Polymer encapsulated drug particles

Abstract

Various embodiments disclosed relate to polymer encapsulated drug particles and drug release coatings comprising the polymer encapsulated drug particles, as well as drug coated balloon catheters for treating, preventing, or reducing recurrence of body lumen stenosis and methods of use thereof. A drug coated balloon catheter for delivering a therapeutic agent to a body lumen stenosis target site includes an elongated balloon. The balloon catheter includes a coating layer covering the outer surface of the balloon. The coating layer comprises: polymer encapsulated drug particles; or a drug release coating comprising polymer encapsulated drug particles; or a therapeutic agent and a first and / or second additive; or a combination thereof.

Description

This application is a divisional application of the patent application with application number 202180029802.3, application date February 19, 2021, and invention name “Polymer-encapsulated drug particles”. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 979,980 filed on February 21, 2020 and U.S. Provisional Patent Application Serial No. 63 / 104,965 filed on October 23, 2020, the disclosures of which are incorporated herein by reference in their entireties.

[0002] The disclosures of the following applications are incorporated herein by reference in their entirety. U.S. Patent Application Serial No. 16 / 135,436 is a continuation-in-part of International Application No. PCT / US2018 / 03108, filed May 4, 2018, which claims the benefit of priority of U.S. Provisional Patent Application Serial No. 62 / 502,212, filed May 5, 2017. U.S. Patent Application Serial No. 16 / 135,436 is also a continuation-in-part of U.S. Patent Application Serial No. 15 / 568,614, filed October 23, 2017, which is a U.S. national phase application under 35 U.S.C. 371 to International Application No. PCT / US2016 / 028652, filed April 21, 2016, which claims the benefit of priority of U.S. Provisional Patent Application Serial No. 62 / 152,559, filed April 24, 2015. U.S. Patent Application Serial No. 16 / 135,436 is also a continuation-in-part of U.S. Patent Application Serial No. 14 / 438,327, filed April 24, 2015, which is a U.S. national phase application filed under 35 U.S.C. 371 from International Application No. PCT / US2013 / 064842, filed October 14, 2013, which claims the benefit of priority of U.S. Provisional Patent Application Serial No. 61 / 795,790, filed October 26, 2012. U.S. Patent Application Serial No. 16 / 135,472 is a continuation-in-part of International Application No. PCT / US2018 / 03108, filed May 4, 2018, which claims the benefit of priority of U.S. Provisional Patent Application Serial No. 62 / 502,212, filed May 5, 2017. U.S. patent application serial number 16 / 135,472 is also a partial continuation application of U.S. patent application serial number 15 / 568,614 filed on October 23, 2017 (which is a U.S. national phase application of international application number PCT / US2016 / 028652 filed on April 21, 2016 under 35 U.SC 371), and PCT / US2016 / 028652 claims the priority benefit of U.S. provisional patent application serial number 62 / 152,559 filed on April 24, 2015. U.S. patent application serial number 16 / 135,472 is also a partial continuation application of U.S. patent application serial number 14 / 438,327 filed on April 24, 2015 (which is a U.S. national phase application of international application number PCT / US2013 / 064842 filed on October 14, 2013 under 35 U.SC 371), and PCT / US2013 / 064842 claims the priority benefit of U.S. provisional patent application serial number 61 / 795,790 filed on October 26, 2012. Technical Field The present application relates to polymer-encapsulated drug particles and a drug-releasing coating comprising the polymer-encapsulated drug particles, as well as a drug-coated balloon catheter for treating, preventing or reducing the recurrence of body lumen stenosis and a method for using the same. Background Art

[0003] Benign prostatic hyperplasia is a noncancerous enlargement of the prostate gland that affects more than 50% of men over the age of 60. Early in life, the prostate gland is the size and shape of a walnut and weighs about 20 grams. Enlargement of the prostate gland appears to be a normal process. As you age, the prostate gland gradually increases in size to twice or more times its normal size. As the prostate gland grows, it presses on the urethra and narrows it, leading to prostatic urethral compression and urinary tract obstruction, which can make urination difficult or impossible.

[0004] In certain populations, the incidence of urethral stricture disease in men is as high as 0.6%. Urethral stricture disease appears to be more common in the elderly population. Patients with urethral strictures experience moderate to severe complications such as lower urinary tract voiding symptoms or urinary retention, recurrent urinary tract infections, and the need for repeat urethral surgery such as dilation, urethrotomy, or urethroplasty.

[0005] Ureteral strictures in the upper urinary tract can be congenital or acquired. Congenital ureteral strictures are most common at the ureteropelvic junction. Most ureteral strictures are acquired and are usually iatrogenic. The most common cause of ureteral strictures is injury during endoscopic, open, or laparoscopic surgery.

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

[0007] Strictures of the alimentary canal or gastrointestinal tract include esophageal strictures, achalasia strictures, biliary strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, and large intestinal strictures. Strictures are classified as benign or malignant by disease type.

[0008] Biliary strictures, also called bile duct strictures, occur when the bile ducts become smaller or narrower. The bile ducts are tubes that carry bile from the liver to the small intestine. When the bile ducts become narrowed, food becomes harder to digest. Biliary strictures can be caused by bile duct damage, swelling, pancreatitis, intestinal damage, and cancer in the bile ducts or pancreas. Symptoms of bile duct strictures include pain, chills and fever, itching, nausea, or vomiting.

[0009] Esophageal strictures are a common problem in gastroenterology and can be caused by malignant or benign lesions. Dysphagia is a symptom experienced by all patients. Most of these patients require palliative care to relieve dysphagia.

[0010] Barrett's disease, also known as Barrett's esophagus, is a disorder in which the mucosal cells of the lower esophagus undergo an abnormal (metaplasic) change from the normal stratified squamous epithelium to a simple columnar epithelium interspersed with goblet cells, which are normally found only in the colon. This change is considered a precancerous lesion because it is associated with a high incidence of further transformation to esophageal adenocarcinoma, a cancer that is often fatal.

[0011] Eosinophilic esophagitis (EoE) is a chronic inflammatory disease. Symptoms of the disease include dysphagia and food impaction, and are often caused by esophageal strictures. Repeated endoscopic dilation of esophageal fibrous strictures in eosinophilic esophagitis using bougies and balloon catheters is used to treat such strictures.

[0012] A lower gastrointestinal stricture is a narrowing of a portion of the intestine that causes problems by slowing or blocking the movement of food through that area. Strictures are caused by recurrent inflammation, cancer, Crohn's disease, and ulcerative colitis. Strictures include esophageal strictures, achalasia strictures, stent strictures, bile duct strictures, stomach 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). Strictures induced by Crohn's disease and ulcerative colitis are common complications of IBD and the surgical procedures that treat them. Over time, the rate of strictures in patients with IBD ranges from 34% to 70%. Some strictures are difficult to cure or recur, requiring repeated endoscopic dilation.

[0014] An anastomosis is a connection or opening between two fluid-carrying body structures. Surgical anastomosis is the connection of two fluid-carrying luminal structures by surgical techniques. Anastomotic stenosis is a narrowing of the anastomosis. Anastomotic stenosis is a common complication of surgical anastomosis and various other surgical procedures (such as radical prostatectomy, bowel resection and gastric bypass). Anastomotic stenosis is usually fibrotic and may be difficult to manage and treat. Anastomotic stenosis may include anastomotic stenosis between two parts of the same body structure or between two different body structures, wherein the body structure may be the esophagus, bile duct, stomach, small intestine, duodenum, jejunum, ileum, colon, rectum, large intestine, colon, rectum, urethra, ureter or bladder neck. Anastomotic stenosis may be colorectal stenosis, post-gastric bypass stenosis, ileocolic stenosis, gastrointestinal stenosis, J-pouch stenosis or bladder neck stenosis (e.g., stenosis). Although balloon dilatation has been shown to be a safe and effective nonsurgical method for the treatment of anastomotic strictures, problems still exist, such as the need for repeated balloon dilatation due to difficult-to-treat or recurrent anastomotic strictures.

[0015] Vaginal stenosis is an abnormal condition where the vagina becomes narrower and shorter due to the formation of fibrous tissue. Vaginal stenosis can negatively impact sexual dysfunction, dyspareunia, and make pelvic exams difficult and painful. The tissue lining the vagina may also be thinner, drier, and contain scar tissue. This condition may cause pain during intercourse or a pelvic exam. Vaginal stenosis is often caused by an episiotomy, radiation therapy to the pelvis, or various types of surgery.

[0016] Chronic obstructive pulmonary disease (COPD) is a term used to classify the two main airflow obstruction diseases, chronic bronchitis and emphysema. About 16 million Americans have COPD, and 80-90% of them have been smokers for most of their lives. COPD is the leading cause of death in the United States. Chronic bronchitis is an inflammation of the bronchial airways. The bronchial airways connect the trachea to the lungs. When inflamed, the bronchi secrete mucus, which causes a chronic cough. Emphysema is an overinflation of the alveoli, or air sacs in the lungs. This condition can cause shortness of breath.

[0017] Asthma is a chronic respiratory disease characterized by inflammation of the airways, excess mucus and airway hyperresponsiveness, as well as symptoms where the airways narrow too much or react too easily to stimuli. Asthma attacks, or attacks, can cause the airways to narrow, which can make it difficult to breathe. Asthma attacks can have a serious impact on a person's life, limiting their ability to participate in many activities. In severe cases, asthma attacks can be life-threatening. Currently, there is no known cure for asthma.

[0018] Chronic sinusitis is an inflammation of the membrane lining of one or more of the sinuses. Chronic sinusitis lasts longer than three weeks and often lasts for several months. In cases of chronic sinusitis, tissue damage is often present. According to the Centers for Disease Control (CDC), 37 million cases of chronic sinusitis are reported each year.

[0019] Radiation (e.g., radiotherapy) is used as a treatment modality for localized cancers. Localized cancers are the most commonly diagnosed cancers. Most patients are diagnosed at an early stage when they are potentially curable. Standard localized treatment options include active surveillance, radical prostatectomy (RP) for prostate cancer, and radiotherapy (RT) which is generally used for all cancer treatments. Radiotherapy can be delivered via external beam radiation therapy (EBRT) or brachytherapy (BT). The side effects associated with each treatment can vary greatly. Localized cancers include prostate cancer, urethra cancer, ureter cancer, esophageal cancer, bile duct cancer, stomach cancer, small intestine cancer, duodenum cancer, jejunal cancer, ileum cancer, colon cancer, rectum cancer, large intestine cancer, and lung cancer. Radiotherapy can cause damage to adjacent healthy tissues, such as strictures. Radiotherapy-induced strictures can include strictures of the urethra, ureter, esophageal strictures, bile duct strictures, stomach strictures, small intestine strictures, duodenal strictures, jejunal strictures, ileal strictures, colon strictures, rectal strictures, and large intestine strictures. Treating radiation-induced strictures can be complicated and difficult. Due to high survival rates, the number of prostate cancer survivors in the United States has increased by 220,000 per year to nearly 2.8 million in 2015, placing a large number of men at risk for short-term or long-term side effects of radiation therapy for prostate cancer. The development of urethral stricture as a side effect of radiation therapy for prostate cancer is particularly problematic.

[0020] Various minimally invasive methods for the treatment of various cancers, large colon polyps, and Barrett's esophagus are routine worldwide. When patients prefer to avoid surgery, various minimally invasive methods are preferred over surgery. Multiple randomized controlled trials and meta-analyses have demonstrated the clinical oncological safety and effectiveness of laparoscopic gastrectomy, robot-assisted gastrectomy, EMR (endoscopic mucosal resection), and ESD (endoscopic submucosal dissection) in the treatment of various stages of cancer and Barrett's esophagus. EMR (endoscopic mucosal resection) and ESD (endoscopic submucosal dissection) are safe and effective for the treatment of early superficial cancers such as esophageal cancer, bile duct cancer, gastric cancer, small intestine cancer, duodenal cancer, jejunal cancer, ileal cancer, colon cancer, rectal cancer, colorectal cancer, ileocolic cancer, and gastrointestinal cancer. EMR and ESD are safe and effective for the treatment of high-grade Barrett's esophagus. Laparoscopic gastrectomy, robotic-assisted gastrectomy, EMR, and ESD are feasible with regard to clinical and oncological safety; however, some patients are noted to experience recurrent malignancies and refractory strictures. The local recurrence rate of cancer after minimally invasive treatment ranges from 2-20%, depending on the type and stage of cancer and the duration of follow-up. The incidence of strictures or stenoses after minimally invasive surgery is approximately 26%-70%. Repeated endoscopic balloon dilatations are required to treat refractory or recurrent strictures or stenoses.

[0021] Cardiovascular disease, or atherosclerosis, is characterized by hardening and narrowing of the arteries due to the deposition of fatty plaques on the lumen of the arteries. Over time, the 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 stenosis of key arteries such as the carotid and coronary arteries can lead to sudden death. Stenotic peripheral arteries such as the iliac, superficial femoral, popliteal, tibial, and peroneal arteries can lead to the need for amputation. If the renal arteries are blocked, chronic kidney disease can result. Currently, drug-coated balloons and drug-eluting stents are used to treat stenosis. These drug-coated devices are still not good enough in terms of reducing long-term mortality, thrombosis rates, and improving efficacy. Better devices are needed to improve safety and effectiveness for cardiovascular disease stenosis.

[0022] Kidney failure is a disease that causes waste products to build up in the blood. To prevent waste products from building up, patients undergo a medical procedure called chronic hemodialysis. During hemodialysis, blood is passed through a dialyzer to remove waste products. The access point for the blood is usually at a special vascular connection set up in the limb, which is called an arteriovenous fistula (AVF) or graft arteriovenous fistula (AVG). An AVF is a special type of anastomosis in which an artery is sutured directly to a vein. An AVG is a different type of anastomosis in which a synthetic or autologous tube facilitates the connection between the artery and vein. AVFs and AVGs often become narrow and cause blood flow obstruction. When this happens, they must be dilated or abandoned to set up a new AVF or AVG to complete the dialysis treatment. Drug-coated balloons are used to dilate narrowed AVFs and AVGs, but better devices are needed to improve safety and effectiveness.

[0023] Heart valve disease is a common condition that plagues the aging population. It is diagnosed by listening to the heartbeat with a stethoscope during a physical exam. Abnormal sounds made by the heart are called murmurs, and different murmurs can indicate specific types of heart valve disease. Types of heart valve disease include stenosis, regurgitation, prolapse, and atresia. Heart valve stenosis is a narrowing or stiffening of the heart valve that causes the valve to not open or close properly. The valve flaps may become thickened, stiffened, or fused together. As a result, the valve cannot open fully, and the heart must then work harder to pump blood through the valve. The result can be hypoxia, or reduced oxygen supply, affecting the entire body, local tissues, or a certain area of ​​the body. Heart valve stenosis can be treated with a procedure called balloon valvuloplasty, or BAV. BAV involves tracking an inflatable balloon through the vascular system to the heart valve and dilating the heart valve annulus. Recently, there has been an increase in the number of BAV procedures performed due to the use of BAV before, after, and / or during transcatheter aortic valve replacement (TAVR) surgery. Restenosis rates at 5–9 months after BAV range from 40–80%, indicating a need for improved devices and techniques. Summary of the invention

[0024] In various embodiments, the present invention provides polymer encapsulated drug particles, including a therapeutic agent and one or more polymers. Optionally, the polymer encapsulated drug particles include a first ionic additive or a zwitterionic additive. When present, the first ionic additive or zwitterionic additive is in 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 comprising a therapeutic agent and one or more polymers. Optionally, the polymer-encapsulated drug particles comprise a first ionic additive or a zwitterionic additive. When present, the first ionic additive or zwitterionic additive is in the polymer-encapsulated drug particles, coated on the surface of the polymer-encapsulated drug particles, or a combination thereof. The coating also comprises a release matrix containing ions or zwitterionic additives. The coating can be located at any suitable position, such as a balloon catheter, a drug-coated catheter, a drug-eluting stent, a drug-eluting stent on a balloon, 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 polymer encapsulated drug particles, the drug particles comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent. The polymer encapsulated drug particles further comprise an ionic additive or a zwitterionic additive. The polymer encapsulated drug particles may be charged polymer encapsulated drug particles.

[0027] Various embodiments provide a method for treating or preventing a non-vascular or vascular stenosis or stenoses. The method comprises inserting a catheter into a body lumen, wherein the catheter comprises a balloon or a stent, the balloon or the stent comprising a drug coating, the drug coating comprising the polymer-encapsulated drug particles. The method comprises expanding the balloon or the stent so that the coating contacts the stenosis, stenoses, or an area in which the stenosis or stenoses are to be prevented. When using a balloon, the method may comprise deflation of the balloon. When using a balloon, the method may further comprise removal of the balloon or the stent from the body lumen.

[0028] Various embodiments provide a method for preparing polymer encapsulated drug particles. The method includes forming a suspension including a therapeutic agent and a polymer. The method includes treating the suspension to reduce the particle size of the suspension. The method also includes adding an aqueous premix to the suspension to form polymer encapsulated drug particles in the suspension. The polymer encapsulated drug particles include the therapeutic agent and the polymer.

[0029] Various embodiments provide a method for preparing polymer encapsulated drug particles. The method includes forming an organic premix, which includes an organic solvent, one or more polymers, a therapeutic agent, and an optional first ionic additive or a zwitterionic additive. The method includes forming an aqueous premix including water and a water-soluble polymer or a surfactant. The method includes adding an organic solvent to the aqueous premix. The method includes combining the aqueous premix and the organic premix together. The method also includes stirring the combined aqueous premix and organic premix to form an emulsion including the polymer encapsulated drug particles.

[0030] In various embodiments, the present invention provides a method for preparing polymer-encapsulated drug particles, the drug particles comprising a therapeutic agent, one or more polymers and an optional first ionic additive or a zwitterionic additive. The method comprises preparing an organic premix by dissolving and mixing one or more polymers, a therapeutic agent and an optional first ionic additive or a zwitterionic additive to form a premix in an organic solvent. The organic solvent can be at least partially miscible with an aqueous solution (e.g., a polar organic solvent). The method includes preparing a second aqueous premix comprising a water-soluble polymer and adding an organic solvent for the first premix. The method includes mixing the organic premix into the aqueous premix, thereby producing an organic solvent in the aqueous coacervate. The method includes also adding water to the coacervate solution to drive the organic solvent out of the coacervate, thereby hardening it into the polymer-encapsulated drug particles.

[0031] Various embodiments provide a method for manufacturing a balloon catheter, wherein the method comprises applying the polymer-encapsulated drug particles or a drug-releasing coating comprising the polymer-encapsulated drug particles to the outside of a balloon of the balloon catheter.

[0032] Various embodiments provide a balloon catheter. The balloon catheter includes an elongated balloon. The balloon catheter also includes a coating covering the outer surface of the balloon. The coating includes: the polymer-encapsulated drug particles; or a drug release coating including the same; or a composition including 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, umimios, analogs thereof, and combinations thereof, and the particle size of the therapeutic agent is 0.2 microns to 10 microns. The first additive includes a water-insoluble or partially water-insoluble additive, which includes at least one alkyl fatty group or cholesterol group, and the molecular weight of the first additive is 50 to 750. The second additive is more hydrophilic or more soluble in water than the first additive, and includes polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The molecular weight of the second additive ranges from 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 elongated balloon and a coating covering the outer surface of the balloon. The coating comprises: the polymer-encapsulated drug particles; or the drug-releasing coating, comprising the polymer-encapsulated drug particles; or a composition comprising two or more additives and an initial drug loading of a therapeutic agent. The therapeutic agent in the composition is selected from mTOR inhibitors, paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimios, analogs thereof, and combinations thereof. The therapeutic agent in the composition is crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. The first additive includes a water-insoluble or partially water-insoluble additive including at least one alkyl fatty group or cholesterol group, the molecular weight of the additive being 50 to 750 (e.g., 50 or greater, or less than, equal to, or greater than 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or 750 or less). The second additive is more hydrophilic or more soluble in water than the first additive and includes polyethylene glycol (—(CH2CH2O)—) or polyglycerol (—(CH2-CHOH-CH2O)—) units. The second additive has a molecular weight range of 750 to 100,000 (e.g., 750 or more, or less than, equal to, or less than 1,000, 2,000, 4,000, 6,000, 8,000, 10,000, 20,000, 40,000, 60,000, 80,000, 90,000, or 100,000 or less). The therapeutic agent particles in the coating have a particle size range of 0.2 microns to 10 microns (e.g., 0.2 microns or greater, or less than, equal to, or greater than 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, 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 where the lumen of a body is narrow or stenotic. The balloon catheter comprises an elongated balloon and a coating covering the outer surface of the balloon. The coating comprises: the polymer-encapsulated drug particles; or the drug-releasing coating, comprising the polymer-encapsulated drug particles; or a composition comprising two or more additives and an initial drug loading of a 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 a combination thereof. The therapeutic agent in the composition is selected from paclitaxel, docetaxel, taxol, analogs thereof, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimios, analogs thereof, 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 ranges from 0.2 microns to 5 microns (e.g., 0.2 microns or greater, or less than, equal to, or greater than 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, 4.8, or 5 microns or less). In embodiments including the composition, the first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, the particle size of the therapeutic agent encapsulated by the additive is larger than the particle size of the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated by the additive in the coating ranges from 0.3 microns to 10 microns (e.g., 0.3 microns or greater, or less than, equal to, or greater than 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 10 microns or less). In embodiments including the composition, the additive-encapsulated therapeutic agent is partially or completely encapsulated such that the therapeutic agent is partially or completely surrounded by the additive in contact with the therapeutic agent (e.g., as discrete particles, or as a partially or completely continuous coating). For example, 25%-100% of the surface area of ​​the additive-encapsulated therapeutic agent may be in contact with the first additive, the second additive, or a combination thereof, or 50-100%, 75-100%, or 1% or more, or less than, equal to, 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 100% or less.The first additive includes a water-insoluble or slightly or partially water-insoluble additive, which includes at least one alkyl fatty group or cholesterol group, and the molecular weight of the first additive can be 50 to 750. In an embodiment including the composition, the melting temperature of the first additive in the coating is lower than the melting temperature of the pure first additive, and the crystallinity of the first additive in the coating is lower than the crystallinity of the pure first additive. The second additive is more hydrophilic or more soluble in water than the first additive and includes polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The molecular weight range of the second additive is 750 to 100,000, or 750 to 50,000, or 750 to 10,000. The body lumen narrowness or stenosis is selected from urethral stenosis, prostatic urethral stenosis, ureteral stenosis, esophageal stenosis, antral stenosis, gastric stenosis, small intestinal stenosis, colonic stenosis, rectal stenosis, large intestinal stenosis, bladder neck stenosis, bile duct 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. The first additive having a cholesterol group is selected from cholesterol, cholesterol acetate, cholesterol phenylacetate, cholesterol laurate, cholesterol palmitate, cholesterol stearate, cholesterol valerate, cholesterol benzoate, cholesterol heptanoate, cholesterol decanoate, cholesterol caproate, cholesterol oleate, cholesterol oleyl carbonate, cholesterol linoleate, cholesterol nonanoate, cholesterol erucate, cholesterol octanoate, 5α-cholestane, 5α-cholestane-3-one and a combination thereof.The water-insoluble or slightly or partially water-insoluble first additive having an alkyl fatty group is selected from the group consisting of alkyl glyceryl ethers, monoglycerides of C8-C12 fatty acids, alkyl alcohols, alkyl ethers, alkyl esters, caprylic acid, monocaprilin, capric acid, monocaprin, lauric acid, dodecylglycerol, tetradecanoic acid (butanoic acid), hexanoic acid (hexanoic acid), octanoic acid (octanoic acid), decanic acid (decanoic acid), dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid acid), tocotrienols, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono- or di- or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, α-tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliolipids, mixed chain triglycerides (neobee), liposomes, derivatives thereof, and combinations thereof.The water-soluble second additive is selected from cholesterol-polyethylene glycol 600 sebacate, polyoxyethyl α-tocopherol 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)-cholesterol sebacate, polyethylene glycol cholesterol, PEG amide ester cholesterol, PEG amide ether cholesterol, mPEG amide ester cholesterol, DSPE-PEG-cholesterol, P EG phospholipids, methylated PEG phospholipids, PEG caprylic / capric diglyceride, PEG8 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 esters, polyglyceryl oleate (Plurol Oleique), 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), polyglyceryl-10 mono / dioleate (CaproI. TM 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.

