Drug-coated balloon catheters for body lumens

Abstract

To provide drug-coated balloon catheters for treating, preventing or reducing the recurrence of a stricture and / or cancer, or for treating benign prostatic hyperplasia (BPH), in a non-vascular body lumen, and methods of using the same.SOLUTION: A drug-coated balloon catheter for delivering a therapeutic agent to a target site of a body lumen stricture includes an elongated balloon having a main diameter. The balloon catheter includes a coating layer overlying an exterior surface of the balloon. The coating layer includes one or more water-soluble additives and an initial drug load of a therapeutic agent. In some embodiments, the balloon catheter includes a length-control mechanism, which stretches and elongates the balloon when it is in a deflated state, giving the balloon a smaller cross-sectional deflated profile for tracking through the body lumen and for removal after treatment.SELECTED DRAWING: Figure 5A

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 809,048 (filed February 22, 2019) and U.S. Provisional Patent Application No. 62 / 859,396 (filed June 10, 2019), the disclosures of which are incorporated herein by reference in their entireties.

[0002] The disclosures of each of the following applications are incorporated herein by reference in their entirety: U.S. Patent Application 16 / 135,436, which is a continuation-in-part of International Application PCT / US2018 / 03108, filed May 4, 2018, which claims the benefit of priority to U.S. Provisional Application 62 / 502,212, filed 5 / 5 / 2017. U.S. Patent Application 16 / 135,436 is also a continuation-in-part of U.S. Patent Application 15 / 568,614, filed October 23, 2017, which is a U.S. national phase application under 35 USC 371 from International Application PCT / US2016 / 028652, filed April 21, 2016, which claims the benefit of priority to U.S. Provisional Application 62 / 152,559, filed April 24, 2015. U.S. patent application 16 / 135,436 is also a continuation-in-part of U.S. patent application 14 / 438,327 (filed April 24, 2015), which is a U.S. national phase application under 35 USC 371 from international application PCT / US2013 / 064842 (filed October 14, 2013), which claims the benefit of priority to U.S. provisional application 61 / 795,790 (filed October 26, 2012). U.S. patent application 16 / 135,472 is a continuation-in-part of international application PCT / US2018 / 03108 (filed May 4, 2018), which claims the benefit of priority to U.S. provisional application 62 / 502,212 (filed 5 / 5 / 2017). U.S. patent application 16 / 135,472 is a continuation-in-part of U.S. patent application 15 / 568,614 (filed October 23, 2017), which is a U.S. national phase 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 62 / 152,559 (filed April 24, 2015). U.S. patent application 16 / 135,472 is a continuation-in-part of U.S. patent application 14 / 438,327 (filed April 24, 2015), which is a U.S. national phase 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 61 / 795,790 (filed October 26, 2012). [Background technology]

[0003] background Benign prostatic hyperplasia is a noncancerous enlargement of the prostate that affects more than 50% of men over the age of 60. Before that, the prostate is the size and shape of a walnut and weighs about 20 g. Prostatic hyperplasia is considered a normal process. With age, the prostate gradually enlarges to more than twice its normal size. As the prostate grows, it compresses and narrows the urethra, causing prostatic urethral compression and urinary obstruction that makes urination difficult or impossible.

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

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

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

[0007] Digestive lumen or digestive tract strictures 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. Disease type classifies strictures as benign or malignant.

[0008] Biliary strictures, also called biliary strictures, occur when the bile duct becomes small or narrowed. The bile duct is the tube that carries bile from the liver to the small intestine. When the bile duct becomes narrow, it becomes difficult to digest food. Biliary strictures can be caused by any injury to the bile duct, swelling, pancreatitis, intestinal injury, and cancer of 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 classified as malignant or benign lesions. Dysphagia is a symptom experienced by all patients. The majority of these patients require symptomatic treatment for relief of dysphagia.

[0010] Digestive strictures are narrowings of a portion of the intestine that cause problems by slowing or blocking the movement of food through this area. Strictures are caused by recurrent inflammation, cancer, Crohn's disease, and ulcerative colitis. Strictures include esophageal strictures, achalasia strictures, in-stent strictures, biliary strictures, gastric strictures, small bowel strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, and large bowel strictures.

