Organic acids and their esters and anhydrides. Examples include acetic acid and anhydride, benzoic acid and anhydride, diethylenetriaminepentaacetic acid dianhydride, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic acid and anhydride, diglycolic acid anhydride, glutaric acid anhydride, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid aspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylate, and 2-pyrrolidone.

[0252] These esters and anhydrides are soluble in organic solvents such as ethanol, acetone, methyl ethyl ketone, and ethyl acetate. Water-insoluble drugs dissolve in organic solvents containing these esters and anhydrides, then easily coat medical devices, and can then be hydrolyzed under high pH conditions. The hydrolyzed anhydrides or esters are water-soluble acids or alcohols, which can effectively deliver the drug from the device into the walls of body lumens.

[0253] Antibacterial agent. The antimicrobial properties of various fatty acids, alkyl glyceryl ethers, and C8-C12 fatty acid monoglycerides have been studied for many years. Research has confirmed that fatty acids, alkyl glyceryl ethers, and monoglycerides can inhibit the growth of numerous types of bacteria and viruses. The coating formulations of the present invention may contain various fatty acids, alkyl glyceryl ethers, and C8-C12 fatty acid monoglycerides, such as caprylic acid, monocaprylin, capric acid, monocaprin, lauric acid, dodecylglycerol, and monolaurin, as additives for the treatment of various nonvascular and vascular stenosis.

[0254] Other compounds having one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties. Additives according to various embodiments may include amino alcohols, alcohols, amines, acids, amides, and hydroxyl acids in both cyclo and linear aliphatic and aromatic groups.Examples include L-ascorbic acid and its salts, D-glucoscorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohol, glucoheptonic acid, glucomonic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gluconic acid lactone, mannolactone (mannoic Lactone, lactone ribonate, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 2-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphate, glucopyranose phosphate, sugar sulfate, sinapic acid, vanillic acid, vanillin diethylamide, vanillin, methylparaben, propylparaben, xylitol, 2-ethoxyethanol, sugar, galactose, glucose, ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose, fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate. These include gallate, tyretamine, ketamine, propofol, lactic acid, acetic acid, salts and amines of any of the organic acids described herein, polyglycidol, glycerol, multiglycerol (e.g., compounds having multiple hydroxyl, amino, carbonyl, carboxyl, or ester moieties), galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol) oligomers, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol), and penta(propylene glycol), poly(propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, as well as derivatives and combinations thereof.

[0255] Furthermore, combinations of additives can be useful for the purposes of the present invention. One embodiment includes a combination or mixture of two additives, for example, a first additive comprising a surfactant and a second additive comprising a compound having one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties.

[0256] Combinations or mixtures of surfactants and small water-soluble molecules (compounds having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties) can have advantages. Formulations containing a mixture of a water-insoluble drug and two additives are in some cases superior to mixtures containing either additive alone. Hydrophobic drugs bind very poorly to water-soluble small molecules compared to their binding to surfactants. They are often in a phase separated from the small water-soluble molecules, which can lead to suboptimal coating uniformity and completeness. Water-insoluble drugs have a higher Log P than both surfactants and small water-soluble molecules. However, the Log P of surfactants is typically higher than the Log P of compounds having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties. Surfactants have a relatively high Log P (usually greater than 0), and water-soluble molecules have a low Log P (e.g., less than 0). Some surfactants, when used as additives in embodiments of the present invention, adhere very strongly to the surface of a medical device with a water-insoluble drug where the drug cannot be rapidly released from the surface of the medical device at the target site. On the other hand, some water-soluble small molecules (having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties) adhere very poorly to pharmaceutical devices that release the drug before the drug reaches the target site in serum during passage of a coated balloon catheter, for example, to a site oriented in the intervening. Surprisingly, by adjusting the concentration ratio of the small hydrophilic molecule and the surfactant in the formulation, the inventors have found that in some cases, when inflated and pressed against the tissue of the lumen wall at the target site of a therapeutic intervention, the coating stability during passage and rapid drug release is superior to formulations containing either additive alone. Further, the presence of the surfactant improves the miscibility and compatibility of the water-insoluble drug and the highly water-soluble molecule. Also, the surfactant improves coating uniformity and completeness by its good adhesion to the drug and the small molecule. The long-chain hydrophobic portion of the surfactant binds the drug firmly, while the hydrophilic portion of the surfactant binds to the small water-soluble molecule.

[0257] The surfactants in the mixture or combination include all the surfactants described herein for use in embodiments of the present invention. The surfactants in the mixture include: PEG sorbitan fatty acid esters; PEG omega-3 fatty acid esters, ethers and alcohols; glycerin fatty acid esters, sorbitan fatty acid esters, PEG glyceryl fatty acid esters, PEG fatty acid esters and alcohols, sugar fatty acid esters, PEG sugar esters, Tween 20, Tween 40, Tween 60, p-Isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, Tween 20, Tween 40, Tween 60, Tween 80, Octoxynol, Octoxynol-9, Monooxynol, Tyroxapol, Sucrose Monopalmitate, Sucrose Monolaurate The following can be selected: decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, and their derivatives.

[0258] Embodiments of compounds having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties in a mixture or combination can include any of the compounds having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties described herein for use in embodiments of the present invention. In various embodiments, the compounds having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties in the mixture have at least one hydroxyl, such as four hydroxyls. In certain embodiments, additives having more than four hydroxyls are utilized, for example, in the case of high molecular weight additives. In some embodiments, the compounds having more than four hydroxyls have a melting point of 120 °C or lower. Large molecules diffuse slowly. If the molecular weight of the additive or compound is high, for example, if the molecular weight exceeds 800, 1000, 1200, 1500, or 2000; large molecules can elute too slowly from the surface of the medical device and thus cannot release the drug in less than two minutes. If these large molecules contain more than four hydroxyls, they have increased hydrophilicity, which is necessary for relatively large molecules to release the drug rapidly. The increased hydrophilicity helps to elute the coating from the balloon, accelerates the release of the drug, and improves or facilitates drug movement through the lipid bilayer water barrier and polar head groups to penetrate the tissue. In one embodiment, the hydroxyl groups are utilized as hydrophilic moieties so as not to react with water-insoluble drugs such as paclitaxel or rapamycin.

[0259] Compounds having one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties in the mixture include L-ascorbic acid and its salts, D-glucoscorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gluconic acid lactone, mannolactone, ribonic acid lactone, lactobionic acid, glucosamine, and glucosamine. Tamin acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, 2-hydroxybenzoate propyl, lysine acetate, gentisic acid, lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphate, glucopyranose phosphate, sugar sulfate, sinapic acid, vanillic acid, vanillin, methylparaben, propylparaben, xylitol, 2-ethoxyethanol, sugar, galactose, glucose, ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose, fructose, cyclodextrin, (2-H (Droxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tyrethamine, ketamine, propofol, lactic acid, acetic acid, salts of any organic acid and amines as described herein, polyglycidol, glycerin, multiple glycerin, galactitol, monolaurin, monocaprin, monocaprylin, monomyristate, monopalmitorein, monoolein, creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartate Hypoxanthine, Theobromine, Theophylline, Adenine, Uracil, Uridine, Guanine, Thymine, Thymidine, Xanthine, Xanthosine, Xanthosine Monophosphate, Caffeine, Allantoin, (2-Hydroxy-ethyl)urea, N,N'-Bis(Hydroxymethyl)urea, Pentaerythritol Ethoxylate, Pentaerythritol Propoxylate, Pentaerythritol Propoxylate / Ethoxylate, Glycerin Ethoxylate, Glycerin Propoxylate, Trimethylolpropane Ethoxylate, Pentaerythritol,Dipentaerythritol, crown ethers, 18-crown-6, 15-crown-5, 12-crown-4, di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol) oligomers, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol), penta(propylene glycol), poly(propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, and their derivatives and combinations are selected.

[0260] A mixture or combination of surfactants and small water-soluble molecules can provide the benefits of both additives or initiate a synergistic effect. Water-insoluble drugs often have poor compatibility with highly water-soluble compounds, and surfactants improve compatibility. Surfactants also improve coating quality, uniformity, and integrity, preventing particles from falling out of the balloon during handling. Surfactants reduce drug loss during passage to the target site. Water-soluble compounds improve drug release from the balloon and drug absorption into the tissue. Experimentally, the combination was remarkably effective in preventing drug release during passage and achieving high drug levels in the tissue after a very short placement of 0.2–2 minutes. Furthermore, in animal studies, it effectively reduced stenosis and slow lumen loss.