[0035] In various embodiments, the present invention provides a method for preventing or treating stenosis of the digestive body lumen or gastrointestinal tract. The method comprises inserting a balloon catheter into a target site in the body lumen including non-vascular stenosis. The balloon catheter comprises an elongated balloon and a coating covering the outer surface of the balloon. The coating comprises: the polymer-encapsulated drug particles; or the drug-releasing coating, comprising the polymer-encapsulated drug particles; or a composition comprising two or more additives and an initial drug loading of a therapeutic agent. The composition comprises a first additive comprising a water-insoluble or partially water-insoluble additive, a second additive that is more hydrophilic or more soluble in water than the first additive, and an initial drug loading of a therapeutic agent, the therapeutic agent being selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimos, analogs thereof, and combinations thereof. In an embodiment including the composition, the first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, the particle size of the therapeutic agent encapsulated by the additive is larger than the particle size of the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated by the additive in the coating ranges from 0.3 microns to 10 microns. The method includes inflating the balloon at the target site so that the coating contacts the wall of the body lumen at a non-vascular stenosis location until the balloon reaches an inflated balloon diameter during the inflation period. The method includes deflation of the balloon after the inflation period. The method includes removing the balloon catheter from the body lumen. Stenosis in the digestive body lumen or gastrointestinal tract includes esophageal stenosis, achalasia stenosis, biliary stenosis, gastric stenosis, small intestinal stenosis, duodenal stenosis, jejunal stenosis, ileal stenosis, colonic stenosis, rectal stenosis, ileoanal J-pouch stenosis, and large intestinal stenosis. Strictures in the alimentary lumen or gastrointestinal tract include esophageal strictures of 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 preventing or treating stenosis or stenoses in a vascular body lumen. The method comprises inserting a balloon catheter into a target site in a body lumen comprising a vascular stenosis or stenoses. The balloon catheter comprises an elongated balloon and a coating covering the outer surface of the balloon. The coating comprises: the polymer-encapsulated drug particles; or the drug-releasing coating, comprising the polymer-encapsulated drug particles; or a composition comprising two or more additives and an initial drug loading of a therapeutic agent. The composition comprises a first additive, a second additive, and an initial drug loading of a therapeutic agent, the therapeutic agent being selected from paclitaxel, docetaxel, taxol, an mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimios, analogs thereof, 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 range of the therapeutic agent is 0.2 microns to 5 microns. In an embodiment including the composition, the first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, the particle size of the therapeutic agent encapsulated by the additive is larger than the particle size of the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated by the additive in the coating ranges from 0.3 microns to 10 microns. The first additive comprises a water-insoluble or slightly or partially water-insoluble additive, which comprises at least one alkyl fatty group or cholesterol group, and the molecular weight of the first additive can be 50 to 750. In an embodiment including the composition, the melting temperature of the first additive in the coating is lower than the melting temperature of the pure first additive, and the crystallinity of the first additive in the coating is lower than the crystallinity of the pure first additive. The second additive is more hydrophilic or more soluble in water than the first additive, and comprises polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The molecular weight of the second additive ranges from 750 to 100,000. The method includes inflating the balloon at the target site so that the coating contacts the wall of the body lumen at the stenosis or stenoses until the balloon reaches an inflated balloon diameter during an inflation period. The method includes deflation of the balloon after the inflation period. The method includes removing 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 includes providing a crystalline therapeutic agent, wherein the therapeutic agent is selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimos, analogs thereof, and combinations thereof. The method includes treating the therapeutic agent so that the particle size of most of the therapeutic agent crystals is 0.2 microns to 5.0 microns. The method includes providing a fluid in which the therapeutic agent is substantially insoluble. The method includes mixing the fluid with the therapeutic agent, a first water-insoluble additive and a second water-soluble additive, wherein the first additive encapsulates the therapeutic agent crystals, and the particle size of the first additive is 0.3 microns to 10 microns. The method includes applying the mixture to the outer surface of the balloon catheter. The first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, the particle size of the therapeutic agent encapsulated by the additive is greater than the particle size of the therapeutic agent itself, and the particle size range of the therapeutic agent encapsulated by the additive in the coating is 0.3 microns to 10 microns.

[0038] In various embodiments, the present invention provides a method for preparing a drug coating solution. The method includes mixing water, a water-miscible solvent, a therapeutic agent, and a water-soluble additive to form a premix. The method includes treating the premix to reduce the particle size of the therapeutic agent. The method includes mixing the water-insoluble additive, the water-soluble additive, water, and the water-miscible solvent to form a second premix. The method includes 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, umimios, analogs thereof, 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 range of the therapeutic agent is 0.2 microns to 5 microns. The first additive, the second additive or a combination thereof encapsulates the therapeutic agent, the particle size of the therapeutic agent encapsulated by the additive is larger than the particle size of the therapeutic agent itself, and the particle size range of the therapeutic agent encapsulated by the additive in the coating is 0.3 microns to 10 microns. The treatment is one of microfluidization, homogenization, homogenizer grinding, high energy or low energy bead milling or high power ultrasonic probe homogenization. The first additive includes a water-insoluble or slightly or partially water-insoluble additive, which includes at least one alkyl fatty group or cholesterol group, and the molecular weight of the first additive can be 50 to 750. The melting temperature of the first additive in the coating is lower than the temperature of the pure first additive (for example, determined by DSC of the coating and DSC of the pure additive). The crystallinity of the first additive in the coating is lower than the crystallinity of the pure first additive (for example, determined by DSC of the coating and DSC of the pure additive). The second additive is more hydrophilic or more soluble in water than the first additive and includes polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The molecular weight of the second additive is 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 includes preparing an aqueous suspension coating solution. Preparing the aqueous suspension includes mixing water, a water-miscible solvent, a therapeutic agent, and a water-soluble additive to form a premix. Preparing the suspension includes treating the premix to reduce the particle size of the therapeutic agent. Preparing the suspension includes mixing a water-insoluble additive, the water-soluble additive, water, and a water-miscible solvent to form a second premix. Preparing the suspension includes mixing the second premix with a first treated premix to form a coating solution. The therapeutic agent can be an mTOR inhibitor (e.g., rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimios, or a combination thereof) or an analog or derivative 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 range of the therapeutic agent is 0.2 microns to 5 microns. The first additive, the second additive, or a combination thereof encapsulates the therapeutic agent, the particle size of the therapeutic agent encapsulated by the additive is larger than the particle size of the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated by the additive in the coating ranges from 0.3 microns to 10 microns. The first additive includes a water-insoluble or slightly or partially water-insoluble additive, which includes at least one alkyl fatty group or cholesterol group, and the molecular weight of the first additive can be 50 to 750. The melting temperature of the first additive in the coating is lower than the melting temperature of the pure first additive. The crystallinity of the first additive in the coating is lower than the crystallinity of the pure first additive. The second additive is more hydrophilic or more soluble in water than the first additive, and includes polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The molecular weight of the second additive is 750 to 100,000, or 750 to 50,000, or 750 to 10,000. The method includes preparing a balloon catheter. Preparing the balloon catheter includes inflating the balloon catheter. Preparing the balloon catheter includes cleaning the balloon surface, such as with an ethanol wipe. Preparing the balloon catheter includes securing the balloon so that it can be mounted horizontally in a coating machine and rotated at a fixed speed. The method includes dispensing the coating solution onto the balloon surface while a nozzle is translated laterally on the balloon. The method includes continuing to rotate the balloon at or above room temperature to evaporate the solvent. 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 a minimally invasive method for treating or preventing non-vascular or vascular stenosis or stenoses. The method includes inserting a catheter having an expandable body through a body lumen containing a stenosis or stenoses so that the expandable body is located inside the stenosis or stenoses. The catheter having an expandable body includes a balloon catheter, a drug-coated catheter, a drug-eluting stent, and a drug-eluting stent folded on a drug-coated balloon. The catheter includes an expandable body having a coating layer covering the outer surface of the expandable body of the catheter. The coating layer includes: the polymer-encapsulated drug particles; or the drug-releasing coating, including the polymer-encapsulated drug particles; or a composition, comprising two or more additives and an initial drug loading amount of a therapeutic agent. The one or more additives are selected from water-insoluble additives, slightly or partially soluble additives, water-soluble additives, or combinations thereof. The method includes expanding the expandable body so that the coating layer contacts the stenotic or narrowed body lumen to a certain diameter and for a period of time. The method includes shrinking the expandable body after the period of time and removing it from the stenosis or the stenotic body lumen. In some embodiments, the method further comprises performing a surgical procedure to dilate, cut, or remove tissue prior to inserting the balloon catheter into the target site.

[0041] Embodiments of the present invention provide a medical device coating formulation, including a therapeutic agent or drug for treating non-vascular and vascular body lumen stenosis, and an additive that enhances the absorption of the drug by body lumen tissue. Some embodiments provide a coating covering an expandable portion of a catheter, the coating having a single layer or multiple layers, containing a single or multiple therapeutic agents. In some embodiments, the layer in contact with the expandable portion of the catheter has no therapeutic agent, and is formulated by a composition that transfers all or most of the coating to the narrow or stenotic when the catheter is expanded. The causes of body lumen stenosis and related diseases may include infection and inflammation caused by pathogens such as bacteria and viruses. In some embodiments, the additive of the coating has antibacterial and antiviral properties. In some embodiments, the coating layer containing the therapeutic agent has a crystalline, amorphous, or a combination of drugs. 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 a component that enhances the adhesion of the coating to the expanded narrow or stenotic lumen surface. In some embodiments, the coating is formulated so that when the catheter is expanded, the coating is transferred to the narrow or stenosis in the form of particles, agglomerated particles, dissolved substances, or a combination thereof. In some embodiments, the size of the transferred particles or agglomerated particles is very small and less than 10 μm, or more preferably less than 5 μm. In some embodiments, the coating layer includes the polymer-encapsulated drug particles or a drug release coating containing the same.

[0042] In various embodiments, the present invention provides a catheter comprising an expandable portion of an elongated body for expanding non-vascular and vascular stenosis or stenoses. In some embodiments, the elongated body is a cylindrical balloon. In some embodiments, the elongated body is a balloon whose shape or longitudinal profile prevents the balloon from migrating in the body lumen it expands.

[0043] In various embodiments, the present invention provides a method of applying a coating solution to an expandable portion of a catheter, evaporating liquid in the coating solution to leave a dry coating on the catheter. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The drawings illustrate generally, by way of example and not by way of limitation, various embodiments of the invention.

[0045] Figure 1 is a perspective view of an embodiment of a balloon catheter of the present invention according to various embodiments (the balloon catheter includes Figure 1 The invention also includes a fixed guidewire balloon catheter, a coaxial integral exchange balloon catheter and a rapid exchange balloon catheter (the details of which are not shown).

[0046] Figures 2A-2C According to various implementation schemes, Figure 1 Cross-sectional view of various embodiments of the distal portion of the balloon catheter along line AA showing exemplary coating layers.

[0047] Figure 3A A balloon catheter having a neck section is shown according to various embodiments.

[0048] Figure 3B A balloon catheter having two neck sections is shown according to various embodiments.

[0049] Figure 3C A balloon catheter having three neck sections is shown according to various embodiments.

[0050] Figures 4A-4D A balloon catheter including an elongated rigid member is shown according to various embodiments.

[0051] Figure 5 An elongated rigid member is shown as a spring according to various embodiments.

[0052] Figure 6 The graph of shows an example of drug coating particle size analysis using a Beckman Coulter LS13 320 particle size analyzer with a liquid analyzer module according to various embodiments.

[0053] Fig. 7A -C shows a SEM image of an example of a sirolimus coated balloon according to various embodiments, Fig. 7A Displays images at 37x magnification, Figure 7B The image is displayed at 1,600x magnification, while Figure 7C Images were displayed at 7,500x magnification.

[0054] Fig. 8A -C shows an exemplary powder X-ray diffraction pattern, obtained on a balloon from: Fig. 8A Crystalline sirolimus drug coating, Figure 8B Dodecylglycerol drug coating, and Figure 8C Sterilize the sirolimus drug coating.

[0055] Fig. 9A -C shows the following DSC scans according to various embodiments: Fig. 9A Crystalline sirolimus drug-coated balloon, Fig. 9B Dodecylglycerol drug-coated balloon, and Fig. 9C Sirolimus drug-coated balloon.

[0056] Fig.10 Shown is a particle size reduction profile of sirolimus obtained using a high pressure homogenizer according to various embodiments.

[0057] Fig.11 Shown are Kaplan-Meier curves for freedom from reintervention for paclitaxel coated balloon treatment in the esophagus and intestine according to various embodiments. DETAILED DESCRIPTION

[0058] Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are partially illustrated in the accompanying drawings.While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplary subject matter is not intended to limit the claims to the disclosed subject matter.

[0059] In this article, the numerical values ​​expressed in the range format should be interpreted in a flexible manner, including not only the numerical values ​​explicitly listed as the range limits, but also all individual numerical values ​​or sub-ranges covered by the range, as if each numerical value and sub-range were explicitly cited. For example, the range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted as including not only about 0.1% to about 5%, but also the individual numerical values ​​(e.g., 1%, 2%, 3% and 4%) and sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the specified range. Unless otherwise specified, the expression "about X to Y" has the same meaning as "about X to about Y". Similarly, unless otherwise specified, the expression "about X, Y or about Z" has the same meaning as "about X, about Y or about Z".

[0060] As used herein, the terms "a", "an" or "the" are used to include one or more, unless the context clearly dictates otherwise. The term "or" is used to refer to a non-exclusive "or" unless otherwise specified. The expression "at least one of A and B" has the same meaning as "A, B, or A and B". In addition, it should be understood that the words or terms used herein, and those not otherwise defined, are intended to be descriptive and not limiting. The use of any section headings is intended to facilitate reading of the present document and should not be construed as limiting the present document; information related to the section heading may appear within or outside that particular section.

[0061] In the methods described herein, the actions may be performed in any order without departing from the principles of the invention unless a temporal or operational order is explicitly enumerated. In addition, specific actions may be performed simultaneously unless the wording of the claims explicitly indicates that they are performed separately. For example, a claimed action of doing X and a claimed action of doing Y may be performed simultaneously in a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0062] As used herein, the term "about" can allow a value or range to vary to a certain extent, for example, within 10%, within 5%, or within 1% of a stated value or a stated range limit, and include the exact stated value or range.

[0063] As used herein, the term "substantially" refers to a majority, or a majority, such as 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 100%. Polymer encapsulated drug particles

[0064] Various embodiments provide polymer encapsulated drug particles. The polymer encapsulated drug particles include a therapeutic agent and one or more polymers that encapsulate the therapeutic agent. Optionally, the polymer encapsulated drug particles include a first ionic additive or a zwitterionic additive. When present, the first ionic additive or zwitterionic additive is in the polymer encapsulated drug particles (e.g., encapsulated by the encapsulating polymer), coated on the surface of the polymer encapsulated drug particles (e.g., on the outer surface of the encapsulating polymer), or a combination thereof. In some embodiments, the polymer encapsulated drug particles include the first ionic additive or zwitterionic additive. In other embodiments, the polymer encapsulated drug particles do not contain the first ionic additive or zwitterionic additive.

[0065] The therapeutic agent can be any suitable therapeutic agent. The therapeutic agent can be selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimos, analogs thereof, and combinations thereof. The therapeutic agent can be crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. The therapeutic agent can be crystalline and / or partially crystalline. The therapeutic agent can have any suitable maximum size (e.g., diameter), such as a maximum size of 0.1 to 29.9 microns, or 0.5 to 15 microns, or 1 to 10 microns, or less than or equal to 29.9 microns and greater than or equal to 0.1 micron, 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 may constitute any suitable proportion of the polymer encapsulated drug particles, for example 5-45 wt%, or 25-35 wt%, or less than or equal to 45 wt% and equal to or greater than 5, 10, 15, 20, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 40 wt%.

[0066] The polymer encapsulating the therapeutic agent in the polymer-encapsulated drug particles can be any suitable one or more polymers. The polymer can be selected from at least one of the following: polylactic acid (PL), polyglycolic acid (GA), polylactic acid / polyglycolic acid copolymer (PLGA), polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycans and their copolymers. The PLGA copolymer can be ester-terminated or can have carboxylic acid end groups. The lactic acid to glycolic acid weight ratio of the PLGA copolymer can be 50:50, 65:35, 75:25 or 85:15. The molecular weight range of the PLGA copolymer can be 20,000g / mol to 300,000g / mol. The one or more polymers can constitute any suitable proportion of the polymer-encapsulated drug particles, such as 30-80wt%, or 50-75wt%, or less than or equal to 80wt% and equal to or greater than 30, 35, 40, 45, 50, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or 75wt%. The polymer can be a neutral polymer. The polymer can be an anionic polymer, a cationic polymer or a zwitterionic polymer, such as any polymer suitable for use as the first ionic additive or zwitterionic additive or the second ionic additive or zwitterionic additive as described herein.

[0067] In the polymer encapsulated drug particles, the polymer encapsulates the therapeutic agent. The diameter of the polymer encapsulated drug particles is greater than the diameter of the encapsulated therapeutic agent particles. As used herein, "encapsulation" can refer to the encapsulating agent (e.g., a polymer as described herein, a first ion or zwitterion additive, and / or a first and second additive) covering 50-100% of the surface area of ​​the encapsulated material (i.e., the therapeutic agent and the optional first ion additive or zwitterion additive), or 60-100%, 75-100%, 90-100%, or equal to or greater than 50%, 55, 60, 65, 70, 75, 80, 85, 90, 92, 94, 96, 98, 99, 99.5, or 99.9% or more.

[0068] The polymer encapsulated drug particles may include a first ionic additive or a zwitterionic additive. The first ionic additive or zwitterionic additive may be in the polymer encapsulated drug particles, coated on the surface of the polymer encapsulated drug particles, or a combination thereof. The first ionic additive or zwitterionic additive may be uniformly distributed within the drug particles (e.g., distributed within the encapsulating polymer together with the therapeutic agent), outside the drug particles (e.g., on the encapsulating polymer), or a combination thereof. The first ionic additive or zwitterionic additive may be coated on the surface of the polymer encapsulated particles. The coating of the first ionic additive or zwitterionic additive may be a part of the polymer encapsulated drug particles, so that the coating of the first ionic additive or zwitterionic additive may be considered in terms of particle size when determining the maximum size of the polymer encapsulated drug particles. The polymer encapsulated drug particles may include 1, 2, 3 or 4 or more first ionic additives or zwitterionic additives, such as 1 or 2 first ionic additives or zwitterionic additives, such as 1 first ionic additive or zwitterionic additive. The one or more first ionic additives or zwitterionic additives can constitute any suitable proportion of the polymer encapsulated drug particles, for example, 0.5-20 wt%, 1-10 wt%, or less than or equal to 20 wt% and greater than or equal to 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16 or 18 wt%.

[0069] The first ionic additive or zwitterionic additive may include cationic molecules, anionic additives or zwitterionic additives. The first ionic additive or zwitterionic additive may increase the zeta potential of the polymer-encapsulated drug particles (i.e., make the zeta potential (zeta potential) more positive). The positive zeta potential of the polymer-encapsulated drug particles may make it adhere to the tissue better and / or make the drug transfer to the tissue better. For example, the positive zeta potential of the polymer-encapsulated drug particles may attract amino groups in peptides or proteins, and / or negatively charged lipids in lipid bilayers in cell membranes (e.g., negative ions on the cell membrane surface), making adhesion stronger. Adhesion enhancement may extend the residence time of the polymer-encapsulated drug particles on the body lumen wall, thereby increasing the drug dosage of the tissue and / or the rate at which the drug is delivered to the tissue. The first ionic additive or zwitterionic additive may include charged polymers, charged lipids, phospholipids, phosphorylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol and combinations thereof.

[0070] The two acyl groups of the charged lipid or the two acyl groups of the charged phospholipid (e.g., the acyl groups of the esters bonded to the triglyceride backbone) include mismatched acyl groups that differ in one or more properties or characteristics. The mismatched acyl groups may differ in length, saturation, substituents thereon, substitution patterns thereon, or combinations thereof. For example, both acyl groups may be saturated, or one may be saturated, one may be 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 acyl groups in which one is saturated and the other is unsaturated. In embodiments with 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 having different lengths, saturations, substituents thereon, and substitution patterns thereon may have different phase transitions or softening temperatures. The phase transition or softening temperature of the charged lipid can affect the properties of the coating, such as coating integrity, drying durability, the rate at which the drug is released from the coating, the rate and / or degree of drug absorption into the tissue, or a combination thereof. Lipids and phospholipids with high phase transition temperatures can cause brittle coatings to break and peel off, resulting in inconsistent drug dosages. Lipids and phospholipids with low phase transition temperatures may be difficult to handle because they may be wet and sticky, making drug dosages inconsistent. The phase transition temperature range of charged lipids and phospholipids is -70 ° C to 80 ° C. The preferred range of phase transition temperature is -30 ° C to 50 ° C. The most preferred phase transition temperature range is -20 ° C to 40 ° C. In some embodiments, the coating may have a mixture of lipids and / or phospholipids so that the phase transition temperature of the coating is within the desired range with desired mechanical properties (dry and flexible, and not sticky or brittle).

[0071] The mismatched acyl length of the charged lipid or charged phospholipid can be 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, the same or different lengths of acyl groups (chain length C6-C34) can cause disturbances, unevenness and / or curvature in the lipid bilayer of the cell membrane, thereby enhancing the penetration of the drug into the tissue. In embodiments of charged lipids or phospholipids having mismatched acyl groups of different lengths, the lengths of the two acyl groups can differ by a length of C1-C28, or C1-C10, or C1-C8, or greater than or equal to 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 C28. For example, the lengths of two acyl groups of different lengths can be 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.

[0072] The charged polymer can be selected from polycation-containing cyclodextrin, aminocyclodextrin or its derivative, aminodextran, histone, protamine, cationized human serum albumin, aminopolysaccharide, chitosan, peptide, poly-L-lysine, poly-L-ornithine, poly(4-hydroxy-L-proline ester), polyethyleneimine, polyacrylamine, polyacrylamine, polyamidoamine dendrimer, cationic polyoxazoline, poly(β-amino ester), PEG-PEI copolymer, PLGA-PEI copolymer, positively charged gelatin (e.g., alkali-treated gelatin), hydroxy End-capped 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)-grafted-(1-triacontene), polylysine, polyarginine, poly(methacrylic acid-N,N-dimethylaminoethyl ester), 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 / methacrylate with quaternary ammonium groups (e.g., Eudragit RS and / or SR), and combinations thereof. An example of a methacrylate with a quaternary ammonium group is trimethylaminoethyl methacrylate chloride.

[0073] The charged lipid may be selected from 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, n-glycero-3-phosphocholine, 1,2-dilauroyl-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-dioleoyl-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, di(eicosenoyl)phosphatidylcholine (1,2-di(eicosenoyl)-sn-glycero-3-phosphocholine, C20:1PC), diarachidonoylphosphatidylcholine (1,2-diarachidonoyl-sn-glycero-3-phosphocholine, C20:0PC), dierucylphosphatidylcholine (1,2-dierucyl-sn-glycero-3-phosphocholine, C22:1PC), di( 1,2-Di(docosahexaenoyl)phosphatidylcholine (1,2-di(docosahexaenoyl)-sn-glycero-3-phosphocholine, C22:6PC), 1,2-di(docosahexaenoyl)phosphatidylcholine (1,2-di(docosahexaenoyl)-sn-glycero-3-phosphocholine, C21:1PC) and 1,2-di(di(di(dicosenoyl)-sn-glycero-3-phosphocholine, C24:1PC), and combinations thereof.

[0074] The first ionic additive or zwitterionic additive can be selected from 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 choline, 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-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 (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 and combinations thereof.

[0075] The first ionic additive or zwitterionic additive may include or be a water-insoluble or slightly or partially water-insoluble additive comprising at least one acyl group. The molecular weight of the first ionic additive or zwitterionic additive may be 50 to 750, 750 to 100,000, or 750 to 50,000, or 750 to 10,000. The melting temperature of the first ionic additive or zwitterionic additive may be lower than the melting temperature of the pure additive. The crystallinity of the first ionic additive or zwitterionic additive may be lower than the crystallinity of the pure additive.

[0076] The polymer encapsulated drug particles can have any suitable zeta potential, such as a negative zeta potential or a positive zeta potential. The zeta potential is the potential at the sliding surface (i.e., at the interface where the flowing fluid is separated from the fluid still attached to the particle surface). The polymer encapsulated drug particles zeta potential can be measured in any suitable manner, such as using electrophoretic light scattering (ELS) or electroacoustic determination. The polymer encapsulated drug particles can have a positive zeta potential, such as greater than 0, or 1-50, or 2-40, 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 zeta potential. The polymer encapsulated drug particles can have a negative zeta potential, for example, less than zero, or -1 to -50, or -2 to -40, or more than or equal to -50 and more 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. The positive zeta potential of the polymer encapsulated drug particles can better adhere to tissues and / or make drugs better transferred to tissues. For example, the positive zeta potential of the polymer encapsulated drug particles can attract amino groups in peptides or proteins, and / or negatively charged lipids (e.g., negative ions on the cell membrane surface) of lipid bilayers in cell membranes, thereby making adhesion better. Adhesion enhancement can prolong the residence time of the polymer encapsulated drug particles on the body luminal wall, thereby improving the rate of tissue drug dosage and / or drug delivery to tissues. In the embodiment of the polymer encapsulated drug particles on or in which the first ionic additive or zwitterionic additive is included, the zeta potential of the polymer encapsulated drug particles can be higher than (i.e., more positive than) the zeta potential of the corresponding polymer encapsulated drug particles without the first ionic additive or zwitterionic additive. The polymer encapsulated drug particles as CPDEP are polymer encapsulated drug particles with a zeta potential that is not zero (e.g., less than or greater than zero), for example, due to the presence of the added first ion or zwitterionic inside the particle, on the particle surface, or a combination thereof and / or the use of one or more charged polymers as encapsulating polymers. The ionic or zwitterionic 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 zwitterionic additive can be oriented away from the particle, and the hydrophobic tail is oriented toward the particle, so that the zeta potential of the polymer encapsulated drug particles is higher.

[0077] The polymer encapsulated drug particles can have any suitable size. The first ionic additive or zwitterionic additive (if present) can be used for particle size determination in combination with the polymer. The maximum size of the polymer encapsulated drug particles can be 0.2 micron to 30 microns, or 0.5 micron to 5 microns, or 0.8 micron to 3 microns, or less than or equal to 30 microns and greater than or equal to 0.2 micron, 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.

[0078] The polymer encapsulated drug particles can be polymer encapsulated drug particles (PEDP), charged polymer encapsulated drug particles (CPEDP), or a combination thereof. The positive charge density or zeta potential of the CPEDP can be higher than (i.e., more positive than) the positive charge density or zeta potential of the PEDP. The positive charge density or zeta potential of the CPEDP can be higher than the positive charge density or zeta potential of the therapeutic agent in the absence of a polymer encapsulating agent. For polymer encapsulated drug particles that are CPEDPs comprising the first ionic additive or zwitterionic additive, the positive charge density or zeta potential of the CPEDP can be higher than the positive charge density or zeta potential of the therapeutic agent in the absence of the first ionic additive or zwitterionic additive.

[0079] The polymer encapsulated drug particles may include one or more antioxidants, such as BHT. The one or more antioxidants may be mixed with the therapeutic agent during particle formation. The one or more antioxidants may account for any suitable proportion of the polymer encapsulated drug particles, such as 0.5-20wt%, or 1-10wt%, or less than 20wt% and greater than or equal to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10wt%.

