Polymer-Encapsulated Drug Particles

Abstract

Various disclosed embodiments relate to polymer-encapsulated drug particles and drug-releasing coatings comprising the same for treating, preventing, or reducing the recurrence of stenosis in a body lumen, as well as drug-coated balloon catheters and methods of using the same. A drug-coated balloon catheter for delivering a therapeutic agent to a target site of a stenosis in a body lumen includes an expanded balloon. The balloon catheter includes a coating layer overlying the outer surface of the balloon. The coating layer includes polymer-encapsulated drug particles; or a drug-releasing coating comprising the polymer-encapsulated drug particles; or a therapeutic agent and a first or second additive; or a combination thereof.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 979,980, filed February 21, 2020, and U.S. Provisional Patent Application No. 63 / 104,965, filed October 23, 2020, the disclosures of which are hereby incorporated by reference in their entireties.

[0002] The disclosures of the following applications are hereby incorporated by reference in their entirety: U.S. Patent Application No. 16 / 135,436, a continuation-in-part of PCT / US2018 / 03108, filed May 4, 2018, which claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 502,212, filed May 5, 2017; and U.S. Patent Application No. 16 / 135,436, a continuation-in-part of U.S. Provisional Patent Application No. 15 / 568,614, filed October 23, 2017, which is a U.S. national stage application under 35 U.S.C. 371 from international application PCT / US2016 / 028652, filed April 21, 2016, which claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 152,559, filed April 24, 2015. U.S. Patent Application No. 16 / 135,436 is also a continuation-in-part of U.S. Provisional Patent Application No. 14 / 438,327, filed April 24, 2015, which is a U.S. national stage application under 35 U.S.C. 371 from International Application PCT / US2013 / 064842, filed October 14, 2013, which claims the benefit of priority to U.S. Provisional Patent Application No. 61 / 795,790, filed October 26, 2012. U.S. Patent Application No. 16 / 135,472 is a continuation-in-part of U.S. Provisional Patent Application No. PCT / US2018 / 03108, filed May 4, 2018, which claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 502,212, filed May 5, 2017. U.S. Patent Application No. 16 / 135,472 is also a continuation-in-part of U.S. Provisional Patent Application No. 15 / 568,614, filed October 23, 2017, which is a U.S. national stage application under 35 U.S.C. 371 from international application PCT / US2016 / 028652, filed April 21, 2016, which claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 152,559, filed April 24, 2015. U.S. Patent Application No. 16 / 135,472 is also a continuation-in-part of U.S. Provisional Patent Application No. 14 / 438,327, filed April 24, 2015, which is a U.S. national stage application under 35 U.S.C. 371 from International Application PCT / US2013 / 064842, filed October 14, 2013, which claims the benefit of priority to U.S. Provisional Patent Application No. 61 / 795,790, filed October 26, 2012. [Background technology]

[0003] (background) Benign prostatic hyperplasia (BPH) 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 is the size and shape of a walnut and weighs approximately 20 grams. Prostatic hyperplasia appears to be a normal process. With age, the prostate gradually increases in size to more than twice its normal size. As the prostate grows, it compresses and narrows the urethra, causing prostatic urethral compression and urinary blockage that makes voiding difficult or impossible.

[0004] Male urethral stricture disease occurs at rates as high as 0.6% in some populations. It appears to be more common in the elderly population. Patients with urethral strictures experience moderate to severe complications, such as lower urinary tract symptoms or urinary retention, recurrent urinary tract infections, and the need for repeated urethral procedures such as dilation, urethrotomy, or urethroplasty.

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

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

[0007] Strictures in the digestive body lumen 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. The type of disease classifies strictures as benign or malignant.

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

[0009] Esophageal strictures are a commonly encountered 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 symptomatic treatment to relieve the dysphagia.

[0010] Barrett's disease, also known as Barrett's esophagus, is a condition in which there is an abnormal (dysplastic) transformation of the mucosal cells lining the lower part of the esophagus from normal stratified squamous epithelium with scattered goblet cells, usually found only in the colon, to simple columnar epithelium. This transformation is considered a precancerous condition because it is associated with a high frequency of further progression to esophageal adenocarcinoma, an often fatal cancer.

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

[0012] A lower gastrointestinal stricture is a narrowing of a section of the intestine that causes problems by slowing or preventing the passage of food through that area. Strictures can be caused by recurrent inflammation, cancer, Crohn's disease, and ulcerative colitis. Strictures include esophageal strictures, achalasia strictures, stent strictures, biliary strictures, gastric strictures, small bowel strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, and large bowel strictures.

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

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

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

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

[0017] Asthma is a chronic respiratory disease characterized by airway inflammation, excessive mucus production, and airway hyperresponsiveness, as well as excessive or too easily narrowed airways that respond to stimuli. Asthma attacks or attacks cause airway narrowing, making breathing difficult. Asthma attacks can limit participation in many activities and have a significant impact on patients' lives. In severe cases, asthma attacks can be life-threatening. Currently, there is no known cure for asthma.

[0018] Chronic sinusitis is inflammation of the membrane lining of one or more paranasal sinuses. Chronic sinusitis lasts longer than three weeks and often continues for months. In cases of chronic sinusitis, tissue damage is usually 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 one of the modes of treatment for localized cancer. Localized cancer is the most commonly diagnosed cancer. The majority of patients are diagnosed at a potentially treatable early stage. Standard localized treatment options include active surveillance, radical prostatectomy (RP) for prostate cancer, and, generally, radiation therapy (RT) for all cancer treatments. Radiation therapy can be delivered via external beam radiation therapy (EBRT) or brachytherapy (BT). Side effects associated with each treatment can vary significantly. Localized cancers include prostate cancer, urethral cancer, urinary tract cancer, esophageal cancer, biliary tract cancer, gastric cancer, small intestine cancer, duodenal cancer, jejunal cancer, ileum cancer, colon cancer, rectal cancer, large intestine cancer, and lung cancer. Radiation treatment can create scars in adjacent healthy tissue, such as strictures. Radiation-induced strictures can include urethral strictures, ureteral strictures, esophageal strictures, bile duct strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, and large intestinal strictures. Treatment of radiation-induced strictures can be complex and difficult. Due to high survival rates, the number of prostate cancer survivors in the United States is increasing by 220,000 per year, to nearly 2.8 million in 2015, leaving many men at risk for short- and long-term side effects of radiation therapy for prostate cancer treatment. The development of urethral strictures as a side effect of radiation therapy for prostate cancer treatment is particularly problematic.

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

[0021] Heart disease, or atherosclerosis, is characterized by the hardening and narrowing of arteries due to the deposition of fatty plaques on the arterial lumen. Over time, plaque buildup can become severe enough to block the flow of oxygen-rich blood to downstream tissues. Atherosclerosis can occur in any artery in the body. Blockage or stenosis of vital arteries, such as the carotid and coronary arteries, can lead to sudden death. Narrowed 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 occur. Current drug-coated balloons and drug-eluting stents are used to treat stenosis. The long-term mortality, thrombosis rates, and efficacy of these drug-coated devices remain poor. Better devices are needed to improve the safety and efficacy of cardiovascular disease stenosis.

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

[0023] Heart valve disease is a common condition affecting the elderly population. It is diagnosed by listening to the heartbeat with a stethoscope during a physical examination. Abnormal sounds made by the heart are called murmurs, and various murmurs can indicate specific types of heart valve disease. Types of heart valve disease include stenosis, regurgitation, prolapse, and atresia. Heart valve stenosis is the narrowing or stiffening of a heart valve that causes it to not open or close properly. The valve flaps may thicken, stiffen, or fuse together. As a result, the valve cannot open sufficiently, and the heart must then work harder to pump blood through the valve. This can result in hypoxia or reduced oxygen supply, affecting the entire body, local tissues, or certain parts of the body. Heart valve stenosis can be treated with a procedure called balloon valvuloplasty (BAV). BAV involves tracking an inflatable balloon through the vasculature to the heart valve and then expanding the heart valve anulus. Recently, the number of BAV procedures being performed has increased as BAVs are utilized before, after, and / or during transcatheter aortic valve replacement (TAVR) procedures. Restenosis rates after BAV range from 40 to 80% at 5 to 9 months, indicating the need for improvements in devices and techniques. Summary of the Invention

[0024] (Summary of the Invention) In various embodiments, the present invention provides polymer-encapsulated drug particles comprising a therapeutic agent and one or more polymers. Optionally, the polymer-encapsulated drug particles include a first ionic or zwitterionic additive. When present, the first ionic or zwitterionic additive (or additive) is within the polymer-encapsulated drug particle, coated on the surface of the polymer-encapsulated drug particle, 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 or zwitterionic additive. When present, the first ionic or zwitterionic additive is within the polymer-encapsulated drug particle, coated on the surface of the polymer-encapsulated drug particle, or a combination thereof. The coating also comprises a release matrix comprising the ionic or zwitterionic additive. The coating can be disposed in any suitable location, such as a balloon catheter, a drug-coated catheter, a drug-eluting stent, a drug-eluting stent on a balloon, a drug-eluting stent on a drug-coated balloon, a stent on a drug-coated balloon, or a combination thereof.

[0026] In various embodiments, the present invention provides a drug-release coating comprising a polymer-encapsulated drug particle comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent. The polymer-encapsulated drug particle also comprises an ionic or zwitterionic additive. The polymer-encapsulated drug particle can be a charged polymer-encapsulated drug particle.

[0027] Various embodiments provide methods for treating or preventing non-vascular or vascular stenosis or stenosis. The method includes inserting a catheter into a body lumen, the catheter including a balloon or stent including a drug coating comprising polymer-encapsulated drug particles. The method includes expanding the balloon or stent to contact the coating layer with the stenosis, stenosis, or the area where stenosis or stenosis is to be prevented. If a balloon is used, the method can include compressing (or deflating) the balloon. Also, if a balloon is used, the method can include removing (or removing) the balloon or stent from the body lumen.

[0028] Various embodiments provide methods of making polymer-encapsulated drug particles. The method includes forming a suspension containing 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 a therapeutic agent and a polymer.

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

[0030] In various embodiments, the present invention provides methods for preparing polymer-encapsulated drug particles containing a therapeutic agent, one or more polymers, and, optionally, a first ionic or zwitterionic additive. The methods include creating an organic premix by solubilizing and mixing one or more polymers, a therapeutic agent, and, optionally, a first ionic or 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 methods include creating a second aqueous premix containing a water-soluble polymer and adding the organic solvent used in the first premix. The methods include mixing the organic premix with the aqueous premix to create an organic solvent-in-water coacervate. The methods further include adding water to the coacervate solution to drive the organic solvent from the coacervate, allowing it to harden into polymer-encapsulated drug particles.

[0031] Various embodiments provide a method of making a balloon catheter, the method comprising applying polymer-encapsulated drug particles or a drug-releasing coating comprising same to the exterior 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 layer overlying the outer surface of the balloon. The coating layer includes polymer-encapsulated drug particles; or a drug-releasing coating including polymer-encapsulated drug particles; 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, an mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, analogs thereof, and combinations thereof, and the therapeutic agent has a particle size of 0.2 microns to 10 microns. The first additive includes a water-insoluble or partially water-insoluble additive including at least one alkyl fatty group or cholesteryl group, and the first additive has a molecular weight of 50 to 750. The second additive is more hydrophilic or more water-soluble than the first additive and contains polyethylene glycol (-(CH2CHO)-) or polyglycerol (-(CH2-CHOH-CHO)-) units. The second additive has a molecular weight in the range of 750 to 100,000.

[0033] In various embodiments, the present invention provides a balloon catheter for delivering a therapeutic agent to a target site in a body lumen. The balloon catheter includes an expanded balloon and a coating layer overlying the outer surface of the balloon. The coating layer includes polymer-encapsulated drug particles; or a drug-releasing coating including polymer-encapsulated drug particles; or a composition including two or more additives and an initial drug load 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, umirolimus, analogs thereof, and combinations thereof. The therapeutic agent in the composition is crystalline, partially crystalline, amorphous (or amorphous), partially amorphous, or a combination thereof. The first additive comprises a water-insoluble or partially water-insoluble additive comprising at least one alkylaliphatic group or cholesteryl group, having a molecular weight of 50 to 750 (e.g., 50 or more, or less than or equal to 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 water-soluble than the first additive and comprises polyethylene glycol (-(CHCHO)-) or polyglycerol (-(CH-CHOH-CHO)-) units. The second additive has a molecular weight in the 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 in the range of 0.2 microns to 10 microns (e.g., 0.2 microns or greater, or less than 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 of narrowing or stenosis in a body lumen. The balloon catheter includes an expanded balloon and a coating layer overlying the outer surface of the balloon. The coating layer includes polymer-encapsulated drug particles; or a drug-releasing coating including polymer-encapsulated drug particles; or a composition including two or more additives and an initial drug load of a therapeutic agent. The balloon includes polyester, polyamide, nylon 12, nylon 11, polyamide 12, a block copolymer of polyether and polyamide, a polyether block amide, polyurethane, a block copolymer of polyether and polyester, or a combination thereof. The therapeutic agent in the composition is selected from paclitaxel, docetaxel, taxol, analogs thereof, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, 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 is in the range of 0.2 microns to 5 microns (e.g., 0.2 microns or greater, or less than 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 less than or equal to 5 microns). In embodiments involving compositions, the first additive, the second additive, or a combination thereof, encapsulates a therapeutic agent, and the therapeutic agent encapsulated in the additive has a particle size larger than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive in the coating is in the range of 0.3 microns to 10 microns (e.g., 0.3 microns or more, or less than or equal to 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 involving compositions, the therapeutic agent is dispersed in an additive (e.g., individual particles,The therapeutic agent encapsulated in the additive is partially or completely encapsulated such that it is partially or completely surrounded by the first additive, the second additive, or a combination thereof (e.g., as a continuous or partially continuous coating). For example, 25% to 100% of the surface area of ​​the therapeutic agent encapsulated in the additive can 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 or equal to 25%, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99%, or less than 100%. The first additive can include a water-insoluble or slightly or partially water-insoluble additive containing at least one alkylaliphatic group or cholesteryl group, and the first additive can have a molecular weight of 50-750. In embodiments involving the composition, the first additive in the coating has a lower melting temperature than the first additive in its pure form, and the first additive in the coating has a lower crystallinity than the first additive in its pure form. The second additive is more hydrophilic or more water-soluble than the first additive, and it contains polyethylene glycol (-(CHCHO)-) or polyglycerol (-(CH-CHOH-CHO)-) units. The second additive has a molecular weight in the range of 750 to 100,000, 750 to 50,000, or 750 to 10,000. The body lumen stricture or stricture disease is selected from urethral stricture, prostatic urethral stricture, ureteral stricture, esophageal stricture, sinus stricture, gastric stricture, small intestinal stricture, colonic stricture, rectal stricture, large intestinal stricture, bladder neck stricture, bile duct stricture, vaginal 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 additives with a cholesteryl group are cholesterol, cholesteryl acetate, cholesteryl phenylacetate, cholesteryl laurate, cholesteryl palmitate, cholesteryl stearate, cholesteryl n-valerate, cholesteryl benzoate, cholesteryl heptylate, cholesteryl decylate, cholesteryl caproate, cholesteryl oleate, cholesteryl oleyl carbonate, cholesteryl linoleate, cholesteryl pelargonate, cholesteryl erucate, cholesteryl caprylate, 5α-cholestane,The water-insoluble or slightly or partially water-insoluble first additive having an alkyl aliphatic group is selected from alkyl glyceryl ethers, monoglycerides of C8-C12 fatty acids, alkyl alcohols, alkyl ethers, alkyl esters, caprylic acid, monocaprylin, capric acid, monocapric acid, lauric acid, dodecylglycerol, butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic ... The lipids are selected from lumitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha linolenic acid, gamma linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di-, or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobee, niosomes, derivatives thereof, and combinations thereof. Water-soluble second additives include cholesteryl-polyethylene glycol 600 sebacate, polyoxyethanyl α-tocopheryl sebacate, methylated polyethylene glycol cholesterol (mPEG cholesterol), polyethylene glycol cholesterol (PEG cholesterol), polyethylene glycol ester cholesterol (PEG cholesterol), polyethylene glycol ether cholesterol (PEG cholesterol), methylated polyethylene glycol-amide-cholesterol (mPEG cholesterol),Polyethylene glycol-amide-cholesterol (PEG cholesterol), polyethylene glycol (PEG)-cholesteryl sebacate, polyethylene glycol cholesterol, PEG amido ester cholesterol, PEG amido ether cholesterol, mPEG amido 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, 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 1L), Polyglyceryl-10 Oleate (Nikkol Decaglyn 1-O), Polyglyceryl-10 Mono / Dioleate (CaproI™ 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 strictures in a digestive body lumen or the gastrointestinal tract. The method includes inserting a balloon catheter into a target site in a body lumen containing a non-vascular stricture. The balloon catheter includes an expanded balloon and a coating layer overlying the balloon's outer surface. The coating layer includes polymer-encapsulated drug particles; or a drug-releasing coating including polymer-encapsulated drug particles; or a composition including two or more additives and an initial drug load of a therapeutic agent. The composition includes a first additive including a water-insoluble or partially water-insoluble additive, a second additive having a higher affinity or water solubility than the first additive, and an initial drug load of a therapeutic agent selected from paclitaxel, docetaxel, taxol, an mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, analogs thereof, and combinations thereof. In an embodiment involving the composition, the first additive, the second additive, or a combination thereof encapsulates a therapeutic agent, the therapeutic agent encapsulated in the additive has a particle size larger than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive in the coating ranges from 0.3 microns to 10 microns. The method includes inflating the balloon at the target site to contact the coating layer with the wall of the body lumen at the location of the non-vascular stenosis until the balloon achieves an inflated balloon diameter for an inflation period. The method includes compressing the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body lumen. Strictures in the digestive body lumen 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, ileo-anal J-pouch strictures, and large intestinal strictures. Strictures in the digestive body 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 a stenosis or stenosis in a vascular body lumen. The method includes inserting a balloon catheter into a target site in a body lumen containing a vascular stenosis or stenosis. The balloon catheter includes an expanded balloon and a coating layer overlying the outer surface of the balloon. The coating layer includes polymer-encapsulated drug particles; or a drug-releasing coating including polymer-encapsulated drug particles; or a composition including two or more additives and an initial drug load of a therapeutic agent. The composition includes a first additive, a second additive, and an initial drug load of a therapeutic agent selected from paclitaxel, docetaxel, taxol, an mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, 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 of the therapeutic agent is in the range of 0.2 microns to 5 microns. In embodiments involving compositions, the first additive, the second additive, or a combination thereof encapsulates a therapeutic agent, and the therapeutic agent encapsulated in the additive has a larger particle size than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive 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 containing at least one alkylaliphatic group or cholesteryl group, and the first additive can have a molecular weight of 50 to 750. In embodiments involving compositions, the first additive in the coating has a lower melting temperature than the first additive in its pure form, and the first additive in the coating has a lower crystallinity than the first additive in its pure form. The second additive is more hydrophilic or more water-soluble than the first additive, and it contains polyethylene glycol (-(CHCHO)-) or polyglycerol (-(CH-CHOH-CHO)-) units. The molecular weight of the second additive is in the range of 750 to 100,000. The method includes inflating a balloon at the target site to contact the coating layer with the wall of the body lumen at the location of the stenosis or stenosis until the balloon achieves an inflated balloon diameter for an inflation period.The method includes compressing the balloon after the inflation period. The method includes withdrawing 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, where the therapeutic agent is selected from paclitaxel, docetaxel, taxol, an mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, analogs thereof, and combinations thereof. The method includes processing the therapeutic agent so that a majority of the therapeutic agent crystals have a particle size between 0.2 microns and 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, where the first additive encapsulates the therapeutic agent crystals, and the first additive has a particle size between 0.3 microns and 10 microns. The method includes applying the mixture to the exterior surface of the balloon catheter. The first additive, the second additive, or a combination thereof encapsulates a therapeutic agent, wherein the therapeutic agent encapsulated in the additive has a particle size larger than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in the additive in the coating is in the range of 0.3 microns to 10 microns.