[0261] Some mixtures or combinations of surfactants and small water-soluble molecules are very stable under heating. They survive the ethylene oxide sterilization process and do not react with water-insoluble drugs, paclitaxel or rapamycin during sterilization. In one embodiment, hydroxyl, ester, and amide groups are utilized because they do not appear to react with therapeutic agents such as paclitaxel or rapamycin. Occasionally, amine and acid groups react with paclitaxel and are unstable under ethylene oxide sterilization, heating, and aging. When the mixtures or combinations described herein are formulated with paclitaxel, a top coat layer can be advantageous in protecting the drug layer from premature drug loss in the device.

[0262] Examples of additives include p-isononylphenoxypolyglycidol, PEG-glyceryl oleate, PEG-glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG-sorbitan monolaurate, PEG-sorbitan monooleate, PEG-sorbitan stearate, octoxynol, octoxynol-9, and n-heptyl-β-D-thioglucoside. Monooxynol, tyroxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-maltoside, n-heptyl-β-D-glucopyranoside, n-dodecyl-β-D-glucopyranoside (Noside, heptanol-N-methylglucamide), n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, cystine, tyrosine, tryptophan, leucine, isoleucine Syn, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine (amino acids), cetothiamine, cyclothiamine, dexpanthenol, niacinamide, nicotinic acid and its salts, pyridoxal 5-phosphate, ascorbic acid nicotinamide, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U (vitamin); albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, -2-macroglobulin, fibronectin, vitronectin, fibrinogen, lipase, benzalkonium chloride, benzethonium chloride,Docecil trimethylammonium bromide, sodium docecil sulfate, dialkylmethylbenzylammonium chloride, and dialkyl esters of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoscorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, glon Lactone acid, mannolactone, ribonate lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, 2-hydroxybenzoate propyl, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate Calcium, ceretin, ketamine, propofol, lactic acid, acetic acid, salts of any organic acid and organic amine, polyglycidol, glycerin, polyglycerin, galactitol, monolaurin, monocaprin, monocaprylin, monomyristate, monopalmitorein, monoolein, creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, ka Phenyline, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerin ethoxylate, glycerin propoxylate, trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5, 12-crown-4, di(ethylene glycol), tri(ethylene glycol),This includes tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol) oligomers, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol), and also block copolymers of penta(propylene glycol), poly(propylene glycol) oligomers, polyethylene glycol, and polypropylene glycol, as well as their derivatives and combinations (compounds having one or more hydroxyl, amino, carbonyl, carboxyl, or ester moieties). Some of these additives are water-soluble and organic solvent-soluble. They have good adhesion and adhere to the surface of polyamide medical devices such as balloon catheters. Therefore, they can be used in the adhesion layer, top layer, and / or drug layer of embodiments of the present invention. Aromatic and aliphatic groups increase the solubility of water-insoluble drugs in the coating solution, while polar groups of alcohols and acids accelerate drug penetration into tissues.

[0263] Other additives according to embodiments of the present invention include hydroxyl ketones, hydroxyl lactones, hydroxyl acids, hydroxyl esters, and hydroxylamides. Examples include gluconolactone, D-glucoheptono-1,4-lactone, glucoctanoic acid lactone, gluconic acid lactone, mannolactone, erythronic acid lactone, ribonic acid lactone, glucuronic acid, gluconic acid, gentisic acid, lactobionic acid, lactic acid, acetaminophen, vanillic acid, sinapic acid, hydroxybenzoic acid, methylparaben, propylparaben, and their derivatives.

[0264] From a structural standpoint, these additives share structural similarities and are compatible with water-insoluble drugs (e.g., paclitaxel and rapamycin). They often contain double bonds such as C=C, C=N, and C=O in aromatic or aliphatic structures. These additives also contain amines, alcohols, esters, amides, anhydrides, carboxylic acids, and / or hydroxyls. They can form hydrogen bonds and / or van der Waals interactions with drugs. They are also useful in the top layer during coating. Compounds containing one or more hydroxyl, carboxyl, or amine groups are particularly useful as additives, for example, because they promote drug release from the device surface and readily replace the next water in the polar head groups and surface proteins of cell membranes, thereby eliminating this obstacle to hydrophobic drug permeability. They accelerate the transfer of hydrophobic drugs from balloons to the lipid layers of cell membranes and tissues, for which they have a very high affinity. Furthermore, they can carry or accelerate the movement of drugs from the balloon into a more aqueous environment, such as the gaps in non-vascular tissue damaged by balloon angiogenesis or stent expansion. Additives such as polyglyceryl fatty acid esters, ascorbic acid esters of fatty acids, sugar esters of fatty acids, alcohols, and ethers have fatty chains that can carry drugs into lipid structures and integrate them into the lipid structure of the target tissue membrane. Some amino acids, vitamins, and organic acids have aromatic C=N groups as well as amino, hydroxyl, and carboxylic acid components in their structure. They have structural portions that can form binding-terminal complexes with hydrophobic drugs such as paclitaxel or rapamycin, and they also have structural portions that promote tissue penetration by removing the barrier between the hydrophobic drug and lipid structure of the cell membrane.

[0265] For example, isononylphenyl polyglycidol (Olin-10G and Surfactant10G), PEG-glyceryl monooleate, sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitan monostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate, polyglyceryl-10 palmitate, and polyglyceryl-10 stearate all have more than four hydroxyl groups in their hydrophilic portions. These hydroxyl groups have a very good affinity for the walls of body lumens and can displace hydrogen-bonded water molecules. At the same time, they have long chains of fatty acids, alcohols, ethers, and esters, which can form complexes with hydrophobic drugs and integrate into the lipid structure of the cell membrane to organize the lipid structure. Furthermore, this deformation or loosening of the lipid membrane of target cells can facilitate the penetration of hydrophobic drugs into the tissue.

[0266] In another example, L-ascorbic acid, thiamine, maleic acid, niacinamide, and 2-pyrrolidone-5-carboxylic acid all possess very high water and ethanol solubility, as well as low molecular weight and small size. They also have structural components containing aromatic C=N, amino, hydroxyl, and carboxylic acid groups. These structures have excellent compatibility with paclitaxel and rapamycin, and can increase the solubility of these water-insoluble drugs in water, thereby enhancing their absorption into tissues. However, they often exhibit poor adhesion to the surface of medical devices. Therefore, when useful for enhancing drug absorption, they are used in combination with other additives in the drug layer and top layer. Vitamins D2 and D3 are particularly useful, especially when used conjugated with paclitaxel, as they themselves possess anti-restenotic effects and reduce thrombosis.

[0267] The relative amounts of therapeutic agents and additives in the coating layer can vary depending on the applicable circumstances. The optimal amount of additives is, for example, a selected therapeutic agent and additive. It can depend on the critical micelle concentration of the surface modifier if it forms micelles, the hydrophilic-lipophilicity (HLB) of the surfactant or the octanol-water partition coefficient (P) of the additive, the melting point of the additive, the water solubility of the additive and / or therapeutic agent, the surface tension of the aqueous solution of the surface modifier, etc.

[0268] Furthermore, other considerations will inform the selection of specific proportions of different additives. These considerations may include the degree of biosensibility of the additives and / or the desired dose of the therapeutic agent to be provided.

[0269] In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a target site of stenosis of a body lumen, wherein the balloon catheter includes a coating layer overlapping the outer surface of the balloon. The coating layer may include polymer-encapsulated drug particles containing the therapeutic agent and one or more polymers that encapsulate the therapeutic agent; or a drug-release coating containing polymer-encapsulated drug particles; or a composition containing the therapeutic agent and one or more additives; or a combination thereof. The therapeutic agent may be selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, their analogs, and combinations thereof. The additives may be non-water-soluble additives selected from cholesteryl acetate, cholesteryl phenylacetate, cholesteryl laurate, cholesteryl palmitate, cholesteryl stearate, cholesteryl n-valerate, cholesteryl benzoate, cholesteryl heptylate, cholesteryl decylate, cholesteryl caproate, cholesteryl oleate, cholesteryl carbonate, cholesteryl linoleate, cholesteryl pelargonate, cholesteryl erucate, cholesteryl caprylate, 5α-cholestane, 5α-cholestane-3-one, and combinations thereof.