[0080] The polymer encapsulated drug particles can be located on any suitable surface intended to deliver the drug to a target location, such as a medical device, 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. The polymer encapsulated drug particles can be part of a coating of a medical device, wherein the coating is a drug-releasing coating. Drug release coating, including polymer encapsulated drug particles

[0081] Various embodiments of the present invention provide a drug release coating. The drug release coating includes the polymer-encapsulated drug particles, which include the therapeutic agent and the one or more polymers that encapsulate the therapeutic agent. Optionally, the polymer-encapsulated drug particles include a first ionic additive or a zwitterionic additive. When present, the first ionic additive or zwitterionic additive is in the polymer-encapsulated drug particles, coated on the surface of the polymer-encapsulated drug particles, or a combination thereof. In some embodiments, the polymer-encapsulated drug particles include the first ionic additive or zwitterionic additive. In other embodiments, the polymer-encapsulated drug particles do not contain the first ionic additive or zwitterionic additive. The drug release coating also includes a release matrix, which includes a second ionic additive or a zwitterionic additive. Any coating (e.g., a drug coating or a drug coating layer) comprising a drug mentioned herein can be or include the drug release coating, which includes the polymer-encapsulated drug particles.

[0082] The polymer encapsulated drug particles can be uniformly dispersed in the release matrix. The polymer encapsulated drug particles can constitute any suitable ratio of the drug release coating, for example 10wt% to 90wt%, 10wt% to 80wt%, 25wt% to 70wt%, 40wt% to 60wt%, or less than or equal to 90wt% and greater than or equal to 10wt%, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 or 85wt%.

[0083] The release matrix can include therapeutic agent particles that are not encapsulated by the polymer (i.e., the polymer of the polymer-encapsulated drug particles), such as crystalline particles of the therapeutic agent. In other embodiments, the release matrix can be substantially free of therapeutic agent particles that are not encapsulated by the polymer. The therapeutic agent particles that are not encapsulated by the polymer can constitute any suitable ratio of the drug release coating, such as 0.001wt% to 50wt%, or 1wt% to 20wt%, or 1wt% to 10wt%, or less than or equal to 50wt% and greater than or equal to 0.001wt%, 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 45wt%. The therapeutic agent particles that are not encapsulated by the polymer can be evenly distributed in the release matrix.

[0084] The molecular structure of the second ionic additive or zwitterionic additive may be the same as the molecular structure of the first ionic additive or zwitterionic additive, or the molecular structure of the second ionic additive or zwitterionic additive may be different from the molecular structure of the first ionic additive or zwitterionic additive. The drug release coating may include 1, 2, 3 or 4 or more second ionic additives or zwitterionic additives, such as 1 or 2 second ionic additives or zwitterionic additives, such as 2 second ionic additives or zwitterionic additives. The one or more second ionic additives or zwitterionic additives may constitute any suitable proportion of the drug release coating, such as 10-80wt%, or 40-60wt%, or less than or equal to 80wt% and greater than or equal to 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or 75wt%.

[0085] The second ionic additive or zwitterionic additive can include cationic molecules, anionic additives or zwitterionic additives. The second ionic additive or zwitterionic additive can increase (i.e., make it more positive than) the zeta potential of the drug release coating, which can enhance the adhesion of the drug release coating to tissues and / or improve the rate at which the drug is transferred from the coating to tissues. For example, the positive zeta potential of the drug release coating can attract amino groups in peptides or proteins, and / or negatively charged lipids (e.g., negative ions on the surface of the cell membrane) of lipid bilayers in cell membranes, thereby making adhesion better. Adhesion enhancement can extend the residence time of the drug release coating on the body luminal wall, thereby improving the drug dosage of the tissue and / or the rate at which the drug is delivered to the tissue. The second ionic additive or zwitterionic additive can include charged polymers, charged lipids, phospholipids, phosphorylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol and combinations thereof. The second ionic additive or zwitterionic additive can migrate to the surface of the drug release coating. The charged head of the ionic or zwitterionic additive may be oriented away from the coating, while the hydrophobic tail is oriented toward the coating, resulting in a higher zeta potential of the coating.

[0086] The two acyl groups of the charged lipid or the two acyl groups of the charged phospholipid (e.g., the acyl groups of the esters bonded to the triglyceride backbone) include mismatched acyl groups that differ in one or more properties or characteristics. The mismatched acyl groups may differ in length, saturation, substituents thereon, substitution patterns thereon, or combinations thereof. For example, both acyl groups may be saturated, or one may be saturated, one may be 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 acyl groups in which one is saturated and the other is unsaturated. In embodiments with 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 having different lengths, saturations, substituents thereon, and substitution patterns thereon may have different phase transitions or softening temperatures. The phase transition or softening temperature of the charged lipid can affect the properties of the coating, such as coating integrity, drying durability, the rate at which the drug is released from the coating, the rate and / or degree of drug absorption into the tissue, or a combination thereof. Lipids and phospholipids with high phase transition temperatures can cause brittle coatings to break and peel off, thereby causing inconsistent drug dosages. Lipids and phospholipids with low phase transition temperatures may be difficult to handle because they may be wet and sticky, which may cause inconsistent drug dosages. The phase transition temperature range of charged lipids and phospholipids is -70°C to 80°C. The preferred range of the phase transition temperature is -30°C to 50°C. The most preferred range of the phase transition temperature is -20°C to 40°C. In some embodiments, the coating may have a mixture of lipids and / or phospholipids that causes the phase transition temperature of the coating to be within the desired range with desired mechanical properties (dry and flexible, and not sticky or brittle).

[0087] The length of the mismatched acyl group of the charged lipid or charged phospholipid can be 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, the acyl groups of the same or different lengths (chain length of C6-C34) produce disturbances, unevenness and / or curvature in the lipid bilayer of the cell membrane, thereby enhancing the penetration of the drug into the tissue. In embodiments of charged lipids or phospholipids having mismatched acyl groups of different lengths, the two acyl groups can differ in length by C1-C28, or C1-C10, or C1-C8, or by greater than or equal to 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 C28. For example, the lengths of two acyl groups of different lengths can be 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.

[0088] The charged polymer can be selected from polycation-containing cyclodextrin, aminocyclodextrin or its derivative, aminodextran, histone, protamine, cationized human serum albumin, aminopolysaccharide, chitosan, peptide, poly-L-lysine, poly-L-ornithine, poly(4-hydroxy-L-proline ester), polyethyleneimine, polyacrylamine, polyacrylamine, polyamidoamine dendrimer, cationic polyoxazoline, poly(β-amino ester), PEG-PEI copolymer, PLGA-PEI copolymer, positively charged gelatin (e.g., alkali-treated gelatin), hydroxy The invention also includes poly(2-methyl-2-oxazoline) terminated with a base, poly(2-ethyl-2-oxazoline), branched polyethyleneimine modified with stearic acid, branched PEI-g-PEG, poly(1-vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate), poly(1-vinylpyrrolidone)-grafted-(1-triacontene), polylysine, polyarginine, poly(methacrylic acid-N,N-dimethylaminoethyl ester), 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 / methacrylate having a quaternary ammonium group (e.g., Eudragit RS and / or SR), and combinations thereof. An example of a methacrylate having a quaternary ammonium group is trimethylaminoethyl methacrylate chloride.

[0089] The charged lipid may be selected from 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-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-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, di(eicosenoyl)phosphatidylcholine (1,2-di(eicosenoyl)-sn-glycero-3-phosphocholine, C20:1PC), diarachidonoylphosphatidylcholine (1,2-diachidonoyl-sn-glycero- 3-phosphocholine, C20:0PC), dierucoylphosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine, C22:1PC), di(docosahexaenoyl)phosphatidylcholine (1,2-di(docosahexaenoyl)-sn-glycero-3-phosphocholine, C22:6PC), heneicosenoylphosphatidylcholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine, C21:1PC), and di(tetracosenoyl)phosphatidylcholine (1,2-di(tetracosenoyl)-sn-glycero-3-phosphocholine, C24:1PC), and combinations thereof.

[0090] The second ionic additive or zwitterionic additive can be selected from 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 choline, 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-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 (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 and combinations thereof.

[0091] The second ionic additive or zwitterionic additive may include or be a water-insoluble or slightly or partially water-insoluble additive comprising at least one acyl group. The molecular weight of the second ionic additive or zwitterionic additive may be 50 to 750, 750 to 100,000, or 750 to 50,000, or 750 to 10,000. The melting temperature of the second ionic additive or zwitterionic additive may be lower than the melting temperature of the pure additive. The crystallinity of the second ionic additive or zwitterionic additive may be lower than the crystallinity of the pure additive.

[0092] The drug-releasing coating can be on any suitable surface intended to deliver a drug to a target location, such as a medical device, 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. Method for treating or preventing nonvascular or vascular stenosis or stenoses, comprising using a polymer-encapsulated drug Medical devices with particles

[0093] Various embodiments provide a method for treating or preventing non-vascular or vascular stenosis or stenoses. The method comprises inserting a catheter comprising a balloon or stent into a body lumen, wherein the balloon or stent comprises polymer-encapsulated drug particles (comprising the therapeutic agent and the polymers of the one or more encapsulated therapeutic agents), or the drug-releasing coating (comprising the polymer-encapsulated drug particles). The method may comprise expanding the balloon or stent so that the coating contacts the stenosis, stenoses, or an area in which the stenosis or stenoses are to be prevented. When using a balloon, the method may comprise shrinking the balloon or stent. When using a balloon, the method may further comprise removing the balloon from the body lumen. When using a stent, it may be a self-expanding stent or a balloon-expandable stent. Method for preparing polymer encapsulated drug particles and / or drug release coatings

[0094] Various embodiments provide methods for preparing the polymer-encapsulated drug particles, the drug particles comprising the therapeutic agent and the one or more polymers that encapsulate the therapeutic agent. The method comprises forming a suspension comprising the therapeutic agent and the polymer. The suspension may comprise undissolved solid therapeutic agent particles. The method comprises treating the suspension to reduce the particle size of the suspension. The method further comprises adding an aqueous premix to the suspension to form polymer-encapsulated drug particles in the suspension. The polymer-encapsulated drug particles may be a final product, or may be an intermediate product requiring additional steps to achieve a specific embodiment of the polymer-encapsulated drug particles of the present invention.

[0095] The treatment may be any suitable treatment to reduce the particle size of the suspension. The treatment may include ultrasonic treatment. The method may also include adding the first ionic additive or zwitterionic additive to the suspension or to the formed polymer encapsulated drug particles to coat the particles with it. The method may also include forming a suspension comprising the therapeutic agent, the polymer and the first ionic additive or zwitterionic additive, so that the formed polymer encapsulated drug particles include the first ionic additive or zwitterionic additive therein, thereon or a combination thereof.

[0096] The method may be a method of forming the drug release coating (comprising the polymer encapsulated drug particles and the release matrix). The method may further comprise adding the second ionic additive or zwitterionic additive to the suspension, optionally stirring the suspension to evenly distribute the polymer encapsulated drug particles, and drying the suspension to form the drug release coating.

[0097] A method for preparing the polymer encapsulated drug particles may include forming an organic premix comprising an organic solvent, the one or more polymers, the therapeutic agent, and optionally the first ionic additive or zwitterionic additive. The method may include forming an aqueous premix comprising water and a water-soluble polymer or surfactant. The method may include adding an organic solvent to the aqueous premix. In some embodiments, the organic solvent of the organic premix and the organic solvent added to the aqueous premix are the same organic solvent. The organic solvent of the organic premix and the organic solvent added to the aqueous premix may be a polar organic solvent. The method may include combining the aqueous premix and the organic premix together. The method may include stirring the combined aqueous premix and the organic premix to form an emulsion comprising the polymer encapsulated drug particles. The method may include adding water to the emulsion comprising the polymer encapsulated particles, for example to harden the formed polymer encapsulated drug particles. The method may include separating the polymer encapsulated drug particles from the combined aqueous premix and the organic premix. The method may include washing the polymer encapsulated drug particles with an aqueous liquid, drying the polymer encapsulated drug particles, or a combination thereof. The aqueous liquid for washing may optionally include one or more water-soluble additives (e.g., any water-soluble additive or ionic or zwitterionic additive described herein) that may coat the polymer encapsulated drug particles during washing. Coating the polymer encapsulated drug particles during washing may change the zeta potential of the polymer encapsulated drug particles.

[0098] The organic solvent of the organic premix and the organic solvent added to the aqueous premix can 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 and isopropanol, diethylamine, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether (Trascutol) 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) chlorinated solvents, such as chloroform or dichloromethane.

[0099] The water-soluble polymer or surfactant of the aqueous premix can be any suitable water-soluble polymer or surfactant, such as any water-soluble polymer or surfactant disclosed herein, such as polyvinyl alcohol, polyethylene glycol, phosphatidylcholine, or a combination thereof. The water-soluble polymer or surfactant can be N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-amino-propyl)amino]butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide, 1,2-di-O-octadecenyl-3-trimethylammonium propane (chloride salt), 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dioleoyl-3-trimethylammonium-propane (chloride salt), N 4 -cholesterol-spermine hydrochloride, 1,2-dioleyl-3-dimethylaminopropane, calcifediol, cholecalciferol, 1α,25-dihydroxyvitamin D3, poly(1-vinylpyrrolidone)-graft-(1-triacontene), poly(1-vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate), poly(2-dimethylaminoethyl methacrylate), branched PEI-g-PEG, stearic acid-modified branched polyethyleneimine, poly(2-ethyl-2-oxazoline), hydroxyl-terminated poly(2-methyl-2-oxazoline), 1-stearoyl-sn-glycero-3-phosphocholine, poly(2-(dimethylamino)ethyl methacrylate), acetylcholine iodide, acetylcholine chloride, or a combination thereof.

[0100] The emulsion formed by combining the organic premix and the aqueous premix can be a coacervate of the organic solvent and water, and the dispersed phase is the organic solvent. Adding water to the coacervate solution can harden the polymer encapsulated drug particles and drive the organic solvent away from the continuous aqueous phase. The mixing used to form the emulsion can be any suitable agitation, such as ultrasonic bath or probe agitation, homogenizer agitation, flow through a packed bed, stirring rod agitation, jet funnel agitation, grinding type agitation, homogenizer or overhead impeller type agitation. The polymer encapsulated drug particles can be collected by any suitable collection method, such as filtration or centrifugation. During the collection process, the particles can be washed with an aqueous liquid. The aqueous washing liquid can optionally include one or more water-soluble additives (such as any water-soluble additive or ionic or zwitterionic additive described herein), which can coat the polymer encapsulated drug particles during washing. Coating the polymer encapsulated drug particles during washing can change the zeta potential of the polymer encapsulated drug particles. Drying the particles can be spray drying, vacuum drying, sublimation or evaporation. The formed polymer encapsulated drug particles can be optionally used to prepare a drug coating solution to form the drug release coating.

[0101] A method for forming the drug release coating may include forming a first mixture, the first mixture comprising the polymer-encapsulated drug particles and an organic solvent. The first mixture may be a dispersion of the polymer-encapsulated drug particles in the organic solvent, such as prepared by a suitable mixing method (such as mixing by an acoustic probe, a stirring rod, a vortexer, an overhead stirrer or a homogenizer). The method may include forming a second mixture comprising the second ionic additive or zwitterionic additive and an organic solvent. The method may include merging the first mixture and the second mixture. In some embodiments, the organic solvent of the first mixture and the second mixture is a non-polar organic solvent, such as hexane, cyclohexane, heptane or pentane. In some embodiments, the organic solvent of the first mixture and the second mixture is the same organic solvent. The method may include drying the combined first mixture and the second mixture to form the drug release coating. The method may include stirring the combined first mixture and the second mixture before drying to uniformly disperse the polymer-encapsulated drug particles therein.

[0102] The second ionic additive or zwitterionic additive used to form the drug release coating can be any suitable material described herein, such as a phospholipid in a non-polar solvent (such as hexane, cyclohexane, heptane or pentane), such as 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-dipalmitoyl-sn-glycero-3-ethylphosphocholine (chloride salt), Lauroyl-sn-glycero-3-phosphocholine (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-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 (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 and combinations thereof. The second premix can be heated to ensure that the phospholipids are completely dissolved. If the second premix is ​​heated, it can be allowed to cool and then added to the first premix. The final mixture of the two premixes can be fully mixed by any suitable mixing method, such as sonic probe mixing, stirring rod, vortexer, overhead stirrer or homogenizer. Method for manufacturing a balloon catheter comprising the polymer-encapsulated drug particles

[0103] Various embodiments of the present invention provide a method for manufacturing a balloon catheter. The method includes applying the polymer-encapsulated drug particles (including the therapeutic agent and one or more polymers encapsulating the therapeutic agent) or the drug release coating (including the polymer-encapsulated drug particles) to the outside of the balloon of the balloon catheter. Drug-coated balloon catheter

[0104] The balloon catheter described throughout this application may include a coating layer, the coating layer comprising: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug release coating, including 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, umimios, analogs thereof, and combinations thereof. The particle size of the therapeutic agent may be 0.2 microns to 10 microns. The first additive may include a water-insoluble or partially water-insoluble additive, which includes at least one alkyl fatty group or a cholesterol group. The molecular weight of the first additive may be 50 to 750. The second additive may be more hydrophilic or more soluble in water than the first additive and may include polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The molecular weight of the second additive may range from 750 to 100,000.

[0105] The balloon catheter can be any suitable balloon catheter described herein. The balloon of the balloon catheter can include 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.

[0106] The balloon catheter can be used to deliver the therapeutic agent to a body lumen stenosis or narrowing, wherein the body lumen stenosis or narrowing is selected from urethral stenosis, prostatic urethral stenosis, ureteral stenosis, esophageal stenosis, antral stenosis, gastric stenosis, small intestinal stenosis, colon stenosis, rectal stenosis, large intestinal stenosis, bladder neck stenosis, bile duct 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.

[0107] The balloon catheter can be used to deliver the therapeutic agent to a target site in a body lumen, wherein the target site in the body lumen is selected from urethral stenosis, prostatic urethral stenosis, ureteral stenosis, esophageal stenosis, antral stenosis, gastric stenosis, small intestinal stenosis, colon stenosis, rectal stenosis, large intestinal stenosis, bladder neck stenosis, bile duct 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.

[0108] In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a narrow or narrow target site of a body lumen, the balloon comprising 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 a combination thereof. In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a narrow target site of a body lumen, the balloon catheter comprising a drug coating covering the outer surface of the balloon. The coating may include: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug-releasing coating, including the polymer-encapsulated drug particles; or a composition, comprising the therapeutic agent and one or more additives; or a combination thereof. The composition may include an initial drug loading of a therapeutic agent, as well as one or more water-insoluble or slightly or partially water-insoluble additives and more than one water-soluble additive. The therapeutic agent may be selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimios, analogs thereof, and combinations thereof. The therapeutic agent may be crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. The particle size range of the therapeutic agent may be 0.2-10 μm or preferably 0.2-5 μm. The first additive, the second additive, or a combination thereof may encapsulate the therapeutic agent, the particle size of the therapeutic agent encapsulated by the additive may be larger than the particle size of the therapeutic agent itself, and the particle size range of the therapeutic agent encapsulated by the additive in the coating may be 0.3 microns to 10 microns. The first additive may include a water-insoluble or slightly or partially water-insoluble additive, which includes at least one alkyl fatty group or cholesterol group. The molecular weight of the first additive may be 50 to 750. The melting temperature of the water-insoluble additive in the coating may be lower than the melting temperature of the pure additive. The crystallinity of the water-insoluble additive in the coating may be lower than that of a pure water-insoluble additive. The water-soluble additive may be more hydrophilic or more soluble in water than a water-insoluble or slightly or partially water-insoluble additive. The water-soluble additive may include polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The molecular weight range of the second additive may be 750 to 100,000, or 750 to 50,000, or 750 to 10,000.

[0109] The water-insoluble or slightly or partially water-insoluble additive can be selected from cholesterol acetate, cholesterol phenylacetate, cholesterol laurate, cholesterol palmitate, cholesterol stearate, cholesterol n-valerate, cholesterol benzoate, cholesterol heptanoate, cholesterol decanoate, cholesterol hexanoate, cholesterol oleate, cholesterol oleate carbonate, cholesterol linoleate, cholesterol nonanoate, cholesterol erucate, cholesterol octanoate, 5α-cholestane, 5α-cholestane-3-one. The water-insoluble or slightly or partially water-insoluble first additive having an alkyl fatty group may be selected from alkyl glyceryl ethers, monoglycerides of C8-C12 fatty acids, alkyl alcohols, alkyl ethers, alkyl esters, caprylic acid, monocaprylic glyceride, capric acid, monocapric glyceride, lauric acid, dodecyl glycerol, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienols, butyric acid, caproic acid, capric acid, lauric acid, myristic acid, palmitic 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- or di- or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha-tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliolipids, mixed chain triglycerides and derivatives thereof, and combinations thereof.

[0110] The water-soluble second additive may include polyoxyethyl alpha-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, PEGylated phospholipids, methylated PEGylated phospholipids, PEG caprylic / capric diglyceride, PEG8 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 esters, polyoleic glyceryl (Plurol Oleique), 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), polyglyceryl-10 mono / dioleate (CaproI TM 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)-Cholesterol Sebacate (Hydrogen Sebacate Diester Bond, Cholesterol, Water Soluble, CAS 69068-97-9): Polyethylene glycol cholesterol (ether linkage, cholesterol-(polyethylene glycol-600)): PEG amide ester cholesterol (ester amide bond, hydroxyl terminated PEG cholesterol, various molecular weights): PEG amide ether cholesterol (methyl terminated, amide ether bond, MW = 550, 1K, 2K, 5K, 10K, 20K, 30K, 40K): mPEG amide cholesterol (methyl terminated, amide ester bond, MW = 550, 1K, 2K, 5K, 10K, 20K, 30K, 40K): DSPE-PEG-Cholesterol: or a combination thereof.

[0111] In one embodiment, the at least one therapeutic agent is applied to the surface of the medical device at a concentration density of about 1 to 20 μg / mm 2 , or about 2 to 6 μg / mm 2 , or about 0.5 μg / mm 2 or less, or less than, equal to, or greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 micrograms / mm 2 or higher. If the medical device is a balloon, these measurements are calculated based on the nominal diameter. In embodiments of the present invention, the weight ratio of the additive to the drug in the coating layer may be about 20 to 0.05, about 10 to 0.1, or about 6 to 0.15.

[0112] 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 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 about 0.05 or less, or less than, equal to, or greater than 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.

[0113] The present invention provides a novel drug-coated balloon catheter and its use. The new method opens the lumen and prevents, reduces or minimizes restenosis and recurrent non-vascular or vascular stenosis. Vascular lumens include arteries, veins or any lumen with blood. Non-vascular lumens include those without blood. The method involves using a medical device including a drug coating in the lumen. The coating may include: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug-releasing coating, including the polymer-encapsulated drug particles; or a composition, including a therapeutic agent and one or more additives; or a combination thereof. The drug coating may have more than one layer and may include an effective amount of a therapeutic agent, such as an anti-inflammatory and anti-proliferative drug (e.g., paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, umimos, mTOR inhibitors, or analogs thereof), one or more water-soluble additives, and one or more water-insoluble or partially water-soluble additives for delivery to the narrow or narrow part of the body lumen. The treatment is applicable to a variety of animals, such as premature newborns to adults.

[0114] Unless otherwise specified, the stretch ratio is defined herein as the ratio of the nominal diameter of the balloon to the body lumen diameter in the balloon catheter treatment area. The nominal diameter of the balloon is the diameter that the balloon reaches in an unrestricted environment at nominal pressure. The body lumen diameter is the average diameter of a narrow or stenotic body lumen or lesion. For the urinary tract, for example, in the urethra and prostatic urethra, the body lumen diameter will be the average diameter of the urinary urethra that blocks the body lumen. The expanded balloon diameter can be the actual diameter of the balloon after expansion, and in some embodiments, it can 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 cavities. During the implementation of the method of the present invention, the stretch ratio can be selected to be any suitable ratio of the actual expanded balloon diameter to the lumen diameter required within the pressure range used during the method. In various embodiments, the stretch ratio of the balloon can be about 1.0 to 40, 1.1 to 40, 1.2 to 40, 1.3 to 40, or 1.4 to 40 (e.g., 1, or greater than, less than, or equal to 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 therebetween); such a stretch ratio can produce a desired ratio of inflated balloon diameter to lumen diameter at the use pressure during the inflation period, which ratio can be the same, similar, or different than the following stretch ratios: for example, about 1.0 to 40, 1.1 to 40, 1.2 to 40, 1.3 to 40, or 1.4 to 40 (e.g., 1, or greater than, less than, or equal to 1.1, 1.2, 1.3, 1.4, 1.5, 1 35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,100,101,102,103,104,105,106,107,108,109,110,111

[0115] Various embodiments of the present invention relate to a coated medical device. The device includes one of the following: a balloon catheter, a fixed guidewire balloon catheter, a coaxial integral exchange balloon catheter, a rapid exchange balloon catheter, an infusion balloon catheter, a septal double balloon, a cutting balloon catheter, a spinous process balloon catheter, or an infusion catheter (e.g., a distal perforated drug infusion tube, a perforated balloon, a septal double balloon, a porous balloon, or a permeable balloon). Figure 1 In one embodiment, the medical device is a balloon catheter. The balloon catheter can be any catheter suitable for the desired purpose, including conventional cylindrical balloon catheters known to those of ordinary skill in the art. For example, the balloon catheter 10 can 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 elongated flexible member 14 extending between the proximal and distal ends. The handle assembly 16 can be connected and / or accommodate one or more suitable medical devices, such as an inflatable medium (e.g., air, saline or contrast agent) source. The flexible member 14 can be a tube made of suitable biocompatible materials and having one or more lumens. At least one lumen is configured to accommodate inflated media and transfer this medium to the balloon 12 to expand it. The balloon catheter can be a quick-change catheter or a coaxial integral exchange catheter, and is made of any suitable biocompatible material. The material of the balloon 12 may include one or more of the following: polyester, polyamide, nylon 12, nylon 11, polyamide 12, block copolymers of polyether and polyamide, Polyurethane and block copolymers of polyether and polyester. The balloon catheter shaft can be made of polyether-amide block copolymers, polyamide, nylon, polyester, polyethylene terephthalate or any other semi-compliant to non-compliant polymer (including their blends). The balloon catheter shaft can also be made of rigid materials such as stainless steel, polycarbonate, titanium, PEEK (polyetheretherketone) or any other rigid biocompatible material.