[0011] Chronic obstructive pulmonary disease (COPD) is a term used to classify two major airflow obstruction disorders: chronic bronchitis and emphysema. Approximately 16 million Americans have COPD, 80-90% of whom have smoked 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 bronchial tubes secrete mucus, causing chronic coughing. Emphysema is the overinflation of the alveoli, or air sacs, in the lungs. This condition causes shortness of breath.

[0012] Asthma is a chronic respiratory disease characterized by inflammation of the airways, excessive mucus production and airway hyperresponsiveness, a condition in which the airways narrow too much or respond too easily to stimuli. Asthma episodes or attacks narrow the airways, which leads to difficulty in breathing. Asthma attacks can have a significant impact on the patient's life, limiting participation in many activities. In severe cases, asthma attacks can be life-threatening. Currently, there is no known cure for asthma.

[0013] Chronic sinusitis is inflammation of the membranes lining one or more sinuses. Chronic sinusitis lasts more than three weeks and often lasts for several months. With chronic sinusitis, there is usually tissue damage. According to the Centers for Disease Control (CDC), 37 million cases of chronic sinusitis are reported annually.

[0014] Radiation (e.g., radiotherapy) is used as a modality of localized cancer treatment. Localized cancers are the most commonly diagnosed cancers. The majority of patients are diagnosed at an early stage, which may be curable. Standard local 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 (EBRT) or brachytherapy (BT). Side effects associated with each treatment can vary considerably. Localized cancers include prostate cancer, urethral cancer, ureteral cancer, esophageal cancer, bile duct cancer, gastric cancer, small intestine cancer, duodenal cancer, jejunal cancer, ileal cancer, colon cancer, rectal cancer, large intestine cancer, and lung cancer. Radiation treatments can cause injury, such as strictures, to adjacent healthy tissue. Radiation treatment-induced strictures may 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 may be complex and difficult. With high survival rates, the number of prostate cancer survivors in the United States is increasing by 220,000 per year, reaching 2.8 million in 2015, and many men are at risk of short-term or 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.

[0015] An anastomosis is a connection or opening between two fluid-carrying body structures. A surgical anastomosis is an anastomosis formed via a surgical technique that connects two fluid-carrying body structures together. An anastomotic stricture is a narrowing of an anastomosis. An anastomotic stricture is a common complication of surgical anastomosis and various other surgical procedures. An anastomotic stricture is usually fibrotic and can be difficult to manage and treat. An anastomotic stricture can include a narrowing of an anastomosis between two parts of the same body structure or between two different body structures, where the body structure can be the esophagus, bile duct, stomach, small intestine, duodenum, jejunum, ileum, colon, rectum, large intestine, colon, rectum, urethra, ureter, or bladder neck. An anastomotic stricture can be a colorectal stricture, a stricture after gastric bypass, an ileocolic stricture, a digestive stricture, a J-pouch stricture, or a bladder neck stricture (e.g., a stricture). Although balloon dilation has been shown to be a safe and effective non-surgical method of management of anastomotic strictures, problems such as repeated balloon dilation due to refractory or recurrent anastomotic strictures still exist.

[0016] Inflammatory bowel disease (IBD) leads to Crohn's disease (CD) and ulcerative colitis (UC). Crohn's disease and ulcerative colitis-induced strictures are common complications of inflammatory bowel disease and surgery for its treatment. The stricture rate in patients with inflammatory bowel disease varies from 34% to 70% over time. Some strictures are refractory or recurrent, requiring repeated endoscopic dilatation procedures for treatment.

[0017] Eosinophilic esophagitis (EoE) is a chronic inflammatory disease. Symptoms of the disease include dysphagia and food impaction, which are often the result of esophageal strictures. Repeated endoscopic dilatation of esophageal fibrostenosing eosinophilic esophagitis strictures using bougies and balloon catheters is used to treat such strictures.