[0270] In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a target site of stenosis or narrowing of a body cavity, wherein the balloon comprises polyester, polyamide, nylon 12, nylon 11, polyamide 12, polyether and polyamide block copolymers, polyether block amide, polyurethane, polyether and polyester block copolymers, or combinations thereof. The balloon catheter includes a coating layer overlapping the outer surface of the balloon. The coating layer comprises a therapeutic agent and polymer-encapsulated drug particles containing one or more polymers that encapsulate the therapeutic agent; or a drug-release coating containing polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or a combination thereof. The therapeutic agent can be selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs, and combinations thereof. The additive comprises at least one alkylaliphatic group or cholesteryl group, and the first additive may be a first additive that is water-insoluble or slightly or partially water-insoluble, having a molecular weight of 50 to 750, and a second additive that is more hydrophilic or more water-soluble than the first additive, contains a -(CH2CH2O)- unit, and has a molecular weight of 750 to 100,000, preferably 1,000 to 50,000, most preferably 2,000 to 10,000. The first additive, which is water-insoluble or slightly or partially water-insoluble and has a cholesteryl group, can be selected from cholesteryl acetate, cholesteryl phenylacetate, cholesteryl laurate, cholesteryl palmitate, cholesteryl stearate, cholesteryl n-valerate, cholesteryl benzoate, cholesteryl heptylate, cholesteryl decylate, cholesteryl caproate, cholesteryl oleate, cholesteryl oleyl carbonate, cholesteryl linoleate, cholesteryl pelargonicate, cholesteryl erucate, cholesteryl caprylate, 5α-cholestane, 5α-cholestane-3-one and combinations thereof. Alkyl aliphatic groups (e.g., C1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,The first additive, which is water-insoluble or slightly or partially water-insoluble, has C4-C30 (such as C4-C30 or higher), alkyl glyceryl ethers, monoglycerides of C8-C12 fatty acids, alkyl alcohols, alkyl ethers, alkyl esters, caprylic acid, monocaprylin, capric acid, monocaprin, lauric acid, dodecylglycerol, butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, mi You can choose from lystic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di-, or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha-tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobees, niosomes, their derivatives, and combinations thereof. The second water-soluble additive is cholesteryl-polyethylene glycol 600 sebacate, polyoxyethanol α-tocopheryl sebacate, methylated polyethylene glycol cholesterol (mPEG cholesterol), polyethylene glycol cholesterol (PEG cholesterol), polyethylene glycol ester cholesterol (PEG cholesterol), polyethylene glycol ether cholesterol (PEG cholesterol), methylated polyethylene glycol-amide-cholesterol (mPEG cholesterol), polyethylene glycol-amide-cholesterol (PEG cholesterol),Polyethylene glycol (PEG)-cholesteryl sebacate, polyethylene glycol cholesterol, PEG amide ester cholesterol, PEG amide ether cholesterol, mPEG amide ester cholesterol, DSPE-PEG-cholesterol, PEGylated phospholipids, methylated PEGylated phospholipids, PEG caprylic / capric diglyceride, PEG-8 caprylic / capric glyceride, PEG caprylate, PEG caprate, PEG caproate, PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), PEG-20 sorbitan monooleate (Tween-80), PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG-30 glyceryl oleate, polyglyceryl fatty acid ester, polyglyceryl oleate (Plurol Polyglyceryl-2 dioleate (Nikkol DGDO), Polyglyceryl-10 trioleate, Polyglyceryl stearate, Polyglyceryl laurate, Polyglyceryl myristate, Polyglyceryl palmitate, Polyglyceryl linoleate, Polyglyceryl-10 laurate (Nikkol Decaglyn 1-L), Polyglyceryl-10 oleate (Nikkol Decaglyn 1-O), Mono / Polyglyceryl-10 dioleate (CaproI (trademark) PEG) 860) Polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-6 linoleate, and combinations thereof can be selected.

[0271] Coating solution. The coating layer may include polymer-encapsulated drug particles containing a therapeutic agent and one or more polymers that encapsulate the therapeutic agent; or a drug-releasing coating containing polymer-encapsulated drug particles; or a composition containing a therapeutic agent and one or more additives; or a combination thereof. Solvents for the preparation of the coating layer may include, for example, one or a combination of the following: (a) water; (b) alkanes such as hexane, octane, cyclohexane, and heptane; (c) aromatic solvents such as benzene, toluene, and xylene; (d) alcohols such as ethanol, propanol, and isopropanol, diethylamide, ethylene glycol-monoethyl ether, transktol, and benzyl alcohol; (e) ethers such as dioxane, dimethyl ether, and tetrahydrofuran; (f) esters / acetates such as ethyl acetate and isobutyl acetate; (g) ketones such as acetone, acetonitrile, diethyl ketone, and methyl ethyl ketone; and (h) mixtures of water and organic solvents such as water / ethanol, water / acetone, water / methanol, and water / tetrahydrofuran. The solvent in the top coating layer can be, for example, methanol, ethanol, and / or acetone.

[0272] Organic solvents such as short-chain alcohols, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, and dimethyl sulfoxide can be useful solvents in embodiments of the present invention because these organic solvents generally break down colloidal aggregates and co-solubilize all components in the coating solution.

[0273] Various embodiments provide methods for preparing coating solutions. The content of the therapeutic agent in the coating solution can be 0.5 to 50% by weight based on the total weight of the solution. The content of the additive in the coating solution can be about 0.1% to about 45% by weight, about 0.2% to about 40% by weight, about 0.3% to about 15% by weight, or less than or about 0.1% by weight, or about 0.2%, 0.3, 0.4, 0.5, 0.6, 0.8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, or less or greater than or about 45% by weight, based on the total weight of the solution. The amount of solvent used depends on the coating process and viscosity. It will evaporate, which will affect the uniformity of the drug additive coating.

[0274] In other embodiments, two or more solvents, two or more therapeutic agents, and / or two or more additives may be used in the coating solution.

[0275] Medical device coatings for delivering drugs to non-vascular tissue or non-vascular stenoses can be prepared from a mixture. The coating can be prepared from a mixture comprising an organic phase containing drug particles dispersed therein, and an aqueous phase containing one or more water-soluble additives. Water-soluble additives can be selected from polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidinone, polypeptides, water-soluble surfactants, water-soluble vitamins, and proteins. Alternatively, the coating can be prepared from a two-phase mixture containing small drug particles suspended in a liquid. The liquid can consist of any of the following reverse solvents suitable for the drug particles: water, heptane, hexane, or cyclohexane (cycleohexane). The suspended drug particles can be stabilized by other additives dissolved in the liquid phase.

[0276] A medical device coating solution for delivering drugs to nonvascular tissue or nonvascular stenosis can be prepared from a mixture. The coating solution can be prepared from a mixture containing water and a water-miscible solvent, a water-soluble additive and a water-insoluble or partially water-soluble additive containing the most insoluble drug dispersed therein. The water-miscible solvent can be one or more selected from acetone, methanol, ethanol, isopropanol, butanol, THF, acetonitrile, dimethylformamide, dimethyl sulfoxide, dioxane, and acetic acid. The water-soluble additive can be selected from water-soluble surfactants, water-soluble salts, water-soluble vitamins, water-soluble sterols, proteins, and mixtures thereof. In one embodiment, some or all of one or more water-soluble additives are dissolved in water and added to a microfluidizer. The drug can then be added for processing in the microfluidizer, and the mixture is treated under high shear conditions and high pressure to reduce the particle size of the drug to less than 10 μm, or more preferably less than 5 μm. Next, water-insoluble or partially water-soluble additives can be dissolved in a water-miscible solvent and added to a microfluidizer for processing under high shear conditions. The processing can be one of the following: microsolution, homogenization, rotor starter-termining, high- or low-energy bead milling, or high-performance ultrasonic probe homogenization.

[0277] In one embodiment, the preparation of the coating solution includes a) mixing water, a water-miscible solvent, a therapeutic agent, and a water-soluble additive to form a premix; b) processing the premix to reduce the particle size of the therapeutic agent; c) mixing an insoluble water additive, a water-soluble additive, water, and a water-miscible solvent to form a second premix; and d) mixing the second premix with the first processed premix to form a coating solution. The therapeutic agent is one of paclitaxel, docetaxel, taxol, an mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs, and combinations thereof; the therapeutic agent is crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. The coating solution is an aqueous suspension of the therapeutic agent. The particle size of the therapeutic agent is in the range of 0.2 microns to 5 microns. The first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, and the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, with the particle size of the therapeutic agent encapsulated in the additive during coating ranging from 0.3 microns to 10 microns. The process is one of micro-solution, homogenization, rotor starter milling, high or low energy bead milling, or high-performance ultrasonic probe homogenization. The first additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one alkyl aliphatic group or cholesteryl group. The first additive can have a molecular weight of 50 to 750. The first additive during coating has a lower melting temperature than the first additive in its pure form. The first additive during coating has a lower degree of crystallinity than the first additive in its pure form. The second additive is more hydrophilic or more water-soluble than the first additive and contains polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The second additive has a molecular weight in the range of 750 to 100,000, or 750 to 50,000, or 750 to 10,000.