[0116] In some embodiments, the balloon may include one neck section and no other neck section, such that the balloon includes two body sections separated by one neck section. The one neck section may be in any suitable position on the balloon, such as approximately centered relative to the length of the balloon, or offset from the middle relative to the length of the balloon. The one neck section may be offset from the middle relative to the length of the balloon and may be at the distal end of the balloon. Figure 3A An embodiment of a balloon is shown in FIG. 1 , which includes a neck section that is offset from the middle relative to the length of the balloon.

[0117] In some embodiments, the balloon can include two neck sections and no other neck section, so that the balloon includes three lobes separated by two neck sections. The diameters of the two neck sections can be approximately the same, or the diameter of one neck section can be smaller than the diameter of the other neck section. The two neck sections can be symmetrically or asymmetrically positioned relative to the middle of the balloon length. The lengths of the three body sections can be approximately equal or can be different. Figure 3B A balloon catheter embodiment with two neck sections and three body sections is shown, wherein the neck sections are symmetrically positioned about the middle of the balloon length, and wherein the three body sections of the balloon are approximately the same length. During use, the distal neck section (e.g., the neck section of the distal end of the balloon catheter first inserted into the body) can anchor and position the balloon at the bladder neck, while the proximal neck section can be located in the prostatic urethra. In some embodiments, the distal body section of the balloon catheter may not contain the therapeutic agent.

[0118] In some embodiments, the balloon may include three neck segments and no other neck segments, so that the balloon includes four segments separated by the three neck segments. The three neck segments may be positioned along the length of the balloon in any suitable manner. The lengths of the four body segments formed by the three neck segments may be equal or different. The diameters of the three neck segments may be the same or different. In some embodiments, two of the neck segments have equal diameters and are smaller than the diameter of the other neck segment. Figure 3CA balloon catheter embodiment is shown having three neck sections, each of the four body sections being approximately equal in length, wherein two of the neck sections are of equal diameter and smaller than the diameter of the other neck section.

[0119] In various embodiments, the present invention provides a balloon catheter for delivering a therapeutic agent to a target site of a body lumen. The balloon catheter may include an elongated balloon having a plurality of body (main) segments and at least one neck segment having a diameter smaller than the diameter of the body segment. The balloon catheter may include an elongated balloon having a main diameter, for example, a plurality of body segments having a main diameter or an average diameter equal to the main diameter. The multi-segment balloon with a smaller diameter of the neck segment mechanically anchors the balloon in the body lumen; therefore, it can prevent the balloon from sliding in the body lumen. If the balloon slides off the target lesion site, it may be missed and may damage the healthy lumen site. The balloon catheter may include at least one neck segment on the balloon having a diameter smaller than the main diameter. The balloon catheter may also include a coating covering the outer surface of the balloon. The coating may include: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug release coating, including the polymer-encapsulated drug particles; or a composition, including a therapeutic agent and one or more additives; or a combination thereof. The coating layer may include one or more water-soluble additives and one or more water-insoluble or partially water-soluble additives, an initial drug loading of a therapeutic agent (e.g., paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimios, analogs thereof, and combinations thereof). In the method of using the balloon catheter, feature (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 strictured or stenosed body lumen at the target site is about 1.0 to about 40; or (b) the inflating includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the stretching ratio of the nominal diameter of the balloon catheter to the diameter of the strictured or stenosed body lumen at the target site is about 1.0 to about 40; (c) the inflating includes inflating to a pressure greater than the nominal pressure of the balloon catheter, and the nominal diameter of the balloon catheter is smaller than the inflated balloon diameter; or (d) a combination of (a), (b) and (c).

[0120] The major diameter of the balloon can be the diameter of the main body section of the balloon when the balloon is inflated. In some embodiments, the inflation pressure used to determine the major diameter can be any pressure that eliminates any folded or creased areas of the balloon and achieves the tension of the balloon. The inflation pressure used to determine the major diameter can be such a pressure that the shape and size of the inflated balloon correspond to the desired shape and size of the balloon during the intended treatment of the body lumen. The inflation pressure used to determine the major diameter can be the nominal pressure of the balloon, so that the nominal diameter of the balloon catheter is equal to the major diameter of the balloon.

[0121] In one embodiment, the drug coated balloon includes two main body sections with the same diameter at both ends, a neck section with a smaller diameter between the two main body sections, and two cones at the proximal and distal balloon bodies. The balloon catheter includes at least one neck section on the balloon with a diameter smaller than the balloon diameter of the main body section. The balloon catheter may include an elongated (e.g., cylindrical) balloon having multiple sections with different diameters. Features (a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or (a) and (b)(c) may exist: (a) the ratio of the inflated balloon diameter to the diameter of the body lumen at the target site is about 1.0 to about 40; or (b) the inflating includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the stretch ratio of the nominal diameter of the balloon catheter to the diameter of the body lumen at the target site is about 1.0 to about 40; (c) the inflating includes inflating to a pressure greater than the nominal pressure of the balloon catheter, and the nominal diameter of the balloon catheter is smaller than the inflated balloon diameter; or (d) a combination of (a), (b) and (c). A multi-segment balloon with a smaller neck can increase the friction between the balloon and the body lumen; therefore, it can prevent the balloon from sliding in the body lumen.

[0122] In some embodiments, a balloon catheter shaft can include an elongated rigid component (eg, a rod, mandrel, or wire) that is longitudinally aligned with the catheter shaft. Figures 4A to 4D A balloon catheter including an elongated rigid member or core wire 505 is shown. Figure 4A An embodiment of balloon inflation is shown, and Figure 4BThe balloon in a non-expanded state is shown. At the proximal end of the catheter shaft, the core wire 505 is attached to the catheter shaft 501 under the stress relief device 508. The core wire 505 extends distally in the catheter shaft 501. In some embodiments, the catheter shaft is made of 72D PEBA polymer. The catheter shaft 501 is made of a material that exhibits a certain amount of elasticity under tension. Below the balloon 503, the core wire 505 is covered by a hypotube 510. The hypotube 510 provides lateral strength for the core wire 505 so that it does not bend when the balloon 503 is expanded. Near the distal end of the catheter, the hypotube 510 and the core wire 505 are coupled to the tip 502. The tip extrusion 506 connects the tip 502 to the hypotube 510 and the core wire 505. The space between the catheter shaft 501 and the core wire 505 is the expanded lumen of the balloon 503, wherein the interior of the balloon 503 is in fluid communication with the Luer hub 507. Although this embodiment may be used with any suitable balloon of the present invention, Figure 4A and 4B A balloon 510 503 is shown having a neck section with polyethylene fibers 504 used to reinforce the neck section.

[0123] The cross-sectional profile of the elongated rigid component can be cylindrical, conical, rectangular, hexagonal or other shapes, and can be made of metal or relatively incompressible non-metallic materials. The elongated component can extend from the proximal side of the balloon to the distal side of the balloon, or from a position close to the proximal side of the balloon to the distal side of the balloon. The elongated component can float freely in the central lumen of the catheter shaft, can be positioned in a dedicated lumen of a multi-lumen catheter shaft, or can extend longitudinally outside the main catheter shaft. The elongated component can be anchored at a single point, two points or more than two points along the catheter shaft. The elongated component can be anchored by directly hot-melting it to the catheter shaft, bonding it or chemically bonding it to the catheter shaft, forging or creasing it to one or more parts of the catheter, overmolding or by any other suitable method. The elongated component can be reinforced along its entire length or along certain sections (e.g., below the balloon) to prevent bending; for example, the elongated metal component can be a reinforcing wire. The reinforcement can be made of any rigid material, such as stainless steel, nitinol (i.e., nickel-titanium alloy), steel, tungsten, iridium, high-temperature alloys (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 with a cylindrical, rectangular, hexagonal, or any suitable outer contour. Figure 4C As shown, the elongated assembly may be disposed within the interior of the reinforcement tube, or along the exterior of the reinforcement tube.

[0124] like Figure 4A and4B As shown, the fossa catheter may include a fossa length control mechanism, and when the fossa is in a contracted state, the fossa length control mechanism stretches and elongates the fossa, thereby making the fossa have a smaller cross-sectional contraction profile, for passing through the body lumen and removing after treatment. When the fossa expands, the length control mechanism may shorten the total length of the fossa and expand to the predetermined expansion diameter and length (for example, as the diameter and length in the molding or forming process) of the fossa. In one embodiment, the power produced by the fossa expansion may be transmitted from the far end of the fossa (for example, by the fossa binding piece of the elongated metal component or by the connector between the catheter tip and the elongated metal component), by elongating the rigid metal component through the fossa shaft and returning to the fossa shaft near the fossa (for example, by elongating the connector between the metal component and the fossa shaft near the fossa near end or near the fossa near end). This power will act as a spring when the fossa shaft material works in the elastic region of its stress-strain curve to the transmission of the fossa shaft. During balloon inflation, as the catheter shaft stretches under tension due to balloon inflation, energy can be stored in the catheter shaft material and can be released by the catheter shaft during deflation to apply pressure to the elongated metal component, thereby stretching 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 An embodiment of a spring 600 is shown, which can be used as Figure 4A and 4D An alternative to the core wire 505 shown in FIG. Figure 5, spring 600 has spring section 601 and guide wire section 602. In some embodiments, spring section 601 can be located at the proximal end of the catheter shaft. The spring can be located in the lumen of the catheter shaft, outside the lumen but in the catheter shaft or outside the catheter shaft. The spring can be in the balloon, or can be separately arranged with the balloon, for example, near the proximal end of the balloon, or a combination thereof. The elongated length of the contracted balloon can be about 0.1mm to about 100mm longer than the expanded balloon length, or greater than about 0.1mm, 0.2, 0.4, 0.6, 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 or about 100mm or longer. The catheter shaft can include various materials to obtain the required 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, other thermoplastic polymers, or combinations thereof. The composition of the catheter shaft can be uniform, or can include a combination of materials distributed along one or more portions of the catheter shaft to produce the required elongation force. Different materials can produce different elastic strains and apply different forces to the stretched rigid metal component to stretch the balloon. The catheter shaft can be an extruded catheter shaft.

[0125] The drug-coated balloon catheter can be used as a medical device for the treatment of benign prostatic hyperplasia (BPH). The balloon catheter can expand the prostatic urethra, and can include a catheter shaft for inserting the urethra and a compliance, semi-compliant or non-compliant balloon for swelling in the prostatic urethra. The balloon can be coated with a coating comprising a therapeutic agent, and when the balloon is enlarged, the therapeutic agent is delivered to prostatic tissue and the prostatic urethra. Any suitable method can be used to position the balloon in the prostate, such as by a separate positioning balloon in the bladder, a positioning balloon in the bulbous urethra, a marker band below the visible balloon under a fluoroscope, or the catheter shaft can be compatible with an endoscope (e.g., a cystoscope), so that it can be placed by direct observation, or the catheter can be arranged side by side with an endoscope. For example, several possible catheter designs make it possible to directly observe the balloon during positioning and swelling.

[0126] In some embodiments, when treating the prostate, the size of the balloon catheter can be such that the catheter body section is located between the bladder neck sphincter (at the bladder outlet) and the external sphincter. In other embodiments, the catheter body section is located above the external sphincter, placed through the prostate, and one or more body sections pass through the bladder neck sphincter and are located in the bladder. In these embodiments, preferably, the neck region of the balloon catheter is aligned with the bladder neck. As discussed herein, an endoscope with an observation function can be used to appropriately adjust the size and placement of the balloon catheter.

[0127] In some embodiments where the balloon catheter comprises a soft tip, an elbow tip, etc., the tip can be used to assist in inserting and passing the device through the urethra. In other embodiments, the balloon catheter comprises a lumen or channel designed to be inserted and moved through the urethra to the target site or prostate.

[0128] Achalasia stenosis is a rare disease that makes it difficult for food and liquids to pass from the esophagus into the stomach. In some embodiments, when treating achalasia stenosis, such as Figure 3A The size of the balloon catheter shown in the invention should make the proximal body section of catheter be located above the achalasia stenosis and the lower esophageal sphincter.In these embodiments, the neck region of the balloon catheter can be aligned with the lower esophageal sphincter neck.As discussed herein, the endoscope with observation function can be used for suitably adjusting the size and placement of the balloon catheter.In the embodiment that the balloon catheter comprises soft tip, the tip can be inserted into sphincter (for example, lower esophageal sphincter) or the stomach to help the balloon catheter be placed in the desired position.

[0129] The balloon catheter can relieve lower urinary tract symptoms (LUTS) caused by BPH by directly expanding the prostate tissue. Using the balloon (the ratio of the balloon diameter after expansion to the body lumen diameter of the target site is 1.0 to 40), or using a balloon (the stretch ratio of the nominal balloon diameter to the body lumen diameter of the target site is 1.0 to 40) to expand the prostate, the commissure incision can be performed on the natural plane that separates the lateral parts in the transition zone of the prostate. At the same time, drugs can be released from the coating into the prostate tissue, for example, which can prevent prostate enlargement and re-narrowing of the newly formed opening.

[0130] In various embodiments, during inflation of the balloon in a body lumen (e.g., during performance of the methods of the 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 body lumen diameter at the treatment site is any suitable ratio, such as about 1.01 to about 40, or about 1.01 to about 15, or about 1.2 to about 10, or about 1.31 to about 8, or less than, equal to, 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 more. In some embodiments, during inflation to nominal pressure, the inflated diameter of the balloon at the target site is equal to the nominal diameter; however, in actual use, some stenosis may prevent the nominal diameter from being achieved, or may restrict the inflated balloon, thereby forming a "dog bone" shape. For balloons of different diameters for various diseases, the nominal balloon diameter at a predetermined pressure (e.g., 2atm, 3atm, 6atm, or 9atm) may be different. For example, the nominal diameter of a urethral stricture balloon may be 6mm, 8mm, 10mm, 12mm, and 14mm, and the balloon lengths are 20mm, 25mm, 30mm, 35mm, 40mm, 45mm, and 50mm for 6mm, 8mm, 10mm, 12mm, and 14mm balloon catheters at an inflation pressure of 4atm, 5atm, 6atm, 8atm, or 12atm. At an inflation nominal pressure of 2atm, 3atm, 4atm, 6atm or 9atm, the nominal diameter of the BPH stenosis balloon can be 25mm, 30mm, 35mm, 40mm and 45mm, and the balloon length is 20mm, 25mm, 30mm, 35mm, 40mm, 45mm, 50mm, 55mm and 60mm balloon catheter. Table 1 shows examples of nominal balloon sizes, nominal pressures and minimum balloon diameter to lumen diameter ratios for treating stenosis of various diseases. The nominal pressure is the pressure required to make the balloon reach its marked nominal diameter in an unconstrained pressure ramp test. The nominal diameter is the expected diameter marked on the product. All physicians purchase balloons and choose the balloons to use based on the nominal diameter. The rated burst pressure is the maximum pressure that the balloon can be inflated to, and there is a very high confidence that it will not burst. This is a labeling requirement for balloon catheters and is calculated based on statistical analysis of the pressures observed when the balloon bursts in an unconstrained pressure ramp test.

[0131] Table 1. Examples of nominal balloon sizes, nominal pressures, and ratios of minimum balloon diameter to stenosis diameter for treating various disease states. These ratios assume a stenosis diameter of 3 mm.

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

[0133] The expanded diameter of the balloon can be any suitable diameter reached during the expansion period or throughout the expansion period, so as to achieve the desired ratio of the expanded balloon diameter to the body lumen diameter. The expanded diameter of the balloon can correspond to the pressure used to expand the balloon during the expansion period. The range of expansion pressure can be the nominal expansion pressure to the rated 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 indicated on the product label. In some embodiments, the expansion pressure can be the nominal pressure of the balloon, and the expanded diameter of the balloon can be approximately equal to the nominal diameter of the balloon, or due to the limitation of stenosis, can be less than the nominal diameter of the balloon. In some embodiments, the expansion pressure of the balloon during the expansion period can be higher or lower than the nominal pressure, and the expanded diameter of the balloon can be correspondingly greater or less than the nominal diameter of the balloon.

[0134] In various embodiments, the balloon catheter of the present invention is compatible with a flexible or rigid endoscope capable of viewing the treatment area, thereby being placed more accurately and more effectively than other balloon catheters. The endoscope can be a gastroscope, an enteroscope, a duodenoscope, a colonoscope, a sigmoidoscope, a rectoscope, an anoscope, a nasal mirror, a bronchoscope, or a cystoscope. In various embodiments, the balloon catheter of the present invention is self-seeking because the neck section of the balloon catheter guides the balloon catheter to the appropriate position (e.g., guided by the neck section of the balloon catheter in the bladder neck, such as the most distal neck section) during expansion, even if the balloon catheter deviates slightly when it begins to expand.

[0135] In various embodiments, the balloon catheter has one or more neck segments separating one or more body segments, and at least one neck segment, or the configuration of the one or more neck segments, of the balloon catheter of the present invention enables the balloon catheter to remain in place more continuously and effectively during treatment to dilate the stenosis and deliver the drug, compared to other balloon catheters lacking such neck segments or neck segment configurations.

[0136] The drug coated balloon catheter can include an elongated balloon body, which has two cones, an enlarged lumen and a guidewire lumen at the distal and proximal ends of a plurality of main body sections, wherein the balloon body includes at least two main body sections with larger diameters and at least one neck section with smaller diameter, wherein the main body section with larger diameter and the neck section are alternately arranged adjacent to each other. The elongated balloon shape can be roughly cylindrical, except any neck section on the balloon, any tapered section (e.g., cone) between the neck section and the main body section with a major diameter, and any tapered or arbitrary shape section at the longitudinal end of the balloon. The elongated balloon can have any suitable profile perpendicular to the longitudinal direction of the balloon, such as a circle (e.g., a cylindrical balloon), an ellipse or a polygon (e.g., a pentagon, a hexagon, a heptagon, an octagon, etc.), or a combination thereof. The diameter of a non-cylindrical balloon can be the maximum or minimum size perpendicular to the longitudinal direction.

[0137] The balloon can have any suitable size. The balloon can be designed to fit the prostatic urethra, with the distal section of the balloon located in the bladder. The main diameter and nominal balloon diameter can range from about 5 mm to about 50 mm, 25 mm to 45 mm, at least 10 mm, at least 15 mm, at least 20 mm, at least 30 mm, such as about 5 mm or less, or less than, equal to or greater than about 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, 49 or about 50 mm or more; the main section diameter range can be independent of any of these ranges or specific sizes. The length of the balloon can be about 20 mm to about 160 mm, 40 mm to about 80 mm, or about 20 mm or less, or less than, equal to, or greater than about 22 mm, 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, 78 mm, or about 80 mm or more. The balloon length and diameter can be selected based on the patient's unique prostate anatomy.

[0138] The neck segment can be a rigid or semi-rigid neck segment such that the diameter of the neck segment (e.g., the portion of the neck segment having the neck segment diameter) remains substantially unchanged during balloon inflation. The neck segment can include a substantially non-elastic (e.g., non-compliant or minimally non-compliant) portion of the balloon, a reinforced portion of the balloon, or a combination thereof. The neck segment can include a non-elastic material distributed around the circumference of the neck segment, such as a suture or monofilament or multifilament of such material as nylon, polyamide, aromatic polyamide, ultra-high molecular weight polyethylene (UHMWPE), polyester, aromatic polyester, polyethylene terephthalate (PET), or a combination thereof.

[0139] The catheter shaft, balloon or combination thereof may include a single or multiple markings along its length to help locate certain anatomical structures and align with them. The markings may have any suitable orientation, such as along the circumferential or longitudinal direction of the catheter shaft or balloon. The markings on the catheter shaft or balloon may be used to help position the balloon in a treatment area, indicating that the balloon has been fully recovered in a sheath, or the device may be positioned in a patient's anatomical structure. The markings on the catheter shaft may be observed using an endoscope, a cystoscope or the naked eye, or the markings may include radiologically distinguishable components, such as radiopaque materials. The markings may be generated by thermally bonding a polymer to a color distinguishable catheter shaft surface, by pad printing, by laser marking or by any other method. Figure 4A and 4B An embodiment of a balloon recapture marker 509 and a positioning marker 511 is shown. The balloon recapture marker 509 can be used when the balloon catheter includes a sheath covering the balloon. When the sheath covers the balloon, the marker 509 can be located just proximal to the proximal end of the sheath. After the user advances the catheter to the desired position, removes the sheath, and inflates the balloon, the user may want to advance the sheath later, thereby covering the balloon for removal. In this case, after the balloon is deflated, the user will advance the sheath distally until the balloon recapture marker 509 is visible. The positioning marker 511 can be used to help the user position the catheter within a body lumen. For example, when the catheter is positioned as shown in FIG. Figure 4A and 4B When the single-necked balloon shown is used for BPH treatment, the positioning mark that can be just located proximal to the proximal end of the balloon can be just located proximal to the external sphincter. In various embodiments, the user can see the mark 511 through the endoscope, and when the mark is just proximal to the external sphincter, the user can be sure that the balloon is correctly positioned.

[0140] The balloon catheter may include a catheter tip at the distal end, which is first inserted into the body. The catheter tip may facilitate passage of the balloon through a body lumen. The tip may be an atraumatic tip that helps prevent damage to the body lumen during insertion. The tip may be an atraumatic elbow tip that is intended to facilitate passage of the catheter through a bend in a body lumen while preventing damage to the lumen wall during insertion. It may be a low durometer biocompatible material that is overmolded onto the catheter shaft or bonded to the catheter shaft. For example, the elbow tip may be made of Or made of liquid silicone rubber.

[0141] In some embodiments, the catheter can include an insertion sheath that covers the balloon during insertion (e.g., a coated and folded / pleated balloon) and can be completely removed from the body during treatment. The sheath can be designed to couple with an obturator or dilator to facilitate reinsertion of the sheath into a body lumen. The sheath can include one material, or more than one material. The sheath can have a laminate construction, in which several different layers of material are combined to form the sheath, or can be constructed using simple extrusion or coextrusion. In one embodiment, the sheath includes: an inner layer, including a fluoropolymer, such as PTFE or FEP; an intermediate reinforcement layer, including a braided or coiled wire, such as stainless steel, nitinol, PEEK, or other material; and an outer layer, including a polymer, such as Nylon, polyurethane or other thermoplastic materials. The hardness of the outer sheath material and the pitch of the braided or coiled reinforcement can be uniform or can vary along the length of the sheath. The obturator can be an extruded tube or can be molded into a specific geometric shape, and can include various materials, such as LDPE, HDPE, PE, PEBA, nylon, silicone, polyurethane or other biocompatible materials. The distal tip of the obturator (inserted into the body) can include a cone, an arc or a combination that is convenient for passing through the body lumen. The sheath and obturator can be overmolded, swaged, pleated or bonded hub connectors so that they can be connected to each other. Alternatively, the obturator can be opened proximally to form a grip feature and form an interference connection with the sheath. After treatment, the obturator and sheath can be inserted through the body lumen to the proximal side of the balloon. Once in place, the obturator can be separated from the sheath, and the sheath can be put back on the deflated balloon to facilitate the removal of the balloon catheter.

[0142] 4 illustrates an embodiment of a balloon catheter for treating BPH, comprising a catheter shaft, a catheter tip, and a Tuohy Borst adapter / stopcock assembly.

[0143] The body segments of the balloon may be formed with the same or similar diameters. In some embodiments, the diameters of the various body segments may differ from each other by as much as 30% when measured at the nominal balloon diameter. Figure 3A , 3B , 3C and 4, the body segments of the balloon are shown to have equal diameters, i.e., the diameter of each body segment is constant. In practice, at higher pressures, the diameter of the body segments will become slightly curved outwards, as the diameter of the middle portion of the body segment may be slightly larger than the diameter of the edge of the body segment near the balloon cone and / or near the neck segment.

[0144] For Figure 3A , 3B , 3C and 4 show balloons having a neck section and a body section, and for Figure 1 The balloon is shown without a neck section. After assembling the balloon catheter, the balloon can be coated with at least one water-soluble additive and drug as discussed herein. In some embodiments where the balloon has multiple body sections, the distal body section can be uncoated. The balloon can be coated according to the methods discussed herein. If a sheath is used, it can be placed over the balloon after the balloon is coated. The catheter is then packaged, sterilized, and labeled as known in the art.

[0145] exist Figure 3A In one embodiment, a balloon having one neck section is shown. Balloon 100 has waist 101, cone 102, first body section 103, neck 104, second body section 105, cone 106, and waist 107. When assembled into a balloon catheter, waists 101 and 107 are attached or bonded to the catheter shaft (not shown), as is known in the art. During expansion, waists 101 and 107 do not expand because they are attached to the catheter shaft. Sections 102, 103, 104, 105, and 106 can all be expanded simultaneously through a single expansion point that communicates with the catheter shaft and an external Luer hub. Figure 3BIn one embodiment, a balloon with two neck sections is shown. Balloon 120 has waist 121, cone 122, first body section 123, first neck 124, second body section 125, second neck 126, third body section 127, cone 128 and waist 129. When assembled into a balloon catheter, as known in the art, waists 121 and 129 will be attached or bonded to the catheter shaft. During expansion, waists 121 and 129 do not expand because they are attached to the catheter shaft. Sections 122, 123, 124, 125, 126, 127 and 128 can all be expanded simultaneously through a single expansion point communicated with the catheter shaft and an external Luer hub. Although the diameters of neck sections 124 and 126 are the same in the current expanded state, they can be the same or different diameters and have the same or different compliance. Figure 3C In one embodiment, a balloon having three neck sections is shown. Balloon 140, having waist 141, cone 142, first body section 143, first neck 144, second body section 145, second neck 146, third body section 147, third neck 148, fourth body section 149, cone 150 and waist 151. When assembled into a balloon catheter, waists 141 and 151 will be attached or bonded to the catheter shaft as known in the art. During expansion, 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 be expanded simultaneously through a single expansion point that is connected to the catheter shaft and the external Luer hub. Although neck sections 144, 146, and 148 are shown as having different diameters in the present expanded state, they may be of the same or different diameters and have the same or different compliances.