[0018] Barrett's disease, also called Barrett's esophagus, is an abnormal (metaplastic) transformation of the mucosal cells lining the lower esophagus from normal stratified squamous epithelium to simple columnar epithelium, with scattered goblet cells normally found only in the colon. This transformation is considered a premalignant condition because it is associated with further progression to esophageal adenocarcinoma, a common and often fatal cancer. Summary of the Invention [Problem to be solved by the invention]

[0019] Various minimally invasive methods used for the treatment of various cancers, large colon polyps and Barrett's esophagus are being performed worldwide. Various minimally invasive methods are gaining favor over surgical approaches when patients prefer to avoid surgery. Several randomized controlled clinical trials and meta-analyses have shown the clinical and oncological safety and effectiveness of laparoscopic gastrectomy, robotic-assisted gastrectomy, EMR (endoscopic mucosal resection) and ESD (endoscopic submucosal dissection) in the treatment of various stages of cancer and Barrett's esophagus. EMR (endoscopic mucosal resection) and ESD (endoscopic submucosal dissection) are safe and effective in the treatment of early-stage superficial cancers such as esophageal cancer, bile duct cancer, gastric cancer, small intestine cancer, duodenal cancer, jejunal cancer, ileal cancer, colon cancer, rectal cancer, colorectal cancer, ileocolonic cancer and gastrointestinal cancer. EMR and ESD are safe and effective in the treatment of high-grade Barrett's esophagus. Laparoscopic gastrectomy, robotic-assisted gastrectomy, EMR and ESD are feasible methods in terms of clinical and oncological safety; however, recurrence of malignant tumors and refractory strictures has been shown in some patients. The local recurrence rate of cancer after minimally invasive procedures is 2-20%, depending on the type and stage of cancer and the number of follow-ups. The incidence of stricture or stenosis after minimally invasive techniques is approximately 26%-70%. Repeated endoscopic balloon dilation is required for the treatment of refractory or recurrent stricture or stenosis. [Means for solving the problem]

[0020] Summary of the Invention In various embodiments, the present invention provides a balloon catheter. The balloon catheter can be used to treat, prevent or reduce stenosis and / or cancer recurrence in non-vascular body lumens. The balloon catheter includes an elongated balloon. The balloon catheter includes a coating layer covering the outer surface of the balloon. The coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. In some embodiments, the balloon catheter also includes a length adjustment mechanism that stretches and elongates the balloon while the balloon is in a deflated state.

[0021] In various embodiments, the present invention provides a method of treating a target site in a non-vascular body lumen. The method can be a method of treating, preventing or reducing stenosis and / or cancer recurrence or treating BPH at a target site in a non-vascular body lumen. The method includes inserting a balloon catheter into the target site in the non-vascular body lumen. The balloon catheter includes an elongated balloon. The balloon catheter also includes a coating layer covering an outer surface of the balloon. The coating layer includes one or more water soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site to contact the coating layer with a wall of the body lumen at the target site until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method also includes withdrawing the balloon catheter from the body lumen.

[0022] In various embodiments, the present invention provides a method for treating a cancer treatment-induced non-vascular stenosis. The method includes inserting a balloon catheter comprising an elongated balloon and a coating layer covering the outer surface of the balloon into a target site in a body cavity comprising a cancer treatment-induced non-vascular stenosis, wherein the coating layer comprises one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site to contact the coating layer with the wall of the body cavity at the location of the cancer treatment-induced non-vascular stenosis until the balloon achieves an inflated balloon diameter during the inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the cancer treatment is a radiation treatment. In some embodiments, the stenosis is a urethral stenosis, a ureteral stenosis, an esophageal stenosis, a paranasal sinus stenosis, a gastric stenosis, a small intestinal stenosis, a colonic stenosis, a rectal stenosis, a large intestinal stenosis, a bladder neck stenosis, or a bile duct stenosis. In some embodiments, the cancer treatment is a prostate radiation treatment, wherein the stenosis is a bladder neck stenosis. In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter at the target site, the inflation and deflation process, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, yielding of the target site, release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stenosis or target site.