[0278] Medical device coating. The medical devices and coating layers of embodiments of the present invention can be manufactured by various methods. The coating solution may include polymer-encapsulated drug particles containing a therapeutic agent and one or more polymers encapsulating the therapeutic agent; or a drug-releasing coating containing polymer-encapsulated drug particles; or a composition containing a therapeutic agent and one or more additives; or a combination thereof. Coating techniques such as casting, fixed-volume liquid dispensing, metering (e.g., dispersing a fixed amount of coating solution based on volume into a balloon or stent), spinning, spraying, immersion (e.g., dipping), inkjet printing, electrostatic technology, and combinations thereof can be used to apply the coating solution to the medical device. During the application of the coating solution, the balloon can be at least partially inflated. Metering can be performed by any suitable method, such as pumping the liquid coating solution from a storage area to a nozzle that is proximal to the surface of the medical device (e.g., the surface of a balloon or stent that has been at least partially inflated). The nozzle can dispense liquid from it, which can then be immediately transferred outside the medical device by its proximity to the nozzle (for example, the nozzle can get very close to a balloon or stent that the liquid emerging from the nozzle can come into contact with, and can be transferred outside the medical device before forming a small amount of liquid that leaves the nozzle). The nozzle can dispense liquid outside the medical device in such a way that virtually no liquid is lost. The medical device can rotate around its longitudinal axis while dispensing liquid from the nozzle. The nozzle may be attached to or extended in a programmable xy stage, such as along the outside of the medical device parallel to the longitudinal axis of a cylindrical balloon, or along the profile of a medical device shaped into a non-cylindrical shape, such as a discontinuous medical device like a balloon or stent, to allow it to move during dispensing.In some embodiments, the medical device can rotate about its longitudinal axis during dispensing, and the nozzle can be moved parallel to the longitudinal axis of the medical device (e.g., similar to the movement of a chisel on a spinning cylindrical piece of wood in a woodturner's lathe) so that substantially all of the medical device surface is coated with the coating solution. . The nozzle can be moved once along the length of the medical device, or it can be moved by making a plurality of passes back and forth along the length of the medical device. If the medical device is a stent, the stent can be coated in the manufactured, crimped, expanded diameter, or intermediate diameter.

[0279] The choice of application technique can depend on the viscosity and surface tension of the solution. In some embodiments of the present invention, measurements can be utilized to more easily control the uniformity of the coating layer thickness as well as the concentration of the therapeutic agent applied to the medical device.

[0280] In one embodiment of the present invention, the balloon is inflated or partially inflated, and the coating solution is applied to the inflated balloon by measuring it while the balloon is inflating and rotating it along its longitudinal axis. The balloon is then compressed, folded, and allowed to dry before being placed in a sheath.

[0281] The description of the embodiments of the application device, fixture, and measurement technique is by way of example. Any suitable measurement or other technique can be used to coat the balloon catheter.

[0282] After a medical device is coated with a coating solution, the coated medical device can be subjected to drying, allowing the solvent in the coating solution to evaporate. This creates a coating matrix on the medical device containing the therapeutic agent. One example of a drying technique involves placing the coated medical device in an oven at approximately 20°C or higher for about 24 hours. Other suitable methods for drying the coating solution can be used. The time, temperature, and relative humidity can be modified depending on the specific additives and therapeutic agents.

[0283] In one embodiment, a method for coating a balloon catheter includes preparing an aqueous suspension coating solution, comprising: mixing water, a water-miscible solvent, a therapeutic agent and a water-soluble additive to form a premix; processing the premix to reduce the particle size of the therapeutic agent; mixing an insoluble water additive, a water-soluble additive, water and a water-miscible solvent to form a second mixture; and mixing the second mixture with the first processed premix to form a coating solution, wherein the therapeutic agent is selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs and combinations thereof; the therapeutic agent is crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof; the coating solution is an aqueous suspension of the therapeutic agent; and the particle size of the therapeutic agent is in the range of 0.2 microns to 5 microns. The first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, and the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, with the particle size of the therapeutic agent encapsulated in the additive during coating ranging from 0.3 microns to 10 microns. The first additive includes a water-insoluble or slightly or partially water-insoluble additive containing at least one alkyl aliphatic group or cholesteryl group. The first additive may have a molecular weight of 50 to 750. The first additive during coating has a lower melting temperature than the first additive in its pure form. The first additive during coating has a lower degree of crystallinity than the first additive in its pure form. The second additive is more hydrophilic or more water-soluble than the first additive and contains polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The second additive has a molecular weight in the range of 750 to 100,000, or 750 to 50,000, or 750 to 10,000. The method includes preparing a balloon catheter, which involves inflating the balloon catheter; cleaning the surface of the balloon; and fixing the balloon so that it can be mounted horizontally inside a coating machine and rotated at a fixed speed.The method includes distributing a coating solution onto the surface of the balloon while a nozzle moves laterally across the balloon. The method includes continuous...

Claims

1. Therapeutic agents; and One or more polymers for encapsulating the therapeutic agent; and First ionic or amphoteric additive Polymer-encapsulated drug particles comprising the first ionic or amphoteric additive, wherein the first ionic or amphoteric additive is located within the polymer-encapsulated drug particles, coated on the surface of the polymer-encapsulated drug particles, or a combination thereof.

2. The polymer-encapsulated drug particle according to claim 1, wherein the polymer-encapsulated drug particle has a positive zeta potential.

3. The polymer-encapsulated drug particle according to claim 2, wherein the polymer-encapsulated drug particle has a zeta potential greater than zero (0).

4. The polymer-encapsulated drug particles according to any one of claims 2 to 3, wherein the polymer-encapsulated drug particles have a zeta potential of -1 to -50 or 1 to 50.

5. The polymer-encapsulated drug particles according to any one of claims 2 to 4, wherein the polymer-encapsulated drug particles have a zeta potential of -2 to -40 or 2 to 40.

6. Polymer-encapsulated drug particles according to any one of claims 1 to 5, wherein the therapeutic agent is crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof.

7. Polymer-encapsulated drug particles according to any one of claims 1 to 6, wherein the therapeutic agent is crystalline and / or partially crystalline.

8. The polymer-encapsulated drug particle according to any one of claims 1 to 7, wherein the polymer is at least one polymer selected from polylactic acid (PL), polyglycolic acid (GA), polylactic acid / polyglycolic acid copolymer (PLGA), polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosominoglycan and its copolymers.

9. The polymer-encapsulated drug particle according to any one of claims 1 to 8, wherein the polymer is a neutral polymer.

10. The polymer-encapsulated drug particle according to any one of claims 1 to 8, wherein the polymer is a cationic, anionic, or amphoteric polymer.

11. The polymer-encapsulated drug particles according to any one of claims 1 to 10, wherein the polymer-encapsulated drug particles have a maximum dimension of 0.2 microns to 30 microns.

12. The polymer-encapsulated drug particles according to any one of claims 1 to 11, wherein the therapeutic agent has a maximum size of 0.1 to 29.9 microns.

13. The polymer-encapsulated drug particle according to any one of claims 1 to 12, wherein the polymer-encapsulated drug particle is a polymer-encapsulated drug particle (PEDP) and / or a charged polymer-encapsulated drug particle (CPEDP).

14. The polymer-encapsulated drug particle according to claim 13, wherein the positive charge density of the CPEDP is higher than that of the PEDP.

15. The polymer-encapsulated drug particle according to any one of claims 13 to 14, wherein the positive charge density of the CPEDP is higher than that of the therapeutic agent in the absence of the polymer encapsulant.

16. Polymer-encapsulated drug particles according to any one of claims 13 to 15, wherein the zeta potential of the CPEDP is higher than that of PEDP.

17. The polymer-encapsulated drug particle according to any one of claims 13 to 16, wherein the zeta potential of the CPEDP is higher than that of the therapeutic agent in the absence of the polymer encapsulant.

18. The polymer-encapsulated drug particle according to any one of claims 1 to 17, wherein the first ionic or amphoteric additive is contained within the polymer-encapsulated drug particle.

19. Polymer-encapsulated drug particles according to any one of claims 1 to 18, wherein the first ionic or amphoteric additive comprises a cationic molecule, an anionic additive, or an amphoteric additive.

20. The polymer-encapsulated drug particle according to any one of claims 1 to 19, wherein the first ionic or amphoteric additive is coated on the surface of the polymer-encapsulated drug particle.

21. The polymer-encapsulated drug particles according to claim 20, wherein the zeta potential of the polymer-encapsulated drug particles is higher than that of corresponding polymer-encapsulated drug particles that do not have a surface coating of the first ionic or amphoteric additive.

22. Polymer-encapsulated drug particles according to any one of claims 1 to 21, wherein the first ionic or amphoteric additive comprises charged polymers, charged lipids, phospholipids, phosphocholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and combinations thereof.

23. The polymer-encapsulated drug particle according to claim 22, wherein two acyl groups of the charged lipid or two acyl groups of the charged phospholipid include mismatched acyl groups.

24. The polymer-encapsulated drug particle according to claim 23, wherein the mismatched acyl group has a length of C6 to C34.

25. The polymer-encapsulated drug particle according to any one of claims 23 to 24, wherein the mismatched acyl group differs in length, degree of saturation, substituents thereof, substitution pattern thereof, or combination thereof.