[0146] In various embodiments, the balloon catheter can be assembled with a sheath. The catheter assembly and endoscope (e.g., cystoscope) are inserted into the prostatic urethra through the urethra and are located side by side near the external sphincter. Using the real-time video feed of the endoscope, the external sphincter can be located. The balloon can be located near the external sphincter and in the prostatic urethra. Balloon expansion, drug release, and balloon contraction can be observed endoscopically. Coating design and formulation

[0147] 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 may include a coating applied to the outer surface of the balloon catheter. The coating may include: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug-releasing coating, including the polymer-encapsulated drug particles; or a composition, including a therapeutic agent and one or more additives; or a combination thereof. The coating may include a composition, including a therapeutic agent and one or more additives. The additive may be any suitable additive. The coating may include one additive, or the layer may include more than one additive, such as a water-soluble first additive and a water-soluble second additive. For example, as Figure 2A In the illustrated embodiment, the balloon 12 is coated with a layer 20 comprising: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug-releasing coating, including polymer-encapsulated drug particles; or a composition, including a therapeutic agent and one or more additives; or a combination thereof. In some embodiments, the layer consists essentially of the therapeutic agent and the additive, for example, the layer includes only the therapeutic agent and the additive without any other substantially important components. In some embodiments, the device may optionally include an adhesive layer. For example, as Figure 2B As shown in the illustrated embodiment, the balloon 12 is coated with an adhesion layer 22. The adhesion layer may be covered by a layer 24, wherein the layer 24 comprises: the polymer-encapsulated drug particles, comprising the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug-releasing coating, comprising polymer-encapsulated drug particles; or a composition, comprising a therapeutic agent and one or more additives; or a combination thereof. The adhesion layer is a separate layer beneath the drug coating, which improves the adhesion of the drug coating to the outer surface of the medical device and protects the integrity of the coating. For example, if the drug and additive have different adhesion to the medical device, the adhesion layer can prevent different losses of the components and maintain the ratio of the drug to the additive of the coating during delivery to the target site of therapeutic intervention. In addition, the adhesion layer can serve to promote the rapid release of the coating layer components from the surface of the device when in contact with the tissue of the target site. In other embodiments, the device may include a top layer. For example, as Figure 2C In the illustrated embodiment, the balloon 12 is coated with an adhesive layer 22, a coating layer 26 including a therapeutic agent and covering the adhesive layer, and a top layer 28. The top layer can reduce the loss of the drug layer before contact with the target tissue, such as during the transfer of the balloon 12 to the site of therapeutic intervention, or at the initial moment of inflation of the balloon 12 before the coating layer 20 is pressed into direct contact with the target tissue.

[0148] In various embodiments, the coating covering the catheter balloon portion has a single layer or multiple layers containing one or more therapeutic agents. In some embodiments, the layer in contact with the expandable portion of the catheter does not have a therapeutic agent and is formulated with a composition that allows the entire or most coating to be transferred to a narrow or stenotic area when the balloon catheter is expanded. In some embodiments, the layer in contact with the catheter balloon portion does not have a therapeutic agent and is formulated with a composition that allows the coating to adhere to the balloon.

[0149] Embodiments of the present invention relate to balloon catheters with rapid drug release coatings and methods for preparing such coated devices. The drug release coating may include: polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug release coating, including the polymer-encapsulated drug particles; or a composition, including a therapeutic agent and one or more additives; or a combination thereof. According to an embodiment of the present invention, the therapeutic agent does not need to be delayed or released for a long time, but for example, the therapeutic agent is released in a very short time to provide a therapeutic effect when in contact with the tissue. The purpose of an embodiment of the present invention is to promote rapid and effective absorption of drugs by target tissues during temporary deployment of the device at the target site. Other embodiments of the present invention relate to balloon catheters with drug coatings, which include therapeutic agent particles encapsulated in additives or encapsulated in one or more polymers. After the drug-coated balloon is inflated, the therapeutic agent particles are embedded in the lumen wall and long-term drug delivery is performed.

[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: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug release coating, including the polymer-encapsulated drug particles; or a composition, including 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. The layer can also include a water-insoluble or partially water-insoluble additive, or the layer can include more than one water-insoluble or partially water-insoluble additive. In some embodiments, the therapeutic agent and the excipient are dispersed in one of the coating layers. The dispersion can range from a molecular dispersion to a dispersion of drug particles of tens of microns in size. In one embodiment, the size of the therapeutic agent is 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, with no 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 at least one therapeutic agent is applied to the surface of the medical device at a concentration density of about 1 to 20 μg / mm 2 , or about 2 to 6 μg / mm 2 , or about 0.5 μg / mm 2 or less, or less than, equal to, or greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 micrograms / mm 2 or greater. If the medical device is a balloon, these measurements are calculated based on the nominal diameter. In embodiments of the present invention, the weight ratio of the additive to the drug in the coating layer may be about 20 to 0.05, about 10 to 0.1, or about 6 to 0.15.

[0152] 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 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 about 0.05 or less, or less than, equal to, or greater than 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.

[0153] The drug coating can cover any suitable proportion of the outer surface of the balloon (e.g., the proportion of the surface that reaches the main diameter of the balloon during inflation to nominal pressure, excluding the neck and terminal cone), such as from about 1% to about 100%, or from about 50% to about 100%, to about 80% to about 100%, or about 10% or less, or less than, equal to, or greater than 20%, 30, 40, 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or about 100% or more.

[0154] The balloon may have a residual amount of drug thereon after removal. Any suitable residual amount of drug may remain after removal, such as greater than, equal to, or less than about 70 wt%, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5 wt%, or about 0 wt%.

[0155] In some embodiments, the one or more additives, or the one or more polymers, or the first and / or second ionic additives or zwitterionic additives, can promote rapid release of the therapeutic agent from the balloon, and thereby the rapid release includes: the amount of the therapeutic agent drug remaining on the balloon after the balloon is inflated at the non-vascular body lumen target site for an inflation period of about 0.1 minutes to 10 minutes and is subsequently removed from the non-vascular lumen.

[0156] The coating layer covering the exterior of the medical device may include one or more water-soluble additives (eg, a water-soluble first additive, a water-soluble second additive, and a water-soluble third additive).

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

[0158] In some embodiments, the additive is at least one of a surfactant and a compound. The coating covering the exterior 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 additive may be a neutral, anionic, cationic, or zwitterionic additive. The water-insoluble additive may be a neutral, anionic, cationic, or zwitterionic additive.

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

[0160] The device is capable of releasing the therapeutic agent and delivering the therapeutic agent to the tissue in about 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 in tissue. The water and ethanol solubility of the additive can be at least 1 mg / mL, and the therapeutic agent can be water-insoluble.

[0162] In some embodiments, the layer covering the outer surface of the medical device may include a therapeutic agent and at least two additives, wherein each additive includes a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion is at least one of a hydrophobic portion, a portion having affinity for the therapeutic agent through hydrogen bonding, and a portion having affinity for the therapeutic agent through van der Waals interactions, and wherein each additive is soluble in a polar organic solvent and is soluble in water. In one aspect of this embodiment, the polar organic solvent is selected from methanol, ethanol, isopropanol, acetone, dimethylformamide, tetrahydrofuran, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, ethyl acetate and chloroform and mixtures of these polar organic solvents with water. In another aspect of this embodiment, the device also includes a top layer covering the surface of the layer on the outer surface of the medical device to reduce the loss of the drug during transfer to the target tissue through the balloon body. Methods of treating strictures and stenosis

[0163] The present invention provides a new method for treating body lumen stenosis with long-term and lasting effects. The new method opens the lumen and prevents, reduces or minimizes restenosis and recurrent non-vascular or vascular stenosis. Vascular lumens include arteries, veins or any lumen with blood. Non-vascular lumens include those without blood. The method includes delivering a drug coating, which includes: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug release coating, including the polymer-encapsulated drug particles; or a composition, including a therapeutic agent and one or more additives; or a combination thereof. The drug coating may have more than one layer and include an effective amount of a therapeutic agent, such as an anti-inflammatory drug and an antiproliferative drug (e.g., paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimios, analogs thereof, and drugs of combinations thereof). The coating may include one or more water soluble additives and one or more water insoluble or partially water soluble additives for stenoses or stenosis. The treatment is suitable for a variety of animals, such as premature newborns to adults.

[0164] In various embodiments, the present invention provides a minimally invasive method for treating or preventing non-vascular stenosis of the upper and lower urinary tracts. These urinary tract strictures may include: urethral strictures induced by trauma, iatrogenic urethral strictures, idiopathic urethral strictures, ureteral strictures, bladder neck contractures induced by prostate cancer treatment or stricture incision, and benign prostatic hyperplasia (BPH) induced by lateral lobe and / or median lobe obstruction. The method includes inserting the balloon catheter through the urethra and moving it to the urinary tract stricture. The balloon catheter includes an elongated balloon and a drug coating. The method includes expanding the balloon so that the coating layer contacts the urinary tract stricture tissue until the balloon reaches the expanded balloon diameter during the expansion period. The method includes shrinking the balloon after the expansion period and withdrawing it from the urethra. In some embodiments, the method also includes performing a surgical procedure, such as prostate cancer treatment, BPH treatment or stricture incision, before inserting the balloon catheter into the target site. In some embodiments, prostate cancer treatment includes radical prostatectomy (RP), radiation therapy, cryotherapy, or high-intensity focused ultrasound (HIFU). In some embodiments, BPH surgery includes transurethral resection of the prostate, selective laser vaporization of the prostate, or holmium laser enucleation of the prostate. In some embodiments, stricture incision includes hot knife or cold knife urethrotomy or direct visual internal urethrotomy (DVIU).

[0165] In various embodiments, the present invention provides a method for treating benign prostatic hyperplasia. The method includes 1) inserting a rigid cystoscope with a sheath (including an optical element and a mirror bridge with a flushing function) into the urethra and moving the tip of the cystoscope into the bladder. The method includes 2) removing the mirror bridge and the optical element and 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 includes 3) reinserting the reassembled cystoscope (optical element and mirror bridge with flushing function) side by side with the drug-coated balloon shaft, allowing the coating to hydrate in the irrigating fluid until the coating is soaked, and then bringing the tip of the cystoscope and the proximal edge of the balloon side by side close to the external sphincter. The method includes 3) inflating to an initial pressure (e.g., 0.5atm, 1atm, or 1.5atm) and maintaining the initial pressure until the pressure no longer decreases, for 1-2 minutes. The method includes 4) expanding to the next higher pressure, an increase of 0.5, 1 or 1.5 atm compared to the previous pressure, and maintaining this higher pressure until the pressure no longer decreases, for 1-2 minutes. The method includes 5) repeating the steps of 4) until the prostate tissue yields and the commissure incision is achieved. The method includes 6) keeping the balloon expanded for 1 minute to 7 days, 1 minute to 1 day or 1-10 minutes to release the drug into the tissue and prevent bleeding. The method includes 7) deflated the balloon catheter. The method includes 8) removing the cystoscope and balloon catheter assembly from the body lumen. Features (a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or (a) and (b)(c) may exist: (a) the ratio of the inflated balloon diameter to the target body lumen diameter is about 1.0 to about 40; or (b) the inflating includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the stretching ratio of the nominal diameter of the balloon catheter to the target body lumen diameter is about 1.0 to about 40; or (c) the inflating includes inflating to a pressure greater than the nominal pressure of the balloon catheter, and the nominal diameter of the balloon catheter is smaller than the inflated balloon diameter; (d) a combination of (a), (b) and (c).

[0166] In some embodiments, when treating the prostate, it is preferred to place the proximal balloon waist in the external sphincter so that the external sphincter does not expand. It is also preferred to size the balloon so that when the balloon waist is in the external sphincter, the balloon neck (e.g., the distal-most balloon neck) is aligned with the bladder neck. This arrangement provides a holding force so that the balloon does not slip during expansion. If the balloon neck cannot be aligned with the bladder neck, it is best to slowly inflate the balloon so that the prostate can yield when the balloon is inflated.

[0167] Once correctly positioned, the balloon is inflated, for example using an inflating device with a pressure gauge. The balloon can be slowly inflated to yield the prostate tissue and reduce the tendency of the balloon to slide into the bladder from the proximal side and slide backward from the distal side. Although balloons with single or multiple neck shapes can prevent balloon movement by aligning the most distal neck with the bladder neck, in some abnormal cases, such as median lobe enlargement (e.g., about 10-15% of cases), the balloon neck may not remain aligned with the bladder neck during the inflating period, so other techniques may help to further prevent balloon migration. In some instances, inflating at a rate of about 0.5 to 1 atm / minute can prevent balloon movement. As the tissue yields, the balloon pressure drops accordingly, and additional fluid can be injected into the balloon without increasing the pressure. When the pressure stabilizes for about 1-2 minutes, the pressure can be increased in increments of 0.5 or 1 atm and maintained in a similar manner. The pressure can be continuously increased according to this method of increasing pressure, so that the pressure stabilizes after the pressure drops, and the pressure continues to be increased until the commissure is cut or separated. Alternatively, very slow inflation can prevent balloon migration to achieve commissure incision or prostate separation. Once commissure incision or prostatic urethra and prostate separation is observed and confirmed by video feed of cystoscope, mechanical decompression can be achieved. The balloon can remain inflated for about 1 minute to 7 days, 1 minute to 1 day, or 1-10 minutes to allow the drug in the coating to transfer to the tissue. After treatment is completed, the balloon can be deflated and the catheter and cystoscope can be removed from the patient's body lumen.

[0168] In some embodiments, when treating the prostate, it may be necessary to pre-dilate the stenosis. In this embodiment, the pre-dilation catheter can be shorter and / or smaller in diameter than the drug-coated balloon treatment catheter. In this case, the pre-dilation catheter is positioned so that the proximal waist of the balloon is located in the external sphincter and the neck area is aligned with the bladder neck. As described herein, the balloon is slowly inflated to help yield the prostate while preventing the balloon from sliding. Once inflated, the pre-dilation balloon is deflated and removed, and then the drug-coated treatment balloon is inserted. The proximal waist of the treatment balloon is aligned with the external sphincter. If the prostate is properly pre-dilated, there is no need to align the balloon neck with the bladder neck because the balloon will not slide as easily as in a body lumen that has not been pre-dilated.

[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 flushing the prostate with water, saline solution, or an aqueous solution comprising at least one water-soluble additive; and inserting a balloon catheter into a target site of the prostate, the balloon catheter comprising a balloon and a coating layer covering the outer surface of the balloon. The coating layer may include: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug-releasing coating, including the polymer-encapsulated drug particles; or a composition, including a therapeutic agent and one or more additives; or a combination thereof. The method may include inflating the balloon until the coating contacts the wall of the benign prostatic hyperplasia or prostate cancer at the target site, and the balloon reaches an inflated balloon diameter during the inflation period; deflating the balloon after the inflation period, wherein the inflation period is 0.1 minutes to 10 minutes; and removing the balloon catheter from the prostate. The ratio of the inflated balloon diameter to the stenotic diameter of the body lumen can be 1.0 to 40, 1.1 to 40, 1.2 to 40, 1.3 to 40, or 1.4 to 40 (e.g., 1, or greater than, less than, or equal to 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). Optionally, the inflating may include inflating to a pressure equal to or greater than a nominal pressure of the balloon catheter.

[0170] In one embodiment, the present invention relates to a method for treating urethral stricture, the method comprising flushing the urethral stricture with water, saline solution, or an aqueous solution comprising at least one water-soluble additive so as to soak or wet the drug coating; inserting a balloon catheter into a target site at the urethral stricture, the balloon catheter comprising a balloon and a coating layer covering the outer surface of the balloon. The coating layer may include: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug-releasing coating, including the 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 the one or more water-insoluble or slightly or partially water-insoluble additives and the one or more water-soluble additives in the coating layer can be about 0.05 to 20. The method may include inflating the balloon until the coating contacts the urethral stricture wall at the target site and the balloon reaches an inflated balloon diameter during the inflating period; defl ucing the balloon after the inflating period, wherein the inflating period is 0.1 minutes to 10 minutes; and removing the balloon catheter from the urethral stricture. The ratio of the inflated balloon diameter to the urethral diameter at the stricture site may be about 1.0 to about 40, or about 1.01 to about 15, or about 1.01 or less, or less than, equal to, 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 more. After dilation, the diameter of the urethral stricture can be 6.7 mm or greater, such as about 6.7 mm to about 20 mm, or about 6.7 mm to about 15 mm, or less than, equal to, or greater than about 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, 15 mm or greater. Optionally, the expansion can include expansion to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0171] In various embodiments, the present invention provides a minimally invasive method for treating or preventing strictures in the gastrointestinal tract or digestive body lumen. Gastrointestinal strictures include esophageal strictures, achalasia strictures, biliary strictures, gastric strictures, gastric strictures induced by gastrectomy, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, ileal anal J-shaped pouch strictures and large intestinal strictures. The strictures include esophageal strictures caused by 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 any anastomotic strictures of the gastrointestinal tract. The method includes inserting a balloon catheter into the stricture of the gastrointestinal tract, and the balloon catheter includes an elongated balloon and a drug coating. The method may include flushing the gastrointestinal stricture with water, a physiological saline solution, or an aqueous solution including at least one water-soluble additive to soak or wet the drug coating. The method includes inflating the balloon at the target site so that the coating contacts the wall of the body lumen at the narrow position of the digestive body lumen until the balloon reaches an inflated balloon diameter during the expansion period. The method includes deflation of the balloon after the expansion period. The method includes removing the balloon catheter from the body lumen. In some embodiments, the method also includes performing a surgical procedure, such as a stricture incision or resection, before inserting the balloon catheter into the target site. In some embodiments, the stricture incision or resection includes acupuncture electrocautery, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).

[0172] In various embodiments, the present invention provides a method for treating or preventing non-vascular stenosis induced by inflammatory diseases (IBD). IBD may include Crohn's disease and ulcerative colitis. In some embodiments, the stenosis is small intestinal stenosis, duodenal stenosis, jejunal stenosis, ileal stenosis, colonic stenosis, rectal stenosis, large intestinal stenosis, colorectal stenosis, ileocolic stenosis or gastrointestinal tract stenosis. The method includes inserting a balloon catheter into a target site in a body lumen including a non-vascular stenosis induced by an inflammatory disease, and the balloon catheter includes an elongated balloon and a drug coating. The method may include flushing the non-vascular stenosis induced by an inflammatory disease with water, a saline solution or an aqueous solution containing at least one water-soluble additive to soak or wet the drug coating. The method includes expanding the balloon at the target site so that the coating contacts the body lumen wall at the non-vascular stenosis position induced by the inflammatory disease until the balloon reaches the expanded balloon diameter during the expansion period. The method includes shrinking the balloon after the expansion period. The method includes removing the balloon catheter from the body lumen.

[0173] In one embodiment, the present invention relates to a method for treating esophageal strictures including achalasia strictures, the method comprising flushing the esophageal stricture with water, saline solution, or an aqueous solution including at least one water-soluble additive, optionally before, during, or after inserting the balloon catheter; inserting the balloon catheter into the target site of the esophageal stricture, the balloon catheter comprising a balloon and the drug coating. The drug-coated balloon catheter can be delivered to the esophageal stricture in a minimally invasive manner by placing an endoscope in the mouth or nose to enter the esophagus. The drug-coated balloon can then be placed through the working channel of the endoscope or moved over a previously placed guidewire so that the working portion of the balloon is centered on the stricture. The endoscope used can be a gastroscope, a colonoscope, an enteroscope, a nasal endoscope, or any other endoscope suitable for moving to the treatment site of the esophageal stricture. The method may include flushing the esophageal stricture with water, a saline solution, or an aqueous solution including at least one water-soluble additive to soak or wet the drug coating. The method may include inflating the balloon until the coating contacts the wall of the esophageal stenosis at the target site and the balloon reaches an inflated balloon diameter during an inflation period; deflating the balloon after the inflation period, wherein the inflation period is 0.1 minutes to 10 minutes; and removing the balloon from the esophageal stenosis. The ratio of the balloon diameter to the esophageal diameter at the stenosis location can be about 1.0 to 40, 1.1 to 40, 1.2 to 40, 1.3 to 40, or 1.4 to 40 (e.g., 1, or greater than, less than, or equal to 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 properties are the same or similar to those given in Table 2, and the elongation rate is slower at higher pressures. Compliance is the percentage change in balloon diameter from nominal diameter to rated burst pressure (RBP) diameter, calculated as: ((diameter @ RBP - diameter @ nominal pressure) / diameter @ nominal pressure) * 100%. Optionally, the expansion may include expansion to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0174] Table 2. Examples of balloon catheter properties for the treatment of esophageal and gastrointestinal strictures.

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

[0176] Table 3. Examples of balloon catheter properties for the treatment of esophageal and gastrointestinal strictures.

[0177] In various embodiments, the present invention provides a minimally invasive method for treating or preventing vaginal stenosis or stricture. The method includes inserting a balloon catheter into the vagina and moving it to the stricture site. The balloon catheter includes an elongated balloon, a coating, or more than one drug coating covering the outer surface of the balloon. The method includes inflating the balloon so that the coating contacts the vaginal wall until the balloon reaches an inflated balloon diameter during an expansion period. The method includes deflated the balloon after the expansion period and removed from the vagina.

[0178] In various embodiments, the present invention provides a minimally invasive method for treating non-vascular stenosis induced by cancer treatment. The method includes inserting a balloon catheter into a target site in a body lumen including non-vascular stenosis induced by cancer treatment, the balloon catheter including an elongated balloon and a drug coating covering the outer surface of the balloon. The method includes inflating the balloon at the target site so that the coating contacts the wall of the body lumen at the location of the non-vascular stenosis induced by cancer treatment until the balloon reaches an inflated balloon diameter during the inflation period. The method includes deflation of the balloon after the inflation period. The method includes removing the balloon catheter from the body lumen. In some embodiments, the cancer treatment is prostate radiation therapy, EMR, or ESD.

[0179] In various embodiments, the present invention provides a minimally invasive method for reducing or preventing cancer recurrence. The method includes inserting a balloon catheter into a target site in a body lumen, wherein the target site is located at, adjacent to, close to, or away from a site where cancer treatment is performed, and the balloon catheter includes an elongated balloon and a drug coating. The method includes inflating the balloon at the target site so that the coating contacts the wall of the body lumen at the target site until the balloon reaches an inflated balloon diameter during the expansion period. The method includes contracting the balloon after the expansion period. The method includes removing the balloon catheter from the body lumen. In some embodiments, the method also includes, before inserting the balloon catheter into the target site, performing cancer treatment in the body lumen at, adjacent to, close to, or away from the target site. In some embodiments, the cancer treatment performed is prostate radiation therapy, transurethral prostatectomy, or gastrointestinal EMR or ESD.

[0180] In various embodiments, the present invention provides a method for treating or reducing the occurrence of non-vascular stenosis induced by surgical anastomosis, including treating the anastomosis when the anastomosis is formed and / or before the stenosis is formed. The method includes inserting a balloon catheter into a target site in a body lumen including a surgical anastomosis-induced non-vascular stenosis, the balloon catheter including an elongated balloon and the drug coating. The method may include flushing the anastomosis site with water, a saline solution, or an aqueous solution including at least one water-soluble additive to soak or wet the drug coating. The method includes inflating the balloon at the target site so that the coating contacts the body lumen wall at the location of the surgical anastomosis-induced non-vascular stenosis until the balloon reaches an inflated balloon diameter during the inflation period. The method includes shrinking the balloon after the inflation period. The method includes removing 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, a gastric stricture, a small intestinal stricture, a duodenal stricture, a jejunal stricture, an ileal stricture, a colonic stricture, a rectal stricture, a large intestinal stricture, a colorectal stricture, a stricture caused by a gastric bypass, an ileocolic stricture, a gastrointestinal stricture, a urethral stricture, a ureteric stricture, a vaginal stricture or stricture, a J-pouch stricture, or a bladder neck stricture. An anastomosis includes joining together two or more body structures, which can be from an autologous source (i.e., the same individual, such as a bowel resection and an arteriovenous fistula), an allogeneic source (i.e., another individual, such as an allogeneic source for an organ transplant), or a xenogeneic source (i.e., a different species, such as a decellularized graft).

[0181] In various embodiments, the present invention provides a method for treating or preventing surgically induced stenosis. Surgical procedures that can induce non-vascular stenosis include needle knife electroresection, episiotomy, urethrotomy, direct vision internal urethrotomy (DVIU), endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). The method includes inserting a balloon catheter into a target site in a body lumen, the target site including non-vascular stenosis induced by needle knife electroresection, urethrotomy, direct vision internal urethrotomy (DVIU), endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD), and the balloon catheter includes an elongated balloon and a drug coating. The method may include flushing the surgical site with water, a saline solution or an aqueous solution including at least one water-soluble additive to soak or wet the drug coating. The method includes expanding the balloon at the surgical site so that the coating contacts the body lumen wall at the surgical site until the balloon reaches the expanded balloon diameter during the expansion period. The method includes deflation of the balloon after the inflation period. The method includes removing the balloon catheter from the body lumen.