[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 mixture. The method includes processing the premix to reduce the particle size of the therapeutic agent. The method includes mixing an insoluble water-soluble additive, a water-soluble additive, water, and a water-miscible solvent to form a second premix. The method includes mixing the second premix with the first processed premix to form a coating solution. The therapeutic agent is selected from paclitaxel, docetaxel, taxol, an mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, 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 is in the range of 0.2 microns to 5 microns. The first additive, the second additive, or a combination thereof encapsulates a therapeutic agent, the encapsulated therapeutic agent having a particle size larger than the therapeutic agent itself, and the particle size of the encapsulated therapeutic agent in the additive in the coating ranges from 0.3 microns to 10 microns. The process is one of microfluidization, homogenization, rotor-stator milling, high or low energy bead milling, or high-power ultrasonic probe homogenization. The first additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one alkylaliphatic or cholesteryl group, and the first additive can have a molecular weight of 50 to 750. The first additive in the coating has a lower melting temperature than the first additive in its pure form (e.g., as determined by DSC of the coating versus DSC of the pure additive). The first additive in the coating has a lower crystallinity than the first additive in its pure form (eg, as determined by DSC of the coating versus DSC of the pure additive).The second additive is more hydrophilic or more water-soluble than the first additive and contains polyethylene glycol (-(CHCHO)-) or polyglycerol (-(CH-CHOH-CHO)-) units. The second additive has a molecular weight in the range of 750 to 100,000, or 750 to 50,000, or 750 to 10,000.

[0039] In various embodiments, the present invention provides a method for coating a balloon catheter. The method includes preparing an aqueous suspension coating solution. The preparation of the aqueous suspension includes mixing water, a water-miscible solvent, a therapeutic agent, and a water-soluble additive to form a premix. The preparation of the suspension includes processing the premix to reduce the particle size of the therapeutic agent. The preparation of the suspension includes mixing an insoluble water-soluble additive, a water-soluble additive, water, and a water-miscible solvent to form a second premix. The preparation of the suspension includes mixing the second premix with the first processed premix to form a coating solution. The therapeutic agent can be an mTOR inhibitor (e.g., rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, or a combination thereof) or an analog or derivative thereof. The therapeutic agent can be crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof. The coating solution is an aqueous suspension of the therapeutic agent. The particle size of the therapeutic agent is in the range of 0.2 microns to 5 microns. The first additive, the second additive, or a combination thereof encapsulates a therapeutic agent, and the therapeutic agent encapsulated in the additive has a particle size larger than the therapeutic agent itself, and the particle size of the therapeutic agent encapsulated in 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 containing at least one alkylaliphatic group or cholesteryl group, and the first additive can have a molecular weight of 50 to 750. The first additive in the coating has a lower melting temperature than the first additive in its pure form. The first additive in the coating has a lower crystallinity than the first additive in its pure form. The second additive is more hydrophilic or more water-soluble than the first additive, and it contains polyethylene glycol (-(CH2CHO)-) or polyglycerol (-(CH2-CHOH-CHO)-) units. The second additive has a molecular weight in the range of 750 to 100,000, or 750 to 50,000, or 750 to 10,000. The method includes preparing a balloon catheter. Preparing the balloon catheter includes inflating the balloon catheter.The preparation of the balloon catheter includes cleaning the surface of the balloon, such as with an ethanol wipe. The preparation of the balloon catheter includes fixing the balloon so that it can be mounted horizontally inside a coating machine and rotated at a fixed speed. The method includes dispensing the coating solution onto the surface of the balloon while a nozzle moves laterally across the balloon. The method includes continuing to rotate the balloon to evaporate the solvent at or above room temperature. The method includes pleating and folding the balloon catheter. The method includes sterilizing the coated balloon catheter.

[0040] In various embodiments, the present invention provides a minimally invasive method for treating or preventing non-vascular or vascular stenosis or stenosis. The method includes inserting a catheter having an expandable body through a body lumen containing the stenosis or stenosis so that the expandable body is within the stenosis or stenosis. Catheters with expandable bodies include balloon catheters, drug-coated catheters, drug-eluting stents, and corrugated drug-eluting stents on drug-coated balloons. The catheter includes an expandable body with a coating layer overlying the outer surface of the expandable body of the catheter. The coating layer comprises polymer-encapsulated drug particles; or a drug-release coating comprising polymer-encapsulated drug particles; or a composition comprising two or more additives and an initial drug load of a therapeutic agent. The one or more additives are selected from a water-insoluble additive, a slightly or partially water-soluble additive, a water-soluble additive, or a combination thereof. The method includes expanding the body to a certain diameter for a period of time to contact the coating layer with the stenotic or constricted body lumen. After the period of time, the method includes contracting the expanded body and retrieving it from the stenotic or constricted 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 medical device (or medical device) coating formulations comprising a therapeutic agent or drug for treating stenosis in non-vascular and vascular body lumens and an additive that enhances drug absorption into the tissue of the body lumen. Some embodiments provide coatings covering the expandable portion of a catheter having a single 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 contain a therapeutic agent and is formulated with components that allow all or a substantial portion of the coating to be transferred to the stenosis or stenosis upon expansion of the catheter. Causes of and associated diseases of stenosis in body lumens include infection and inflammation caused by pathogens such as bacteria and viruses. In some embodiments, the coating comprises an additive with antibacterial and antiviral properties. In some embodiments, the coating layer containing the therapeutic agent comprises a drug that is crystalline, amorphous, or a combination thereof. In some embodiments, the coating layer containing the therapeutic agent comprises at least one hydrophilic component and at least one hydrophobic component. In some embodiments, the coating layer comprises a component that enhances adhesion of the coating to the luminal surface of the dilated stenosis or stenosis. In some embodiments, the coating is formulated so that upon expansion of the catheter, the coating is transferred to the stenosis or stenosis as microparticles, agglomerated microparticles, dissolved substances, or a combination thereof. In some embodiments, the transferred microparticles or agglomerated microparticles have a small size, less than 10 μm, or more preferably less than 5 μm. In some embodiments, the coating layer comprises polymer-encapsulated drug particles or a drug-releasing coating comprising the same.

[0042] In various embodiments, the present invention provides a catheter including an elongated body expandable portion for use in dilating non-vascular and vascular stenoses or stenoses. In some embodiments, the elongated body is a cylindrical balloon. In some embodiments, the elongated body is a balloon having a shape or longitudinal profile that prevents movement of the balloon within the body lumen in which it is expanded.

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

[0044] BRIEF DESCRIPTION OF THE DRAWINGS The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present invention. [Brief explanation of the drawings]

[0045] [Figure 1] FIG. 1 is a perspective view of an embodiment of a balloon catheter according to the present invention, according to various embodiments (the balloon catheter includes a fixed wire-on-wire, rapid exchange balloon catheter details are not shown in FIG. 1). [Figures 2A-2C] 2A-2C are cross-sectional views of different embodiments of the distal portion of the balloon catheter of FIG. 1 at line AA, showing exemplary coating layers according to various embodiments. [Figure 3A] FIG. 3A shows a balloon catheter having one neck, according to various embodiments. [Figure 3B] FIG. 3B shows a balloon catheter having two necks, according to various embodiments. [Figure 3C] FIG. 3C shows a three-necked balloon catheter, according to various embodiments. [Figures 4A-4D]4A-4D show balloon catheters including an elongated rigid member that is a spring, according to various embodiments. [Figure 5] FIG. 5 shows an elongated rigid member that is a spring, according to various embodiments. [Figure 6] FIG. 6 is a chart (or illustration, or diagram) and table showing an example of drug coating particle size analysis using a Beckman Coulter LS 13 320 Particle Sizing Analyzer with a Liquid Analyzer Module, according to various embodiments. [Figure 7A-7C] 7A-C show SEM images of examples of sirolimus, according to various embodiments, with FIG. 7A showing 37x magnification, FIG. 7B showing 1,600x magnification, and FIG. 7C showing 7,500x magnification. [Figures 8A-8C] 8A-C show graphs of typical powder X-ray diffraction graphs obtained from FIG. 8A crystalline sirolimus, FIG. 8B dodecylglycerol, and FIG. 8C sterilized sirolimus drug coating on a balloon. [Figures 9A-9C] 9A-C show plots of DSC scans of FIG. 9A crystalline sirolimus, FIG. 9B dodecylglycerol, and FIG. 9C sirolimus drug coated balloon, according to various embodiments. [Figure 10] FIG. 10 shows a graph of sirolimus particle size reduction obtained with high pressure homogenizers according to various embodiments. [Figure 11] FIG. 11 shows no-reintervention Kaplan-Meier curves for paclitaxel-coated balloon treatment in the esophagus and intestine according to various embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0046] (Detailed Description of the Invention) Reference will now be made to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the scope of the claims to the disclosed subject matter.

[0047] Throughout this document, values ​​expressed in range format should be interpreted in an open manner to include not only the numerical ranges explicitly recited as limits of the range, but also all of the individual numerical values ​​or subranges subsumed within that range, as if those numerical values ​​and subranges were explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within that stated range. The expression "about X to Y" has the same meaning as "about X to about Y" unless otherwise specified. Similarly, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise specified.

[0048] Throughout this document, 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 statement "at least one of A and B" has the same meaning as "A, B, or A and B." Additionally, phrases or terms used or otherwise defined herein should be understood to be for descriptive purposes only and not for purposes of limitation. Any use of section headings is intended to aid in the reading of the document and should not be construed as limiting; information associated with a section heading may occur within or outside that particular section.

[0049] In the methods described herein, acts may be performed in any order without departing from the principles of the invention, unless a temporal or operational order is explicitly recited. Furthermore, specified acts may be performed simultaneously unless express claim language recites that they must be performed separately. For example, a claimed act of performing X and a claimed act of performing Y may be performed simultaneously in a single operation, and the resulting process would be within the literal scope of the claimed process.

[0050] As used herein, the term "about" allows for a degree of variability within a value or range, for example, within 10%, within 5%, or within 1% of the stated limits of the stated value or range, including the exact stated value or range.

[0051] As used herein, the term "substantially" refers to a majority or 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%.

[0052] Polymer-Encapsulated Drug Particles Various embodiments provide polymer-encapsulated drug particles. The polymer-encapsulated drug particles comprise a therapeutic agent and one or more polymers that encapsulate the therapeutic agent. Optionally, the polymer-encapsulated drug particles comprise a first ionic or zwitterionic additive. When present, the first ionic or zwitterionic additive is located within the polymer-encapsulated drug particle (e.g., encapsulated by the encapsulating polymer), coated on the surface of the polymer-encapsulated drug particle (e.g., on the outer surface of the encapsulating polymer), or a combination thereof. In some embodiments, the polymer-encapsulated drug particles comprise a first ionic or zwitterionic additive. In other embodiments, the polymer-encapsulated drug particles do not comprise a first ionic or zwitterionic additive.

[0053] 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, umirolimus, analogs thereof, and combinations thereof. The therapeutic agent is 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 dimension (e.g., diameter), for example, 0.1 to 29.9 microns, 0.5 to 15 microns, 1 to 10 microns, or less than 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 can form any suitable proportion of the polymer-encapsulated drug particles, for example, 5-45% by weight, 25-35% by weight, or up to 45% by weight, and 5, 10, 15, 20, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 40% by weight or more.

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

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

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

[0057] The first ionic or zwitterionic additive can include a cationic molecule, an anionic additive, or a zwitterionic additive. The first ionic or zwitterionic additive can increase the zeta potential (i.e., make the zeta potential more positive) of the polymer-encapsulated drug particles. The positive zeta potential of the polymer-encapsulated drug particles can provide better adhesion to tissues and / or better drug transport 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 in the lipid bilayer of cell membranes (e.g., anions on the surface of cell membranes), resulting in better adhesion. Increased adhesion can extend the stay of the polymer-encapsulated drug particles on the walls of body lumens, leading to higher drug doses and / or a greater percentage of drug delivered to tissues. The first ionic or zwitterionic additive can include a charged polymer, a charged lipid, a phospholipid, a phosphocholine, a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylserine, a phosphatidylinositol, and combinations thereof.

[0058] The two acyl groups of a charged lipid or a charged phospholipid (e.g., an ester attached to a triglyceride backbone) may differ in one or more properties or characteristics, including mismatched acyl groups. Mismatched acyl groups may differ in length, degree of saturation, their substituents, their substitution pattern, or a combination thereof. For example, both acyl groups may be saturated, or one may be saturated and one 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 one saturated and one unsaturated acyl group. In embodiments containing 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 at the same or different positions along the carbon chain. Mismatched or matched acyl groups with different lengths, degrees of saturation, their substituents, and substitution patterns can have different phase transition or softening temperatures. The phase transition or softening temperature of a charged lipid can affect the properties of the coating, such as coating integrity, drying durability, the rate of drug release from the coating, the rate and / or extent of tissue uptake, or a combination thereof. Lipids and phospholipids with high phase transition temperatures can lead to brittle coatings that crack and peel, leading to inconsistent drug dosing. Lipids and phospholipids with low phase transition temperatures can be difficult to handle because they are wet and sticky, which can lead to inconsistent drug dosing. The phase transition temperatures of charged lipids and phospholipids can range from -70°C to 80°C. The preferred range of phase transition temperatures is -30°C to 50°C. The most preferred range of phase transition temperatures is -20°C to 40°C. In some embodiments, the coating is It is possible to have a mixture of lipids and / or phospholipids that allows the phase transition temperature of the coating to be in a desired range with desirable mechanical properties (dry, flexible, not sticky or brittle).

[0059] The mismatched acyl group of the charged lipid or charged phospholipid can have a length of C6 to C34, e.g., 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 having chain lengths of C6 to C34 can create perturbations, irregularities, and / or bends in the lipid bilayer of a cell membrane to enhance drug penetration into tissues. In embodiments comprising charged lipids or phospholipids with mismatched acyl groups that differ in length, the lengths of the two acyl groups can differ by C1 to C28, C1 to C10, or C1 to C8, or C1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or more, or C28 in length. For example, two acyl groups differing in length can have lengths of C12 / C14, C12 / C16, C12 / C18, C12 / C20, C12 / C22, C12 / C24, C12 / C26, C14 / C16, C14 / C18, C14 / C20, C14 / C22, C14 / C24, C14 / C26, C16 / C18, C16 / C20, C16 / C22, C16 / C24, C16 / C26, C18 / C20, C18 / C22, C18 / C24, C18 / C26, C20 / C22, C20 / C24, C20 / C26, C22 / C24, C22 / C26 or C24 / C26.

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

[0061] The charged lipids are 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-dihept ... 1,2-Dioctanoyl-sn-glycero-3-phosphocholine, 1,2-Dinonanoyl-sn-glycero-3-phosphocholine, 1,2-Decanoyl-sn-glycero-3-phosphocholine, 1,2-Diundecanoyl-sn-glycero-3-phosphocholine, 1,2-Dilauroyl-sn-glycero-3-phosphocholine, 1,2-Dimyristoyl-sn-glycero-3-phosphocholine Phosphorus, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phospho 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, dieicosenoyl Phosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoyl phosphatidylcholine (1,2-diarachidonyl-sn-glycero-3-phosphocholine, C20:0 PC), dierucoyl phosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoyl phosphatidylcholine (1,The phosphocholine may be selected from 2-didocosahexaenoyl-sn-glycero-3-phosphocholine (C22:6 PC), heneicosenoyl phosphatidylcholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine (C21:1 PC), and dinervonyl phosphatidylcholine (1,2-dinervonyl-sn-glycero-3-phosphocholine (C24:1 PC), and combinations thereof.

[0062] The first ionic or zwitterionic additive may be 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 Phosphorus, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOP) C), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, and combinations thereof.