26. The charged polymer is polycation-containing cyclodextrin, aminocyclodextrin or its derivatives, aminodextran, histone, protamine, cationized human serum albumin, aminopolysaccharides, chitosan, peptides, poly-L-lysine, poly-L-ornithine, poly(4-hydroxy-L-proline ester), polyethyleneimine, polyallylamine, polypropyleneimine, polyamidoamine dendrimer, cationic polyoxazoline, poly(beta-aminoester), PEG-PEI copolymer, PLGA-PEI copolymer, positively charged gelatin, hydroxy-terminated poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), stearic acid Polymer-encapsulated drug particles according to any one of claims 22 to 25, selected from branched polyethyleneimine, branched PEI-g-PEG, poly(1-vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate, poly(1-vinylpyrrolidone)-graft-(1-triacontene), polylysine, polyarginine, poly(N,N-dimethylaminoethyl methacrylate), cationic copolymer of dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate, anionic copolymer of methacrylic acid / methyl methacrylate, copolymer of ethyl acrylate / methyl methacrylate / methacrylic acid ester having a quaternary ammonium group, and combinations thereof.

27. The charged lipids include 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (chloride salt), 1,2-distearoyl-sn-glycero-3-ethylphosphocholine (chloride salt), cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, 1,2-dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt, 1,2-dihexanoyl-sn-glycero-3-phosphocholine, and 1,2-dihexanoyl-sn-glycero-3-phosphocholine. Butanoyl-sn-glycero-3-phosphocholine, 1,2-dioctanoyl-sn-glycero-3-phosphocholine, 1,2-dinonanoyl-sn-glycero-3-phosphocholine, 1,2-decanoyl-sn-glycero-3-phosphocholine, 1,2-diundecanoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dimiristoyl-sn-glycero-3-phosphocholine Choline, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine Choline (DOPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, dieicocenoyl Phosphatidylcholine (1,2-diecosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonylphosphatidylcholine (1,2-diarachidonyl-sn-glycero-3-phosphocholine, C20:0 PC), diecoylphosphatidylcholine (1,2-diecoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,Polymer-encapsulated drug particles according to any one of claims 22 to 26, selected from 2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), hen-eicosenoylphosphatidylcholine (1,2-hen-eicosenoyl-sn-glycero-3-phosphocholine, C21:1 PC), and dinerbonylphosphatidylcholine (1,2-dinerbonoyl-sn-glycero-3-phosphocholine, C24:1 PC) and combinations thereof.

28. The first ionic or amphoteric additive is 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (chloride salt), 1,2-distearoyl-sn-glycero-3-ethylphosphocholine (chloride salt), cholic acid, deoxycholic acid, chenodeoxycholic acid, litcholic acid, 1,2-dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt, 1,2-dihexanoyl-sn-glycero-3-phosphocholine, 1,2- Diheptanoyl-sn-glycero-3-phosphocholine, 1,2-dioctanoyl-sn-glycero-3-phosphocholine, 1,2-dinonanoyl-sn-glycero-3-phosphocholine, 1,2-decanoyl-sn-glycero-3-phosphocholine, 1,2-diundecanoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dipal Mitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl Polymer-encapsulated drug particles according to any one of claims 1 to 27, selected from oil-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, and combinations thereof.

29. Polymer-encapsulated drug particles according to any one of claims 1 to 28, wherein the first ionic or amphoteric additive comprises a water-insoluble or slightly or partially water-insoluble additive having at least one acyl group, and the first ionic or amphoteric additive has a molecular weight of 50 to 750, 750 to 100,000, or 750 to 50,000, or 750 to 10,000.

30. The polymer-encapsulated drug particle according to any one of claims 1 to 29, wherein the first ionic or amphoteric additive has a lower melting temperature than that of the additive in its pure form.

31. Polymer-encapsulated drug particles according to any one of claims 1 to 30, wherein the first ionic or amphoteric additive has a lower degree of crystallinity than that of the additive in its pure form.

32. Polymer-encapsulated drug particles according to any one of claims 1 to 31, wherein the therapeutic agent is selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, their analogs, and combinations thereof.

33. The polymer-encapsulated drug particles according to any one of claims 1 to 32, wherein the polymer-encapsulated drug particles are located on a balloon catheter, a drug-coated catheter, a drug-eluting stent, a drug-eluting stent on a balloon, a drug-eluting stent on a drug-coated balloon, a stent on a drug-coated balloon, or a combination thereof.

34. Therapeutic drugs; One or more polymers for encapsulating the therapeutic agent; and Release matrix containing a second ionic or amphoteric additive Polymer-encapsulated drug particles containing A drug-releasing coating containing a drug.

35. The drug-releasing coating according to claim 34, wherein the polymer-encapsulated drug particles further comprise a first ionic or amphoteric additive, the first ionic or amphoteric additive is contained within the polymer-encapsulated drug particles, coated on the surface of the polymer-encapsulated drug particles, or a combination thereof.

36. The drug-releasing coating according to claim 35, wherein the second ionic or amphoteric additive has the same molecular structure as the first ionic or amphoteric additive.

37. The drug-releasing coating according to any one of claims 35 to 36, wherein the second ionic or amphoteric additive has a molecular structure different from that of the first ionic or amphoteric additive.

38. The drug-releasing coating according to any one of claims 35 to 37, wherein the polymer-encapsulated drug particles constitute 10% to 80% by weight of the drug-releasing coating as measured by dryness.

39. The drug-releasing coating according to any one of claims 35 to 38, wherein the polymer-encapsulated drug particles constitute 25% to 70% by weight of the drug-releasing coating as measured by dryness.

40. The drug-releasing coating according to any one of claims 35 to 39, wherein the polymer-encapsulated drug particles constitute 40% to 60% by weight of the drug-releasing coating as measured by dryness.

41. The drug-releasing coating according to any one of claims 35 to 40, wherein the release matrix further comprises polymer-encapsulated drug particles of a therapeutic agent that are not polymer-encapsulated.

42. The drug-releasing coating according to claim 41, wherein the therapeutic agent particles that are not encapsulated by the polymer in the polymer-encapsulated drug particles include crystalline particles of the therapeutic agent.

43. The drug-releasing coating according to any one of claims 41 to 42, wherein the therapeutic agent particles that are not encapsulated by the polymer, as described above, are homogeneously distributed in the release matrix.

44. The drug-releasing coating according to any one of claims 35 to 43, wherein the polymer-encapsulated drug particles are homogeneously distributed in the release matrix.

45. The drug-releasing coating according to any one of claims 35 to 44, wherein the second ionic or amphoteric additive comprises a cationic molecule, an anionic additive, or an amphoteric additive.

46. The drug-releasing coating according to any one of claims 35 to 45, wherein the second ionic or amphoteric additive in the release matrix is ​​selected from charged polymers, charged lipids, phospholipids, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and combinations thereof.

47. The drug-releasing coating according to claim 46, wherein two acyl groups of the charged lipid or two acyl groups of the charged phospholipid include mismatched acyl groups.

48. The drug-releasing coating according to claim 47, wherein the mismatched acyl group has a length of C6 to C34.

49. The drug-releasing coating according to any one of claims 47 to 48, wherein the mismatched acyl group differs in length, degree of saturation, substituents thereof, substitution pattern thereof, or combination thereof.

50. The charged polymer is polycation-containing cyclodextrin, aminocyclodextrin or its derivatives, aminodextran, histone, protamine, cationized human serum albumin, aminopolysaccharides, chitosan, peptides, poly-L-lysine, poly-L-ornithine, poly(4-hydroxy-L-proline ester), polyethyleneimine, polyallylamine, polypropyleneimine, polyamidoamine dendrimer, cationic polyoxazoline, poly(beta-aminoester), PEG-PEI copolymer, PLGA-PEI copolymer, positively charged gelatin, hydroxy-terminated poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), stearic acid A drug-releasing coating according to any one of claims 46 to 49, selected from branched polyethyleneimine, branched PEI-g-PEG, poly(1-vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate, poly(1-vinylpyrrolidone)-graft-(1-triacontene), polylysine, polyarginine, poly(N,N-dimethylaminoethyl methacrylate), cationic copolymer of dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate, anionic copolymer of methacrylic acid / methyl methacrylate, copolymer of ethyl acrylate / methyl methacrylate / methacrylic acid ester having a quaternary ammonium group, and combinations thereof.