[0023] In various embodiments, the present invention provides a method for reducing or preventing recurrence of cancer treatment-induced non-vascular stenosis or reducing or preventing recurrence of cancer. The method includes inserting a balloon catheter into a target site in a body cavity, where the target site is at, adjacent to, proximal to, or distal to a site where a cancer treatment was performed, and the balloon catheter includes an elongated balloon and a coating layer covering an outer surface of the balloon, where the coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site to contact the coating layer with a wall of the body cavity at the target site until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the method further includes performing a cancer treatment of the body cavity at, adjacent to, proximal to, or distal to the target site prior to inserting the balloon catheter into the target site. In some embodiments, a cancer treatment-induced non-vascular stenosis is present at the target site, and the method further includes performing a stenotomy at the target site prior to inserting the balloon catheter into the target site. In some embodiments, the stricture incision includes needle knife electroincision, perineotomy, urethrotomy, transurethral internal urethrotomy (DVIU), endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). In some embodiments, the cancer treatment is a radiation treatment. In some embodiments, the stricture is a urethral stricture, a ureteral stricture, an esophageal stricture, a sinus stricture, a gastric stricture, a small intestinal stricture, a colonic stricture, a rectal stricture, a large intestinal stricture, a bladder neck stricture or a bile duct stricture. In some embodiments, the cancer treatment is a prostate radiation treatment, wherein the stricture is a bladder neck stricture. In some embodiments, the method includes using a scope to visualize the insertion and placement of a drug-coated balloon catheter into the target site, the inflation and deflation process, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after balloon deflation, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting a balloon catheter into the stricture or target site.

[0024] In various embodiments, the present invention provides a method for treating a surgical anastomosis-induced non-vascular stenosis. The method includes inserting a balloon catheter comprising an elongated balloon and a coating layer covering the outer surface of the balloon into a target site in a body cavity comprising the surgical anastomosis-induced non-vascular stenosis, wherein the coating layer comprises one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon to contact the coating layer with a wall of the body cavity at the location of the surgical anastomosis-induced non-vascular stenosis until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the stenosis is a fibrotic stenosis. In some embodiments, the stenosis is esophageal stenosis, gastric stenosis, small intestinal stenosis, duodenal stenosis, jejunal stenosis, ileal stenosis, colonic stenosis, rectal stenosis, large intestinal stenosis, colorectal stenosis, stenosis caused by gastric bypass, ileocolic stenosis, digestive stenosis, urethral stenosis, ureteral stenosis, J-pouch stenosis or bladder neck stenosis.In some embodiments, the method includes using a scope to visualize the insertion and placement of a drug-coated balloon catheter into the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after balloon deflation, or any combination thereof.The method may include flushing the target site with water or saline solution through the scope before inserting the balloon catheter into the stenosis or the target site.

[0025] In various embodiments, the present invention provides a method for reducing or preventing the occurrence of surgical anastomosis-induced non-vascular stenosis. The method includes inserting a balloon catheter into a target site in a body cavity, where the target site is a location where a surgical anastomosis has been performed, and the balloon catheter includes an elongated balloon and a coating layer covering the outer surface of the balloon, where the coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site to contact the coating layer with a wall of the body cavity at the target site until the balloon achieves an inflated balloon diameter for an inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the method includes performing the formation of a surgical anastomosis at the target site prior to the insertion of the balloon catheter into the target site. In some embodiments, a surgical anastomosis-induced non-vascular stenosis is present at the target site, and the method further includes performing a stenosis resection at the target site prior to the insertion of the balloon catheter into the target site. In some embodiments, stricture incision includes needle knife electroincision, perineotomy, urethrotomy, transurethral internal urethrotomy (DVIU), endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).In some embodiments, stricture is fibrous stricture.In some embodiments, stricture is esophageal stricture, bile duct stricture, gastric stricture, small intestine stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, large intestine stricture, colorectal stricture, stricture caused by gastric bypass, ileocolic stricture, digestive tract stricture, urethral stricture, ureteral stricture, J-pouch stricture or bladder neck stricture. In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter at the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stenosis or target site.