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

[0064] The polymer-encapsulated drug particles can have any suitable zeta potential, such as a negative zeta potential or a positive zeta potential. Zeta potential is the potential at the slip plane (i.e., at the interface separating the mobile fluid from the fluid that remains attached to the surface of the particle). The zeta potential of the polymer-encapsulated drug particles can be measured by any suitable method, such as using electrophoretic light scattering (ELS) or electroacoustic measurements. The polymer-encapsulated drug particles can have a positive zeta potential, such as a zeta potential of greater than zero (0), 1 to 50, or 2 to 40, or less than 50, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, or 45 or greater. The polymer-encapsulated drug particles can have a negative zeta potential, such as a zeta potential less than zero (0), or between -1 and -50, or between -2 and -40, or more positive than or equal to -50 and more positive than or equal to -45, -40, -35, -30, -25, -20, -18, -16, -14, -12, -10, -8, -6, -5, -4, -3, -2, -1, or -0.5. The positive zeta potential of the polymer-encapsulated drug particles can provide better adhesion to tissues and / or better drug transport through 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 in the lipid bilayer of a cell membrane (e.g., anions on the surface of the cell membrane), resulting in better adhesion. Increased adhesion can prolong the stay of the polymer-encapsulated drug particles on the walls of the body lumen, leading to higher drug doses and / or a greater percentage of drug delivered to the tissue. In embodiments of polymer-encapsulated drug particles that contain a first ionic or zwitterionic additive thereon, the zeta potential of the polymer-encapsulated drug particle can be higher (i.e., more positive) than that of a corresponding polymer-encapsulated drug particle that does not contain the first ionic or zwitterionic additive. Polymer-encapsulated drug particles that are CPDEPs are polymer-encapsulated drug particles that have a non-zero zeta potential, for example, due to the presence of a first ionic or zwitterionic additive inside the particle, on the surface of the particle, or a combination thereof, and / or the use of one or more charged polymers as the encapsulating polymer. The ionic or zwitterionic additive in the CPDEP particle can migrate to and / or be applied to the surface of the CPDEP particle. The charged head of the ionic or zwitterionic additive can be oriented away from the particle, and the hydrophobic tail can be oriented toward the particle, so that the zeta potential of the polymer-encapsulated drug particle is higher.

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

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

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

[0068] The polymer-encapsulated drug particles can be on any suitable surface intended for drug delivery to a target location, for example, on 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 on the medical device, and the coating is a drug-releasing coating.

[0069] Drug-releasing coatings comprising polymer-encapsulated drug particles Various embodiments of the present invention provide a drug-release coating. The drug-release coating comprises a polymer-encapsulated drug particle comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent. Optionally, the polymer-encapsulated drug particle comprises a first ionic or zwitterionic additive. The first ionic or zwitterionic additive, if present, is coated on the surface of the polymer-encapsulated drug particle, the polymer-encapsulated drug particle, or a combination thereof. In some embodiments, the polymer-encapsulated drug particle comprises a first ionic or zwitterionic additive. In other embodiments, the polymer-encapsulated drug particle does not comprise a first ionic or zwitterionic additive. The drug-release coating also comprises a release matrix comprising a second ionic or zwitterionic additive. Any drug-containing coating (e.g., drug coating or drug coating layer) referred to herein may be or comprise a drug-release coating comprising a polymer-encapsulated drug particle.

[0070] The polymer-encapsulated drug particles can be homogeneously dispersed in the release matrix. The polymer-encapsulated drug particles can be formed in any suitable proportion of the drug-release coating, for example, 10% to 90% by weight, 10% to 80% by weight, 25% to 70% by weight, 40% to 60% by weight, or 90% or less and 10%, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85% or more by weight.

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

[0072] The second ionic or zwitterionic additive can have the same molecular structure as the first ionic or zwitterionic additive, or the second ionic or zwitterionic additive can have a different molecular structure from the first ionic or zwitterionic additive. The drug-release coating can include one, two, three, or four or more second ionic or zwitterionic additives, e.g., one or two second ionic or zwitterionic additives, e.g., two second ionic or zwitterionic additives. The one or more second ionic or zwitterionic additives can form any suitable proportion of the drug-release coating, e.g., 10-80 wt%, 40-60 wt%, or up to 80 wt%, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 wt% or more.

[0073] The second ionic or zwitterionic additive can include a cationic molecule, an anionic additive, or a zwitterionic additive. The second ionic or zwitterionic additive can increase the zeta potential (i.e., make it more positive) of the drug-release coating, which can increase the adhesion of the drug-release coating to tissue and / or increase the rate of drug migration from the coating to tissue. For example, the positive zeta potential of the drug-release coating can attract amino groups in peptides or proteins and / or negatively charged lipids in the lipid bilayer in cell membranes (e.g., anions on the surface of cell membranes), resulting in better adhesion. Increased adhesion can extend the stay of the drug-release coating on the wall of a body lumen, leading to higher drug doses and / or greater rates of drug delivery to tissue. The second ionic or zwitterionic additive can include charged polymers, charged lipids, phospholipids, phosphocholines, phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylinositols, and combinations thereof. The second ionic or zwitterionic additive can migrate to the surface of the drug-release coating. The charged head of the ionic or zwitterionic additive can be oriented away from the coating and the hydrophobic tail can be oriented toward the coating, resulting in a higher zeta potential for the coating.

[0074] The two acyl groups of a charged lipid or a charged phospholipid (e.g., an ester attached to a triglyceride backbone) comprise mismatched acyl groups, which differ in one or more properties or characteristics. The mismatched acyl groups can differ in length, degree of saturation, their substituents, their substitution pattern, or a combination thereof. For example, both acyl groups can be saturated, or one can be saturated and one can be unsaturated, or both can 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 one saturated and one unsaturated acyl group. In embodiments containing two unsaturated acyl groups, the unsaturated acyl groups can have double bonds at the same or different carbon positions, or can have multiple double bonds at the same or different positions along the carbon chain. Mismatched or matched acyl groups with different lengths, degrees of saturation, their substituents, and substitution patterns can have different phase transition or softening temperatures. The phase transition or softening temperature of a charged lipid can affect the properties of the coating, such as coating integrity, drying durability, the rate of drug release from the coating, the rate and / or extent of tissue uptake, or a combination thereof. Lipids and phospholipids with high phase transition temperatures can lead to brittle coatings that crack and peel, leading to inconsistent drug dosing. Lipids and phospholipids with low phase transition temperatures can be difficult to handle because they are wet and sticky, which can lead to inconsistent drug dosing. The phase transition temperatures of charged lipids and phospholipids can range from -70°C to 80°C. The preferred range of phase transition temperatures is -30°C to 50°C. The most preferred range of phase transition temperatures is -20°C to 40°C. In some embodiments, the coating is It is possible to have a mixture of lipids and / or phospholipids that allows the phase transition temperature of the coating to be in a desired range with desirable mechanical properties (dry, flexible, not sticky or brittle).

[0075] The mismatched acyl group of the charged lipid or charged phospholipid can have a length of C6 to C34, e.g., 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 having chain lengths of C6 to C34 can create perturbations, irregularities, and / or bends in the lipid bilayer of a cell membrane to enhance drug penetration into tissues. In embodiments comprising charged lipids or phospholipids with mismatched acyl groups that differ in length, the lengths of the two acyl groups can differ by C1 to C28, C1 to C10, or C1 to C8, or C1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or more, or C28 in length. For example, two acyl groups differing in length can have lengths of C12 / C14, C12 / C16, C12 / C18, C12 / C20, C12 / C22, C12 / C24, C12 / C26, C14 / C16, C14 / C18, C14 / C20, C14 / C22, C14 / C24, C14 / C26, C16 / C18, C16 / C20, C16 / C22, C16 / C24, C16 / C26, C18 / C20, C18 / C22, C18 / C24, C18 / C26, C20 / C22, C20 / C24, C20 / C26, C22 / C24, C22 / C26 or C24 / C26.

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

[0077] The charged lipids are 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-dihept ... 1,2-Dioctanoyl-sn-glycero-3-phosphocholine, 1,2-Dinonanoyl-sn-glycero-3-phosphocholine, 1,2-Decanoyl-sn-glycero-3-phosphocholine, 1,2-Diundecanoyl-sn-glycero-3-phosphocholine, 1,2-Dilauroyl-sn-glycero-3-phosphocholine, 1,2-Dimyristoyl-sn-glycero-3-phosphocholine Phosphorus, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phospho 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, dieicosenoyl Phosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoyl phosphatidylcholine (1,2-diarachidonyl-sn-glycero-3-phosphocholine, C20:0 PC), dierucoyl phosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoyl phosphatidylcholine (1,The phosphocholine may be selected from 2-didocosahexaenoyl-sn-glycero-3-phosphocholine (C22:6 PC), heneicosenoyl phosphatidylcholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine (C21:1 PC), and dinervonyl phosphatidylcholine (1,2-dinervonyl-sn-glycero-3-phosphocholine (C24:1 PC), and combinations thereof.

[0078] The second ionic or zwitterionic additive may be 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 Phosphorus, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOP) C), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, and combinations thereof.

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

[0080] The drug-releasing coating can be on any suitable surface intended for drug delivery to a target location, for example, on 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 combinations thereof.

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

[0082] Methods for Making Polymer-Encapsulated Drug Particles and / or Drug-Release Coatings Various embodiments provide methods for making polymer-encapsulated drug particles comprising a therapeutic agent and one or more polymers that encapsulate the therapeutic agent. The method includes forming a suspension comprising the therapeutic agent and a polymer. The suspension can contain undissolved solid therapeutic agent particles. 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 can be the final product or can be an intermediate in further processing to achieve particular embodiments of the polymer-encapsulated drug particles of the present invention.

[0083] The treatment can be any suitable treatment that reduces the particle size of the suspension. The treatment can include sonication. The method can further include adding a first ionic or zwitterionic additive to the suspension or the formed polymer-encapsulated drug particles to coat the particles thereon. The method can further include forming a suspension containing a therapeutic agent, a polymer, and a first ionic or zwitterionic additive such that the formed polymer-encapsulated drug particles contain the first ionic or zwitterionic additive therein, thereon, or a combination thereof.

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

[0085] A method for making polymer-encapsulated drug particles can include forming an organic premix containing an organic solvent, one or more polymers, a therapeutic agent, and, optionally, a first ionic or zwitterionic additive. The method can include forming an aqueous premix containing water and a water-soluble polymer or surfactant. The method can 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 can be a polar organic solvent. The method can include combining the aqueous premix and the organic premix together. The method can include stirring the combined aqueous premix and organic premix to form an emulsion containing the polymer-encapsulated drug particles. The method can include adding water to the emulsion containing the polymer-encapsulated particles to harden the formed polymer-encapsulated drug particles. The method can include separating the polymer-encapsulated drug particles from the combined aqueous premix and organic premix. The method can include washing the polymer-encapsulated drug particles with an aqueous liquid, drying the polymer-encapsulated drug particles, or a combination thereof. The aqueous liquid used for washing can optionally contain one or more water-soluble additives, such as any of the water-soluble additives described herein or ionic or zwitterionic additives, which can coat the polymer-encapsulated drug particles during washing. Coating the polymer-encapsulated drug particles during washing can alter the zeta potential of the polymer-encapsulated drug particles.

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

[0087] The water-soluble polymer or surfactant of the aqueous premix can be any suitable water-soluble polymer or surfactant, such as any of the water-soluble polymers or surfactants disclosed herein, such as polyvinyl alcohol, polyethylene glycol, phosphatidylcholine, or combinations thereof. The water-soluble polymer or surfactant can be N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-aminopropyl)amino]butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide, 1,2-di-O-octadekenyl-3-trimethylammonium propane (chloride salt), 1,2-distearoyl-3-dimethylammonium propane, 1,2-dioleoyl-3-trimethylammonium propane (chloride salt), N 4-cholesteryl-spermine HCl salt, 1,2-dioleyloxy-3-dimethylaminopropane, calcidiol, cholecalciferol, 1α and 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), hydroxy-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.

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

[0089] A method for forming a drug-release coating can include forming a first mixture containing polymer-encapsulated drug particles and an organic solvent. The first mixture can be a dispersion of polymer-encapsulated drug particles in an organic solvent, for example, by a suitable mixing method, such as sonic probe mixing, a stir bar, a vortexer, an overhead stirrer, or a rotor stirrer. The method can include forming a second mixture containing a second ionic or zwitterionic additive and an organic solvent. The method can include combining the first and second mixtures. In some embodiments, the organic solvents of the first and second mixtures are nonpolar organic solvents such as hexane, cyclohexane, heptane, or pentane. In some embodiments, the organic solvents of the first and second mixtures are the same organic solvent. The method can include drying the combination of the first and second mixtures to form a drug-release coating. The method can include stirring the combination of the first and second mixtures prior to drying to homogeneously disperse the polymer-encapsulated drug particles therein.

[0090] The second ionic or zwitterionic additive used to form the drug-release coating may be any suitable material described herein, for example, a phospholipid, 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, or the like, in a non-polar solvent such as hexane, cyclohexane, heptane, or pentane. , 1,2-dilauroyl-sn-glycero-3-phosphoglycerol (sodium salt), 1,2-dihexanoyl-sn-glycero-3-phosphocholine, 1,2-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 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-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-Palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine, 1,2-Dimyristoyl-sn-glycero-3-phosphocholine, 1,2-Dipalmi ... The second premix may be phospholipids such as oleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine, and combinations thereof. The second premix may be heated to ensure complete dissolution of the phospholipids. The second premix may then be allowed to cool once heated, and then added to the first premix.The final mixture of the two mixtures can be thoroughly mixed by any suitable mixing method, for example, sonic probe mixing, a stir bar, a vortex mixer, an overhead stirrer, or a rotor stator.

[0091] Methods for Making Balloon Catheters Containing Polymer-Encapsulated Drug Particles - Patent application Various embodiments of the present invention provide methods of making a balloon catheter, the methods comprising applying polymer-encapsulated drug particles comprising one or more polymers encapsulating a therapeutic agent and a therapeutic agent- or drug-releasing coating comprising same to the exterior of a balloon of the balloon catheter.

[0092] Drug-Coated Balloon Catheter The balloon catheters described throughout this application may include a coating layer containing polymer-encapsulated drug particles comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent; a drug-releasing coating containing polymer-encapsulated drug particles; or a composition; or a combination thereof. The composition may include a therapeutic agent; 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, umirolimus, analogs thereof, and combinations thereof. The therapeutic agent may have a particle size of 0.2 microns to 10 microns. The first additive may include a water-insoluble or partially water-insoluble additive containing at least one alkylaliphatic group or cholesteryl group. The first additive may have a molecular weight of 50 to 750. The second additive can be more hydrophilic or more water-soluble than the first additive and can include polyethylene glycol (-(CHCHO)-) or polyglycerol (-(CH-CHOH-CHO)-) units. The second additive can have a molecular weight in the range of 750 to 100,000.

[0093] The balloon catheter can be any suitable balloon catheter described herein. The balloon of the balloon catheter can comprise 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.

[0094] The balloon catheter can be used to deliver a therapeutic agent to a body lumen stricture or stenosis, where the body lumen stricture or stenosis is selected from urethral stricture, prostatic urethral stricture, ureteral stricture, esophageal stricture, antral stricture, gastric stricture, small intestinal stricture, colonic stricture, rectal stricture, large intestinal stricture, bladder neck stricture, biliary stricture, vaginal stenosis, in-stent restenosis, coronary artery stenosis, superficial femoral artery stenosis, popliteal artery stenosis, anterior tibial artery stenosis, posterior tibial artery stenosis, and peroneal artery stenosis.

[0095] The balloon catheter can be used to deliver a therapeutic agent to a target site in a body lumen, the target site in the body lumen being selected from urethral stricture, prostatic urethral stricture, ureteral stricture, esophageal stricture, antral stricture, gastric stricture, small intestinal stricture, colonic stricture, rectal stricture, large intestinal stricture, bladder neck stricture, bile duct stricture, 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.

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

[0097] The water insoluble or slightly or partially water insoluble additive may be selected from cholesteryl acetate, cholesteryl phenylacetate, cholesteryl laurate, cholesteryl palmitate, cholesteryl stearate, cholesteryl n-valerate, cholesteryl benzoate, cholesteryl heptylate, cholesteryl decylate, cholesteryl caproate, cholesteryl oleate, cholesteryl oleyl carbonate, cholesteryl linoleate, cholesteryl pelargonate, cholesteryl erucate, cholesteryl caprylate, 5α-cholestane, 5α-cholestan-3-one. The water-insoluble or slightly or partially water-insoluble first additive having an alkyl aliphatic group can be selected from alkyl glyceryl ethers, monoglycerides of C8 to C12 fatty acids, alkyl alcohols, alkyl ethers, alkyl esters, caprylic acid, monocaprylin, capric acid, monocapric acid, lauric acid, dodecylglycerol, butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristyl alcohol, hydroxybenzoate ... The lipid peroxide may be selected from the group consisting of carboxylic acids, ...

[0098] The water-soluble second additives are polyoxyethanyl α-tocopheryl sebacate, methylated polyethylene glycol cholesterol (mPEG cholesterol), PEG amido ether cholesterol, PEG amido ester cholesterol, mPEG amido ether cholesterol, mPEG amido ester cholesterol, DSPE-PEG-cholesterol, PEGylated phospholipids, methylated PEGylated phospholipids, PEG caprylic / capric diglyceride, PEG8 caprylic / capric glyceride, and caprylic P EG, PEG caprate, PEG caproate, PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), PEG-20 sorbitan monooleate (Tween-80), PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG-30 glyceryl oleate, polyglyceryl fatty acid 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, Polyglyceryl-10 Oleate, Polyglyceryl-10 Mono / Dioleate (CaproI™ PEG 860), Polyglyceryl-10 Stearate, Polyglyceryl-10 Laurate, Polyglyceryl-10 Myristate, Polyglyceryl-10 Palmitate, Polyglyceryl-10 Linoleate, Polyglyceryl-6 Stearate, Polyglyceryl-6 Laurate, Polyglyceryl-6 Myristate, Polyglyceryl-6 Palmitate, Polyglyceryl-6 Linoleate, Polyethylene Glycol (PEG)-Cholesteryl Sebacate (Disebacate Diester Linkage, Cholesterol, Water Soluble, CAS 69068-97-9):

[0099] [ka]

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

[0101] [ka]

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

[0103] [ka]

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

[0105] [ka]

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

[0107] [ka]

[0108] DSPE-PEG-Cholesterol:

[0109] [ka]

[0110] or a combination thereof.

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

[0112] The weight ratio of the therapeutic agent in the coating layer to the total weight of the 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 or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 or more.