51. The charged lipids include 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (chloride salt), 1,2-distearoyl-sn-glycero-3-ethylphosphocholine (chloride salt), cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, 1,2-dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt, 1,2-dihexanoyl-sn-glycero-3-phosphocholine, and 1,2-dihexanoyl-sn-glycero-3-phosphocholine. Butanoyl-sn-glycero-3-phosphocholine, 1,2-dioctanoyl-sn-glycero-3-phosphocholine, 1,2-dinonanoyl-sn-glycero-3-phosphocholine, 1,2-decanoyl-sn-glycero-3-phosphocholine, 1,2-diundecanoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dimiristoyl-sn-glycero-3-phosphocholine Choline, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine Choline (DOPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, dieicocenoyl Phosphatidylcholine (1,2-diecosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonylphosphatidylcholine (1,2-diarachidonyl-sn-glycero-3-phosphocholine, C20:0 PC), diecoylphosphatidylcholine (1,2-diecoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,A drug-releasing coating according to any one of claims 46 to 50, selected from 2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), hen-eicosenoylphosphatidylcholine (1,2-hen-eicosenoyl-sn-glycero-3-phosphocholine, C21:1 PC), and dinerbonylphosphatidylcholine (1,2-dinerbonoyl-sn-glycero-3-phosphocholine, C24:1 PC) and combinations thereof.

52. The second ionic or amphoteric additive is 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (chloride salt), 1,2-distearoyl-sn-glycero-3-ethylphosphocholine (chloride salt), cholic acid, deoxycholic acid, chenodeoxycholic acid, litcholic acid, 1,2-dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt, 1,2-dihexanoyl-sn-glycero-3-phosphocholine, 1,2- Diheptanoyl-sn-glycero-3-phosphocholine, 1,2-dioctanoyl-sn-glycero-3-phosphocholine, 1,2-dinonanoyl-sn-glycero-3-phosphocholine, 1,2-decanoyl-sn-glycero-3-phosphocholine, 1,2-diundecanoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dipal Mitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleo A drug-releasing coating according to any one of claims 46 to 51, selected from yl-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, and combinations thereof.

53. The drug-releasing coating according to any one of claims 46 to 52, wherein the second ionic or amphoteric additive comprises a water-insoluble or slightly or partially water-insoluble additive having at least one acyl group, and the second ionic or amphoteric additive has a molecular weight of 50 to 750, 750 to 100,000, or 750 to 50,000, or 750 to 10,000.

54. The drug-releasing coating according to any one of claims 46 to 53, wherein the second ionic or amphoteric additive in the coating has a lower melting temperature than that of the additive in its pure form.

55. The drug-releasing coating according to any one of claims 46 to 54, wherein the second ionic or amphoteric additive in the coating has a lower degree of crystallinity than that of the additive in its pure form.

56. The drug-releasing coating according to any one of claims 35 to 55, wherein the coating is on a balloon catheter, a drug-coated catheter, a drug-eluting stent, a drug-eluting stent on a balloon, a drug-eluting stent on a drug-coated balloon, a stent on a drug-coated balloon, or a combination thereof.

57. Methods for treating or preventing nonvascular or vascular stenosis or stenosis, Inserting a catheter containing a balloon or stent according to either claim 56 or 33 into a body cavity; Expanding a balloon or stent to bring a coating layer into contact with an area of ​​stenosis, stenosis, or an area where stenosis or stenosis is to be prevented; If a balloon is used, the method further includes compressing the balloon; and If a balloon is used, the method further comprises removing the balloon from a body cavity.

58. To form a suspension comprising the therapeutic agent, the polymer, and the first ionic or amphoteric additive; Processing the suspension to reduce the particle size of the suspension; and A method for producing polymer-encapsulated drug particles according to any one of claims 1 to 33, comprising adding an aqueous premix to the suspension to form polymer-encapsulated drug particles in the suspension.

59. The method according to claim 58, wherein the processing includes ultrasonic processing.

60. The method according to any one of claims 58 to 59, wherein adding the first ionic or amphoteric additive to the suspension coats polymer-encapsulated drug particles formed with the first ionic or amphoteric additive.

61. The method according to any one of claims 58 to 60, further comprising adding a second ionic or amphoteric additive to the suspension to form a drug-releasing coating according to any one of claims 34 to 56, and optionally stirring the suspension to homogenize polymer-encapsulated drug particles therein.

62. To form an organic premix comprising an organic solvent, one or more polymers, the therapeutic agent, and the first ionic or amphoteric additive; To form an aqueous premix containing water and a water-soluble polymer or surfactant; Adding an organic solvent to the aqueous premix; Combining the aqueous premix and the organic premix together; The process involves stirring the combined aqueous premix and organic premix to form an emulsion containing the polymer-encapsulated drug particles. A method for producing polymer-encapsulated drug particles according to any one of claims 1 to 33.

63. The method according to claim 62, wherein the therapeutic agent, one or more polymers, and the first ionic or amphoteric additive are dissolved in the organic premix.

64. The method according to any one of claims 62 to 63, wherein the organic solvent in the organic premix and the organic solvent added to the aqueous premix are the same organic solvent.

65. The method according to any one of claims 62 to 64, wherein the organic solvent in the organic premix and the organic solvent added to the aqueous premix are polar organic solvents.

66. The method according to any one of claims 62 to 65, further comprising adding water to the emulsion containing the polymer-encapsulated particles.

67. The method according to any one of claims 62 to 66, further comprising separating the polymer-encapsulated drug particles from the combined aqueous premix and organic premix.

68. The method according to any one of claims 62 to 67, further comprising washing the polymer-encapsulated drug particles with an aqueous liquid, drying the polymer-encapsulated drug particles, or a combination thereof.

69. To form a first mixture comprising the polymer-encapsulated drug particles and an organic solvent; To form a second mixture comprising a second ionic or amphoteric additive and an organic solvent; Combining the first mixture and the second mixture; and Drying the first mixture and the second mixture combined to form the drug-releasing coating according to claim 34. The method according to any one of claims 62 to 68, including

70. The method according to claim 69, wherein the organic solvents of the first mixture and the second mixture are nonpolar organic solvents.

71. The method according to any one of claims 69 to 70, further comprising stirring the combined first and second mixtures prior to drying in order to homogeneously distribute the polymer-encapsulated drug particles.

72. A method for preparing a balloon catheter, comprising applying polymer-encapsulated drug particles according to any one of claims 1 to 33 or a drug-releasing coating according to any one of claims 34 to 56 to the outside of the balloon of the balloon catheter.

73. Stretched balloon; and A coating layer overlapping the outer surface of the balloon A balloon catheter comprising the coating layer, Polymer-encapsulated drug particles according to any one of claims 1 to 33, A drug-releasing coating according to any one of claims 34 to 56, or A therapeutic agent selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs and combinations thereof, the therapeutic agent having a particle size of 0.2 microns to 10 microns, A first additive comprising a water-insoluble or partially water-insoluble additive containing at least one alkyl aliphatic group or cholesteryl group, and A more affinity or more water-soluble additive than the first additive, which is polyethylene glycol (-(CH ２ CH ２ O)-) or polyglycerol (-(CH ２ -CHOH-CH ２ A second additive containing units O)-), wherein the second additive has a molecular weight in the range of 750 to 100,000, or a combination thereof. composition containing The balloon catheter, including the balloon catheter.

74. The balloon catheter according to claim 73, wherein the balloon comprises polyester, polyamide, nylon 12, nylon 11, polyamide 12, a block copolymer of polyether and polyamide, a polyether block amide, polyurethane, a block copolymer of polyether and polyester, or a combination thereof.

75. The balloon catheter according to any one of claims 73 to 74, wherein the balloon catheter is for delivering a therapeutic agent to a stenosis or narrowing of a body cavity, and the stenosis or narrowing of a body cavity is selected from urethral stenosis, prostatic urethral stenosis, ureteral stenosis, esophageal stenosis, sinus stenosis, gastric stenosis, small intestinal stenosis, colonic stenosis, rectal stenosis, large intestinal stenosis, bladder neck stenosis, bile duct stenosis, vaginal stenosis, restenosis within a stent, coronary artery stenosis, superficial femoral artery stenosis, popliteal artery stenosis, anterior tibial artery stenosis, posterior tibial artery stenosis, and peroneal artery stenosis.

76. The balloon catheter according to any one of claims 73 to 75, wherein the balloon catheter is for delivering a therapeutic agent to a target site in the body lumen, and the target site in the body lumen is selected from urethral stricture, prostatic urethral stricture, ureteral stricture, esophageal stricture, sinus stricture, gastric stricture, small intestinal stricture, colonic stricture, rectal stricture, large intestinal stricture, bladder neck stricture, bile duct stricture, vaginal stricture, in-stent restenosis, coronary artery stenosis, superficial femoral artery stenosis, popliteal artery stenosis, anterior tibial artery stenosis, posterior tibial artery stenosis, and peroneal artery stenosis.

77. The balloon catheter according to any one of claims 73 to 76, wherein the first additive, the second additive, or a combination thereof encapsulates a therapeutic agent.

78. The balloon catheter according to claim 77, wherein the therapeutic agent enclosed in the additive has a larger particle size than the therapeutic agent itself.