[0026] In various embodiments, the present invention provides a method for treating an inflammatory disease-induced non-vascular stenosis. The method includes inserting a balloon catheter comprising an elongated balloon and a coating layer covering the outer surface of the balloon into a target site in a body cavity comprising an inflammatory disease-induced non-vascular stenosis, wherein the coating layer comprises one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site such that the coating layer contacts the wall of the body cavity at the location of the inflammatory disease-induced non-vascular stenosis until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the inflammatory disease is Crohn's disease. In some embodiments, the inflammatory disease is ulcerative colitis. In some embodiments, the stenosis is 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, an ileocolic stenosis, or a gastrointestinal stenosis. In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter at the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stenosis or target site.

[0027] In various embodiments, the present invention provides a method for reducing or preventing the occurrence of inflammatory disease treatment-induced non-vascular stenosis. The method includes inserting a balloon catheter into a target site in a body cavity, where the target site is a site where an inflammatory disease treatment has been performed, and the balloon catheter includes an elongated balloon and a coating layer covering an outer surface of the balloon, where the coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site to contact the coating layer with a wall of the body cavity at the target site until the balloon achieves an inflated balloon diameter for an inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the method further includes performing an inflammatory disease treatment at the target site prior to inserting the balloon catheter into the target site. In some embodiments, an inflammatory disease treatment-induced stenosis is present at the target site, and the method further includes performing a stenotomy at the target site prior to inserting the balloon catheter into the target site. In some embodiments, the stenotomy includes needle knife electrodissection or endoscopic mucosal resection (EMR). In some embodiments, the inflammatory disease is Crohn's disease. In some embodiments, the inflammatory disease is ulcerative colitis. In some embodiments, the stenosis is small intestinal stenosis, duodenal stenosis, jejunal stenosis, ileal stenosis, colonic stenosis, rectal stenosis, large intestinal stenosis, colorectal stenosis, ileocolonic stenosis or digestive stenosis. In some embodiments, the method includes using a scope to visualize the insertion and placement of a drug-coated balloon catheter into the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after balloon deflation, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope before inserting the balloon catheter into the stenosis or target site.

[0028] In various embodiments, the present invention provides a method for treating a gastrectomy-induced non-vascular stenosis. The method includes inserting a balloon catheter into a target site in a body cavity containing a gastrectomy-induced non-vascular stenosis, the balloon catheter including an elongated balloon and a coating layer covering the outer surface of the balloon, where the coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site such that the coating layer contacts the wall of the body cavity at the location of the gastrectomy-induced non-vascular stenosis until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter into the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of the drug from the wall of the target site after balloon deflation, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope before inserting the balloon catheter into the stenosis or target site.

[0029] In various embodiments, the present invention provides a method for reducing or preventing the occurrence of gastrectomy-induced non-vascular stenosis. The method includes inserting a balloon catheter into a target site in a body cavity, where the target site is a site where a gastrectomy has been performed, and the balloon catheter includes an elongated balloon and a coating layer covering the outer surface of the balloon, where the coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site to contact the coating layer with the wall of the body cavity at the target site until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the method further includes performing a gastrectomy at the target site before inserting the balloon catheter into the target site. In some embodiments, a gastrectomy-induced non-vascular stenosis is present at the target site, and the method further includes performing a stenosis dissection at the target site before inserting the balloon catheter into the target site. In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter at the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stenosis or target site.

[0030] In various embodiments, the present invention provides a method of treating a needle knife electrodissection, perineotomy, urethrotomy, transurethral internal urethrotomy (DVIU), endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) induced non-vascular stenosis, the method comprising inserting a balloon catheter into a target site in a body cavity comprising a needle knife electrodissection, perineotomy, urethrotomy, transurethral internal urethrotomy (DVIU), endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) induced non-vascular stenosis, the balloon catheter comprising an elongated balloon and a coating layer covering an outer surface of the balloon, wherein the coating layer comprises one or more water soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating a balloon at the target site such that the coating layer contacts the wall of the body cavity at a location of non-vascular stenosis induced by needle knife electrodissection, urethrotomy, transurethral internal urethrotomy (DVIU), EMR (endoscopic mucosal resection) or endoscopic submucosal dissection (ESD) until the balloon achieves an inflated balloon diameter for an inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the electrodissection, perineal resection, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is for the treatment of esophageal cancer, bile duct cancer, gastric cancer, small intestine cancer, duodenal cancer, jejunal cancer, ileal cancer, colon cancer, rectal cancer, colorectal cancer, ileocolonic cancer or gastrointestinal cancer. In some embodiments, electrotomy, episiotomy, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is a procedure for removing polyps from the colon, where stricture is colonic stricture.In some embodiments, electrotomy, episiotomy, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is a procedure for Barrett's esophagus, where stricture is esophageal stricture.In some embodiments, stricture is esophageal stricture, bile duct stricture, small intestine stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, colorectal stricture, ileocolic stricture or digestive stricture.In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter at the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stenosis or target site.