[0113] The present invention provides novel drug-coated balloon catheters and their uses. The new method opens the lumen and prevents, reduces, or minimizes restenosis and recurrent non-vascular or vascular stenosis. The lumen of a vessel includes an artery, a vein, or any lumen containing blood. A non-vascular lumen includes those lumens that do not contain blood. The method includes using a medical device within the lumen that contains a drug coating. The coating can include polymer-encapsulated drug particles comprising a therapeutic agent and one or more polymers that encapsulate the therapeutic agent; or a 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 drug coating can have more than one layer and can 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, umirolimus, an mTOR inhibitor, or analogs thereof), for delivery to a body lumen narrowing or stenosis, one or more water-soluble additives, and one or more water-insoluble or partially water-soluble additives. Treatments are intended for a variety of animals, from premature newborns to adult humans.

[0114] Unless otherwise specified, the stretch ratio is defined herein as the ratio of the nominal diameter of the balloon to the diameter of the body lumen in the area treated by the balloon catheter. The nominal diameter of a balloon is the diameter the balloon achieves in an unrestricted environment at nominal pressure. The lumen diameter is the average diameter of the stricture or stricture, or luminal lesion. For the urinary tract, for example, in the urethra and prostatic urethra, the body lumen diameter would be the average diameter of the urethra draining the obstructed body lumen. The inflated balloon diameter can be the actual diameter of the balloon after inflation, which in some embodiments can be equal to, smaller than, or larger 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 for treating non-vascular lumens than other catheters. During the performance of the methods of the present invention, the stretch ratio can be selected to be any appropriate ratio that achieves the desired ratio of actual inflated balloon diameter to lumen diameter at the range of pressures used during the method.In various embodiments, the balloon stretch ratio is 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 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 1 Such a stretch ratio can result in a desired ratio of inflated balloon diameter to lumen diameter at the pressure used during inflation, which can be the same as, similar to, or different from the stretch ratio, e.g., about 1.0-40, 1.1-40, 1.2-40, 1.3-40, or 1.4-40 (e.g., 1 or 2, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 3.9, 3.10, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 3.19, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25, 3.26, 3.27, 3.28, 3.29, 3.30, 3.31, 3.32, 3.33, 3.34, 3.35, 3.36, 3.37, 3.38, 3.39, 3.39, 3.40, 3.41, 3.42, 3.43, 3.44, 3.45, 3.46, 3.47, 3.48, 3.49, 3.50, 3.51, 3.52, 3.53, 3.54, 3.55, 3.56, 3.57, 3.58, 3.59, 3.60, 3 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or less than or equal to 40, or any value therebetween).

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

[0116] In some embodiments, the balloon can include one neck and no other neck, such that the balloon includes two main sections separated by a neck. The neck can have any suitable location on the balloon, such as approximately centered relative to the balloon or off-center relative to the balloon. The neck can be off-center relative to the length of the balloon and can be at the distal end of the balloon. An embodiment of a balloon including a neck that is off-center relative to the length of the balloon is shown in FIG. 3A.

[0117] In some embodiments, the balloon can include two necks, such that the balloon includes three lobes separated by two necks, and the other neck is absent. The two necks can have approximately the same diameter, or one of the necks can have a smaller diameter than the other neck. The two necks can be positioned symmetrically or asymmetrically about the center of the balloon length. The three main portions can have approximately equal lengths or different lengths. Figure 3B shows an embodiment of a two-necked balloon catheter with three main portions, where the necks are positioned symmetrically about the center of the balloon length and the three main portions of the balloon have approximately the same length. During use, the distal neck (e.g., the neck at the distal end of the balloon catheter that is inserted first into the body) can be positioned to anchor the balloon at the bladder neck, while the proximal neck can be positioned at the prostatic urethra. The distal neck of the balloon catheter, which is first inserted into the body, can be located to anchor the balloon at the bladder neck, while the proximal neck can be positioned at the prostatic urethra. In some embodiments, the distal main portion of the balloon catheter can be free of a therapeutic agent.

[0118] In some embodiments, the balloon can include three necks, such that the balloon includes four sections separated by three necks, and no other necks. The three necks can be arranged in any suitable manner along the length of the balloon. The four main sections formed by the three necks can have equal or different lengths. The three necks can have equal or different diameters. In some embodiments, two of the necks have equal diameters that are smaller than the diameters of the other necks. Figure 3C shows an embodiment of a three-neck balloon catheter with four main sections, each having approximately equal lengths, and two of the necks have equal diameters that are smaller than the diameters of the other necks.

[0119] In various embodiments, the present invention provides a balloon catheter for delivering a therapeutic agent to a target site in a body lumen. The balloon catheter can include an elongated balloon having at least one neck with a diameter smaller than a plurality of main or body sections and the main section. The balloon catheter can include an elongated balloon having a major diameter, such as a plurality of main sections having the major diameter or an average diameter equal to the major diameter. A multi-section balloon with smaller diameter necks mechanically anchors the balloon within the body lumen; thus, it can prevent the balloon from slipping within the body lumen. If the balloon slips away from the targeted diseased site, it can be missed, potentially damaging healthy sites in the lumen. The balloon catheter can include at least one neck on the balloon with a diameter smaller than the major diameter. The balloon catheter can also include a coating layer overlying the outer surface of the balloon. The coating can include polymer-encapsulated drug particles comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent; or a 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 coating layer can include one or more water-soluble additives and one or more water-insoluble or partially water-soluble additives, an initial drug load of a therapeutic agent (e.g., paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, analogs thereof, and combinations thereof).In the method of using a balloon catheter, feature (a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or (a), (b) and (c), or (a), (b) and (c) can be present: (a) the ratio of the inflated balloon diameter to the body lumen diameter of the stenosis or stenosis at the target site is about 1.0 to about 40; or (b) the inflation comprises inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the body lumen diameter of the stenosis or stenosis at the target site is about 1.0 to about 40; or (c) the inflation comprises inflating to a pressure greater than the nominal pressure of the balloon catheter, and the nominal diameter of the balloon catheter is less than the inflated balloon diameter; or (d) a combination of (a), (b), and (c).

[0120] When the balloon is inflated, the major diameter of the balloon can be the diameter of the main part of the balloon. In some embodiments, the inflation pressure used to determine the major diameter can be any pressure that removes any folded or creased areas of the balloon and achieves tension on the balloon. The inflation pressure used to determine the major diameter is a pressure at which the inflated balloon has a shape and size corresponding 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 such 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 comprises two main sections at both ends with the same diameter, one neck section with a smaller diameter between the two main sections, and two cones at the proximal and distal balloon body. The balloon catheter comprises at least one neck section on the balloon with a diameter smaller than the balloon diameter of the main section. The balloon catheter can comprise an elongated cylindrical balloon with multiple sections with various diameters. Feature (a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or (a), (b) and (c), or (a), (b) and (c) can be present: (a) the ratio of the inflated balloon diameter to the body lumen diameter at the target site is about 1.0 to about 40; or (b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the body lumen diameter at the target site is about 1.0 to about 40; or (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 less than the inflated balloon diameter; or (d) a combination of (a), (b), and (c). A multiple-segmented balloon with a smaller neck can increase friction between the balloon and the body lumen; thus, it can prevent the balloon from slipping within the body lumen.

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

[0123] The elongated rigid component can have a cross-sectional profile that is cylindrical, tapered, rectangular, hexagonal, or another shape and can be made from a relatively incompressible metallic or non-metallic material. The elongated component can extend from the proximal side of the balloon to the distal side of the balloon, or from a location near the proximal side of the balloon to the distal side of the balloon. The elongated component can be free-floating within the central lumen of the catheter shaft, or can be located in a dedicated lumen within a multilumen catheter shaft, or can run 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 fusing it directly to the catheter shaft with heat, adhesively or chemically bonding it to the catheter shaft, bending it with a die, or by swaging or crimping it onto one or more sections of the catheter, overmolding, or any other suitable method. The elongated component can be reinforced along its entire length or along a portion, such as under a balloon to prevent buckling; for example, the elongated metal component can be reinforced wire. The reinforcement can be constructed of any rigid material, such as stainless steel, nitinol (i.e., a nickel-titanium alloy), steel, tungsten, iridium; superalloys containing elements including nickel (Ni), chromium (Cr), aluminum (Al), titanium (Ti), tungsten (W), niobium (Nb), tantalum (Ta), and cobalt (Co), or polyetheretherketone (PEEK), and can have any suitable cross-sectional shape. In some embodiments, the reinforcement is a tube that is cylindrical, rectangular, hexagonal, or has any suitable external profile. The elongated component can be positioned inside the reinforcement tube, as shown in FIG. 4C, or along the outside of the reinforcement tube.

[0124] As shown in Figures 4A and 4B, the catheter can include a balloon length management mechanism that stretches the balloon when it is in a compressed (or deflated) state, giving the balloon a smaller cross-section for tracking through a body lumen and removal after treatment. When the balloon is inflated, the length management mechanism can shorten the balloon's overall length, allowing it to expand to a predetermined inflated diameter and length for the balloon (e.g., created during a molding or forming process). In one embodiment, the force generated from balloon inflation could be transferred from the distal end of the balloon, for example, via the balloon bond to the elongated metal component, or via the connection between the catheter tip and the elongated metal component, back through the catheter shaft by the elongated rigid metal component, to the catheter shaft proximal to the balloon, for example, via the balloon proximal end or a connection between the elongated metal component and the catheter shaft proximal to the balloon proximal end. This transfer of force to the catheter shaft would allow the catheter shaft material to act as a spring, operating in the elastic region of the catheter shaft material's stress-strain curve. Energy can be stored in the catheter shaft material during balloon inflation when the catheter shaft is stretched under tension by balloon inflation, and can be released by the catheter shaft to push against the stretched metal component during deflation to stretch 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 management mechanism. FIG. 5 shows an embodiment of spring 600, which can be used in place of core wire 505 shown in FIGS. 4A and 4D. Referring to FIG. 5, spring 600 has spring portion 601 and wire portion 602. In some embodiments, spring portion 601 can be located at the proximal end of the catheter shaft. The spring can be located within the catheter shaft lumen, outside the lumen but within the catheter shaft, or outside the catheter shaft.The spring can be within the balloon, or can be located separately from the balloon, such as proximal to the proximal end of the balloon, or a combination thereof. Compared to the length of the inflated balloon, the expanded length of the compressed balloon can be about 0.1 mm longer to about 100 mm longer, or can be less than or equal to about 0.1 mm, 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 more, or about 100 mm or more. The catheter shaft can comprise a variety of materials to achieve the desired amount of balloon expansion force, such as polyamide, nylon (e.g., nylon 6,6, or nylon 12), polyether block amide (PEBA) (e.g., 35D PEBA, 55D PEBA, or 72D PEBA), polyurethane, silicone, rubber, another thermoplastic polymer, or a combination thereof. The catheter shaft can be homogeneous in composition or can include a combination of materials distributed along one or more portions of the catheter shaft to create a desired elongation force. Different materials can result in different elastic strains and different forces applied to the elongated rigid metal component for balloon elongation. The catheter shaft can be an extruded catheter shaft.

[0125] A drug-coated balloon catheter can be a medical device for treating benign prostatic hyperplasia (BPH). The balloon catheter can dilate the prostatic urethra and can include a catheter shaft for insertion into the urethra and a compliant, semi-compliant, or non-compliant balloon for inflation in the prostatic urethra. The balloon can be coated with a coating containing a therapeutic agent that is delivered to the prostatic tissue and prostatic urethra upon inflation. The balloon can be positioned within the prostate using any suitable method, such as a separate location balloon in the bladder, a location balloon in the bulbous urethra, or a marker band below the balloon visible under fluoroscopy. Alternatively, the catheter shaft can be scope-compatible (cystoscope-) compatible, allowing placement via direct visualization, and the catheter can be lined with a scope. For example, some possible catheter designs allow direct visualization of the balloon during positioning and inflation.

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

[0127] In some embodiments, where the balloon catheter includes a flexible tip, Coude tip, etc., the tip can be used to aid in device insertion and tracking through the urethra. In other embodiments, the balloon catheter includes a lumen or channel intended to allow insertion and tracking through the urethra to a target site or prostate.

[0128] Achalasia strictures are rare disorders that make it difficult for food and liquid to pass from the esophagus to the stomach. In some embodiments, when treating achalasia strictures, a balloon catheter, such as that shown in FIG. 3A, should be sized so that the proximal body portion of the catheter is in the achalasia stricture and above the lower esophageal sphincter. In these embodiments, the neck region of the balloon catheter can be aligned with the lower esophageal sphincter neck. As mentioned herein, a scope equipped with visualization can be used to properly size and position the balloon catheter. In embodiments in which the balloon catheter includes a flexible tip, the tip can be inserted into the sphincter (e.g., the lower esophageal sphincter) or stomach to aid in placing the balloon catheter at the desired location.

[0129] Balloon catheters can alleviate lower urinary tract symptoms (LUTS) due to BPH through direct dilation of prostate tissue. Dilation of the prostate with a balloon having a ratio of inflated balloon diameter to body lumen diameter at the target site of 1.0 to 40, or a balloon having a stretch ratio of nominal balloon diameter to body lumen diameter at the target site of 1.0 to 40, can create a commissurotomy in the natural plane separating the lateral sections of the metastatic prostate. Simultaneously, drugs can be released from the coating into the prostate tissue, which can, for example, prevent prostate dilation and re-narrowing of the newly formed orifice.

[0130] In various embodiments, during inflation of the balloon in the body lumen (e.g., during performance of the methods of the invention), the nominal balloon diameter of the catheter (e.g., the diameter normally achieved at the nominal pressure) can be such that the ratio of the nominal balloon diameter to the diameter of the body lumen at the treatment location is any suitable ratio, e.g., from about 1.01 to about 40, from about 1.01 to about 15, or from about 1.2 to about 10, or from about 1.31 to about 8, or less than or equal to 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 greater, or about 40 or greater. In some embodiments, the inflated diameter of the balloon at the target site during inflation to the nominal pressure is equal to the nominal diameter; however, during actual use, some stenosis can prevent the nominal diameter from being achieved or can restrict the inflated balloon to form a "dog-bone" shape. The nominal balloon diameter for a given pressure (e.g., 2 atmospheres, 3 atmospheres, 6 atmospheres, or 9 atmospheres) can be different for different diameters of balloon for various diseases. For example, the nominal diameter of a urethral stricture balloon can be 6 mm, 8 mm, 10 mm, 12 mm, and 14 mm for 6 mm, 8 mm, 10 mm, 12 mm, and 14 mm balloon catheters with inflation of 4 atmospheres, 5 atmospheres, 6 atmospheres, 8 atmospheres, or 12 atmospheres, and for balloon lengths of 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, and 50 mm. The nominal diameter of a BPH stenosis balloon can be 25 mm, 30 mm, 35 mm, 40 mm, and 45 mm for balloon lengths of 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, and 60 mm for balloon catheters at nominal inflation pressures of 2 atmospheres, 3 atmospheres, 4 atmospheres, 6 atmospheres, or 9 atmospheres. Table 1 shows examples of nominal balloon sizes, nominal pressures, and ratios of minimum balloon diameter to lumen diameter for use in treating stenosis in various diseases. The nominal pressure is the pressure required to bring the balloon to its labeled nominal diameter in an unconstrained pressure ramp test.The nominal diameter is the desired diameter that the product will be labeled with. Every physician purchases and selects balloons for use by their nominal diameter. The rated burst pressure is the maximum pressure to which the balloon can be inflated with very high confidence that it will not burst, and is a labeling requirement for balloon catheters calculated from statistical analysis of the pressures observed when the balloon bursts in a free pressure gradient test.

[0131] [Table 1]

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

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

[0134] In various embodiments, the balloon catheters of the present invention are compatible with a range of softness (or flexibility) or rigidity, allowing visualization of the treatment zone and allowing for more precise and efficient placement than other balloon catheters. The scope can be a gastroscope, enteroscope, duodenoscope, colonoscope, sigmoidoscope, rectoscope, anoscope, rhinoscope, bronchoscope, or cystoscope. In various embodiments, the balloon catheters of the present invention are selfish in that the neck of the balloon catheter directs the balloon catheter to the appropriate position during inflation (e.g., at the neck of the balloon catheter, such as the distal-most neck at the bladder neck), even if the balloon catheter is slightly off-position at the beginning of inflation.

[0135] In various embodiments, the balloon catheter has one or more necks separating one or more main sections, and at least one neck, or an arrangement of one or more necks, of the balloon catheter of the present invention allows the balloon catheter to remain in place more consistently and effectively to dilate stenoses and deliver drugs compared to other balloon catheters lacking such a neck or arrangement of necks.

[0136] The drug-coated balloon catheter can include an elongated balloon body with multiple main sections, two cones at the distal and proximal ends of the balloon body, an inflation lumen, and a wire lumen. The balloon body includes at least two main sections with larger diameters and at least one neck section with a smaller diameter, with the main sections with larger diameters and the neck sections aligned alternatively or adjacently. The elongated balloon can have a generally cylindrical shape, except for any neck sections on the balloon, any tapered sections (e.g., cones) between the necks and the main sections with the major diameters, and any tapered or shaped sections at the longitudinal ends of the balloon. The elongated balloon can have any suitable profile taken 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, hexagon, heptagon, 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 within the prostatic urethra, with the distal portion of the balloon positioned in the bladder. The major diameter and nominal balloon diameter can be in the range of about 5 mm to about 50 mm, 25 mm to 45 mm, at least 10 mm, at least 15 mm, at least 20 mm, or at least 30 mm, e.g., about 5 mm or less, or less than or equal to 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, or 48 mm, or about 50 mm or more; the major diameter can independently be within any of these ranges or specific sizes. The balloon length can be about 20 mm to about 160 mm, 40 mm to about 80 mm, or about 20 mm or less, or less than or equal to 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. Balloon length and diameter can be selected based on the patient's unique prostate anatomy.