79. The balloon catheter according to any one of claims 77 to 78, wherein the particle size of the therapeutic agent encapsulated in the additive in the coating is in the range of 0.3 microns to 10 microns.

80. The balloon catheter according to any one of claims 73 to 79, wherein the first additive in the coating has a lower melting temperature than that of the first additive in its pure form.

81. The balloon catheter according to any one of claims 73 to 80, wherein the first additive in the coating has a lower degree of crystallinity than that of the first additive in its pure form.

82. The balloon catheter according to any one of claims 73 to 81, wherein the first additive having a cholesteryl group is selected from cholesterol, cholesteryl acetate, cholesteryl phenylacetate, cholesteryl laurate, cholesteryl palmitate, cholesteryl stearate, cholesteryl n-valerate, cholesteryl benzoate, cholesteryl heptylate, cholesteryl decylate, cholesteryl caproate, cholesteryl oleate, cholesteryl carbonate oleyl, cholesteryl linoleate, cholesteryl pelargonate, cholesteryl erucate, cholesteryl caprylate, 5α-cholestane, 5α-cholestane-3-one, and combinations thereof.

83. The first additive comprising at least one alkyl aliphatic group is alkylglyceryl ether, monoglycerides of C8-C12 fatty acids, alkyl alcohol, alkyl ether, alkyl ester, caprylic acid, monocaprylin, capric acid, monocaprin, lauric acid, dodecylglycerol, butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitic acid A balloon catheter according to any one of claims 73 to 82, selected from tleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di-, or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha-tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobee, niosomes, derivatives thereof, and combinations thereof.

84. The second additive is cholesteryl-polyethylene glycol 600 sebacate, polyoxyethanol α-tocopheryl sebacate, methylated polyethylene glycol cholesterol (mPEG cholesterol), polyethylene glycol cholesterol (PEG cholesterol), polyethylene glycol ester cholesterol (PEG cholesterol), polyethylene glycol ether cholesterol (PEG cholesterol), methylated polyethylene glycol-amide-cholesterol (mPEG cholesterol), polyethylene glycol-amide-cholesterol (PEG cholesterol), polyethylene glycol (PEG)-cholesteryl sebacate, polyethylene glycol cholesterol, PEG amide ester cholesterol, PEG amide ether cholesterol, mPEG amide ester cholesterol, DSPE-PEG-cholesterol, PEG-phospholipids, methylated PEG-phospholipids, PEG caprylic acid / capric acid diglyceride, PEG-8 caprylic acid / capric acid glyceride, PEG caprylate, PEG caprate, PEG caproate, PEG monolaurate. -20 sorbitan (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), PEG-20 sorbitan monooleate (Tween-80), PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG-30 glyceryl oleate, polyglyceryl fatty acid ester, polyglyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl stearate, laurin Polyglyceryl acid, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl linoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono / dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,A balloon catheter according to any one of claims 73 to 83, selected from polyglyceryl-6 linoleate and combinations thereof.

85. A balloon catheter for delivering a therapeutic agent to a target site of stenosis or narrowing of a body cavity, wherein the balloon catheter is Stretched balloon; and The coating layer includes a coating layer that overlaps the outer surface of the balloon, and the coating layer is Polymer-encapsulated drug particles according to any one of claims 1 to 33, A drug-releasing coating according to any one of claims 34 to 56, A therapeutic agent selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs and combinations thereof, wherein the therapeutic agent has a particle size of 0.2 microns to 5 microns. The first additive, and A second additive, or those combinations A composition comprising, The balloon comprises polyester, polyamide, nylon 12, nylon 11, polyamide 12, polyether and polyamide block copolymers, polyether block amides, polyurethane, polyether and polyester block copolymers, or combinations thereof; The therapeutic agent is crystalline, partially crystalline, or a combination thereof; The first additive, the second additive, or a combination thereof encapsulates a therapeutic agent, and the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive during coating is in the range of 0.3 microns to 10 microns; The first additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one alkylaliphatic group or cholesteryl group, wherein the first additive has a molecular weight of 50 to 750; The first additive in the coating has a lower melting point than the first additive in its pure form; The first additive in the coating has a lower degree of crystallinity than that of the first additive in its pure form; The second additive is more hydrophilic or more water-soluble than the first additive, and polyethylene glycol (-(CH ２ CH ２ O)-) or polyglycerol (-(CH ２ -CHOH-CH ２ The second additive contains units of 0-), and the second additive has a molecular weight in the range of 750 to 100,000; Stenosis or narrowing of a body cavity is selected from urethral stricture, prostatic urethral stricture, ureteral stricture, esophageal stricture, sinus stricture, gastric stricture, small intestinal stricture, colonic stricture, rectal stricture, large intestinal stricture, bladder neck stricture, bile duct stricture, vaginal stricture, restenosis within a stent, coronary artery stricture, superficial femoral artery stricture, popliteal artery stricture, anterior tibial artery stricture, posterior tibial artery stricture, and peroneal artery stricture; The first additive having a cholesteryl group is selected from cholesterol, cholesteryl acetate, cholesteryl phenylacetate, cholesteryl laurate, cholesteryl palmitate, cholesteryl stearate, cholesteryl n-valerate, cholesteryl benzoate, cholesteryl heptylate, cholesteryl decylate, cholesteryl caproate, cholesteryl oleate, cholesteryl oleyl carbonate, cholesteryl linoleate, cholesteryl pelargonicate, cholesteryl erucate, cholesteryl caprylate, 5α-cholestane, 5α-cholestane-3-one, and combinations thereof; The first water-insoluble additive having an alkyl aliphatic group, which is water-insoluble or slightly or partially water-insoluble, is alkylglyceryl ether, monoglycerides of C8-C12 fatty acids, alkyl alcohol, alkyl ether, alkyl ester, caprylic acid, monocaprylin, capric acid, monocaprin, lauric acid, dodecylglycerol, butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid Selected from palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di-, or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha-tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobees, niosomes, their derivatives and combinations thereof, The aforementioned water-soluble second additive is cholesteryl-polyethylene glycol 600 sebacate, polyoxyethanol α-tocopheryl sebacate, methylated polyethylene glycol cholesterol (mPEG cholesterol), polyethylene glycol cholesterol (PEG cholesterol), polyethylene glycol ester cholesterol (PEG cholesterol), polyethylene glycol ether cholesterol (PEG cholesterol), methylated polyethylene glycol-amide-cholesterol (mPEG cholesterol), polyethylene glycol-amide-cholesterol (PEG cholesterol), polyethylene glycol (PEG)-cholesteryl sebacate, polyethylene glycol cholesterol, PEG amide ester cholesterol, PEG amide ether cholesterol, mPEG amide ester cholesterol, DSPE-PEG-cholesterol, PEG-phospholipids, methylated PEG-phospholipids, PEG caprylic acid / capric acid diglyceride, PEG-8 caprylic acid / capric acid glyceride, PEG caprylate, PEG caprate, PEG caproate, P monolaurate EG-20 sorbitan (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), PEG-20 sorbitan monooleate (Tween-80), PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG-30 glyceryl oleate, polyglyceryl fatty acid ester, polyglyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl stearate, lau Polyglyceryl phosphate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl linoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono / dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,Selected from polyglyceryl-6 linoleate and combinations thereof, The aforementioned balloon catheter.

86. A method for preventing or treating strictures in the internal lumen of the digestive body or the gastrointestinal tract, Inserting a balloon catheter into a target site in a body lumen, including a non-vascular stenosis, the balloon catheter The stretched balloon and, The balloon includes a coating layer that overlaps the outer surface, and the coating layer is Polymer-encapsulated drug particles according to any one of claims 1 to 33, A drug-releasing coating according to any one of claims 34 to 56, A therapeutic agent selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs and combinations thereof, wherein the therapeutic agent has a particle size of 0.2 microns to 10 microns. A first additive comprising a water-insoluble or partially water-insoluble additive, and A second additive having greater affinity or greater water solubility than the first additive, or those combinations A composition comprising, Inflating the balloon at the target site to bring the coating layer into contact with the wall of the body lumen at the location of the non-vascular stenosis until the balloon achieves the inflated balloon diameter for the inflation period; Compressing the balloon after the inflation period; and This includes retrieving the balloon catheter from the body lumen, The first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive in the coating is in the range of 0.3 microns to 10 microns; The stricture in the internal lumen of the digestive body or gastrointestinal tract includes esophageal stricture, achalasia stricture, biliary stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, ileoanal J-type sac stricture, large intestinal stricture, or a combination thereof; and The method wherein the stricture in the gastrointestinal lumen or gastrointestinal tract includes esophageal stricture due to eosinophilic esophagitis, radiation-induced stricture, Crohn's disease-induced stricture, ulcerative colitis-induced stricture, chronic inflammatory bowel disease (IBD)-induced stricture, surgical anastomotic stricture, or a combination thereof.