[0031] In various embodiments, the present invention provides a method for reducing or preventing the occurrence of needle knife electrodissection, episiotomy, urethrotomy, transurethral internal urethrotomy (DVIU), endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) induced non-vascular stenosis. The method includes inserting a balloon catheter into a target site (e.g., a resection site) in a body cavity, where the target site is a site where needle knife electrodissection, episiotomy, urethrotomy, DVIU, EMR or ESD has been performed, and the balloon catheter includes an elongated balloon and a coating layer covering an outer surface of the balloon, where the coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site to contact the coating layer with the wall of the body cavity at the target site until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the method further comprises performing a needle knife electrodissection, an episiotomy, a urethrotomy, DVIU, EMR or ESD at the target site prior to inserting the balloon catheter into the target site. In some embodiments, the target site comprises a needle knife electrodissection, an episiotomy, a urethrotomy, a transurethral internal urethrotomy (DVIU), an endoscopic mucosal resection (EMR) or an endoscopic submucosal dissection (ESD) induced non-vascular stenosis, and the method further comprises performing a stenosis incision at the target site prior to inserting the balloon catheter into the target site. In some embodiments, the electrotomy, episiotomy, urethrotomy, transurethral internal urethrotomy (DVIU), endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is for the treatment of esophageal cancer, bile duct cancer, gastric cancer, small intestine cancer, duodenal cancer, jejunal cancer, ileal cancer, colon cancer, rectal cancer, colorectal cancer, ileocolonic cancer or gastrointestinal cancer. In some embodiments, the electrotomy, episiotomy, urethrotomy, transurethral internal urethrotomy (DVIU), endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is for the treatment of Barrett's esophagus, where the resection site is an esophageal stricture.In some embodiments, the target site or resection site is an esophageal site, a bile duct site, a small intestinal site, a duodenal site, a jejunal site, an ileal site, a colonic site, a rectal site, a colorectal site, an ileocolic site, or a gastrointestinal site. In some embodiments, the method includes using a scope to visualize the insertion and placement of a drug-coated balloon catheter into the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stricture or target site.

[0032] In various embodiments, the present invention provides a method for treating bladder neck stenosis. The method includes inserting a balloon catheter into a target site in a body cavity that includes a bladder neck stenosis, the balloon catheter including an elongated balloon and a coating layer covering the outer surface of the balloon, where the coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site such that the coating layer and the wall of the body cavity are in contact at the location of the bladder neck stenosis until the balloon achieves an inflated balloon diameter for an inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the bladder neck stenosis is fibrotic. In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter into the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of the drug from the wall of the target site after balloon deflation, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope before inserting the balloon catheter into the stenosis or the target site.

[0033] In various embodiments, the present invention provides a method for reducing or preventing the occurrence of prostate cancer treatment or stricture tomography-induced bladder neck stenosis. The method includes inserting a balloon catheter into a target site in a body cavity, where the target site is in the bladder neck, proximal to, adjacent to, or distal to a prostate cancer treatment or stricture tomography site, and the balloon catheter includes an elongated balloon and a coating layer covering the outer surface of the balloon, where the coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site to contact the coating layer with the wall of the body cavity at the target site until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the method further includes performing a prostate cancer treatment or stricture tomography before inserting the balloon catheter into the target site. In some embodiments, the stricture incision comprises needle knife electroincision, perineotomy, urethrotomy, transurethral internal urethrotomy (DVIU), endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). In some embodiments, the target site comprises prostate cancer treatment or stricture incision-induced bladder neck stenosis, and the method further comprises performing stricture incision before inserting a 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 bladder neck stenosis is fibrotic. In some embodiments, the method comprises using a scope to visualize the insertion and placement of a drug-coated balloon catheter into the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after balloon deflation, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting a balloon catheter into the stricture or target site.