[0138] The neck can be a rigid or semi-rigid neck in which the diameter of the neck (e.g., the portion of the neck having the neck diameter) remains substantially static during inflation of the balloon. The neck can comprise an inelastic material circulated around the neck, such as a suture or a monofilament or multifilament of such material, for example, 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 can include single or multiple markings along their length to aid in positioning and alignment with certain anatomical structures. The markings can have any suitable orientation, such as circumferential or longitudinal along the catheter shaft or balloon. Markings on the catheter shaft or balloon can be used to aid in positioning the balloon in the treatment area, indicate that the balloon is fully retracted in the sheath, or locate the device within the patient's anatomy. The markings on the catheter shaft can be visualized using an endoscope, cystoscope, or the naked eye, or the markings can include a radiologically identifiable component, such as a radiopaque material. The markings can be created by thermally bonding a polymer to the surface of the catheter shaft with a distinguishable color via pad printing, laser marking, or any other method. Figures 4A and 4B show embodiments of a balloon recapture mark 509 and a positioning mark 511. The balloon recapture mark 509 can be used if the balloon catheter includes a sheath covering the balloon. If a sheath covers the balloon, mark 509 can be located just proximal to the proximal end of the sheath. After the user advances the catheter to the desired location, removes the sheath, and inflates the balloon, the user may want to advance the sheath back so that the balloon is covered for removal. In this case, after compression, the user would advance the sheath distally until recapture mark 509 is visible. Positioning mark 511 can be used to assist the user in positioning the catheter within the body lumen. For example, if a single-neck balloon is used to treat BPH, as shown in FIGS. 4A and 4B, the positioning mark, which can be located just proximal to the proximal end of the balloon, can be located just proximal to the external sphincter. In various embodiments, the user can see mark 511 through the scope, and if the mark is just proximal to the external sphincter, the user can be confident that the balloon is properly positioned.

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

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

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

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

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

[0145] In Figure 3A, in one embodiment, a balloon with one neck is shown. Balloon 100 has waist 101, cone 102, first body section 103, neck 104, second body section 105, cone 106, and waist 107. As known in the art, when assembled into a balloon catheter, waists 101 and 107 will be attached or bonded to the catheter shaft (not shown). During inflation, 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 inflated simultaneously by a single inflation point in communication with the catheter shaft and external Luer hub. In Figure 3B, in one embodiment, a balloon with two necks is shown. Balloon 120 has waist 121, cone 122, first body 123, first neck 124, second body 125, second neck 126, third body 127, cone 128, and waist 129. As known in the art, when assembled into a balloon catheter, waists 121 and 129 will be attached, bonded, or the like, to the catheter shaft. During swelling, waists 121 and 129 do not expand because they are attached to the catheter shaft. Portions 122, 123, 124, 125, 126, 127, and 128 can all be simultaneously inflated through a single swelling point in communication with the catheter shaft and external Luer hub. While necks 124 and 126 are shown as being the same diameter upon swelling, they can be the same or different diameters with the same or different compliances. In Figure 3C, in one embodiment, a balloon with three necks is shown. It has a balloon 140, a waist 141, a cone 142, a first body 143, a first neck 144, a second body 145, a second neck 146, a third body 147, a third neck 148, a fourth body 149, a cone 150 and a waist 151.As is known in the art, when assembled into a balloon catheter, waists 141 and 151 will be attached, bonded, or the like, to the catheter shaft. During swelling, waists 141 and 151 do not expand because they are attached to the catheter shaft. Portions 142, 143, 144, 145, 146, 147, 148, 149, and 150 can all expand simultaneously through a single swelling point at the catheter shaft and in communication with the external Luer hub. While necks 144, 146, and 148 are shown with different diameters in the swollen state, they can be the same or different diameters with different compliances.

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

[0147] Coating Design and Formulation In one embodiment, the present invention provides a balloon catheter for delivering a therapeutic agent to tissue, such as vascular or non-vascular tissue. The device can include a coating applied to the outer surface of the balloon catheter. The coating can include polymer-encapsulated drug particles comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent; or a drug-releasing coating comprising the polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or a combination thereof. A layer can include a composition comprising a therapeutic agent and one or more additives. The additive can be any suitable additive. A layer can include one additive, or a layer can include more than one additive, such as a water-soluble first additive and a water-soluble second additive. For example, as shown in the embodiment depicted in FIG. 2A, balloon 12 is coated with layer 20 comprising a therapeutic agent and polymer-encapsulated drug particles comprising one or more polymers encapsulating the therapeutic agent; or a drug-releasing coating comprising the polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or a combination thereof. In some embodiments, the layer consists essentially of the therapeutic agent and additives, e.g., the layer contains only the therapeutic agent and additives without other materially significant components. In some embodiments, the device can optionally include an adhesive layer. For example, as shown in the embodiment depicted in FIG. 2B, balloon 12 is coated with adhesive layer 22. Layer 24 can overlie the adhesive layer, and layer 24 comprises a therapeutic agent and polymer-encapsulated drug particles comprising one or more polymers encapsulating the therapeutic agent; or a drug-release coating comprising polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or a combination thereof. The adhesive layer, which is a separate layer underlying the drug coating layer, improves adhesion of the drug coating layer to the outer surface of the medical device and protects the coating integrity. For example, if the drug and additives differ in their adhesion to the medical device, the adhesive layer can prevent differential loss of components and maintain the drug-to-additive ratio in the coating during passage to the target site for therapeutic intervention.Additionally, the adhesive layer can function to promote rapid release of the coating layer components from the device surface upon contact with tissue at the target site. In other embodiments, the device can include a top layer. For example, as shown in the embodiment depicted in FIG. 2C, balloon 12 is coated with adhesive layer 22, coating layer 26 containing a therapeutic agent and overlying the adhesive layer, and top layer 28. The top layer can reduce loss of the drug layer before it is brought into contact with the target tissue, for example, during passage of balloon 12 to the site of therapeutic intervention or during the first moment of inflation of balloon 12, before coating layer 20 is pressed into direct contact with the target tissue.

[0148] In various embodiments, the coating covering the balloon portion of the catheter has a single layer or multiple layers containing one or more therapeutic agents. In some embodiments, the layer adjacent to the expandable portion of the catheter does not have a therapeutic agent and is formulated with components that allow all or a substantial portion of the coating to be transferred to the stenosis or stenosis upon inflation of the balloon catheter. In some embodiments, the layer adjacent to the balloon portion of the catheter does not have a therapeutic agent and is formulated with components that allow the coating to adhere to the balloon.

[0149] Embodiments of the present invention relate to balloon catheters with rapid drug-releasing coatings and methods for preparing such coated devices. The drug-releasing coating may comprise polymer-encapsulated drug particles comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent; or a drug-releasing coating comprising polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or combinations thereof. The therapeutic agent according to embodiments of the present invention does not require delayed or extended release; instead, the therapeutic agent is released over a very short period of time, for example, to provide a therapeutic effect upon contact with tissue. An objective of embodiments of the present invention is to promote rapid and efficient drug uptake by target tissue during temporary device placement at the target site. Another embodiment of the present invention relates to a balloon catheter with a drug coating comprising particles of a therapeutic agent encapsulated in an additive or encapsulated by one or more polymers. After inflation of the drug-coated balloon, the particles of the therapeutic agent embed into the lumen wall, providing long-term drug delivery.

[0150] In one embodiment, the present invention provides a balloon catheter for delivering a therapeutic agent to tissue, such as vascular or non-vascular tissue. The device includes a layer applied to the outer surface of the balloon catheter. The layer includes a therapeutic agent and polymer-encapsulated drug particles comprising one or more polymers encapsulating the therapeutic agent; a drug-releasing coating comprising polymer-encapsulated drug particles; a composition comprising a therapeutic agent and one or more additives; or a combination thereof. The additive can be any suitable additive. A layer can include one additive, or a layer can include more than one additive, such as a water-soluble first additive and a water-soluble second additive. A layer can also include a water-insoluble or partially water-soluble additive, or a layer can include more than one water-insoluble or partially water-soluble additive. In some embodiments, the therapeutic agent and excipients are dispersed in one of the coating layers. The range of dispersion can vary from a molecular dispersion to a dispersion with drug particles tens of microns in size. In one embodiment, the therapeutic agent is less than 10 μm in size, and in another embodiment, the therapeutic agent is 5 μm or less in size. 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, lacking molecular orientation. Techniques for determining whether a drug is crystalline or amorphous include powder X-ray diffraction (pXRD), modulated differential scanning calorimetry (mDSC), or confocal Raman spectroscopy.

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

[0152] The weight ratio of the therapeutic agent in the coating layer to the total weight of the 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 or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 or more.

[0153] The drug coating can cover any suitable percentage of the balloon's exterior surface (e.g., the percentage of the balloon's surface that attains its major diameter during inflation to a nominal pressure, excluding the neck and end cone), from about 1% to about 100%, or from about 50% to about 100%, or from about 80% to about 100%, or less than or equal to about 10%, or less than or equal to 20%, 30, 40, 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or more, or more than about 100%.

[0154] The balloon can have a residual amount of drug thereon after retrieval. Any suitable residual amount of drug, for example, greater than or less than about 70%, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5%, or about 0% by weight, can remain after retrieval.

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

[0156] The coating layer overlying the exterior of the medical device can 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 can include a first water-soluble additive that is a surfactant, such as PEG sorbitan monolaurate, PEG sorbitan monooleate, or a combination thereof. The water-soluble additive can include a second water-soluble additive that is a compound having one or more groups that are hydroxyl, amine, carbonyl, carboxyl, or ester, such as sorbitol, sorbitan, xylitol, gluconolactone, or a combination thereof. The drug coating can include both the first water-soluble additive and the second water-soluble additive. In some embodiments, the distal end of the balloon can be free of a therapeutic agent.

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

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

[0160] The device may be 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 into tissue. The additive can have a solubility in water and ethanol of at least 1 mg / mL. Alternatively, the therapeutic agent can be water-insoluble.

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

[0163] Methods for treating stenosis and stenosis. The present invention provides a novel method for treating stenosis of a body lumen to have long-term and sustained effects. The new method opens the lumen and prevents, reduces, or minimizes restenosis and recurrent non-vascular or vascular stenosis. A blood vessel (or vascular) lumen includes an artery, vein, or any lumen that contains blood. A non-vascular lumen includes those lumens that do not contain blood. The method includes delivering a drug coating comprising a therapeutic agent and polymer-encapsulated drug particles comprising one or more polymers encapsulating the therapeutic agent; or a drug-release coating comprising polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or a combination thereof. The drug coating can have more than one layer and contains an effective amount of a therapeutic agent, for example, an anti-inflammatory and anti-proliferative drug (e.g., paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, analogs thereof, and combinations thereof). The coating may include one or more water-soluble additives and one or more water-insoluble or partially water-soluble additives for treatment of stenosis or stenosis. The treatment is intended for a variety of animals, from premature newborns to adult humans.

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

[0165] In various embodiments, the present invention provides a method for treating benign prostatic hyperplasia. The method includes: 1) inserting a sheathed, rigid cystoscope (including optics and a bridge with irrigation capability) into the urethra and tracking the cystoscope tip into the bladder. The method includes: 2) removing the bridge and optic, 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 with the optic and bridge with irrigation capability alongside the drug-coated balloon catheter, hydrating the coating in irrigation fluid until the coating is soaked, and positioning the tip of the scope and the proximal edge of the balloon side-by-side near the external sphincter. The method includes: 3) inflating to an initial pressure (e.g., 0.5 atmospheres, 1 atmosphere, or 1.5 atmospheres) and maintaining the initial pressure until the pressure no longer drops for 1 to 2 minutes. The method includes 4) inflating to a next higher pressure, including an increase of 0.5, 1, or 1.5 atmospheres from the previous pressure, and maintaining the higher pressure until the pressure no longer decreases for 1 to 2 minutes. The method includes 5) repeating step 4) until prostate tissue deflects (or yields) and a commissurotomy is formed. The method includes 6) leaving the balloon inflated for 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to release drug into the tissue and prevent bleeding. The method includes 7) compressing the balloon catheter. The method includes 8) retrieving the scope and balloon catheter assembly from the body lumen.Features (a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or (a), (b) and (c), or (a), (b) and (c) can be present: (a) the ratio of the inflated balloon diameter to the body lumen diameter at the target site is about 1.0 to about 40; or (b) the inflation comprises inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the body lumen diameter at the target site is about 1.0 to about 40; or (c) the inflation comprises inflating to a pressure greater than the nominal pressure of the balloon catheter, and the nominal diameter of the balloon catheter is less than the inflated balloon diameter; or (d) a combination of (a), (b), and (c).

[0166] In some embodiments, when treating the prostate, it is preferable to position the balloon waist proximal to the external sphincter so that the external sphincter is not dilated. It is also preferable to size the balloon so that, when the balloon waist is at the external sphincter, the balloon neck (e.g., the most distal balloon neck) is aligned with the bladder neck. This positioning provides holding forces to prevent the balloon from slipping during inflation. If the balloon neck cannot be aligned with the bladder neck, it may be preferable to inflate the balloon slowly to allow the prostate to yield as the balloon is inflated.

[0167] Once properly positioned, the balloon is inflated using, for example, an inflation device including a pressure gauge. The balloon can be inflated slowly, allowing the prostate tissue to flex and reducing the tendency of the balloon to slip proximally into the bladder and slip distally back. Single- or multi-neck balloon configurations can prevent balloon migration by aligning the most distal neck with the bladder neck in some abnormal conditions, such as a dilated middle lobe (e.g., approximately 10-15% of cases). However, if the balloon neck does not stay aligned with the bladder neck during inflation, additional techniques can be useful to prevent balloon migration. In some instances, inflation at a rate of approximately 0.5-1 atmospheres per minute can prevent balloon migration. As the tissue flexes, the balloon pressure correspondingly decreases, allowing additional fluid to be injected into the balloon without increasing the pressure. If the pressure remains stable for approximately 1-2 minutes, the pressure can be increased and maintained in 0.5 or 1 atmosphere intervals in a similar manner. The pressure can be increased continuously, and this method of increasing pressure can be followed by a pressure drop followed by stabilization and continued pressure increase until commissurotomy or splitting (or splitting) is achieved. Alternatively, a very slow inflation can prevent balloon migration to achieve commissurotomy or prostate splitting. Once commissurotomy or splitting of the prostatic urethra and prostate is observed and confirmed with a video feed from the scope, mechanical decompression can be achieved. The balloon can be left inflated for approximately 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to allow the drug in the coating to migrate into the tissue. Once the procedure is complete, the balloon can be compressed, and the catheter and scope can be removed from the patient's body lumen.

[0168] In some embodiments, when treating the prostate gland, it may be desirable to pre-dilatate the stricture. In this embodiment, the pre-dilatation catheter may be shorter and / or have a smaller diameter than the drug-coated balloon treatment catheter. In this scenario, the pre-dilatation catheter is positioned with the proximal waist of the balloon in the neck region aligned with the external sphincter and the bladder neck. The balloon is slowly inflated as described herein to help deflect the prostate gland while protecting it against balloon slippage. Once inflated, the pre-dilatation balloon is compressed and removed, and the drug-coated treatment balloon is inserted. The proximal waist of the treatment balloon is aligned with the external sphincter. If the prostate gland is properly pre-dilated, it is not necessary to align the balloon neck with the bladder neck so that the balloon does not slip as much as it would in a non-pre-dilatation body lumen.

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

[0170] In one embodiment, the present invention relates to a method for treating urethral stricture, comprising flushing the urethral stricture with water, saline solution, or an aqueous solution containing at least one water-soluble additive to soak or wet the drug coating; inserting a balloon catheter into a target site of the urethral stricture, the balloon catheter comprising a balloon and a coating layer overlying the balloon's outer surface. The coating layer may comprise polymer-encapsulated drug particles comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent; or a drug-release coating comprising polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or a combination thereof. The weight ratio of the therapeutic agent in the coating layer to the total weight of one or more water-insoluble or slightly or partially water-insoluble additives and one or more water-soluble additives may be about 0.05 to 20. The method may also comprise inflating the balloon until the coating layer contacts the wall of the urethral stricture at the target site and achieves an inflated balloon diameter for an inflation period; compressing the balloon after the inflation period, the inflation period being 0.1 to 10 minutes; and withdrawing the balloon catheter from the urethral stricture. The ratio of the inflated balloon diameter to the urethral diameter at the location of the stricture can be about 1.0 to about 40, about 1.01 to about 15, or about 1.01 or less, or less than or equal to 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 greater than about 40. After dilation, the diameter of the urethral stricture can be 6.7 mm or greater, e.g., about 6.7 mm to about 20 mm, or about 6.7 mm to about 15 mm, or less than or equal to 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, or greater than 15 mm. Optionally, inflating can include inflating to a pressure equal to or exceeding 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, gastrectomy-induced gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, ileo-anal J-pouch strictures, and large intestinal strictures. Strictures include esophageal strictures due to eosinophilic esophagitis or Barrett's esophagus, radiation-induced strictures, Crohn's disease-induced strictures, ulcerative colitis-induced strictures, chronic inflammatory bowel disease (IBD)-induced strictures, and anastomotic strictures anywhere in the gastrointestinal tract. The method includes inserting a balloon catheter into the gastrointestinal stricture, the balloon catheter including a stretched balloon and a drug coating. The method includes flushing the gastrointestinal 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 includes inflating the balloon at the target site to contact the coating layer with the wall of the body lumen at the location of the digestive body lumen stricture until the balloon achieves an inflated balloon diameter for an inflation period. The method includes retrieving the balloon catheter from the body lumen. In some embodiments, the method further includes performing a surgical procedure, such as a strictureotomy or resection, prior to inserting the balloon catheter into the target site. In some embodiments, the strictureotomy or resection comprises needle knife electroincision, endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD).