[0182] Various embodiments of the present invention relate to a method for treating non-vascular body lumen stenosis by using an endoscope to observe the stenosis. The endoscope can be a gastroscope, enteroscope, duodenoscope, colonoscope, sigmoidoscope, rectoscope, anoscope, rhinoscope, bronchoscope or cystoscope. The endoscope can be used to ensure that the balloon catheter is properly positioned in the targeted lumen. The method includes inserting the endoscope into a body lumen, which can be any body orifice (such as the mouth, nose, anus, ear canal, vagina or urethra), and passing through the stenosis to observe it. A guide wire can be delivered through the working channel of the endoscope so that it passes through the stenosis before inserting the balloon catheter. The method includes inserting Figure 1The method may include inserting a balloon catheter on a guidewire and an endoscope side by side into a target site in a body lumen or the balloon catheter is in a working channel of an endoscope. The method may include flushing the body lumen with water, saline solution, or an aqueous solution including at least one water-soluble additive before, during, or after inserting the balloon into the target site. The method includes inflating the balloon until the coating contacts a narrow wall in the body lumen at the target site and the balloon reaches an inflated balloon diameter during 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)(c) may exist: (a) the ratio of the inflated balloon diameter to the diameter of the body lumen stenosis at the target site is about 1.0 to about 40; (b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the stretch ratio of the nominal diameter of the balloon catheter to the diameter of the body lumen stenosis at the target site is about 1.0 to about 40; (c) the inflation includes inflating to a pressure greater than the nominal pressure of the balloon catheter, and the nominal diameter of the balloon catheter is smaller than the inflated balloon diameter; (d) a combination of (a), (b) and (c). The method includes deflation of the balloon after the inflation period. The method also includes removing the balloon catheter from the stenosis and the endoscope, and removing the endoscope from the body lumen.

[0183] In various embodiments, the present invention provides a method for treating or preventing vascular stenosis. The vascular stenosis can be one of 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 stenosis, posterior tibial artery stenosis, peroneal artery stenosis, and other arterial stenosis of the foot. The method includes inserting a balloon catheter and / or a stent into a target site in a vascular system, the balloon catheter including an elongated balloon and a balloon and / or a stent including the drug coating. The method includes expanding the balloon and / or expanding the stent at the target site so that the coating layer contacts the inner lumen wall and expands the stenosis until the balloon reaches the expanded balloon diameter during the expansion period or until the stent reaches the expanded diameter. The method may include shrinking the balloon after the expansion period. The method may include removing the balloon catheter from the body lumen. In various embodiments, a sheath covering the coated balloon and / or coated stent may be used to prevent washing away during the process of advancing the balloon catheter or stent to the target site in the blood vessel.

[0184] In some embodiments, when treating a stenotic artery, it may be necessary to pre-dilate the stenosis with an uncoated pre-dilation balloon catheter and then treat it with a drug-coated balloon. In some embodiments, the pre-dilation balloon catheter has cutting or scoring elements on the balloon for destroying calcified plaque. In some embodiments, the pre-dilation catheter can be shorter and / or smaller in diameter than the drug-coated balloon treatment catheter. In this case, the pre-dilation catheter is positioned so that the center of the balloon body is aligned with the center of the stenosis. Once inflated, the pre-dilation balloon is deflated and removed, and then the drug-coated treatment balloon is inserted. The size of the drug-coated balloon is selected so that the balloon diameter and balloon length are greater than the diameter and length of the pre-dilation balloon catheter to ensure that the drug coating contacts the entire lumen wall of the pre-dilated stenosis.

[0185] In some embodiments, when treating a stenotic artery, it may be desirable to reduce or remove tissue from the stenosis with an atherectomy device prior to treatment with a drug coated balloon. Any suitable type of atherectomy device may be used, such as a laser type, a directional type, a rotary type, or a jet type. After performing an atherectomy, an angiogram may be performed, and the size of the drug coated balloon may be selected so that the balloon diameter and balloon length are sufficient to ensure that the drug coating contacts the entire lumen wall of the stenosis with reduced volume.

[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 stenosis, posterior tibial artery stenosis, peroneal artery stenosis, and other arterial stenosis of the foot. The method includes inserting a balloon catheter into a target site of in-stent restenosis, the balloon catheter including an elongated balloon and the drug coating. The method includes inflating the balloon at the target site so that the coating contacts the inner lumen wall and expanding the stenosis until the balloon reaches an inflated balloon diameter during the inflation period. The method includes deflation of the balloon after the inflation period. The method includes removing the balloon catheter from the body lumen.

[0187] In various embodiments, the present invention provides a method for treating or preventing a stenotic arteriovenous fistula. The method includes inserting a balloon catheter into a target site in a vascular system, the balloon catheter including an elongated balloon and the drug coating. The method includes inflating the balloon at the target site so that the coating contacts the inner lumen wall and dilating the stenosis until the balloon reaches an inflated balloon diameter during an inflating period. The method includes deflation of the balloon after the inflating period. The method includes removing the balloon catheter from the body lumen.

[0188] In various embodiments, the present invention provides a method for treating or preventing heart valve stenosis. The method includes inserting a balloon catheter into a target site in a heart valve, the balloon catheter including an elongated balloon and the drug coating. The method includes inflating the balloon at the target site so that the coating contacts the inner lumen wall and expands the heart valve stenosis until the balloon reaches an inflated balloon diameter during the inflating period. The method includes deflated the balloon after the inflating period. The method includes removing 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 (e.g., any balloon catheter described herein) into a target site in a body lumen. In some embodiments, the balloon is inflated until the drug coating contacts the stenotic wall and the stenosis expands, transferring the drug to the stenosis. In some embodiments, the balloon is inflated until the drug coating contacts the stenotic wall, and the inflation expands the stenosis to increase its diameter so that contact with the stenosis can cause the drug to be transferred circumferentially to the stenotic wall. In some embodiments, the balloon portion including the drug (e.g., in embodiments where the surface area is less than 100% of the drug coating) can uniformly contact the stenosis. In other embodiments, the contact of various portions of the balloon surface with the stenosis is uneven.

[0190] In various embodiments, the method includes measuring the body lumen stenosis to be treated. The diameter of the distal and proximal healthy tissue and the length of the stenosis can be evaluated to select the drug-coated balloon to be used. The doctor will select the balloon based on the diameter of the body lumen stenosis and make the stretch ratio of the balloon nominal diameter to the body lumen stenosis diameter reach 1.0-40. Then, the doctor can inflate the balloon to at least the nominal pressure, and in some cases, the balloon can be inflated to exceed the nominal pressure until the rated burst pressure of the balloon. The pressure range used during the expansion period can be called the working pressure range of the drug-coated balloon. In some cases, the method may include exceeding the rated burst pressure of the balloon. Because the nominal diameter of the balloon is determined without any restrictions, the expanded diameter of the balloon at the stenosis during treatment will be approximately equal to, less than, or greater than the nominal diameter. When at or above or below the burst pressure, the expanded diameter of the balloon can be less than the nominal diameter, equal to the nominal diameter, or can exceed the nominal diameter. For example, the measured value of the body lumen stenosis diameter can be 10 mm. The physician may select a drug coated balloon with a nominal diameter of 14 mm, a nominal pressure of 6 atm, and a rated burst pressure of 10 atm. The stretch ratio is 1.4. The physician will inflate the balloon to at least 6 atm, in some cases to 8 atm or 10 atm, and in some cases to more than 10 atm, to achieve the desired inflated balloon diameter during treatment.

[0191] Various embodiments provide a method of treating strictures of benign prostatic hyperplasia (BPH), strictures of the urethra, strictures of the ureter, strictures of the vagina or stenosis, prostate cancer, strictures of the esophagus, strictures of the bile duct, strictures of the stomach, strictures of the small intestine, strictures of the duodenum, strictures of the jejunum, strictures of the ileum, strictures of the colon, strictures of the rectum, strictures of the large intestine, strictures of the colorectum, strictures after gastric bypass, strictures of the ileum, strictures of the gastrointestinal tract, strictures of the J-pouch, strictures of the bladder neck (e.g., strictures), strictures of eosinophilic esophagitis fibrosis, strictures induced by Crohn's disease (CD) and ulcerative colitis (UC), strictures induced by radiation, strictures induced by endoscopic resection (EMR and ESD), strictures related to anastomosis, strictures of achalasia, strictures induced by gastrectomy, strictures of asthma or chronic obstructive pulmonary disease (COPD). The method is a method for treating a body lumen stenosis, such as a urethral stenosis, a benign prostatic hyperplasia (BPH) stenosis, a ureteral stenosis, an esophageal stenosis, an antral stenosis, a gastric stenosis, a small intestinal stenosis, a duodenal stenosis, a jejunal stenosis, an ileal stenosis, a colonic stenosis, a rectal stenosis, a large intestinal stenosis, and a biliary tract stenosis. The stenosis in the body lumen can be a benign prostatic hyperplasia (BPH) stenosis, a urethral stenosis, or an esophageal stenosis. The method can be a method for treating benign prostatic hyperplasia, prostate cancer, or a combination thereof, wherein the body lumen is a prostate.

[0192] The body lumen may be a prostate, wherein inserting the balloon catheter comprises positioning the balloon catheter in the prostate using an endoscope (e.g., a flexible or rigid endoscope, such as a cystoscope). The balloon catheter may include an endoscope, and the method may include positioning the target site using a video feed of the endoscope. The method may include positioning the balloon catheter at the target site using a video feed of the endoscope.

[0193] The body lumen may be a prostate, the balloon may have a plurality of body sections divided by one or more necks, and inserting the balloon catheter may include positioning one of the balloon catheter body sections in the prostate and positioning a second body section of the balloon catheter in the bladder.

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

[0195] The expansion cycle can be any suitable expansion period, for example, from about 0.1 minute to about 10 minutes, from about 0.5 minute to about 2 minutes, or about 0.1 minute 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, or about 10 minutes or more.

[0196] The inflation can include increasing the pressure within the balloon at any suitable rate (e.g., which can exclude times when the pressure drops due to tissue yielding, and during which the pressure can be maintained), such as from about 0.1 atm / minute to about 10 atm / minute, or from about 0.5 to about 1.5 atm / minute, or about 0.1 atm / minute or less, or less than, equal to, or greater than about 0.2 atm / minute, 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, or about 10 atm / minute or more.

[0197] Embodiments of the present invention relate to treating body lumen strictures by delivering an effective amount of a therapeutic agent, such as an anti-inflammatory and antiproliferative drug (e.g., rapamycin, paclitaxel, or its analogs.) The strictures in the body lumen include vascular strictures, urethral strictures, ureteral strictures, vaginal strictures or strictures, esophageal strictures, achalasia strictures, stent strictures, antral strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, large intestinal strictures, and bile duct strictures. Embodiments of the present invention relate to methods for treating at least one of the following: vascular stenosis, benign prostatic hyperplasia (BPH), urinary tract problems, prostate cancer, colorectal stenosis, post-gastric bypass stenosis, ileocolic stenosis, gastrointestinal stenosis, J-pouch stenosis, bladder neck stenosis (e.g., stenosis), fibrostenotic 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) stenosis. According to an embodiment, the method comprises inflating the balloon catheter and releasing the drug to the stenotic wall, deflated the balloon; removing the balloon catheter, wherein the residual drug is about 1-70% of the total drug load on the balloon catheter, wherein the drug in the body lumen wall can be about 0.1-25% of the total drug load on the balloon catheter. In one aspect of this embodiment, the additive enhances absorption of the drug in body tissues with luminal stenoses. Therapeutic agents

[0198] The therapeutic agent that can be used in the embodiment of the present invention can be any drug or bioactive material. The therapeutic agent can be a hydrophobic therapeutic agent, an antiproliferative therapeutic agent, an anti-inflammatory agent or a combination thereof. The drug can be in various physical states, such as a molecular distribution form, a crystal form or a cluster form. Examples of particularly useful drugs in the embodiments of the present invention are lipophilic substantially water-insoluble drugs, such as paclitaxel, docetaxel, taxol, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimios, its analogs, and combinations thereof, daunorubicin, doxorubicin, lapacone, vitamin D2 and / or D3, its analogs or derivatives, or combinations thereof. The therapeutic agent, such as an antiproliferative drug (e.g., paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, umimios, everolimus, mTOR inhibitors (i.e., drugs that inhibit the mechanistic target of rapamycin) or their analogs), can be delivered to the body lumen wall for the treatment of constriction or stenosis.

[0199] Other drugs that can be used in embodiments of the present invention include, but are not limited to, glucocorticoids (e.g., dexamethasone, betamethasone), hirudin, angiopeptides, aspirin, growth factors, antisense agents, anticancer agents, antiproliferative agents, oligonucleotides, and more generally, antiplatelet agents, anticoagulants, antimitotic agents, antioxidants, antimetabolites, antichemotactic agents, anti-inflammatory agents, and combinations thereof.

[0200] Some drugs that can be used in various embodiments (e.g., particularly for use in the airways, sinuses, and other nasal cavities, but also for urethral applications) are corticosteroids, such as budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone furoate, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cortisone, betamethasone, triamcinolone acetonide, etc. Some other suitable drugs are terbutaline, albuterol, ipratropium bromide, pirbuterol, epinephrine, salmeterol, levalbuterol, formoterol, etc.; the drug can be a bronchodilator or a vasoconstrictor.

[0201] Also useful in embodiments of the invention are polynucleotides, antisense RNA, RNAi or siRNA, for example, that inhibit inflammation and / or smooth muscle cell or fibroblast proliferation.

[0202] Antiplatelet agents may include drugs such as aspirin and dipyridamole. Aspirin is classified as an analgesic, antipyretic, anti-inflammatory and antiplatelet. Dipyridamole is a drug similar to aspirin because it has antiplatelet properties. Dipyridamole is also classified as a coronary vasodilator. Anticoagulants used in embodiments of the present invention may include drugs such as heparin, protamine, hirudin and tick anticoagulant protein. Antioxidants may include probucol. Antiproliferative agents may include drugs such as amlodipine and doxazosin. Antimitotic agents and antimetabolites that can be used in embodiments of the present invention include drugs such as methotrexate, azathioprine, vincristine, vinblastine, 5-fluorouracil, doxorubicin and mitomycin. Antibiotics used in embodiments of the present invention include penicillin, cefoxitin, oxacillin, tobramycin and gentamicin. Antioxidants suitable for embodiments of the present invention include probucol. Furthermore, genes or nucleic acids or parts thereof can be used as therapeutic agents in embodiments of the present invention. Furthermore, collagen synthesis inhibitors, such as tranilast, can be used as therapeutic agents in embodiments of the present invention.

[0203] For example, photosensitizers used in photodynamic therapy or radiotherapy, including various porphyrin compounds (eg, porphyrin sodium) can also be used as drugs in embodiments of the present invention.

[0204] Drugs used in the embodiments of the present invention also include everolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, cranamicin, clarithromycin, troleandomycin, polyphylline, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan, ifosfamide, trolofosamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, trooxosulfan, temozolomide, thiotepa, daunorubicin, mycobacterium, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, actinomycin, methotrexate, fludarabine, fludarabine-5'-dihydrogen phosphate, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxyurea, miltefosine, pentostatin, aldesleukin, retinoic acid, asparaginase, pegaspargase, anastrozole, exemestane, letrozole, formestane, aminoglutethimide, doxorubicin, azithromycin, spiramycin, cepharanthin, smc-proliferation inhibitor-2w, epothilone A and B, mitoxantrone, azathioprine, mycophenolate mofetil, c-myC-reverse sense, b-myc-antisense, betulinic acid, camptothecin, lapachol, β-lapachone, podophyllotoxin, betulinol, podophyllotoxin 2-ethyl hydrazide, morasporastatin (rhuGM-CSF), peginterferon a-2b, lenograstim (r-HuG-CSF), filgrastim, polyethylene glycol, dacarbazine, basiliximab, daclizumab, selectins (cytokine antagonists), CETP inhibitors, cadherins, mitogen inhibitors, COX-2 inhibitors, NFkB, angiopeptide, ciprofloxacin, camptothecin, fluroblastin, monoclonal antibodies (which can be used to inhibit muscle cell proliferation), bFGF antagonists, probucol, prostaglandins, 1,11-dimethoxy ferroxetine, 1-hydroxy-11-methoxyferroxetine, scopoletin, colchicine, NO donors (e.g., pentaerythritol tetranitrate and syndnoeimine), S-nitroso derivatives, tamoxifen, staurosporine, β-estradiol, α-estradiol, estriol, estrone, ethinylestradiol, fosestrol, medroxyprogesterone, estradiol cypionate, estradiol benzoate, tranilast, urophylla propionate and other terpenoids (which may be used in cancer therapy), verapamil, tyrosine kinase inhibitors (tyrosine phosphorylation inhibitors), cyclosporine A, 6-α-hydroxy-paclitaxel, baccatin, taxotere and other macrocyclic oligomers of tricarbon dioxide (MCS) and their derivatives, murfibutazone, acemetacin,Diclofenac, clonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiosuccinate, oxacerol, celecoxib, β-sitosterol, adenosine methionine, myricaine, polidocanol, novanillamide, levomenthol, benzocaine, aescin, ellipticine, D-24851 (Calbiochem), colchicine, cytochalasin AE, indanol acin, nocodazole, S100 proteins, bacitracin, vitronectin receptor antagonists, azelastine, tissue inhibitors of guanidyl cyclase stimulator of metalloproteinases-1 and -2, free nucleic acids, nucleic acids incorporated into viral transmitters, DNA and RNA fragments, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotides, VEGF inhibitors, IGF-1, products from the antibiotic group (e.g., cefadroxil, cefazolin, cefaclor, cefotaxime, tolbutamide, cefotaxime ... active agents of nabdomyosarcoma, gentamicin, penicillins (e.g., dicloxacillin, oxacillin), sulfonamides, metronidazole), antithrombotic agents (e.g., argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumarin, enoxaparin, desulfated and N-reacetylated heparin, tissue plasminogen activator, CpIIb / IIIa platelet membrane receptor, factor Xa inhibitor antibodies, heparin, hirudin, r-hirudin, PPACK, protamine, urokinase zymogens, streptokinase, warfarin, urokinase), vasodilators (e.g., dipyridamole, trapidil, nitrosoferricyanide), PDGF antagonists (e.g., triazolopyrimidines and seramin), ACE inhibitors (e.g., captopril, cilazapril, lisinopril, enalapril, losartan), thio-based protease inhibitors, prostacyclins, valperprost, interferon alpha, beta, and gamma, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis modulators (e.g., p65 NF-kB or Bc1-xL antisense oligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, boswellic acid and its derivatives, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone, mitomycin, procainamide, retinoic acid), quinidine, disopyramide, flecainamide, propafenone, sotalol, amiodarone, natural and synthetic steroids (e.g., cyclohexine A, betulinol, maquiroside A) A), ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone), nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., fenoprofen, ibuprofen, indomethacin, naproxen,phenylbutazone) and other antiviral agents (e.g., acyclovir, ganciclovir, and zidovudine), antifungal agents (e.g., clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine), antiprotozoal agents (e.g., chloroquine, mefloquine, quinine), and natural terpenes such as hippocaesculin, barramundigenin-C21-angelate, 14-dehydroagrostistachin, agroskerin, agros tistachin), 17-hydroxyagrostistachin, ovatodiolids, 4,7-oxycyclofenanthenic acid, baccharinoids B1, B2, B3 and B7, radix scutellariae saponins, bruceano1 A, B and C, bruceanoside C, bruceanoside N and P, isodeoxycholic acid, bruceanolide A and B, gingerol A, B, C and D, ursolic acid, hyptatic acid A acid A), zevoterpenoid, iso-germanicin, maytansinol, chamotrin A, chamotrin A and B, chamotrin B, chamotrin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-a-senecioyloxychaparrin, chamotrin A and B, ranelnol, triptolide, and magnetoside, strophanthin), aristolochic acid, aminopterin, hydroxyaminopterin, anemonin, proanemonin, berberine, cheliburin chloride chloride), cictoxin, fangji alkaloids, bombrestatin A and B, roots containing jujube isoflavone A, curcumin, dihydro-photopiperine, photopiperine chloride, 12-β-hydroxypregnadien-3,20-dione, ginkgo phenol, ginkgol, ginkgolic acid, coreopsis tinctorius, oxalis pine, N-oxidized oxalis pine, tricholoma quinoline, and inonotus obliquus alcohol, glycoside 1a, podophyllotoxin, acanthoside A and B, larreatin, malloterin, mallotochromanol, isobutyryl malloterin, maquiroside A, marchantin A, maytansine, lycoridicin, lycoridin, hydnopodipine, schefflerine, biparthenolide, oxidized yellow heart pine alkaloid, aristolochic acid lactone-AII,Bisparthenolide, schizotoxin A, ghalakinoside, ursolic acid, deoxyprospermum officinale, psychorubin, ricin A, sanguinarine, manwuwheat acid acid), methyl pearlin, sphatheliachromen, stizophyllin, mansonine, strebloside, strychnine, dihydrousambarensine, hydrousambarensine, strychnopentamine, strychnophylline, usambarensine, berberine, limonene, oxyyellow heartwood pine, daphnetin, larch resin, methoxylarch resin, syringaresinol, umbelliferone, afromoson, acetylvismione B, desacetylvismione A, and vismione A and B.

[0205] Combinations of drugs can also be used in embodiments of the present invention. Some combinations have additive effects because they have different mechanisms, such as paclitaxel and rapamycin, paclitaxel and active vitamin D, paclitaxel and lapachone, rapamycin and active vitamin D, rapamycin and lapachone. Due to the additive effect, the dosage of the drug can also be reduced. These combinations can alleviate the complications of using high-dose drugs.

[0206] Some drugs considered particularly suitable for use in the airways, sinuses, and other nasal cavities that are used in various embodiments are corticosteroids such as budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone furoate, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cortisone, betamethasone, triamcinolone acetonide, and the like.

[0207] In one embodiment of the balloon catheter, the weight of the therapeutic agent (e.g., a hydrophobic therapeutic agent) in the coating layer to the total weight of one or more additives in the coating layer 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 about 0.05 or less, or less than, equal to, or greater than 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 weight of the therapeutic agent in the coating layer to the total weight of the one or more additives in the coating layer (e.g., the total weight of the first and second additives in the coating layer, or the total weight of the first, second and third additives in the coating layer) is 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 about 0.05 or less, or less than, equal to or greater than 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. additive

[0208] The excipients of the embodiments of the present invention can facilitate rapid elution of the drug and allow the drug to penetrate well into the tissue at the disease site. Therefore, the coating of the embodiments of the present invention increases the absorption rate and / or absorption degree of the anti-proliferative therapeutic agent in non-vascular lesion tissue or non-vascular body lumen. In the embodiments of the present invention, the coating device delivers the anti-proliferative therapeutic agent to the non-vascular tissue in a very short deployment time of less than 10 minutes, less than 2 minutes, and reduces the re-narrowing and recurrence of non-vascular body lumen stenosis.

[0209] In some embodiments, the additive reduces the crystal size and particle count of the therapeutic agent, and wherein the additive is water soluble and the therapeutic agent is not water soluble. The additive may have an acid, ester, ether or alcohol fatty chain, wherein the fatty chain may be directly inserted into the lipid membrane structure of the tissue. The additive may penetrate the lipid membrane structure of the tissue and rearrange it. 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 of a surfactant and a compound, and wherein the molecular weight of the additive is 50 to 750 g / mol (e.g., 50 g / mol or greater, or less than, equal to, or greater than 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 750 g / mol or less). The compound may have more than four hydroxyl groups. In some embodiments, the compound having more than four hydroxyl groups has a melting point of 120° C. or less, and the compound is an alcohol or ester. In some embodiments, the therapeutic agent is insoluble in water or only slightly soluble in water.

[0210] In one aspect of this embodiment, the additive enhances the absorption of the drug into tissues of non-vascular and vascular body lumens. In another aspect of this embodiment, the additive includes a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion is at least one of a hydrophobic portion, a portion having affinity for the therapeutic agent through hydrogen bonds, and a portion having affinity for the therapeutic agent through van der Waals interactions. The drug affinity portion of the additive can be combined with a lipophilic drug, such as rapamycin or paclitaxel or its analogs. The hydrophilic portion accelerates diffusion and enhances the penetration of the drug into tissues. It can promote the rapid removal of the drug from the medical device during deployment at the target site by preventing hydrophobic drug molecules from agglomerating with each other and agglomerating to the device, increasing the solubility of the drug in the intercellular space, and / or accelerating the drug cavity to reach the lipid bilayer of the target tissue cell membrane through the polar head group. The two parts of the additive of various embodiments of the present invention can work together to promote the rapid release of the drug from the surface of the device during deployment and absorption by the target tissue (by accelerating the contact of the drug with the drug having a high affinity tissue), while preventing the drug from being released prematurely from the surface of the device before the device is deployed to the target site.

[0211] In embodiments of the present invention, the therapeutic agent is rapidly released and easily absorbed after the medical device contacts the tissue. For example, certain embodiments of the device of the present invention include a drug-coated balloon catheter, which delivers therapeutic agents such as lipophilic antiproliferative drugs (such as paclitaxel or rapamycin) to non-vascular tissues at high drug concentrations by short, direct pressure contact during balloon expansion. For example, the lipophilic drug is retained in the target tissue at the delivery site, where it inhibits hyperplasia and restenosis, but allows epithelial formation. In these embodiments, the coating formulation of the present invention is not only conducive to the rapid release of the drug from the balloon surface during deployment and transfer to the target tissue, but also prevents the drug from diffusing from the device through the tortuous anatomical structure before reaching the target site, and leaves the device before the drug coating is pressed into direct contact with the body lumen surface in the initial stage of balloon expansion.