[0034] In various embodiments, the present invention provides a method for treating esophageal fibrostenotic strictures of eosinophilic esophagitis. The method includes inserting a balloon catheter into a target site in a body cavity containing esophageal fibrostenotic strictures of eosinophilic esophagitis, the balloon catheter including an elongated balloon and a coating layer covering an outer surface of the balloon, where the coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site to contact the coating layer with the wall of the body cavity at the location of the esophageal fibrostenotic stricture of eosinophilic esophagitis until the balloon achieves an inflated balloon diameter for an inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter into the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after balloon deflation, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting a balloon catheter into the stricture or target site.

[0035] In various embodiments, the present invention provides a method for treating achalasia. The method includes inserting a balloon catheter into a target site in a body cavity including the lower esophageal sphincter, the balloon catheter including an elongated balloon and a coating layer covering the outer surface of the balloon, where the coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site such that the coating layer contacts the wall of the body cavity at the location of the lower esophageal sphincter until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter into the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of the drug from the wall of the target site after balloon deflation, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stricture or target site.

[0036] In various embodiments, the present invention provides a method of treating benign prostatic hyperplasia (BPH). The method includes inserting a balloon catheter into a target site in a body cavity, the prostatic urethra. The balloon catheter includes an elongated balloon. The balloon catheter also includes a coating layer covering an outer surface of the balloon. The coating layer includes one or more water soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon to contact the coating layer and the target site at the prostatic urethra until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity.

[0037] In various embodiments, the present invention provides a method of treating a urethral stricture, which is a trauma-induced stricture, an idiopathic stricture, and / or an iatrogenic stricture. The method includes inserting a balloon catheter into a target site in a body cavity that contains the urethral stricture. The balloon catheter includes an elongated balloon. The balloon catheter also includes a coating layer covering an outer surface of the balloon. The coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site to contact the coating layer with a wall of the body cavity at the target site until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method also includes withdrawing the balloon catheter from the body cavity.

[0038] In various embodiments, the present invention provides a method of treating a target site in a non-vascular body lumen. The method includes inserting an uncoated balloon catheter into the non-vascular body lumen to the target site. The method includes inflating the uncoated balloon catheter at the target site such that the balloon contacts the wall of the body lumen at the target site until the balloon achieves an inflated balloon diameter for an inflation period. The method includes deflating the uncoated balloon after the inflation period. The method includes withdrawing the uncoated balloon catheter from the body lumen. The method includes flushing the target site with water or saline. The method includes inserting a balloon catheter into the target site. The balloon catheter includes an elongated balloon and a coating layer covering an outer surface of the balloon, wherein the coating layer includes one or more water soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site such that the coating layer contacts the wall of the body lumen at the target site until the balloon achieves an inflated balloon diameter for an inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body lumen. The method also includes using a scope in a body cavity containing the target site to visualize insertion of the drug-coated balloon catheter into the target site, inflation of the drug-coated balloon at the target site, deflation of the drug-coated balloon at the target site, or a combination thereof.

[0039] In various embodiments, the present invention provides a method of treating a target site in a non-vascular body cavity. The method includes performing a needle knife electrodissection, a perineotomy, a urethrotomy, a transurethral internal urethrotomy (DVIU), an endoscopic mucosal resection (EMR) or an endoscopic submucosal dissection (ESD) at the target site. The method includes flushing the target site with water or saline. The method includes inserting a balloon catheter into the target site in the non-vascular body cavity. The balloon catheter includes an elongated balloon and a coating layer covering an outer surface of the balloon, where the coating layer includes one or more water-soluble additives and an initial drug loading amount of a therapeutic agent. The method includes inflating the balloon at the target site to contact the coating layer with a wall of the body cavity at the target site until the balloon achieves an inflated balloon diameter for the inflation period. The method includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body cavity. The method also includes using a scope in a body cavity containing the target site to visualize insertion of the drug-coated balloon catheter into the target site, inflation of the drug-coated balloon at the target site, deflation of the drug-coated balloon at the target site, or a combination thereof.