[0172] In various embodiments, the present invention provides methods for treating or preventing inflammatory disease-induced (IBD) nonvascular stenosis. IBD can include Crohn's disease and ulcerative colitis. In some embodiments, the stenosis is a small intestinal stenosis, duodenal stenosis, jejunal stenosis, ileal stenosis, colonic stenosis, rectal stenosis, large intestinal stenosis, colorectal stenosis, ileocolonic stenosis, or gastrointestinal stenosis. The method includes inserting a balloon catheter into a target site of a body lumen containing the inflammatory disease-induced nonvascular stenosis, the balloon catheter comprising an expanded balloon and a drug coating. The method can include flushing the inflammatory disease-induced nonvascular stenosis with water, a saline solution, or an aqueous solution comprising at least one water-soluble additive to soak or wet the drug coating. The method includes inflating a balloon at the target site to contact the wall of the body lumen at the location of the inflammatory disease-induced nonvascular stenosis with the coating layer until the balloon achieves an expanded balloon diameter for the inflation period. The method can include compressing the balloon after the inflation period. The method includes retrieving 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, optionally comprising flushing the esophageal stricture with water, saline solution, or an aqueous solution containing at least one water-soluble additive prior to, during, or after insertion of a balloon catheter; and inserting the balloon catheter into a target site in the esophageal stricture, the balloon catheter comprising a balloon and a drug coating. The drug-coated balloon catheter can be delivered to the esophageal stricture in a minimally invasive manner by placing an endoscope through the mouth or nose to access the esophagus. The drug-coated balloon can then be placed through the working channel of the scope or tracked over a previously placed guidewire so that the working portion of the balloon is centered in the stricture. The scope used can be a gastroscope, colonoscope, enteroscope, nasoscope, or other endoscope suitable for tracking to the esophageal stricture treatment site. The method can include flushing the esophageal stricture with water, saline solution, or an aqueous solution containing at least one water-soluble additive to soak or wet the drug coating. The method can include inflating the balloon until the coating layer contacts the wall of the esophageal stricture at the target site and achieves an inflated balloon diameter for an inflation period; compressing the balloon after the inflation period, wherein the inflation period is 0.1 minutes to 10 minutes; and withdrawing the balloon catheter from the esophageal stricture. The ratio of the inflated balloon diameter to the esophageal diameter at the location of the stricture can be about 1.0-40, 1.1-40, 1.2-40, 1.3-40, or 1.4-40 (e.g., 1, or greater than or less than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or less than or equal to 40, or any value therebetween). In some embodiments, the balloon catheter properties are equal to or similar to those given in Table 2, with growth rates that slow at higher pressures.Compliance is the percent change in balloon diameter from nominal diameter to estimated burst pressure (RBP) diameter, calculated as (diameter @ RBP - diameter @ nominal pressure) / diameter @ nominal pressure) x 100%. Optionally, inflation can include inflating to a pressure equal to or exceeding the nominal pressure of the balloon catheter.

[0174] [Table 2]

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

[0176] [Table 3]

[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 following it to the site of stricture. The balloon catheter includes an expanded balloon, a coating layer, or one or more drug coating layers overlying the outer surface of the balloon. The method includes inflating the balloon to bring the coating layer into contact with the vaginal wall until the balloon achieves an expanded balloon diameter for an expansion period. The method includes compressing the balloon and withdrawing it from the vagina after the expansion period.

[0178] In various embodiments, the present invention provides a minimally invasive method for treating cancer treatment-induced non-vascular stenosis. The method includes inserting a balloon catheter into a target site in a body lumen containing the cancer treatment-induced non-vascular stenosis, the balloon catheter comprising an expanded balloon and a drug coating layer overlying the outer surface of the balloon. The method includes inflating the balloon at the target site to contact the wall of the body lumen and the coating layer at the location of the cancer treatment-induced non-vascular stenosis until the balloon achieves an expanded balloon diameter for an expansion period. The method includes compressing the balloon after the expansion period. The method includes withdrawing the balloon catheter from the body lumen. In some embodiments, the cancer treatment is prostate radiation treatment, 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, the target site being the site of a previously performed cancer treatment, or being adjacent, proximal, or distal to it, and the balloon catheter comprising an expanded balloon and a drug coating. The method includes inflating the balloon at the target site to bring the coating layer into contact with the wall of the body lumen at the target site until the balloon achieves an expanded balloon diameter for an inflation period. The method includes compressing the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body lumen. In some embodiments, the method further includes performing a cancer treatment in a body lumen adjacent, proximal, or distal to the target site prior to inserting the balloon catheter into the target site. In some embodiments, the cancer treatment is prostate radiation treatment, transurethral resection of the prostate, or EMR or ESD of the gastrointestinal tract.

[0180] In various embodiments, the present invention provides methods for treating or reducing the occurrence of surgical anastomosis-induced nonvascular stenosis, including treating an anastomosis at the time of anastomosis formation and / or before a stenosis forms. The method includes inserting a balloon catheter into a target site in a body lumen containing the surgical anastomosis-induced nonvascular stenosis, the balloon catheter including an expanded balloon and a drug coating. The method can 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 can include inflating the balloon at the target site to contact the wall of the body lumen and the coating layer at the location of the surgical anastomosis-induced nonvascular stenosis until the balloon achieves an expanded balloon diameter for an expansion period. The method can include compressing the balloon after the expansion period. The method can include withdrawing the balloon catheter from the body lumen. In some embodiments, the stenosis is a fibrotic stenosis. In some embodiments, the stenosis is an esophageal 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, a colorectal stenosis, a stenosis resulting from gastric bypass, an ileocolic stenosis, a gastrointestinal stenosis, a urethral stenosis, a ureteral stenosis, a vaginal stenosis or stricture, a J-pouch stenosis, or a bladder neck stenosis. When an anastomosis involves two or more body structures joined together, one or more body structures can be derived from an autologous source (i.e., from the same individual, e.g., in a bowel resection, an arteriovenous fistula), an allogeneic source (i.e., from another individual, e.g., in an organ transplant), or a xenogeneic source (i.e., from a different species, e.g., a decellularized transplant).

[0181] In various embodiments, the present invention provides methods for treating or preventing surgically-induced strictures. Surgical procedures that can induce nonvascular strictures include needle knife electrotomy, episiotomy, urethrotomy, direct visual intraurethrotomy (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, including needle knife electrotomy-, urethrotomy-, direct visual intraurethrotomy (DVIU), endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD), induced nonvascular strictures, where the balloon catheter includes an expanded balloon and a drug coating. The method can also include flushing the surgical site with water, saline solution, or an aqueous solution containing at least one water-soluble additive to soak or wet the drug coating. The method includes inflating a balloon at the surgical site to contact the coating layer with a wall of the body lumen at the surgical site until the balloon achieves an inflated balloon diameter for an inflation period. The method includes compressing the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body lumen.

[0182] Various embodiments of the present invention relate to a method for treating a stricture in a nonvascular body lumen using an endoscope to visualize the stricture. The endoscope can be a gastroscope, enteroscope, duodenoscope, colonoscope, sigmoidoscope, rectoscope, anoscope, nasoscope, bronchoscope, or cystoscope. The scope can be used to ensure proper placement of a balloon catheter within 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 traversing the stricture site to visualize the stricture. A guidewire can be delivered through the working channel of the endoscope so that it passes through the stricture before inserting the balloon catheter. The method includes inserting the balloon catheter of FIG. 1 or 4B into a target site in the body lumen. The method can include inserting the guidewire and the balloon catheter on the endoscope side-by-side or through the working channel of the endoscope into the target site in the body lumen. The method can include flushing the body lumen with water, a saline solution, or an aqueous solution including at least one water-soluble additive prior to, during, or after insertion of the balloon into the target site. The method can also include inflating the balloon until the coating layer contacts a wall of the stenosis in the body lumen at the target site and the balloon achieves an inflated balloon diameter for an inflation period. Features (a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or (a), (b) and (c), or (a), (b) and (c) can be present: (a) the ratio of the inflated balloon diameter to the body lumen stenosis diameter at the target site is about 1.0 to about 40; or (b) the inflation comprises inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the body lumen stenosis diameter at the target site is about 1.0 to about 40; or (c) the inflation comprises inflating to a pressure greater than the nominal pressure of the balloon catheter, and the nominal diameter of the balloon catheter is less than the inflated balloon diameter; or (d) a combination of (a), (b), and (c).The method also includes withdrawing the balloon catheter from the stenosis and the endoscope, and withdrawing 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, posterior tibial artery, peroneal artery, and other arteries of the leg. The method includes inserting a balloon catheter into a target site in a blood vessel, the balloon catheter including an expanded balloon and a balloon and / or stent including a drug coating. The method includes contacting the inner lumen wall with the coating layer and expanding the balloon and / or stretching the stent at the target site to dilate the stenosis until the balloon achieves the expanded balloon diameter for the inflation period or the stent achieves the expanded diameter. The method can include compressing the balloon after the inflation period. The method can also include withdrawing the balloon catheter from the body lumen. In various embodiments, a sheath covering the coated balloon and / or coated stent can be used to prevent the drug from being washed away while the balloon catheter or stent is advanced to the target site in the blood vessel.

[0184] In some embodiments, when treating a stenosed artery, it may be preferable to predilate the stenosis with an uncoated predilation balloon catheter before treating it with a drug-coated balloon. In some embodiments, the predilation balloon catheter has a cutting or scoring element on the balloon that is used to disrupt calcified plaque. In some embodiments, the predilation catheter can be shorter and / or have a smaller diameter than the drug-coated balloon treatment catheter. In this scenario, the predilation catheter is positioned so that the center of the balloon body is aligned with the center of the stenosis. Once inflated, the predilation balloon is compressed and removed, and 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 larger than the predilation balloon catheter to ensure that the drug coating contacts the wall of the entire lumen of the predilated stenosis.

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

[0186] In various embodiments, the present invention provides methods for the treatment or prevention of in-stent restenosis, including, but not limited to, coronary artery stenosis, superficial femoral artery stenosis, popliteal artery stenosis, anterior tibial artery, posterior tibial artery, peroneal artery, and other arteries of the leg. The method includes inserting a balloon catheter into a target site of in-stent restenosis, the balloon catheter comprising an expanded balloon and a drug coating. The method includes inflating the balloon at the target site to contact the inner lumen wall with the coating layer and dilate the stenosis until the balloon achieves an expanded balloon diameter for the inflation period. The method includes compressing the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body lumen.

[0187] In various embodiments, the present invention provides methods for the treatment or prevention of stenosed arteriovenous fistulas. The method includes inserting a balloon catheter into a target site in a blood vessel, the balloon catheter including an expanded balloon and a drug coating. The method includes inflating the balloon at the target site to contact the wall of the interior lumen with the coating layer and dilate the stenosis until the balloon achieves an expanded balloon diameter for an expansion period. The method includes compressing the balloon after the expansion period. The method includes withdrawing the balloon catheter from the body lumen.

[0188] In various embodiments, the present invention provides methods for treating or preventing a stenotic heart valve. The method includes inserting a balloon catheter into a target site within the heart valve, the balloon catheter including an expanded balloon and a drug coating. The method includes inflating the balloon at the target site to contact the wall of the interior lumen with the coating layer and dilate the heart valve stenosis until the balloon achieves an expanded balloon diameter for an expansion period. The method includes compressing the balloon after the expansion period. The method includes withdrawing the balloon catheter from the body lumen.

[0189] In various embodiments, the present invention provides a method for treating a body lumen, comprising inserting a balloon catheter, such as any of the balloon catheters described herein, into a target site in the body lumen. In some embodiments, the balloon is inflated until the drug coating layer contacts the wall of the stenosis, dilating the stenosis with concomitant migration of the drug into the stenosis. In some embodiments, the balloon is inflated until the drug coating layer contacts the wall of the stenosis, dilating the stenosis to increase its diameter so that contact with the stenosis can provide sufficient peripheral migration of the drug to the wall of the stenosis. In some embodiments, the portion of the balloon containing the drug (e.g., in embodiments comprising less than 100% of the surface area covered with the drug) can uniformly contact the stenosis. In other embodiments, contact of various portions of the balloon's surface with the stenosis is non-uniform.

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

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

[0192] The body lumen can be the prostate, and inserting the balloon catheter can include using a scope (e.g., flexible or rigid, such as a cystoscope) to position the balloon catheter in the prostate, such as a flexible or rigid cystoscope. The balloon catheter can include a scope, and the method can include using a video feed from the scope to locate the target site. The method can include using a video feed from the scope to position the balloon catheter at the target site.

[0193] The body cavity can be the prostate, the balloon can have multiple main portions divided by one or more necks, and inserting the balloon catheter can include placing one of the main portions of the balloon catheter in the prostate and placing a second main portion of the balloon catheter in the bladder.

[0194] The insertion can include placing at least one neck of the balloon in the bladder neck. The at least one neck of the balloon catheter can be a distal neck, and the insertion can include placing the distal neck in the bladder neck. The balloon catheter can include a proximal neck, and the insertion can include placing the proximal neck in the prostatic urethra.

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

[0196] Inflation can include increasing the pressure in the balloon at any suitable rate (e.g., excluding periods during which pressure drop due to tissue yielding and pressure can be maintained during these times), e.g., from about 0.1 atmospheres / minute to about 10 atmospheres / minute, or from about 0.5 to about 1.5 atmospheres / minute, or less than or equal to about 0.1 atmospheres / minute, or less than or equal to about 0.2 atmospheres / 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 atmospheres / minute, or more than about 10 atmospheres / minute).

[0197] Embodiments of the present invention are directed to the treatment of strictures in body lumens by delivery of an effective amount of a therapeutic agent, such as an anti-inflammatory and anti-proliferative drug (e.g., rapamycin, paclitaxel, or analogs thereof). Strictures in body lumens include vascular strictures, urethral strictures, ureteral strictures, vaginal strictures, strictures, esophageal strictures, achalasia strictures, strictures in stents, antral strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, large intestinal strictures, and biliary strictures. Embodiments of the present invention are directed to methods of treating at least one of vascular stenosis, benign prostatic hyperplasia (BPH), urethral problems, prostate cancer, colorectal strictures, strictures after gastric bypass, ileocolonic strictures, gastrointestinal strictures, J-pouch strictures, bladder neck strictures (e.g., stenosis), fibrotic strictures, eosinophilic esophagitis strictures, Crohn's disease (CD)- and ulcerative colitis (UC)-induced strictures, radiation-induced strictures, endoscopic resection (EMR and ESD)-induced strictures, surgery-related anastomotic strictures, achalasia strictures, gastrectomy-induced strictures, asthma, and chronic obstructive pulmonary disease (COPD). According to an embodiment, the method includes inflating the balloon catheter to release a drug into the wall of the stenosis, compressing the balloon, and withdrawing the balloon catheter, wherein the remaining drug can be about 1-70% of the total drug load on the balloon catheter, and the drug in the wall of the body lumen 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 into the tissue of the stenosis in the body lumen.

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

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

[0200] Some drugs that may be useful in various embodiments, particularly for respiratory tract, nasal and other nasal cavities, as well as urethral applications, are corticosteroids, such as budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cortisone, betamethasone, triamcinolone acetonide, etc. Some other suitable drugs are terbutaline, albuterol, ipratropium, pirbuterol, epinephrine, salmeterol, levalbuterol, formoterol, etc.; the drug may be a bronchodilator or a vasoconstrictor.

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

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

[0203] Also useful as drugs in embodiments of the present invention are photosensitizing agents for photodynamic or radiotherapy, including various porphyrin compounds such as porfimers. Furthermore, the drugs used in the embodiments of the present invention include everolimus, somatostatin, tacrolimus, roxithromycin, duramycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, and the like. vindesine, vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan, ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, temozolomide, thiotepa, daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin Isin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine-5'-dihydrogen diphosphate, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase, pegaspargase, Anastrozole, exemestane, letrozole, formestane, aminoglutethimide, adriamycin, azithromycin, spiramycin, cepharanthine, smc proliferation inhibitor-2w, epothilone A and B, mitoxantrone, azathioprine, mycophenolate mofetil, c-myc-antisense, b-myc-antisense, betulinic acid, camptothecin, lapachol, beta-lapachone, podophyllotoxin, betulin, podophyllic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b, lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab, daclizumab, selectin (cytokine antagonist),CETP inhibitors, cadherins, cytokinin inhibitors, COX-2 inhibitors, NFkB, angiopeptin, ciprofloxacin, camptothecin, fluoroblastin, monoclonal antibodies (which inhibit muscle cell proliferation), bFGF antagonists, probucol, prostaglandins, 1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one, scopoletin, colchicine, NO donors such as pentaerythritol tetranitrate and syndnoeimines, S-nitroso derivatives, tacrolimus, erythropoietin ... Moxifen, staurosporine, beta-estradiol, a-estradiol, estriol, estrone, ethinylestradiol, fosfestrol, medroxyprogesterone, estradiol cypionate, estradiol benzoate, tranilast, camebacaurine and other terpenoids, which are applied in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), cyclosporin A, 6-a-hydroxypaclitaxel, baccatin, taxotere and macrocyclic oligonucleotides of carbon suboxide (MCS). mers and their derivatives, mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium gold thiomalate, oxaceprol, celecoxib, β-sitosterin, ademetionine, mirtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, elliptic Syn, D-24851 (Calbiochem), colcemid, cytochalasin AE, indanosine, nocodazole, S-100 protein, bacitracin, vitronectin receptor antagonist, azelastine, guanidyl cyclase stimulator tissue inhibitor 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,Active agents from the group of antibiotics such as cefadroxil, active agents from the group of antibiotics, for example cefadroxil, cefazolin, cefaclor, cefotaxime, tobramycin, gentamicin, penicillins, for example dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotics, for example argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulfated and N-reacetylated heparin, tissue plasminogen activator, GpIIb / IIIa platelet membrane receptor, factors Xa inhibitor antibodies, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators such as dipyramidol, trapidil, nitroprusside, PDGF antagonists such as triazolopyrimidines and seramin, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thiol protease inhibitors, prostacyclin, bapiprost, interferon alpha, beta and gamma, histamine antagonists, serotonin blockers, cell death inhibitors, cell death modulators, p65 NF-kB or BcI-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, mutamycin, procainamide, retinoic acid, quinidine, disopyramide, flecamide, propafe non, sotalol, amidorone, natural and synthetically derived steroids such as bryophylline A, inotodiol, maquiloside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal anti-inflammatory drugs (NSAIDS) such as fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, and antiviral agents such as acyclovir,Ganciclovir and zidovudine, antifungal agents such as clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprozoal agents such as chloroquine, mefloquine, quinine, further natural terpenoids such as hippocaesculin, balintgenol-C21-angelate, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolides lids), 4,7-oxycycloanisomelic acid, baccarinoids B1, B2, B3 and B7, tubeimoside, bruceanol A, B and C, bruceantinoside C, yadandiosides N and P, isodeoxyelephanpine, tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hyptatic acid acid A, zeolin, iso-iridogermanal, maytenfoliol, efsanthin A, excissanin A and B, longicaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-a-senecioyloxychaparrin, taxamairin A and B, regenilol, triptolide, further cymarin, apocymarin, aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburin chloride chloride), cictoxin, cinococlin, bombrestatin A and B, cudraisoflavonei A,Curcumin, dihydronitidine, nitidine chloride, 12-beta-hydroxypregnadiene-3,20-dione, bilobol, ginkgolic acid, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, glycoside 1a, podophyllotoxin, justicidin A and B, larreatin, maloterin, malotochromanol, isobutyrylmalloto chromanol), maquiloside A, marchantin A, maytansine, lycoridicin, margetine, pancratistatin, liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-AII, bisparthenolidine, periplocoside A, galakinoside, ursolic acid, Deoxypsorospermin (psychorubin), ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, sphatheliachromen, stizophyllin, mansonine, strebluside, akagerin, dihydrousambarencin, hydroxyusambarine, strychnopentamine, strychnophylline, usambarine ( usambarine, usambarensine, berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferone, afromoson, acetylvismione B,Includes desacetylvismione A, and vismione A and B.