87. A method for the prevention or treatment of stenosis or narrowing of a vascular body lumen, Inserting a balloon catheter into a target site in a body lumen, including narrowing or stenosis of a blood vessel; the balloon catheter is The stretched balloon, and The coating layer includes a coating layer that overlaps the outer surface of the balloon, and the coating layer is Polymer-encapsulated drug particles according to any one of claims 1 to 33, A drug-releasing coating according to any one of claims 34 to 56, Therapeutic agents including paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, their analogs and combinations thereof. The first additive, and A second additive, or Including those combinations, The therapeutic agent is crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. The particle size of the aforementioned therapeutic agent is in the range of 0.2 microns to 5 microns. The first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive within the coating is in the range of 0.3 microns to 10 microns; The first additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one alkylaliphatic group or cholesteryl group, and the first additive has a molecular weight of 50 to 750. The first additive in the coating has a lower melting temperature than that of the first additive in its pure form. The first additive in the coating has a lower degree of crystallinity than that of the first additive in its pure form. The second additive is more hydrophilic or more water-soluble than the first additive, and contains polyethylene glycol (-(CH ２ CH ２ O)-) or polyglycerol (-(CH ２ -CHOH-CH ２ O)-) units, and The molecular weight of the second additive is in the range of 750 to 100,000; Inflating the balloon at the target site to bring the coating layer into contact with the wall of the body cavity at the location of the stenosis or stenosis until the balloon achieves the inflated balloon diameter for the inflation period; Compressing the balloon after the inflation period; and To retrieve the balloon catheter from the body cavity. The method, including the method described above.

88. Processing therapeutic agents selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umilolimus, their analogs, and combinations thereof, such that the majority of therapeutic agent crystals have a particle size of 0.2 microns to 5.0 microns; The therapeutic agent is a mixture of the therapeutic agent, a first water-insoluble additive, and a second water-soluble additive, and a fluid that is substantially insoluble with the therapeutic agent; and The mixture is applied to the outer surface of the balloon catheter, the first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive during coating is in the range of 0.3 microns to 10 microns. A method for preparing a covered balloon catheter, including [a specific component].

89. moreover, Inflating the balloon catheter; To clean the surface of the balloon; and The balloon can be mounted horizontally inside the coating machine and fixed so that it rotates at a fixed speed. To prepare a balloon catheter that includes; Distributing the mixture onto the surface of the balloon while the nozzle moves laterally across the balloon; and The method according to claim 88, further comprising continuing to rotate the balloon to evaporate the solvent at room temperature or above room temperature.

90. moreover, Folding and creasing the balloon catheter; and The method according to claim 89, comprising sterilizing the covered balloon catheter.

91. The method according to any one of claims 88 to 90, wherein the first additive is selected from cholesterol, cholesteryl acetate, cholesteryl phenylacetate, cholesteryl laurate, cholesteryl palmitate, cholesteryl stearate, cholesteryl n-valerate, cholesteryl benzoate, cholesteryl heptylate, cholesteryl decylate, cholesteryl caproate, cholesteryl oleate, cholesteryl carbonate, cholesteryl linoleate, cholesteryl pelargonicate, cholesteryl erucate, cholesteryl caprylate, 5α-cholestane, 5α-cholestane-3-one, and combinations thereof.

92. The first additive is alkyl glyceryl ether, monoglycerides of C8-C12 fatty acids, alkyl alcohol, alkyl ether, alkyl ester, caprylic acid, monocaprylin, capric acid, monocaprin, lauric acid, dodecylglycerol, butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearyl acid The method according to any one of claims 88 to 91, selected from phospholipids, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di-, or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha-tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobee, niosomes, derivatives thereof, and combinations thereof.

93. The aforementioned water-soluble second additive is cholesteryl-polyethylene glycol 600 sebacate, polyoxyethanol α-tocopheryl sebacate, methylated polyethylene glycol cholesterol (mPEG cholesterol), polyethylene glycol cholesterol (PEG cholesterol), polyethylene glycol ester cholesterol (PEG cholesterol), polyethylene glycol ether cholesterol (PEG cholesterol), methylated polyethylene glycol-amide-cholesterol (mPEG cholesterol), polyethylene glycol-amide-cholesterol (PEG cholesterol), polyethylene glycol (PEG)-cholesteryl sebacate, polyethylene glycol cholesterol, PEG amide ester cholesterol, PEG amide ether cholesterol, mPEG amide ester cholesterol, DSPE-PEG-cholesterol, PEG-phospholipids, methylated PEG-phospholipids, PEG caprylic acid / capric acid diglyceride, PEG-8 caprylic acid / capric acid glyceride, PEG caprylate, PEG caprate, PEG caproate, P monolaurate EG-20 sorbitan (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), PEG-20 sorbitan monooleate (Tween-80), PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG-30 glyceryl oleate, polyglyceryl fatty acid ester, polyglyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl stearate, lau Polyglyceryl phosphate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl linoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono / dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,The method according to any one of claims 88 to 92, selected from polyglyceryl-6 linoleate and combinations thereof.

94. To form a premix, mix water, a water-miscible solvent, a therapeutic agent, and a water-soluble additive; Processing the premix to reduce the particle size of the therapeutic agent; To form a second premix, mix an insoluble water additive, a water-soluble additive, water, and a water-miscible solvent; Mixing the second premix with the first treated premix to form a coating solution; The therapeutic agent is selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, their analogs, and combinations thereof; The therapeutic agent is crystalline, partially crystalline, or a combination thereof; The coating solution is an aqueous suspension of the therapeutic agent; The particle size of the therapeutic agent is in the range of 0.2 microns to 5 microns; The first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, and the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive within the coating is in the range of 0.3 microns to 10 microns; The aforementioned process is one of the following: micro-solution preparation, homogenization, rotor starter-termining, high- or low-energy bead milling, or high-performance ultrasonic probe homogenization; The first additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one alkylaliphatic group or cholesteryl group, and the first additive has a molecular weight of 50 to 750; The first additive in the coating has a lower melting point than that of the first additive in its pure form; The first additive in the coating has a lower degree of crystallinity than that of the first additive in its pure form; and The second additive is more hydrophilic or more water-soluble than the first additive, and contains polyethylene glycol (-(CH ２ CH ２ O)-) or polyglycerol (-(CH ２ -CHOH-CH ２ The second additive contains units O)-), and the second additive has a molecular weight in the range of 750 to 100,000. A method for preparing a drug coating solution, including the following.

95. To form a premix, mix water, a water-miscible solvent, a therapeutic agent, and a water-soluble additive; Processing the premix to reduce the particle size of the therapeutic agent; To form the second premix described above, an insoluble water additive, the water-soluble additive, water, and a water-miscible solvent are mixed; Mixing the second premix with the first treated premix to form a coating solution; The therapeutic agent is selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, their analogs, and combinations thereof; The therapeutic agent is crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof; The coating solution is an aqueous suspension of the therapeutic agent; The particle size of the therapeutic agent in the coating solution is in the range of 0.2 microns to 5 microns; The water-soluble additive, the water-insoluble additive, or a combination thereof encapsulates the therapeutic agent, and the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive within the coating is in the range of 0.3 microns to 10 microns; The first additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one alkylaliphatic group or cholesteryl group, and the first additive has a molecular weight of 50 to 750; The first additive in the coating has a lower melting point than that of the first additive in its pure form; The first additive in the coating has a lower degree of crystallinity than that of the first additive in its pure form; The second additive is more hydrophilic or more water-soluble than the first additive, and contains polyethylene glycol (-(CH ２ CH ２ O)-) or polyglycerol (-(CH ２ -CHOH-CH ２ To prepare an aqueous suspension coating solution comprising 0)-) units, wherein the second additive has a molecular weight in the range of 750 to 100,000; Inflating the balloon catheter; To clean the surface of the balloon; and To fix the balloon so that it can be mounted horizontally inside the coating machine and rotated at a fixed speed; Distributing the coating solution onto the surface of the balloon while the nozzle moves laterally across the balloon; and Continuing to rotate the balloon to evaporate the solvent at room temperature or above room temperature; Folding and creasing the balloon catheter; and Sterilize the covered balloon catheter. Prepare a balloon catheter that includes A method for covering a balloon catheter, including [the specified method].

96. Inserting a balloon or stent according to either claim 56 or 33 into a target site of a heart valve; The balloon is brought into contact with the wall of the body cavity and the coating layer until it achieves the inflated balloon diameter for the inflation period, and the balloon is inflated at the target site to dilate the cardiac valve stenosis; Compressing the balloon after the inflation period; and To retrieve the balloon catheter from the body cavity. Methods for treating or preventing narrowed heart valves, including [specific examples of such methods].

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