[0212] The additive according to certain embodiments has a drug affinity part and a hydrophilic part. The drug affinity part is a hydrophobic part and / or has affinity to the therapeutic agent through hydrogen bonding and / or van der Waals interactions. The drug affinity part may include aliphatic and aromatic organic hydrocarbon compounds, such as benzene, toluene and alkanes. These parts are insoluble in water. They can either bind hydrophobic drugs (similar to their structures) or bind lipids of cell membranes. The drug affinity part may include functional groups that can form hydrogen bonds with drugs and themselves. The hydrophilic part may include hydroxyl, amine, amide, carbonyl, carboxylic acid and anhydride, ethylene oxide, ethylene glycol, polyethylene glycol, ascorbic acid, amino acids, amino alcohols, glucose, sucrose, sorbitan, glycerol, polyols, phosphates, sulfates, organic salts and substituted molecules thereof. For example, one or more hydroxyl, carboxyl, acid, amide or amine may be advantageous because they are easy to replace water molecules hydrogen-bonded to polar head groups and cell membrane surface proteins, and can play a role in removing the barrier between hydrophobic drugs and cell membrane lipids. These moieties are soluble in water and polar solvents.Additives according to embodiments of the present invention have components that can both bind to the drug and promote rapid removal of the drug from the medical device and into the target tissue during deployment.

[0213] The additive described in the embodiment of the present invention can be a surfactant and / or a compound with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties. The surfactant includes an ionic surfactant, a nonionic surfactant, an aliphatic surfactant and an aromatic surfactant. The compound with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties is selected from amino alcohols, hydroxycarboxylic acids and anhydrides, ethylene oxide, ethylene glycol, amino acids, peptides, proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyols, phosphates, sulfates, organic acids, esters, salts, vitamins and their substituted molecules.

[0214] The terms "hydrophilic" and "hydrophobic" are relative terms. For use as additives in various embodiments of the present invention, the compounds include a polar or charged hydrophilic portion and a non-polar hydrophobic (lipophilic) portion.

[0215] An empirical parameter commonly used in medicinal chemistry to characterize the relative hydrophilicity and hydrophobicity of a drug compound is the partition coefficient, P, the ratio of the concentrations of unionized compounds in the two phases of a mixture of two immiscible solvents (usually octanol and water) such that 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 drug compounds with log P < 5 have higher membrane permeability. In certain embodiments of the present invention, for example, the log P of the additive is less than the log P of the drug to be formulated (e.g., the log P of paclitaxel is 7.4). A large difference in log P between the drug and the additive can promote phase separation of the drug. 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 from the surface of the device to which the drug may be tightly adhered in an aqueous environment, thereby accelerating the delivery of the drug to the tissue at the intervention site during a short deployment period. In certain embodiments of the present invention, the log P of the additive is a negative value. 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 can be used as a measure of relative hydrophilicity and hydrophobicity, it is only a rough guide for defining suitable additives for use in embodiments of the present invention.

[0216] Suitable additives that can be used in embodiments of the present invention include, but are not limited to, organic and inorganic pharmaceutical excipients, natural products and their derivatives (e.g., sugars, vitamins, amino acids, peptides, proteins, and fatty acids), low molecular weight oligomers, surfactants (anionic surfactants, cationic surfactants, nonionic and ionic surfactants), and mixtures thereof. The additives described herein that can be used in the present invention are for exemplary purposes only and are not intended to be comprehensive. Many other additives can be used for the purposes of the present invention. The additives can include the first ionic additive or zwitterionic additive, the second ionic additive or zwitterionic additive, or a combination thereof. Surfactants

[0217] In the embodiment including surfactant, the surfactant can be any surfactant suitable for pharmaceutical composition. Such surfactant can be anionic, cationic, zwitterionic or nonionic surfactant. Mixtures of surfactants are also within the scope of various embodiments of the present invention, as are the combinations of surfactants and other additives. Surfactants usually have one or more long fatty chains (such as fatty acids) that can be directly inserted into the lipid bilayer of the cell membrane to form a part of the lipid structure, while other components of the surfactant loosen the lipid structure and enhance the penetration and absorption of drugs. The contrast agent iopromide does not have these characteristics.

[0218] An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of surfactants is the hydrophilic-lipophile balance ("HLB" value). Surfactants with lower HLB values ​​are more hydrophobic and more soluble in oils, while surfactants with higher HLB values ​​are more hydrophilic and more soluble in aqueous solutions. Using the HLB value as a rough guide, hydrophilic surfactants are generally considered to be those compounds with an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, hydrophobic surfactants are compounds with an HLB value less than about 10. In certain embodiments of the present invention, higher HLB values ​​are used because increased hydrophilicity can promote the release of hydrophobic drugs from the device surface. In one embodiment, the surfactant additive has an HLB greater than 10. The additive HLB may be greater than 14. Alternatively, surfactants with a lower HLB can be used to prevent drug loss prior to deployment of the device at the target site, such as loss of drug from a top coating layer over a drug layer containing a very hydrophilic additive.

[0219] The HLB value of a surfactant is only a rough guide and is commonly used in the formulation of, for example, industrial, pharmaceutical, and cosmetic emulsions. For many important surfactants (including several polyethoxylated surfactants), it has been reported that the HLB value can vary by as much as about 8 HLB units, depending on the empirical method chosen for determining the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Keeping these inherent difficulties in mind and using the HLB value as a guide, as described herein, it is possible to determine whether the hydrophilicity or hydrophobicity of a surfactant is suitable for embodiments of the present invention. PEG-fatty acids and PEG-fatty acid mono- and diesters

[0220] The present invention relates to the invention relates to the hydrophilic surfactant of the present invention. The hydrophilic surfactant of the present invention comprises the following: polyethylene glycol (PEG) is a kind of polyethylene glycol, and the polyoxyethylene ...

[0221] Polyethylene glycol fatty acid diesters are also suitable for use as surfactants in the compositions of embodiments of the present invention. Hydrophilic surfactants include PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, and PEG-32 dioleate. The HLB value ranges from 5 to 15.

[0222] In general, mixtures of surfactants may also be used in embodiments of the present invention, including mixtures of two or more commercial surfactants and mixtures of a surfactant with another additive or additives.Several PEG-fatty acid esters are commercially available as mixtures or monoesters and diesters. Polyethylene glycol glycerol fatty acid ester

[0223] The hydrophilic surfactant may include PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate. Alcohol-oil transesterification products

[0224] Many surfactants with different hydrophobicity or hydrophilicity can be prepared by reacting alcohol or polyol with various natural and / or hydrogenated oils. The most commonly used oil is castor oil or hydrogenated castor oil, or edible vegetable oil, such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil or almond oil. Alcohol includes glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol and pentaerythritol. Among these alcohol oil transesterification surfactants, hydrophilic surfactants have PEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT TMTO), PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic / capric glycerides (Labrasol), and PEG-6 caprylic / capric glycerides (Softigen 767). For example, this class of hydrophobic surfactants includes PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil TM M2125CS), PEG-6 almond oil (Labrafil TM M 1966CS), PEG-6 apricot kernel oil (Labrafil TM M 1944CS), PEG-6 olive oil (Labrafil TM M 1980CS), PEG-6 peanut oil (Labrafil TM M 1969CS), PEG-6 hydrogenated palm kernel oil (Labrafil TM M 2130BS), PEG-6 palm kernel oil (Labrafil TM M 2130CS), PEG-6 trioleylglycerol (Labrafil TM b M 2735CS), PEG-8 corn oil (Labrafil TM WL 2609BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almond glycerides (Crovol A40). Polyglycerol fatty acid

[0225] The polyglycerol esters of fatty acids are also surfactants suitable for embodiments of the present invention. Among the polyglycerol fatty acid esters, hydrophobic surfactants include polyolein (Plurol Oleique), polyglyceryl-2 oleate (Nikkol DGDO), polyglyceryl-10 trioleate, polystearate, polylaurin, polymyristyl glyceryl, polypalmitic glyceride and polylinoleic glyceride. Hydrophilic surfactants include polyglyceryl-10 laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn 1-O) and polyglyceryl-10 mono- and dioleate (CaproI TMPEG 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. Propylene glycol fatty acid esters

[0226] Esters of propylene glycol and fatty acids are suitable surfactants for use in embodiments of the present invention. Among 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 TM 200) and propylene glycol dicaprylate (Captex TM 800). Sterols and sterol derivatives

[0227] Sterols and sterol derivatives are suitable surfactants for use in embodiments of the present invention. Derivatives include polyethylene glycol derivatives. This type of surfactant is PEG-24 cholesterol ether (Solulan C-24). Polyethylene glycol sorbitan fatty acid esters

[0228] A variety of 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). PEG-20 sorbitan monooleate (Tween-80). In some embodiments, laurates are used because they have shorter lipid chains than oleates, thereby enhancing drug absorption. Sugar and its derivatives

[0229] Sugar derivatives are suitable surfactants for use in embodiments of the present invention. Such surfactants 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. Polyethylene glycol alkylphenol

[0230] Several PEG-alkylphenol surfactants are available (eg, PEG-10-100 nonylphenol and PEG-15-100 octylphenol ether, tyloxapol, octylphenol polyether, octylphenol polyether-9, nonoxynol ether) and are suitable for use in the present invention. Polyoxyethylene-polyoxypropylene (POE-POP) block copolymer

[0231] POE-POP block copolymers are a unique class of polymeric surfactants. The unique structure of the surfactant with well-defined ratios and positions of the hydrophilic POE and hydrophobic POP portions provides a variety of surfactants suitable for use in embodiments of the present invention. These surfactants are available under a variety of trade names, including Synperonic PE series (ICI); Pluronic TM Series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare and Plurodac. The generic term for these polymers is "Poloxamers" (CAS 9003-11-6). The molecular formula for these polymers is: HO(C2H4O) a (C3H6O) b (C2H4O) a H, wherein "a" and "b" represent the number of polyoxyethylene and polyoxypropylene units, respectively.

[0232] Such hydrophilic surfactants include Poloxamers 108, 188, 217, 238, 288, 338 and 407. Such hydrophobic surfactants include Poloxamers 124, 182, 183, 212, 331 and 335. Sorbitan fatty acid esters

[0233] Sorbitan esters of fatty acids are surfactants suitable for use in embodiments of the present invention. Among these esters, hydrophobic surfactants include sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40) and sorbitan monooleate (Span-80), sorbitan monostearate.

[0234] Sorbitan monopalmitate is an amphiphilic derivative of vitamin C (with vitamin C activity) that can play two important roles in a solubilizing system. First, it has 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: the solubility of ascorbic acid in water is about 30 wt / wt% (very close to the solubility of sodium chloride, for example). Second, when the pH is raised, a portion of the ascorbyl palmitate is converted to a more soluble salt, such as sodium ascorbyl palmitate. Ionic surfactants

[0235] Ionic surfactants, including cationic, anionic and zwitterionic surfactants, are hydrophilic surfactants suitable for 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, cetylpyridinium chloride, dodecyltrimethylammonium bromide, cetyltrimethylammonium chloride, trimethyl-tetradecylammonium chloride, trimethyloctylammonium chloride, lauryltriethylammonium chloride, DOTAP-1,2-dioleoyl-3-trimethylammonium-propane (chloride salt or methyl sulfate), DOTMA-1,2-di-O-octadecenyl-3-trimethylammonium propane (chloride salt), DC-cholesterol-3β-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride, DODMA-1,2-dioleyl-3- Dimethylaminopropane, GL67-N4-cholesterol-spermine hydrochloride, DDAB-dimethyldioctadecyl ammonium (bromide salt), MVL5-N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-amino-propyl)amino]butylformamido)ethyl]-3,4-di[oleyl]-benzamide, EPC-1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (chloride salt), sodium dodecyl sulfate, dialkylmethylbenzyl ammonium chloride, edrophonium chloride, domiphen bromide, sodium sulfosuccinate dialkyl ester, dioctyl sodium sulfosuccinate, sodium cholate and sodium taurocholate. They can be dissolved in organic solvents (such as ethanol, acetone and toluene) and water. This is particularly useful for medical device coatings because it simplifies the preparation and coating process and has good adhesion properties. Water-insoluble drugs are usually dissolved in organic solvents.

[0236] Some of the surfactants described herein are very stable when heated. They survive the ethylene oxide sterilization process. They do not react with drugs such as paclitaxel or rapamycin during the sterilization process. Hydroxyl, ester, and amide groups are used because they are less likely to react with the drug, while amine and acid groups often react with paclitaxel or rapamycin during the sterilization process. In addition, the surfactant additive improves the integrity and quality of the coating layer so that the drug particles do not fall off during the processing process. When the surfactants described herein are formulated with paclitaxel, experiments have shown that it can protect the drug from premature release during device delivery, while promoting rapid release and elution of paclitaxel at the target site during a very short deployment time of 0.2 to 10 minutes. It can be experimentally determined that the absorption rate of the drug by the target site tissue is very high. Compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties

[0237] 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, xanthine nucleoside, 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 ethers, 18-crown-6, 15-crown-5, 12-crown-4, N-acetylglucosamine, N-octyl-D-glucamide, C6-ceramide, dihydro-C6-ceramide, sphingomyelin, galactosylsphingomyelin, lactosylsphingomyelin, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-capryl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG caprylic / capric diglyceride, PEG 8 caprylic / capric glyceride, PEG caprylate, PEG 8 caprylate (e.g., ), PEG caprate, PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monocaproate, glyceryl monolaurate, glyceryl monocaprin, glyceryl monocaprylin, glyceryl monomyristate, glyceryl monopalmitoleate, and glyceryl monooleate.

[0238] Compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties include amino alcohols, hydroxycarboxylic acids, esters, anhydrides, hydroxyketones, hydroxylactones, hydroxyesters, phosphate sugars, sulfate sugars, ethylene oxide, ethylene glycol, amino acids, peptides, proteins, sorbitan, glycerol, polyols, phosphate esters, sulfate esters, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids, and their substituted molecules. In certain embodiments, hydrophilic compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties having a molecular weight of less than 5,000-10,000 are used. In other embodiments, the molecular weight of the additive with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties is less than 1000-5,000, or less than 750-1,000, or less than 750. In these embodiments, the molecular weight of the additive should be less than the molecular weight of the drug to be delivered. In addition, the molecular weight of the additive should be higher than 80, because molecules with a molecular weight of less than 80 evaporate easily and will not remain in the coating of the medical device. Small molecules can diffuse rapidly. They can be easily released from the delivery balloon to accelerate the release of the drug, so they can diffuse out of the drug when it binds to the body luminal tissue.

[0239] In certain embodiments, additives with more than four hydroxyl groups are used, such as in the case of high molecular weight additives. Macromolecules diffuse slowly. If the molecular weight of the additive or compound is high, such as a molecular weight of more than 800, more than 1000, more than 1200, more than 1500, or more than 2000, the rate at which the macromolecules are eluted from the surface of the medical device is too slow to release the drug within 2 minutes. If these macromolecules contain more than four hydroxyl groups, they will increase the hydrophilicity, which is necessary for the rapid release of drugs by larger molecules. Enhanced hydrophilicity can help wash the coating off the balloon, accelerate the release of the drug, and improve and / or promote the penetration of the drug through the polar head groups of the water barrier and lipid bilayer into the tissue. In one embodiment, a hydroxyl group is used as a hydrophilic part because it is less likely to react with water-insoluble drugs (such as paclitaxel or rapamycin). In some embodiments, the melting point of the compound with more than four hydroxyl groups is 120°C or lower. In some embodiments, the compound with more than four hydroxyl groups has three adjacent hydroxyl groups, which are all on one side of the molecule in the stereo configuration. For example, sorbitol and xylitol have three adjacent hydroxyl groups, which are all on one side of the molecule in stereo configuration, while galactitol is not. This difference affects the physical properties of the isomers, such as melting temperature. The stereo configuration of three adjacent hydroxyl groups can enhance drug binding. This will improve the compatibility of water-insoluble drugs and hydrophilic additives, and improve tissue uptake and absorption of drugs.

[0240] Some of the compounds described herein that have one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties are very stable when heated. They are preserved during ethylene oxide sterilization 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 may not be preserved during such sterilization, and they will 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 are less likely to react with therapeutic agents (such as paclitaxel or rapamycin). Sometimes, amine and acid groups do react with paclitaxel, for example, experiments have shown that benzoic acid, gentisic acid, diethanolamine and ascorbic acid are unstable during ethylene oxide sterilization, heating and aging, and react with paclitaxel. When the compounds described herein are formulated with paclitaxel, the top coating can help prevent premature drug loss before deployment at the target site during device delivery, because hydrophilic small molecules sometimes release drugs too easily. The compounds herein can rapidly elute the drug from the balloon during deployment at the target site. Surprisingly, even when the coating contains these additives, some drug may be lost during the delivery of the device to the target site, and in experiments, drug uptake by tissues is high after only 0.2-10 minutes of deployment, for example, using additive hydroxylactones, such as ribonolactone and gluconolactone. Fat-soluble vitamins and their salts

[0241] In addition to vitamins A, D, E, and K in their various forms and provitamin forms, which are considered fat-soluble vitamins, several other vitamins and vitamin sources or closely related compounds are also fat-soluble and have polar groups and high octanol-water partition coefficients. Clearly, this general class of compounds has a history of safe use and a high benefit-risk ratio, making them useful as additives in embodiments of the present invention.

[0242] Examples of the following fat-soluble vitamin derivatives and / or sources may also be used 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, hydroxymethylriboflavin, octothiamine, propylthiamine, riboflavin, phenylthiamine, dihydrovitamin K1, menadione acetate, menadione butyryl, menadione sulfate, menadione, vitamin K1, vitamin K1 oxide, vitamin K2, and vitamin K--S (II). Folic acid also belongs to this type, and although it is water-soluble at physiological pH, it can be formulated in the form of a free acid. Other derivatives of fat-soluble vitamins for use in embodiments of the present invention can be easily obtained by well-known chemical reactions with hydrophilic molecules. Water-soluble vitamins and their amphiphilic derivatives

[0243] Many different forms of vitamin B, C, U, pantothenic acid, folic acid and some vitamins / provitamins associated with menadione are considered to be water-soluble vitamins. These vitamins can also be conjugated or compounded with hydrophobic moieties or multivalent ions to form amphiphilic forms with higher octanol-water partition coefficients and polar groups. Similarly, such compounds can have low toxicity and high benefit-risk ratios, making them useful as additives in embodiments of the present invention. Salts of these vitamins can also be used as additives of the present invention. Examples of water-soluble vitamins and derivatives include, but are not limited to, acetylthiamine, benfotiamine, pantothenic acid, cimetropium, cyclothiamine, dexpanthenol, nicotinamide, nicotinic acid, 5-pyridoxal phosphate, ascorbic acid nicotinamide, riboflavin, riboflavin phosphate, thiamine, folic acid, menadione diphosphate, menadione sodium bisulfite, menadoxil, vitamin B12, vitamin K5, vitamin K6, vitamin K6 and vitamin U. In addition, as described above, folic acid is soluble in water in the form of salts in a wide pH range including physiological pH.

[0244] The compound that has amino or other basic groups can be by with the acid containing hydrophobic group, for example fatty acid (especially lauric acid, oleic acid, myristic acid, palmitic acid, stearic acid or 2-ethylhexanoic acid), low solubility amino acid, benzoic acid, salicylic acid or acidic fat-soluble vitamin (such as riboflavin) carry out simple acid-base reaction and modify.Other compounds can be obtained by reacting another group (such as hydroxyl) on this type of acid and vitamin to form ester bonds etc.The derivative containing acidic group water-soluble vitamin can be generated in the reaction with for example containing hydrophobic group reactant (such as stearylamine or riboflavin), to produce the compound that can be used for embodiments of the present invention.The connection of palmitate chain and vitamin C produces ascorbyl palmitate. Amino acids and their salts

[0245] Alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, histidine, proline, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine and derivatives thereof are other useful additives in embodiments of the present invention.

[0246] Certain amino acids in zwitterionic and / or salt forms with monovalent or multivalent ions have polar groups, higher octanol-water partition coefficients, and can be used in embodiments of the present invention. In the context of this disclosure, we use "low solubility amino acids" to refer to amino acids with a 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.

[0247] Amino acid dimers, glycoconjugates and other derivatives are also useful. Hydrophilic molecules can be linked to hydrophobic amino acids, or hydrophobic molecules can be linked to hydrophilic amino acids, by simple reactions well known in the art to prepare additional additives useful in embodiments of the present invention.

[0248] Catecholamines, such as dopamine, levodopa, carbidopa, and DOPA, may also be used as additives. Oligopeptides, peptides and proteins

[0249] Oligopeptides and peptides can be used as additives because hydrophobic and hydrophilic amino acids can be easily coupled and a variety of amino acid sequences can be tested to maximize drug penetration into tissues.

[0250] In various embodiments of the invention, proteins can also be used as additives. For example, serum albumin is a useful additive because it is water soluble and contains significant hydrophobic moieties to bind drugs: paclitaxel is 89% to 98% bound to protein after intravenous infusion in humans, while rapamycin is 92% bound to protein, primarily (97%) bound to albumin. In addition, the solubility of paclitaxel in PBS is increased by more than 20 times after the addition of BSA. Albumin is naturally present in serum at high concentrations and is therefore very safe for human use.

[0251] Other useful proteins include, but are not limited to, other albumins, immunoglobulins, caseins, hemoglobin, lysozyme, immunoglobulins, alpha-2-macroglobulin, fibronectin, vitronectin, fibrinogen, lipase, and the like. Organic acids, their esters and anhydrides

[0252] Examples include acetic acid and anhydride, benzoic acid and anhydride, diethylenetriaminepentaacetic dianhydride, ethylenediaminetetraacetic dianhydride, maleic acid and anhydride, succinic acid and anhydride, diglycolic anhydride, glutaric anhydride, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, aspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and 2-pyrrolidone.

[0253] These esters and anhydrides are soluble in organic solvents, such as ethanol, acetone, methyl ethyl ketone, ethyl acetate. The water-insoluble drug can be dissolved in an organic solvent along with these esters and anhydrides, and then easily coated on a medical device, and then hydrolyzed under high pH conditions. The hydrolyzed anhydride or ester is an acid or alcohol, which is water-soluble and can effectively carry the drug out of the device and into the body lumen wall. Antimicrobial agents

[0254] The antimicrobial properties of various fatty acids, alkyl glyceryl ethers and C8-C12 fatty acid monoglycerides have been studied for many years. Studies have shown that fatty acids, alkyl glyceryl ethers and monoglycerides can inhibit the growth of a variety of bacteria and viruses. The coating formulation of the present invention can include various fatty acids, alkyl glyceryl ethers and C8-C12 fatty acid monoglycerides, such as caprylic acid, caprylic acid, capric acid, capric acid, lauric acid, dodecyl glycerol and monolaurin, as one of the additives for treating various non-vascular and vascular stenosis. Other compounds having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties

[0255] Additives according to various embodiments may include amino alcohols, alcohols, amines, acids, amides, and hydroxy acids having cyclic and linear aliphatic and aromatic groups. Examples are L-ascorbic acid and its salts, D-glucosaccharoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucosamine, amino alcohols, glucoheptonic acid, gluconic acid, hydroxyketones, hydroxylactones, gluconolactone, gluceptolactone, glucocinolactone, gulonic acid lactone, mannolactone, ribonolactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sorbitol, glucitol, phosphate sugars, pyranose glucose phosphate, sulfate sugars, erucic acid, vanillic acid, diethylamine, vanillin, methylparahydroxybenzoate, propylparahydroxybenzoate, xylitol, 2-ethoxyethanol, sugars, galactose, glucose, ribose, mannose, xylose Sugar, sucrose, lactose, maltose, arabinose, lyxose, fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, salts of any organic acid and amine described herein, polyglycidol, glycerol, polyglycerol (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, and derivatives and compositions thereof.

[0256] Combinations of additives may also be used for the purposes of the present invention. One embodiment includes a combination or mixture of two additives, for example, a first additive including a surfactant and a second additive including a compound having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties.

[0257] The surfactant and water-soluble small molecule (compound with one or more hydroxyl, amine, carbonyl, carboxyl or ester part) combination or mixture are all advantageous. The preparation comprising two kinds of additives and water-insoluble drug mixture is better than the preparation comprising only a mixture of any one kind of additive in some cases. The combination of hydrophobic drugs and small molecules with excellent water solubility is worse than surfactant. They are usually separated from the water-soluble small molecules, which can cause the uniformity and integrity of the coating to be poor. The Log P of the water-insoluble drug is higher than the Log P of the surfactant and the water-soluble small molecule. However, the Log P of the surfactant is usually higher than the Log P of the compound with one or more hydroxyl, amine, carbonyl, carboxyl or ester part. The Log P of the surfactant is relatively high (usually higher than 0), while the Log P of the water-soluble molecule is low (for example, lower than 0). Some surfactants, when used as additives in embodiments of the present invention, have very strong adhesion to water-insoluble drugs and medical device surfaces, so that the drug cannot be quickly released from the medical device surface at the target site. On the other hand, some water-soluble small molecules (having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties) have poor adhesion to the medical device, so that they release the drug before the drug reaches the target site, for example, releasing the drug into the serum during the delivery of the coated balloon catheter to the target site of intervention. Surprisingly, by adjusting the concentration ratio of the hydrophilic small molecule and the surfactant in the preparation, the inventors found that in some cases, the stability of the coating during delivery and the rapid release of the drug when it is expanded and pressed against the lumen wall tissue at the target site of therapeutic intervention are better than the preparations including only any additive. In addition, the presence of the surfactant improves the miscibility and compatibility of water-insoluble drugs and highly water-soluble molecules. The surfactant also improves the uniformity and integrity of the coating by good adhesion to the drug and small molecules. The long-chain hydrophobic part of the surfactant is tightly bound to the drug, while the hydrophilic part of the surfactant is bound to the water-soluble small molecule.

[0258] The surfactant in the mixture or combination includes all surfactants described herein for use in embodiments of the present invention. The surfactant in the mixture can be selected from PEG sorbitan fatty acid esters; PEG ω-3 fatty esters, ethers and alcohols; glycerol fatty acid esters, sorbitan fatty acid esters, PEG glycerol fatty acid esters, PEG fatty acid esters and alcohols, sugar fatty acid esters, PEG sugar esters, Tween 20, Tween 40, Tween 60, p-isononylphenoxy polyglycidol, PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polylaurin, polyolein, polymyristin, polypalmitin, 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 monolaurate Acid, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, Tween 20, Tween 40, Tween 60, Tween 80, octylphenol polyether, octylphenol polyether-9, nonoxynol ether, tyloxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-pyranoglucoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β- D-pyranoglucoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-pyranoglucoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-pyranoglucoside, nonanoyl-N-methylglucamide, n-nonyl-β-D-pyranoglucoside, octanoyl-N-methylglucamide, n-octyl-β-D-pyranoglucoside, octyl-β-D-thioglucoside and their derivatives.