[0204] In addition, drug combinations can be used in the 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 rapachone, rapamycin and active vitamin D, rapamycin and rapachone.Due to additive effects, the dose of drug can also be reduced.These combinations can reduce the complications caused by using high doses of drug.

[0205] Some drugs used in various embodiments that may be particularly suitable for the respiratory tract, nasal passages, and other nasal cavities are corticosteroids, such as budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cortisone, betamethasone, triamcinolone acetonide, and the like.

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

[0207] Additives. Additives according to embodiments of the present invention can promote rapid drug elution and excellent penetration of drugs into tissues at disease sites. Thus, coatings according to embodiments of the present invention provide an enhanced rate and / or extent of absorption of antiproliferative therapeutic agents in nonvascular diseased tissues or nonvascular body lumens. In embodiments of the present invention, the coated devices deliver antiproliferative therapeutic agents to nonvascular tissues during very short deployment times of less than 10 minutes, even less than 2 minutes, reducing re-narrowing and recurrence of stenosis in nonvascular body lumens.

[0208] In some embodiments, the additive reduces the crystal size and number of particles of the therapeutic agent, the additive is water-soluble, and the therapeutic agent is not water-soluble.The additive can have an acid, ester, ether, or alcohol fatty chain, and the fatty chain can directly insert into the lipid membrane structure of tissue.The additive can penetrate and rearrange into the lipid membrane structure of tissue.The additive can have one or more functional groups that have affinity for drugs through hydrogen bonding and / or van der Waals interaction. In some embodiments, the additive can be at least one of a surfactant and a compound, and the additive has a molecular weight of 50 to 750 g / mol (e.g., 50 g / mol or more, or less than or equal to 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 can have more than four hydroxyls. In some embodiments, the compound with more than four hydroxyls has a melting point of 120°C or less, and the compound is an alcohol or an ester. In some embodiments, the therapeutic agent is not water-soluble or is only slightly water-soluble.

[0209] In one aspect of this embodiment, the additive enhances drug absorption into tissues in non-vascular and vascular body lumens. In another aspect of this embodiment, the additive comprises a hydrophilic portion and a drug-affinity portion, the drug-affinity portion being 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. The drug-affinity portion of the additive can bind lipophilic drugs such as rapamycin, paclitaxel, or their analogs. The hydrophilic portion accelerates diffusion and increased penetration of the drug into tissues. It can promote rapid drug transfer from the medical device during deployment at the target site by preventing hydrophobic drug molecules from aggregating with each other and the device, increasing drug solubility in interstitial spaces, and / or accelerating drug transport through polar head groups into the lipid bilayer of the target tissue's cell membrane. The additives of various embodiments of the present invention can have two parts that work together to promote rapid release of the drug from the device surface and uptake by the target tissue during deployment (by accelerating drug contact with tissues for which the drug has a high affinity), while preventing premature release of the drug from the device surface prior to device deployment at the target site.

[0210] In embodiments of the present invention, the therapeutic agent is rapidly released after the medical device contacts tissue and is readily absorbed. For example, certain embodiments of the device of the present invention include a drug-coated balloon catheter that delivers a therapeutic agent, such as a lipophilic antiproliferative drug (e.g., paclitaxel or rapamycin), to non-vascular tissue through brief, direct pressure contact of high drug concentrations during balloon expansion. For example, the lipophilic drug is retained in the target tissue at the delivery site, which inhibits hyperplasia and allows restenosis to re-epithelialize. In these embodiments, the coating formulation of the present invention not only promotes rapid release of the drug from the balloon surface and migration of the drug to the target tissue during deployment, but also prevents the drug coating from diffusing away from the device during migration through tortuous anatomy prior to reaching the target site and from migrating away from the device during the initial phase of balloon expansion before being forced into direct contact with the surface of the body lumen.

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

[0212] In embodiments of the present invention, the additive can be a surfactant and / or a compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties. Surfactants include ionic, nonionic, aliphatic, and aromatic surfactants. The compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties is selected from amino alcohols, hydroxyl carboxylic acids and anhydrides, ethyl oxide, ethyl glycol, amino acids, peptides, proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyhydric alcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, and their substituted molecules.

[0213] The terms "hydrophilic" and "hydrophobic" are relative terms. To function as an additive in various embodiments of the present invention, a compound contains a polar or charged hydrophilic portion and a non-polar hydrophobic (lipophilic) portion.

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

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

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

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

[0218] For example, the HLB value of a surfactant is generally used as a rough guide to allow the formulation of emulsions for industrial, pharmaceutical, and cosmetic applications. It has been reported that for many important surfactants, including some polyethoxylated surfactants, the HLB value can vary by as much as about 8 HLB units, depending on the empirical method used to determine 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, surfactants with suitable hydrophilicity or hydrophobicity for use in embodiments of the present invention can be identified, as described herein.

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

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

[0221] Also, in general, mixtures of surfactants are useful in embodiments of the present invention, including mixtures of two or more surfactants, as well as mixtures of surfactants with another additive or additives. Some PEG fatty acid esters are sold commercially as mixtures or as mono- and diesters.

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

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

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

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

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

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

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

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

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

[0231] Hydrophilic surfactants in this class include Poloxamers 108, 188, 217, 238, 288, 338, and 407. Hydrophobic surfactants in this class include Poloxamers 124, 182, 183, 212, 331, and 335.

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

[0233] The amphiphilic derivative of vitamin C, sorbitan monopalmitate (which possesses vitamin C activity), can perform two important functions in solubilized systems. First, it possesses effective polar groups that can tailor the microenvironment. These polar groups are the same groups that make vitamin C itself (ascorbic acid) one of the most water-soluble organic solid compounds available: ascorbic acid is soluble at approximately 30% w / w in water (very close to the solubility of, e.g., sodium chloride). Second, increasing the pH converts the ratio of ascorbyl palmitate to more soluble salts, such as sodium ascorbyl palmitate.

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

[0235] Some of the surfactants described herein are highly stable under heat. They survive ethylene oxide sterilization. They do not react with drugs such as paclitaxel or rapamycin during sterilization. Hydroxyl, ester, and amide groups are not likely to react with drugs, whereas amine and acid groups often react with paclitaxel or rapamycin during sterilization. Furthermore, surfactant additives improve the integrity and quality of the coating layer, resulting in less particle size reduction during handling. When formulated with paclitaxel, the surfactants described herein have been experimentally shown to promote rapid release and elution of paclitaxel at the target site during very short deployment times of 0.2 to 10 minutes while protecting the drug from premature release during the device delivery process. Drug absorption by tissues at the target site has been experimentally determined to be high.

[0236] A compound containing one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties. Compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties include creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerol ethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crown ethers, 18-crown-6, 15-crown-5, 12-crown-4, N-alanine ... Cetylglucosamine, N-octyl-D-gluconamide, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin, galacrocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N-oleoyl-D - including sphingosine, PEG caprylic / capric diglyceride, PEG8 caprylic / capric glyceride, PEG caprylate, PEG8 caprylate (e.g., Labrasol®), PEG caprate, PEG caproate, glyceryl monocaprylate, glyceryl monocaprate and glyceryl monocaproate, monolaurin, monocaprin, monocaprylin, monomyristin, monopalmitolein and monoolein

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

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

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

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

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

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

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

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

[0245] Certain amino acids, in their zwitterionic and / or salt forms with monovalent or polyvalent ions, have polar groups, relatively high octanol-water partition coefficients, and are useful in embodiments of the present invention. In the context of this disclosure, applicants take "low-solubility amino acids" to mean 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.

[0246] Also useful are amino acid dimers, glycoconjugates, and other derivatives. Through simple reactions well known in the art, hydrophilic molecules can be linked to hydrophobic amino acids, or hydrophobic molecules can be linked to hydrophilic amino acids, to make additional additives useful in embodiments of the invention.

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

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

[0249] Proteins are also useful as additives in various embodiments of the present invention. For example, serum albumin is a useful additive because it is water-soluble and contains significant hydrophobic moieties for binding drugs: paclitaxel is 89% to 98% protein-bound after intravenous injection in humans, while rapamycin is 92% protein-bound, primarily (97%) to albumin. Furthermore, paclitaxel solubility in PBS increases more than 20-fold with the addition of BSA. Albumin is naturally present in high concentrations in serum and is thus very safe for human use.

[0250] Other useful proteins include, without limitation, other albumins, immunoglobulins, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, vitronectin, fibrinogen, lipase and the like.

[0251] Organic acids and their esters and anhydrides. 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 aspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and 2-pyrrolidone.

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

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

[0254] Other compounds with one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties. Additives according to various embodiments can include amino alcohols, alcohols, amines, acids, amides and hydroxyl acids in both cyclo and linear aliphatic and aromatic groups.Examples are L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, gluccomic acid, hydroxyl ketones, hydroxyl lactones, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, gulonic acid lactone, mannolic acid lactone), ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, 2-hydroxybenzoic acid propyl, lysine acetate, gentisic acid, lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphate, glucopyranose phosphate, sugar sulfate, sinapic acid, vanillic acid, vanillic acid diethylamide, vanillin, methylparaben, propylparaben, xylitol, 2-ethoxyethanol, sugar, galactose, glucose, ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose, fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate gallate), tiletamine, ketamine, propofol, lactic acid, acetic acid, salts and amines of any of the organic acids described herein, polyglycidol, glycerol, multiglycerols (e.g., compounds with 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 combinations thereof.

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

[0256] Combinations or mixtures of surfactants and small water-soluble molecules (compounds with one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties) can be advantageous. Formulations containing a mixture of two additives with a water-insoluble drug are sometimes superior to mixtures containing either additive alone. Hydrophobic drugs bind water-soluble small molecules much poorer than they bind surfactants. They are often phase-separated from small water-soluble molecules, which can lead to suboptimal coating uniformity and integrity. Water-insoluble drugs have a higher Log P than both surfactants and small water-soluble molecules. However, the Log P of surfactants is typically higher than the Log P of compounds with one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties. Surfactants have a relatively high Log P (usually above 0), while water-soluble molecules have a low Log P (e.g., below 0). Some surfactants, when used as additives in embodiments of the present invention, adhere very strongly to water-insoluble drugs and the surface of medical devices, preventing the drug from being rapidly released from the surface of the medical device at the target site. On the other hand, some water-soluble small molecules (bearing one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties) adhere very poorly to pharmaceutical devices, releasing the drug before reaching the target site, for example, into the serum during passage of a coated balloon catheter to the intended site of intervention. Surprisingly, by adjusting the concentration ratio of small hydrophilic molecules and surfactants in the formulation, the inventors found that in certain cases, coating stability during passage and rapid drug release when expanded and pressed against the tissue of the lumen wall at the target site of therapeutic intervention was superior to formulations containing either additive alone. Furthermore, the presence of surfactants improves the miscibility and compatibility of water-insoluble drugs and highly water-soluble molecules. Surfactants also improve coating uniformity and integrity due to their good adhesion to drugs and small molecules. The long-chain hydrophobic portion of the surfactant tightly binds the drug, while the hydrophilic portion of the surfactant binds to water-soluble small molecules.

[0257] The surfactants in the mixture or combination include any of the surfactants described herein for use in embodiments of the present invention. The surfactants in the mixture include PEG sorbitan fatty acid esters; PEG omega-3 fatty acid esters, ethers and alcohols; glycerin fatty acid esters, sorbitan fatty acid esters, PEG glyceryl fatty acid esters, PEG fatty acid esters and alcohols, sugar fatty acid esters, PEG sugar esters, Tween 20, Tween 40, Tween 60, p-isononylphenoxy polyglycidol, PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, Tween 20, Tween 40, Tween 60, Tween 80, Octoxynol, Octoxynol-9, Monoxynol, Tyloxapol, 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, octyl-β-D-thioglucopyranoside and derivatives thereof.

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

[0259] Compounds in the mixture that have one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties are: L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohol, glucoheptonic acid, gluccomic acid, hydroxyl ketones, hydroxyl lactones, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone, mannolactone, ribonic acid lactone, lactobionic acid, glucosamine, glucosamine, Glucocorticoids, Benzyl Alcohol, Benzoic Acid, Hydroxybenzoic Acid, Propyl 2-Hydroxybenzoate, Lysine Acetate, Gentisic Acid, Lactobionic Acid, Lactitol, Sorbitol, Glucitol, Sugar Phosphate, Glucopyranose Phosphate, Sugar Sulfate, Sinapic Acid, Vanillic Acid, Vanillin, Methylparaben, Propylparaben, Xylitol, 2-Ethoxyethanol, Sugar, Galactose, Glucose, Ribose, Mannose, Xylose, Sucrose, Lactose, Maltose, Arabinose, Lyxose, Fructose, Cyclodextrin, (2-Hydroxyethylcellulose) (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 as described herein, polyglycidol, glycerin, polyglycerol, galactitol, monolaurin, monocaprin, monocaprylin, monomyristin, monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame cereal, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerin ethoxylate, glycerin propoxylate, trimethylolpropane ethoxylate, pentaerythritol,The copolymer is selected from 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 derivatives and combinations thereof.

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

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

[0262] Examples of additives include p-isononylphenoxypolyglycidol, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, octoxynol, octoxynol-9, and n-heptyl-β-D-thioglucoside. Monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-maltoside, n-heptyl-β-D-glucopyranoside, n-dodecyl-β-D-glucopyranoside n-Hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-Octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, cystine, tyrosine, tryptophan, leucine, isoleucine Ingredients include: niacin, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine (amino acids), cetotiamine, cyclothiamine, dexpanthenol, niacinamide, nicotinic acid and its salts, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K7, and vitamin U (vitamins); albumin, immunoglobulins, casein, hemoglobin, lysozyme, immunoglobulins, 2-macroglobulin, fibronectin, vitronectin, fibrinogen, lipase, benzalkonium chloride, benzethonium chloride.Docecyl trimethyl ammonium bromide, sodium docecyl sulfate, dialkylmethylbenzylammonium chloride, and dialkyl ester of sodium sulfosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gluconolactone Acid lactone, mannolactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, 2-hydroxybenzoic acid propyl, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate lecithin, tiletamine, ketamine, propofol, lactic acid, acetic acid, salts of any organic acid and organic amine, polyglycidol, glycerin, polyglycerin, galactitol, monolaurin, monocaprin, monocaprylin, monomyristin, monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, kaolin ... Phenyne, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerin ethoxylate, glycerin propoxylate, trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5, 12-crown-4, di(ethylene glycol), tri(ethylene glycol),These additives include 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 (compounds having one or more hydroxyl, amino, carbonyl, carboxyl, or ester moieties). Some of these additives are water-soluble and organic solvent-soluble. They have good adhesive properties and adhere to the surface of polyamide medical devices such as balloon catheters. Therefore, they can be used in the attachment 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 alcohol and acid polar groups accelerate drug penetration into tissues.

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

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

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

[0266] In another example, L-ascorbic acid, thiamine, maleic acid, niacinamide, and 2-pyrrolidone-5-carboxylic acid all have very high aqueous and ethanol solubilities, low molecular weights, and small sizes. They also contain structural components containing aromatic C=N, amino, hydroxyl, and carboxylic acid groups. These structures are highly compatible with paclitaxel and rapamycin, increasing the solubility of these water-insoluble drugs in water and enhancing their absorption into tissues. However, they often exhibit poor adhesion to the surface of medical devices. Therefore, when useful for enhancing drug absorption, they are often used in combination with other additives in the drug and top layers. Vitamins D2 and D3, especially when combined with paclitaxel, are particularly useful for their antirestenotic effects and for reducing thrombosis.

[0267] The relative amounts of therapeutic agent and additive in the coating layer can vary depending on the applicable circumstances. The optimal amount of additive can be determined, for example, by the particular therapeutic agent and additive selected. The surface modifier may depend on the critical micelle concentration of the surface modifier if it 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 an aqueous solution of the surface modifier, etc.

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

[0269] In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a target site of a stricture in a body lumen, the balloon catheter comprising a coating layer overlying the outer surface of the balloon. The coating layer can comprise a polymer-encapsulated drug particle comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent; or a drug-releasing coating comprising the polymer-encapsulated drug particle; or a composition comprising a therapeutic agent and one or more additives; or a combination thereof. The therapeutic agent can be selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, analogs thereof, and combinations thereof. The additive can be a non-water-soluble additive selected from cholesteryl acetate, cholesteryl phenylacetate, cholesteryl laurate, cholesteryl palmitate, cholesteryl stearate, cholesteryl n-valerate, cholesteryl benzoate, cholesteryl heptylate, cholesteryl decylate, cholesteryl caproate, cholesteryl oleate, cholesteryl oleyl carbonate, cholesteryl linoleate, cholesteryl pelargonate, cholesteryl erucate, cholesteryl caprylate, 5α-cholestane, 5α-cholestan-3-one, and combinations.