[0259] Embodiments of compounds having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties in a mixture or combination may include any compound having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties described herein for embodiments of the present invention. In various embodiments, the compound having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties in the mixture has at least one hydroxyl, such as four hydroxyl groups. In certain embodiments, additives having more than four hydroxyl groups are used, such as for high molecular weight additives, more than four hydroxyl groups. In some embodiments, the melting point of compounds having more than four hydroxyl groups is 120°C or lower. Macromolecules diffuse slowly. If the molecular weight of the additive or compound is high, such as a molecular weight of more than 800, more than 1000, more than 1200, more than 1500 or more than 2000, the rate at which the macromolecules are eluted from the surface of the medical device is too slow to release the drug within 2 minutes. If these macromolecules contain more than four hydroxyl groups, their hydrophilicity will increase, which is necessary for the rapid release of drugs by larger molecules. Increased hydrophilicity facilitates elution of the coating from the balloon, accelerates drug release, and improves or promotes drug penetration through the polar head group of the water barrier and lipid bilayer. In one embodiment, hydroxyl is used as the hydrophilic moiety because it is less likely to react with water-insoluble drugs such as paclitaxel or rapamycin.

[0260] The compound having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties in the mixture is selected from L-ascorbic acid and its salts, D-glucosaccharoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucosamine, amino alcohol, glucoheptonic acid, gluconic acid, hydroxyketone, hydroxylactone, gluconolactone, glucoheptonic acid lactone, glucocinolide, gulonic acid lactone, mannolactone, ribonolactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, 4-hydroxybenzoic acid propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactitol, sorbitol, glucitol, phosphate sugar, pyranose glucose phosphate, sulfate sugar, erucic acid, vanillic acid, vanillin, methyl paraben, propyl paraben, 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, tiletamine, ketamine, propofol, lactic acid, acetic acid, any of the above Salts of any organic acid and amine, polyglycidol, glycerol, polyglycerol, galactitol, glyceryl monolaurate, glyceryl monocaprate, glyceryl monocaprylate, glyceryl monomyristate, glyceryl monopalmitoleate, glyceryl monooleate, creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthine riboside, xanthine monophosphate, caffeine, allantoin, (2-hydroxyethyl) urea, N,N'-bis(hydroxymethyl) urea, pentaerythritol ethoxylate, pentaerythritol Tetraol propoxylates, pentaerythritol propoxylates / ethoxylates, glycerol ethoxylates, glycerol propoxylates, trimethylolpropane ethoxylates, 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) and penta(propylene glycol), poly(propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, and derivatives and combinations thereof.

[0261] A mixture or combination of a surfactant and a water-soluble small molecule can have the advantages of both additives or work synergistically. The water-insoluble drug tends to have poor compatibility with highly water-soluble compounds, while the surfactant improves compatibility. The surfactant also improves coating quality, uniformity and integrity, and drug particles do not fall off the balloon during handling. The surfactant reduces drug losses during delivery to the target site. The water-soluble compound improves the release of the drug from the balloon and its absorption in the tissue. Experiments have shown that the combination is unexpectedly effective in preventing drug release during delivery and achieving high tissue drug levels after a very short 0.2 to 2 minute deployment. In addition, in animal studies, it effectively alleviated stenosis and reduced subsequent drug losses in the lumen.

[0262] Some mixtures or combinations of surfactants and water-soluble small molecules are very stable when heated. They survive the ethylene oxide sterilization process and do not react with water-insoluble drugs (paclitaxel or rapamycin) during the sterilization process. In one embodiment, hydroxyl, ester, amide groups are used because they are less likely to react with therapeutic agents (such as paclitaxel or rapamycin). Sometimes amine and acid groups do react with paclitaxel and are unstable during ethylene oxide sterilization, heating and aging. When the mixtures or combinations described herein are formulated with paclitaxel, a top coating may be advantageous to protect the drug layer and avoid premature loss of drug during deployment of the device.

[0263] Examples of the additive include p-isononylphenoxy polyglycidol, PEG glyceryl oleate, PEG glyceryl stearate, polylaurin, polyolerin, polymyristyl glyceryl, polypalmitin, 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 monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, octylphenol polyether, octylphenol polyether-9, nonoxynol ether, tyloxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methyl glucamide, n-decyl-β-D-pyranoglucoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-pyranoglucoside glucoside, n-dodecyl-β-D-maltoside, heptyl-N-methylgluconamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylgluconamide, n-nonyl-β-D-glucopyranoside, octanoyl-N-methylgluconamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine, tyrosine , tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid and methionine (amino acids), cimetropium, cyclothiazine, dexpanthenol, niacinamide, niacin and its salts, pyridoxal 5-phosphate, niacinamide ascorbyl, riboflavin, riboflavin phosphate, thiamine, folic acid, menadione diphosphate, menadione sodium bisulfite, menadoxine, vitamin B12, vitamin K5, vitamin K6, vitamin K6 and vitamin U (vitamins);Albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, alpha-2-macroglobulin, fibronectin, vitronectin, fibrinogen, lipase, benzalkonium chloride, benzethonium chloride, dodecyltrimethylammonium bromide, sodium dodecyl sulfate, dialkylmethylbenzylammonium chloride and dialkyl esters of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucosaccharoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucosamine, amino alcohol, glucoheptonic acid, gluconic acid, hydroxyl ketone, hydroxy lactone, glucoheptonic acid, glucosamine, hydroxy hydroxy lactone, glucoheptonic acid, hydroxy hydroxy hydroxy lactone ... Acid lactone, gulonic acid lactone, mannolactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, 4-hydroxybenzoic acid propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactitol, erucic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, any Salts of organic acids and organic amines, polyglycidol, glycerol, polyglycerol, galactitol, glyceryl monolaurate, glyceryl monocaprate, glyceryl monocaprylate, glyceryl monomyristate, glyceryl monopalmitoleate, glyceryl monooleate, creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthine nucleoside, xanthine monophosphate, caffeine, allantoin, (2-hydroxyethyl) urea, N,N'-bis(hydroxymethyl) urea, pentaerythritol ethoxylate, pentaerythritol Tetraol propoxylates, pentaerythritol propoxylates / ethoxylates, glycerol ethoxylates, glycerol propoxylates, trimethylolpropane ethoxylates, 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. (Compounds having one or more hydroxyl, amino, carbonyl, carboxyl or ester moieties). Some of these additives are soluble in water and in organic solvents. They have good adhesive properties and can adhere to the surface of polyamide medical devices (e.g., balloon catheters). Therefore, they can be used in the adhesive 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, and polar groups of alcohol and acid accelerate the penetration of drugs into tissues.

[0264] Other additives according to embodiments of the present invention include hydroxyketones, hydroxylactones, hydroxyacids, hydroxyesters and hydroxyamides. Examples are gluconolactone, D-glucose heptadecanoe-1,4-lactone, gluconolactone, gulonic acid lactone, mannolactone, erythrolactone, ribonolactone, glucuronic acid, gluconic acid, gentisic acid, lactobionic acid, lactic acid, acetaminophen, vanillic acid, erucic acid, hydroxybenzoic acid, methylparaben, propylparaben and derivatives thereof.

[0265] From a structural point of view, these additives have structural similarities and are compatible with water-soluble drugs such as paclitaxel and rapamycin. They generally contain double bonds in aromatic or aliphatic structures, such as C=C, C=N, C=O. These additives also contain amines, alcohols, esters, amides, anhydrides, carboxylic acids and / or hydroxyl groups. They can form hydrogen bonds and / or van der Waals interactions with the drug. They can also be used in the top layer of the coating. For example, compounds containing one or more hydroxyl, carboxyl or amine groups are particularly useful as additives because they help release the drug from the surface of the device and easily displace water near the polar head groups of the cell membrane and surface proteins, thereby removing this barrier to the permeability of hydrophobic drugs. They accelerate the movement of hydrophobic drugs from the balloon to the lipid layers of the cell membrane and tissues, and the hydrophobic drugs have a very high affinity for these lipid layers. The additives can also carry or accelerate the drug out of the balloon into a more water-containing environment, such as the intercellular space, such as the intercellular space of non-vascular tissues damaged by balloon angioplasty or stent expansion. Additives such as polyglycerol fatty acid esters, fatty acid ascorbate, sugar esters, fatty acid alcohols and ethers have fatty chains that can be integrated into the lipid structure of the target tissue membrane, thereby carrying the drug into the lipid structure. Some amino acids, vitamins and organic acids have aromatic C=N groups as well as amino, hydroxyl and carboxyl components in their structures. They have structural parts that can bind or complex with hydrophobic drugs (such as paclitaxel or rapamycin), and they also have structural parts that promote tissue penetration by removing the barrier between the hydrophobic drug and the cell membrane lipid structure.

[0266] For example, isononylphenyl polyglycidol (Olin-10 G and Surfactant-10G), PEG glycerol monooleate, sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitan monostearate, polyglycerol-10 oleate, polyglycerol-10 laurate, polyglycerol-10 palmitate, and polyglycerol-10 stearate all have more than four hydroxyl groups in their hydrophilic parts. These hydroxyl groups have a good affinity for the body lumen wall and can replace water molecules bound to hydrogen. At the same time, they have long chains of fatty acids, alcohols, ethers, and esters, which can both complex with hydrophobic drugs and integrate into the lipid structure of the cell membrane to form a part of the lipid structure. This deformation or loosening of the lipid membrane of the target cell can further accelerate the penetration of hydrophobic drugs into the tissue.

[0267] In another example, L-ascorbic acid, thiamine, maleic acid, nicotinamide and 2-pyrrolidone-5-carboxylic acid have very high water and ethanol solubility, low molecular weight and small size. They also have structural components including aromatic C=N, amino, hydroxyl and carboxyl groups. These structures have good compatibility with both paclitaxel and rapamycin, can improve the solubility of these water-insoluble drugs in water, and enhance their absorption in tissues. However, they generally have poor adhesion to the surface of medical devices. Therefore, they are used in combination with other additives in the drug layer and the top layer to enhance drug absorption. Vitamins D2 and D3 are particularly useful because they themselves have anti-restenotic effects and reduce thrombosis, especially when used in combination with paclitaxel.

[0268] The relative amounts of the therapeutic agent and additive in the coating layer may vary depending on the application. The optimal amount of the additive may depend on, for example, the specific therapeutic agent and additive selected, the critical micelle concentration when the surface modifier forms micelles, the hydrophilic-lipophilic balance (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.

[0269] Other considerations will further inform the selection of specific ratios of different additives. These considerations may include the bioacceptability of the additives and / or the desired dosage of the therapeutic agent to be provided.

[0270] In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a target site of a body lumen stenosis, the balloon catheter comprising a coating layer covering the outer surface of the balloon. The coating layer may include: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug release coating, including the polymer-encapsulated drug particles; or a composition, comprising a 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, umimos, analogs thereof, and combinations thereof. The additive may be a water-insoluble additive selected from the following: cholesterol acetate, cholesterol phenylacetate, cholesterol laurate, cholesterol palmitate, cholesterol stearate, cholesterol n-valerate, cholesterol benzoate, cholesterol heptanoate, cholesterol decanoate, cholesterol caproate, cholesterol oleate, cholesterol oleyl carbonate, cholesterol linoleate, cholesterol nonanoate, cholesterol erucate, cholesterol octanoate, 5α-cholestane, 5α-cholestane-3-one and combinations thereof.

[0271] In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a narrow or narrow target site of a body lumen, the balloon comprising 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 a combination thereof. The balloon catheter comprises a coating layer covering the outer surface of the balloon. The coating layer comprises: the polymer-encapsulated drug particles, comprising the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug release coating, comprising the polymer-encapsulated drug particles; or a composition comprising a 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, umimos, analogs thereof, and combinations thereof. The additive may be a first water-insoluble or slightly or partially water-insoluble additive comprising at least one alkyl fatty group or a cholesterol group, the first additive having a molecular weight of 50 to 750; or a second water-soluble additive which is more hydrophilic or more soluble in water than the first additive and comprises -(CH2CH2O)- units, having a molecular weight of 750 to 100,000, preferably 1000 to 50,000, and most preferably 2000 to 10,000. The first water-insoluble or slightly or partially water-insoluble additive having a cholesterol group may be selected from cholesterol acetate, cholesterol phenylacetate, cholesterol laurate, cholesterol palmitate, cholesterol stearate, cholesterol n-valerate, cholesterol benzoate, cholesterol heptanoate, cholesterol decanoate, cholesterol caproate, cholesterol oleate, cholesterol oleyl carbonate, cholesterol linoleate, cholesterol nonanoate, cholesterol erucate, cholesterol octanoate, 5α-cholestane, 5α-cholestane-3-one, and combinations thereof.The water-insoluble or slightly or partially water-insoluble first additive has an alkyl fatty group (e.g., C4-C30, such as equal to or greater than 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, 28, 29 or C30), which can be selected from alkyl glyceryl ethers, monoglycerides of C8-C12 fatty acids, alkyl alcohols, alkyl ethers, alkyl esters, caprylic acid, monocaprylic glyceride, capric acid, monocapric glyceride, lauric acid, dodecylglycerol, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosenoic acid, 1-hydroxy-1,1-di-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1,1-d-1-oxo-1The water-soluble second additive can be selected from cholesterol polyethylene glycol 600 sebacate, polyoxyethyl α-tocopherol 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)-cholesterol sebacate, polyethylene glycol cholesterol, PEG amide ester cholesterol, PEG amide ether cholesterol, mPEG amide ester cholesterol, DSPE-PEG-cholesterol, PEGylated phospholipids, methylated PEG 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, and PEG-30 glyceryl oleate, polyglyceryl fatty acid esters, polyoleylglycerol (Plurol Oleique), 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), polyglyceryl-10 mono / dioleate (CaproI. TM 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. Coating solution

[0272] The coating layer may include: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug-releasing coating, including the polymer-encapsulated drug particles; or a composition, including a therapeutic agent and one or more additives; or a combination thereof. The solvent for preparing the coating layer can include, for example, one of the following or a combination thereof: (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, diethylamine, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether (Trascutol) and benzyl alcohol, (e) ethers, such as dioxane, dimethyl ether and tetrahydrofuran, (f) ester / acetate, such as ethyl acetate and isobutyl acetate, (g) ketones, such as acetone, acetonitrile, diethyl ketone and methyl ethyl ketone, and (h) a mixture of water and an organic solvent, such as water / ethanol, water / acetone, water / methanol, water / tetrahydrofuran. The solvent in the top coating can be, for example, methanol, ethanol and / or acetone.

[0273] Organic solvents, such as short chain alcohols, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, dimethyl sulfoxide, and the like, can be useful solvents in embodiments of the present invention because these organic solvents generally break up colloidal aggregates and co-dissolve all components in the coating solution.

[0274] Various embodiments provide a method for preparing a coating solution. The content of the therapeutic agent in the coating solution can be 0.5-50wt% of the total weight of the solution. The content of the additive in the coating solution can be about 0.1wt% to about 45wt%, about 0.2wt% to about 40wt%, about 0.3wt% to about 15wt%, or about 0.1wt% or less, or less than, equal to or greater than about 0.2wt%, 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, 40 or about 45wt% or more based on the total weight of the solution. The amount of solvent used depends on the coating process and viscosity. It will affect the uniformity of the drug additive coating, but it will evaporate.

[0275] 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.

[0276] The coating of the medical device for delivering drugs to non-vascular tissue or non-vascular stenosis can be prepared by a mixture. The coating can be prepared by a mixture, and the mixture includes an organic phase containing drug particles dispersed therein and an aqueous phase containing one or more water-soluble additives. The water-soluble additive can be selected from polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polypeptide, water-soluble surfactant, water-soluble vitamin and protein. Alternatively, the coating can be prepared by a two-phase mixture containing small particles of the drug suspended in a liquid. The liquid can be composed of any antisolvent suitable for the drug particles, such as water, heptane, hexane or cyclohexane. The suspended drug particles can be stabilized by other additives dissolved in the liquid phase.

[0277] The coating solution of the medical device for delivering the drug to non-vascular tissue or non-vascular stenosis can be prepared by a mixture. The coating solution can be prepared by a mixture including: water and a water-miscible solvent, a water-soluble additive and a water-insoluble or partially water-soluble additive (containing a large portion of insoluble drug particles 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, all or part of the one or more water-soluble additives are dissolved in water and added to a microfluidizer. Next, the drug can be added to the microfluidizer for processing, and the mixture is processed 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, the water-insoluble or partially water-soluble additive can be dissolved in the water-miscible solvent and added to the microfluidizer and processed under high shear conditions. The processing can be one of microfluidization, homogenization, homogenizer grinding, high-energy or low-energy bead milling, or high-power ultrasonic probe homogenization.

[0278] In one embodiment, preparing a coating solution comprises: a) mixing water, a water-miscible solvent, a therapeutic agent, and a water-soluble additive to form a premix; b) treating the premix to reduce the particle size of the therapeutic agent; c) mixing a water-insoluble additive, the water-soluble additive, water, and a water-miscible solvent to form a second premix; d) mixing the second premix with the first treated premix to form a coating solution. The therapeutic agent is one of paclitaxel, docetaxel, taxol, mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimios, analogs thereof, 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 ranges from 0.2 microns to 5 microns. The first additive, the second additive or a combination thereof encapsulates the therapeutic agent, the particle size of the therapeutic agent encapsulated by the additive is greater than the particle size of the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated by the additive in the coating ranges from 0.3 microns to 10 microns. The treatment is one of microfluidization, homogenization, homogenizer grinding, high-energy or low-energy bead milling or high-power ultrasonic probe homogenization. The first additive includes a water-insoluble or slightly or partially water-insoluble additive, which includes at least one alkyl fatty group or cholesterol group. The molecular weight of the first additive can be 50 to 750. The melting temperature of the first additive in the coating is lower than the melting temperature of the pure first additive. The crystallinity of the first additive in the coating is lower than the crystallinity of the pure first additive. The second additive is more hydrophilic or more soluble in water than the first additive and includes polyethylene glycol (-(CH2CH2O)-) or polyglycerol (-(CH2-CHOH-CH2O)-) units. The molecular weight of the second additive is 750 to 100,000, or 750 to 50,000, or 750 to 10,000. Medical device coatings

[0279] The medical device and coating described in the embodiment of the present invention can be made according to various methods. The coating solution may include: the polymer-encapsulated drug particles, including the therapeutic agent and the one or more polymers encapsulating the therapeutic agent; or the drug release coating, including the polymer-encapsulated drug particles; or a composition, comprising a therapeutic agent and one or more additives; or a combination thereof. Coating techniques can be used to apply the coating solution to the medical device, such as casting, fixed volume liquid distribution, metering (for example, distributing a fixed amount of coating solution to a balloon or stent according to volume), spin coating, spraying, dipping (for example, soaking), inkjet printing, electrostatic technology, and a combination of these processes. In the process of applying the coating solution, the balloon can be at least partially expanded. Metering can be performed in any suitable manner, such as by pumping a liquid coating solution from a reservoir to a nozzle close to the surface of the medical device (for example, the surface of at least a partially expanded balloon, or the surface of the stent). The nozzle can dispense liquid from it, and since the outside of the medical device is close to the nozzle, the liquid can be immediately transferred thereto (for example, the nozzle can be very close to the balloon or stent, so that the liquid flowing from the nozzle can contact and transfer to the outside of the medical device before forming a droplet leaving the nozzle). The nozzle can dispense liquid to the outside of the medical device, so that there is basically no liquid loss. During the liquid distribution from the nozzle, the medical device can rotate around its longitudinal axis. The nozzle can be attached to a programmable xy platform to be able to move during the distribution process, such as along the outside of the medical device parallel to the longitudinal axis of the cylindrical balloon or stent or along the contour of a non-cylindrical medical device (such as a balloon) or a non-continuous medical device (such as a stent). In some embodiments, the medical device can rotate around its longitudinal axis during distribution, and the nozzle can move parallel to the longitudinal axis of the medical device so that substantially all surfaces of the medical device are coated with the coating solution (for example, similar to the movement of a woodworking chisel on a cylindrical wood block rotating on a lathe). The nozzle can move once along the length of the medical device, or it can move back and forth and pass along the length of the medical device many times. If the medical device is a stent, the stent may be coated at the manufactured diameter, the gathered diameter, or the expanded diameter, or a diameter therebetween.

[0280] The choice of application technique may depend on the viscosity and surface tension of the solution.In some embodiments of the present invention, metering techniques may be used because it is easier to control the uniformity of the coating thickness and the concentration of the therapeutic agent applied to the medical device.

[0281] In one embodiment of the invention, the balloon is inflated or partially inflated and the coating solution is applied to the inflated balloon by metering while the balloon is inflated and rotated along its longitudinal axis. The balloon is then dried before being deflated, folded and sheathed.

[0282] Embodiments of applicators, fixtures, and metering techniques are described as examples.Any suitable metering or other technique may be used to coat the balloon catheter.

[0283] After coating the medical device with the coating solution, the coated medical device can be dried, wherein the solvent in the coating solution is evaporated. This produces a coating matrix on the medical device containing the therapeutic agent. An example of a drying technique is to place the coated medical device in an oven at about 20° C. or higher for about 24 hours. Any other suitable method of drying the coating solution can be used. The time, temperature, and relative humidity can vary with the specific additives and therapeutic agents.

[0284] In one embodiment, a method for coating a balloon catheter comprises: 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; treating the premix to reduce the particle size of the therapeutic agent; mixing a water-insoluble additive, the water-soluble additive, water, and the water-miscible solvent to form a second premix; mixing the second premix with the first treated premix to form a coating solution; wherein the therapeutic agent is selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimios, analogs thereof, and ...

Claims

1. A drug release coating comprising: Polymer encapsulated drug particles comprising therapeutic agents, one or more polymers that encapsulate the therapeutic agent, and a first ionic additive or a zwitterionic additive; and A release matrix comprising a second ionic additive or a zwitterionic additive, wherein the second ionic additive or the zwitterionic additive comprises a mismatched charged phospholipid, wherein the two acyl groups of the mismatched charged phospholipid comprise mismatched acyl groups, wherein the mismatched acyl groups differ in length, saturation, substituents thereon, substitution patterns thereon, or a combination thereof.

2. The drug release coating according to claim 1, wherein the length of the mismatched acyl group is C6-C34. The drug release coating according to claim 1 , wherein the mismatched acyl groups differ in length.

4. The drug release coating according to claim 1, wherein the second ionic additive or zwitterionic additive comprises 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-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.

5. The drug release coating according to claim 1, wherein the release matrix further comprises 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-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or a combination thereof. 6 . The drug release coating according to claim 1 , wherein the polymer encapsulated drug particles account for 10 wt % to 80 wt % of the drug release coating on a dry basis.

7. The drug-releasing coating according to claim 1, wherein the one or more polymers account for 30 wt% to 80 wt% of the polymer-encapsulated drug particles, the first ionic additive or zwitterionic additive accounts for 0.5 wt% to 20 wt% of the polymer-encapsulated drug particles, and the weight ratio of the first ionic additive or zwitterionic additive to the one or more polymers in the polymer-encapsulated drug particles is 1:3 to 1:

60.

8. The drug-releasing coating according to claim 1, wherein the one or more polymers account for 50 wt% to 70 wt% of the polymer-encapsulated drug particles, the first ionic additive or zwitterionic additive accounts for 2 wt% to 10 wt% of the polymer-encapsulated drug particles, and the weight ratio of the first ionic additive or zwitterionic additive to the one or more polymers in the polymer-encapsulated drug particles is 1:5 to 1:

30.

9. The drug-releasing coating according to claim 1, wherein the polymer is at least one polymer selected from the group consisting of polylactic acid (PL), polyglycolic acid (GA), polylactic acid / polyglycolic acid copolymer (PLGA), polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycan, and copolymers thereof.

10. The drug-releasing coating of claim 1, wherein the one or more polymers include PLGA having a weight ratio of lactic acid to glycolic acid of 85:

15.

11. The drug-releasing coating of claim 1, wherein the therapeutic agent is selected from the group consisting of paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umimios, analogs thereof, and combinations thereof.

12. The drug-releasing coating of claim 1, wherein the therapeutic agent is sirolimus.

13. The drug-releasing coating according to claim 1, wherein: The polymer encapsulated drug particles have a maximum dimension greater than or equal to 0.2 microns and less than or equal to 30 microns as measured using laser refractometry.

14. The drug-releasing coating according to claim 1, wherein the second ionic additive or zwitterionic additive has a different molecular structure from the first ionic additive or zwitterionic additive.

15. The drug-releasing coating of claim 1, wherein the first ionic additive or the zwitterionic additive comprises a phospholipid.

16. The drug release coating of claim 1, wherein the first ionic additive or zwitterionic additive comprises 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-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 a combination thereof.

17. The drug release coating of claim 1, wherein the first ionic additive or zwitterionic additive comprises 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-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or a combination thereof.

18. The drug-releasing coating of claim 1, wherein the drug-releasing coating comprises one or more antioxidants, the antioxidant comprising butylated hydroxytoluene (BHT).

19. The drug-releasing coating of claim 1, further comprising pentaerythritol ethoxylate.

20. The drug-releasing coating of claim 1, wherein: The second ionic additive or zwitterionic additive includes 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), The release matrix also includes 1,2-dihexanoyl-sn-glycero-3-phosphocholine and / or 1,2-diheptanoyl-sn-glycero-3-phosphocholine, The drug release coating also includes butylated hydroxytoluene (BHT), and The drug-releasing coating further comprises pentaerythritol ethoxylate.

21. A balloon catheter, comprising: stretching the balloon; and A coating layer covering the outer surface of the balloon, wherein the coating layer comprises the drug-releasing coating according to claim 1.

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