[0270] In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a target site of a narrowing or stenosis in a body lumen, wherein the balloon comprises polyester, polyamide, nylon 12, nylon 11, polyamide 12, a block copolymer of polyether and polyamide, a polyether block amide, polyurethane, a block copolymer of polyether and polyester, or a combination thereof. The balloon catheter comprises a coating layer overlying the outer surface of the balloon. The coating layer comprises a polymer-encapsulated drug particle comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent; a drug-releasing coating comprising the polymer-encapsulated drug particle; a composition comprising a therapeutic agent and one or more additives; or a combination thereof. The therapeutic agent can be selected from paclitaxel, docetaxel, taxol, an mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, analogs thereof, and combinations thereof. The additive comprises at least one alkylaliphatic group or cholesteryl group, and the first additive can be a water-insoluble or slightly or partially water-insoluble first additive having a molecular weight of 50 to 750, and the second additive can be more hydrophilic or more water-soluble than the first additive and comprises -(CHCHO)- units and has a molecular weight of 750 to 100,000, preferably 1000 to 50,000, and most preferably 2000 to 10,000. The water-insoluble or slightly or partially water-insoluble first additive having a cholesteryl group can be selected from cholesteryl acetate, cholesteryl phenylacetate, cholesteryl laurate, cholesteryl palmitate, cholesteryl stearate, cholesteryl n-valerate, cholesteryl benzoate, cholesteryl heptylate, cholesteryl decylate, cholesteryl caproate, cholesteryl oleate, cholesteryl oleyl carbonate, cholesteryl linoleate, cholesteryl pelargonate, cholesteryl erucate, cholesteryl caprylate, 5α-cholestane, 5α-cholestan-3-one, and combinations thereof. The alkyl aliphatic group (e.g., C1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 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, 80The water-insoluble or slightly or partially water-insoluble first additive having a C4 to C30 amino acid residue, such as C27, 28, 29 or C30 or more, is selected from the group consisting of alkyl glyceryl ethers, monoglycerides of C8 to C12 fatty acids, alkyl alcohols, alkyl ethers, alkyl esters, caprylic acid, monocaprylin, capric acid, monocapric acid, lauric acid, dodecylglycerol, butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienols, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, mica, The lipid soluble fatty acid may be selected from ristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha linolenic acid, gamma linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di-, or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobees, niosomes, derivatives thereof, and combinations thereof. The water-soluble second additives are cholesteryl-polyethylene glycol 600 sebacate, polyoxyethanyl α-tocopheryl sebacate, methylated polyethylene glycol cholesterol (mPEG cholesterol), polyethylene glycol cholesterol (PEG cholesterol), polyethylene glycol ester cholesterol (PEG cholesterol), polyethylene glycol ether cholesterol (PEG cholesterol), methylated polyethylene glycol-amide-cholesterol (mPEG cholesterol), polyethylene glycol-amide-cholesterol (PEG cholesterol),Polyethylene glycol (PEG)-cholesteryl sebacate, polyethylene glycol cholesterol, PEG amidoester cholesterol, PEG amidoether cholesterol, mPEG amidoester 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, 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™ 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.

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

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

[0273] Various embodiments provide methods for preparing a coating solution. The content of the therapeutic agent in the coating solution can be 0.5 to 50 wt % based on the total weight of the solution. The content of the additive in the coating solution can be about 0.1 wt % to about 45 wt %, about 0.2 wt % to about 40 wt %, about 0.3 wt % to about 15 wt %, or about 0.1 wt % or less, or less than or equal to about 0.2 wt %, 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 45 wt % 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 will evaporate.

[0274] In other embodiments, more than one solvent, more than one therapeutic agent, and / or more than one additive may be used in the coating solution.

[0275] Medical device coatings for drug delivery to nonvascular tissues or nonvascular stenoses can be prepared from mixtures. The coatings can be prepared from mixtures containing an organic phase with drug particles dispersed therein and an aqueous phase with one or more water-soluble additives. The water-soluble additives can be selected from polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidinone, polypeptides, water-soluble surfactants, water-soluble vitamins, and proteins. Alternatively, the coatings can be prepared from two-phase mixtures containing small drug particles suspended in a liquid. The liquid can consist of a suitable antisolvent 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.

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

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

[0278] Medical device coatings. The medical devices and coating layers of the present embodiments can be prepared by various methods. The coating solution can include polymer-encapsulated drug particles comprising a therapeutic agent and one or more polymers encapsulating the therapeutic agent; or a drug-release coating comprising polymer-encapsulated drug particles; or a composition comprising a therapeutic agent and one or more additives; or combinations thereof. Coating techniques such as casting, fixed-volume liquid dispensing, metering (e.g., dispensing a fixed amount of coating solution based on volume onto a balloon or stent), spinning, spraying, dipping (e.g., immersion), inkjet printing, electrostatic techniques, and combinations of these processes can be used to apply the coating solution to the medical device. The balloon can be at least partially inflated during application of the coating solution. Metering can be performed in any suitable manner, such as by pumping the liquid coating solution from a reservoir to a nozzle proximal to the surface of the medical device (e.g., the surface of an at least partially inflated balloon or stent). The nozzle can dispense liquid therefrom, which can be immediately displaced outside the medical device due to its proximity to the nozzle (e.g., the nozzle can be very close to a balloon or stent, which liquid emerging from the nozzle can contact and displace outside the medical device before forming a small amount of liquid leaving the nozzle). The nozzle can dispense liquid outside the medical device such that substantially none of the liquid is lost. The medical device can rotate about its longitudinal axis during dispensing of liquid from the nozzle. The nozzle may be attached to or extendable on a programmable xy stage to allow it to move during dispensing, such as along the exterior of the medical device parallel to the longitudinal axis of a cylindrically shaped balloon, or along the profile of a non-cylindrically shaped medical device, such as a discontinuously shaped medical device such as a balloon or stent.In some embodiments, the medical device can be rotated about its longitudinal axis during dispensing, and the nozzle can be moved parallel to the longitudinal axis of the medical device (e.g., similar to the movement of a chisel over a piece of spinning, cylindrical wood in a woodworker's lathe) so that substantially all of the surface of the medical device is coated with the coating solution. The nozzle can be moved once along the length of the medical device, or it can be moved back and forth making multiple passes along the length of the medical device. If the medical device is a stent, the stent can be coated in a fabricated, crimped, expanded diameter, or intermediate diameter.

[0279] The choice of application technique can depend on the viscosity and surface tension of the solution, a measurement that can be utilized in some embodiments of the present invention to make it easier to control the uniformity of the coating layer thickness as well as the concentration of the therapeutic agent applied to the medical device.

[0280] In one embodiment of the invention, the balloon is inflated or partially inflated, and the coating solution is applied to the inflated balloon by measuring it as it expands and rotating it along its longitudinal axis. The balloon is then compressed, folded, and allowed to dry before being sheathed.

[0281] The described embodiments of application devices, fixtures, and measurement techniques are examples. Any suitable measurement or other technique can be used to coat the balloon catheter.

[0282] After the medical device is coated with the coating solution, the coated medical device can be subjected to drying, which evaporates the solvent in the coating solution. This produces a coating matrix on the medical device that contains the therapeutic agent. One example of a drying technique is placing the coated medical device in an oven at about 20°C or higher for about 24 hours. Other suitable methods of drying the coating solution can be used. The time, temperature, and relative humidity can vary depending on the particular additive and therapeutic agent.

[0283] In one embodiment, a method of coating a balloon catheter includes preparing an aqueous suspension coating solution comprising mixing water, a water-miscible solvent, a therapeutic agent, and a water-soluble additive to form a premix; processing the premix to reduce the particle size of the therapeutic agent; mixing an insoluble water-soluble additive, a water-soluble additive, water, and a water-miscible solvent to form a second mixture; and mixing the second mixture with the first processed premix to form a coating solution, wherein the therapeutic agent is selected from paclitaxel, docetaxel, taxol, an mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, analogs thereof, and combinations thereof; the therapeutic agent is crystalline, partially crystalline, amorphous, partially amorphous, or combinations thereof; the coating solution is an aqueous suspension of the therapeutic agent; and the particle size of the therapeutic agent is in the range of 0.2 microns to 5 microns. The first additive, the second additive, or a combination thereof encapsulates a therapeutic agent, and the therapeutic agent encapsulated in the additive has a particle size larger than the therapeutic agent itself, with the particle size of the therapeutic agent encapsulated in the additive in the coating ranging from 0.3 microns to 10 microns. The first additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one alkylaliphatic group or cholesteryl group. The first additive can have a molecular weight of 50 to 750. The first additive in the coating has a lower melting temperature than the first additive in its pure form. The first additive in the coating has a lower crystallinity than the first additive in its pure form. The second additive is more hydrophilic or more water-soluble than the first additive and contains polyethylene glycol (-(CH2CHO)-) or polyglycerol (-(CH2-CHOH-CHO)-) units. The second additive has a molecular weight in the range of 750 to 100,000, or 750 to 50,000, or 750 to 10,000. The method includes preparing a balloon catheter by inflating the balloon catheter; cleaning the surface of the balloon; and fixing the balloon in a coating machine so that the balloon can be mounted horizontally and rotated at a fixed speed.The method includes dispensing a coating solution onto the surface of the balloon while a nozzle moves laterally across the balloon. The method includes continuing to rotate the balloon at room temperature or above room temperature to evaporate the solvent. The method includes crimping and folding the balloon catheter. The method includes sterilizing the balloon.

[0284] Balloon preparation. Various embodiments of the present invention provide methods for forming a balloon. The methods can include placing a tube containing balloon material or extruding the balloon material into any suitable shaped mold, for example, a shaped balloon mold including a proximal cone, at least one body portion, at least one neck having a diameter smaller than the at least one body portion, at least one other body portion, and a distal cone. The methods can include heating the balloon material tube to a temperature above its glass transition temperature, pressurizing the interior of the balloon material tube, and stretching the balloon material to reduce the balloon thickness. The methods can also include expanding the balloon material tube into contact with the interior of the mold.

[0285] Various embodiments of the present invention provide methods for forming a balloon and then deflation to achieve a large diameter range. The method includes placing a tube containing balloon material into a balloon mold, the balloon mold having a shape including a proximal cone, at least one body portion, and a distal cone. The method includes pressurizing the interior of the balloon material tube. The method includes expanding the balloon material tube into contact with the interior of the mold at a pressure of 200-400 psi and a temperature of 100-200°C. The formed balloon is then deflated by annealing the balloon at a lower temperature than the molding process, preferably at 1-30 psi, at 70-90°C for 3-30 seconds, at a low inflation pressure for a predetermined amount of time. Once the balloon is deflated, it can be attached to a catheter shaft and coated with a drug. Any of the manufacturing techniques, methods of treating a body lumen, or balloons described in the following patents, which are hereby incorporated by reference as if reproduced in their entirety, can be used in embodiments of the present invention: U.S. Patent Nos. 7,163,522 and 7,108,826.

[0286] Extendable neck. In various embodiments, the balloon catheter of the present invention does not include an expandable neck. In other embodiments, the balloon of the balloon catheter includes at least one expandable neck. The balloon can include a...

Claims

1. Therapeutic agents; a first ionic or zwitterionic additive; and One or more polymers encapsulating the therapeutic agent and the first ionic or zwitterionic excipient.

1. A polymer-encapsulated drug particle comprising: The first ionic or zwitterionic additive forms 0.5% to 20% by weight of the polymer-encapsulated drug particle, and the first ionic or zwitterionic additive is selected from the group consisting of 1,2-dihexanoyl-sn-glycero-3-phosphocholine, 1,2-diheptanoyl-sn-glycero-3-phosphocholine, 1,2-dioctanoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero 1,2-dinonanoyl-sn-glycero-3-phosphocholine, 1,2-didecanoyl-sn-glycero-3-phosphocholine, 1,2-diundecanoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or a combination thereof; the polymer-encapsulated drug particles have a largest dimension of 1 micron to 5 microns; Polymer-encapsulated drug particles.

2. 10. The polymer-encapsulated drug particle of claim 1, wherein the first ionic or zwitterionic additive further comprises polylysine.

3. 10. The polymer-encapsulated drug particle of claim 1, wherein the therapeutic agent is amorphous, partially amorphous, or a combination thereof.

4. 10. The polymer-encapsulated drug particle of claim 1, wherein the therapeutic agent is crystalline or partially crystalline.

5. 2. The polymer-encapsulated drug particle of claim 1, wherein the polymer is at least one polymer selected from polylactic acid (PL), polyglycolic acid (GA), polylactic acid / polyglycolic acid copolymer (PLGA), polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycan, and copolymers thereof.

6. 2. The polymer-encapsulated drug particle of claim 1, wherein the first ionic or zwitterionic additive further comprises a charged polymer, a charged lipid, a charged phospholipid, a phosphocholine, a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylserine, a phosphatidylinositol, and combinations thereof.

7. The polymer-encapsulated drug particle of claim 6, wherein two acyl groups of the charged lipid or two acyl groups of the charged phospholipid comprise mismatched acyl groups, and the mismatched acyl groups differ by length, degree of saturation, their substituents, their substitution pattern, or a combination thereof.

8. 2. The polymer-encapsulated drug particle of claim 1, wherein the first ionic or zwitterionic additive comprises a water-insoluble or slightly or partially water-insoluble additive containing at least one acyl group, and the first ionic or zwitterionic additive has a molecular weight of 50 to 10,000.

9. 2. The polymer-encapsulated drug particle of claim 1, wherein the therapeutic agent is selected from paclitaxel, docetaxel, taxol, an mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, daunorubicin, doxorubicin, analogs thereof, and combinations thereof.

10. 2. The polymer-encapsulated drug particles of claim 1, wherein the polymer-encapsulated drug particles are on a balloon catheter, a drug-coated catheter, a drug-eluting stent, a drug-eluting stent on a balloon, a drug-eluting stent on a drug-coated balloon, a stent on a drug-coated balloon, or a combination thereof.

11. 10. The polymer-encapsulated drug particle of claim 1; and Release matrix containing a second ionic or zwitterionic additive A drug-releasing coating comprising:

12. 12. The drug release coating of claim 11, wherein the second ionic or zwitterionic additive has the same molecular structure as the first ionic or zwitterionic additive.

13. 12. The drug-release coating of claim 11, wherein the second ionic or zwitterionic additive has a different molecular structure than the first ionic or zwitterionic additive.

14. 13. The drug release coating of claim 12, wherein the second ionic or zwitterionic additive in the release matrix is ​​selected from a charged molecule, an anionic molecule, a charged polymer, a charged lipid, a phospholipid, a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylserine, a phosphatidylinositol, and combinations thereof.

15. 13. The drug-releasing coating of claim 12, wherein the coating is on a balloon catheter, a drug-coated catheter, a drug-eluting stent, a drug-eluting stent on a balloon, a drug-eluting stent on a drug-coated balloon, a stent on a drug-coated balloon, or a combination thereof.

16. forming a suspension comprising the therapeutic agent, the polymer, and the first ionic or zwitterionic additive; treating the suspension to reduce the particle size of the suspension; and 2. The method of claim 1, further comprising adding an aqueous premix to the suspension to form polymer-encapsulated drug particles in the suspension, the aqueous premix comprising water and a water-soluble polymer or surfactant.

17. 17. The method of claim 16, further comprising adding a second ionic or zwitterionic additive to the suspension to form a drug-release coating, and optionally stirring the suspension to homogenize the polymer-encapsulated drug particles therein.

18. forming an organic premix comprising an organic solvent, the one or more polymers, the therapeutic agent, and the first ionic or zwitterionic additive; forming an aqueous premix comprising water and a water soluble polymer or surfactant; adding an organic solvent to said aqueous premix; combining the aqueous premix and the organic premix together; and agitating the combined aqueous premix and organic premix to form an emulsion comprising the polymer-encapsulated drug particles. A method for making the polymer-encapsulated drug particles of claim 1.

19. forming a first mixture comprising the polymer-encapsulated drug particles and an organic solvent; forming a second mixture comprising a second ionic or zwitterionic additive and an organic solvent; combining the first mixture and the second mixture; and drying the combined first mixture and second mixture to form a drug-release coating.

20. The method of claim 18, further comprising:

20. 12. A method of making a balloon catheter, comprising applying the drug-releasing coating of claim 11 to the exterior of the balloon of the balloon catheter.

21. 2. The polymer-encapsulated drug particle of claim 1, wherein the one or more polymers comprise PLGA having a weight ratio of lactic acid to glycolic acid of about 85:15 and / or PLGA having a weight ratio of lactic acid to glycolic acid of about 75:

25.

22. 12. The drug release coating of claim 11, wherein the second ionic or zwitterionic additive is selected from 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 and combinations thereof.

23. 12. The drug release coating of claim 11, wherein the release matrix comprises poly-L-lysine, polylysine, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or a combination thereof.

24. 12. The drug release coating of claim 11, wherein the release matrix comprises particles of a second therapeutic agent that are not encapsulated by a polymer, and the particles of the second therapeutic agent are selected from paclitaxel, docetaxel, taxol, mTOR inhibitors, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, analogs thereof, and combinations thereof.

25. Therapeutic agents; a first ionic or zwitterionic additive; and One or more polymers encapsulating the therapeutic agent and the first ionic or zwitterionic excipient. a polymer-encapsulated drug particle comprising: Release matrix containing a second ionic or zwitterionic additive 1. A drug release coating comprising: The first ionic or zwitterionic additive may be 1,2-dihexanoyl-sn-glycero-3-phosphocholine, 1,2-diheptanoyl-sn-glycero-3-phosphocholine, 1,2-dioctanoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dinonanoyl-sn-glycero-3-phosphocholine, glycero-3-phosphocholine, 1,2-didecanoyl-sn-glycero-3-phosphocholine, 1,2-diundecanoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or a combination thereof; the polymer-encapsulated drug particles have a largest dimension of between 1 micron and 5 microns; 10. The drug release coating of claim 1, wherein the second ionic or zwitterionic additive is selected from 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 and combinations thereof.

26. The polymer-encapsulated drug particle of claim 1, wherein the first ionic or zwitterionic additive comprises 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

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