[0040] Various embodiments of the present invention provide a method of treating benign prostatic hyperplasia (BPH). The method includes inserting a first sheath including a pre-dilation balloon catheter including a pre-dilation balloon into the urethra. The method includes removing the first sheath from the urethra while leaving the pre-dilation catheter in the urethra. The method includes inserting a cystoscope into the urethra. The method includes using a cystoscope to visualize placement of the pre-dilation balloon in the prostatic urethra. The method includes inflating the pre-dilation balloon to dilate the prostatic urethra with the pre-dilation balloon to ensure an initial commissural incision of the prostatic urethra. The method includes deflating the pre-dilation balloon. The method includes using a cystoscope to confirm that the pre-dilation balloon has made the initial commissural incision. The method includes removing the cystoscope from the urethra. The method includes reinserting the first sheath into the urethra through the pre-dilation balloon catheter. The method includes pulling the pre-dilation balloon into the first sheath. The method includes removing the first sheath including the pre-dilation balloon catheter from the urethra. The method includes inserting a second sheath including a drug-coated balloon catheter into the urethra, the drug-coated balloon catheter including a drug-coated balloon, the drug-coated balloon including a coating layer over an outer surface, the coating layer including one or more water soluble additives and an initial drug load of a therapeutic agent. The method includes removing the second sheath from the urethra while leaving the drug-coated balloon catheter in the urethra. The method includes inserting a cystoscope into the urethra. The method includes using the cystoscope to visualize the placement of the drug-coated balloon in the prostatic urethra. The method includes inflating the drug-coated balloon to contact the coating layer with the prostatic urethra. The method includes removing the cystoscope from the urethra. The method includes maintaining the drug-coated balloon in an inflated state for at least five minutes. The method includes deflating the drug-coated balloon. The method includes reinserting the second sheath into the urethra through the drug-coated balloon catheter. The method includes pulling the drug-coated balloon into the second sheath. The method also includes removing the second sheath including the drug-coated balloon catheter from the urethra.

[0041] In various embodiments, the present invention provides a method of treating benign prostatic hyperplasia (BPH). The method includes inserting a first sheath into the urethra. In some embodiments, the first sheath includes an optical device that allows visualization of proper placement during insertion. In other embodiments, the first sheath includes an obturator to facilitate insertion. The method includes inserting a pre-dilatation balloon catheter including a pre-dilatation balloon into the first sheath until the pre-dilatation balloon enters the prostatic urethra, and then removing the first sheath. A guidewire may be used to facilitate sheath tracking. The method includes removing the first sheath. The method includes inserting a cystoscope into the urethra with the pre-dilatation balloon catheter. The method includes using the cystoscope to visualize placement of the pre-dilatation balloon in the prostatic urethra. The method includes inflating the pre-dilatation balloon to dilate the prostatic urethra with the pre-dilatation balloon to form an initial commissural incision of the prostatic urethra. The method includes deflating the pre-dilatation balloon. The method includes using the cystoscope to confirm that the pre-dilatation balloon has created an initial commissural incision. The method includes removing the cystoscope from the urethra. The method includes reinserting the first sheath over the pre-dilatation balloon and pulling the pre-dilatation balloon into the first sheath. When the first sheath is a second sheath, the method includes removing the pre-dilatation balloon from the first sheath while leaving the first sheath in place; or removing the pre-dilatation balloon and the first sheath from the urethra and inserting a second sheath including a cystoscope or obturator into the urethra (e.g., the second sheath is the same as or different from the first sheath). If a second sheath is used, the method includes removing the cystoscope or obturator after the second sheath is properly positioned. A guidewire may be used to facilitate sheath tracking. The method includes inserting a drug-coated balloon catheter into the second sheath, the drug-coated balloon catheter including a drug-coated balloon, the drug-coated balloon including a coating layer covering an outer surface, the coating layer including one or more water-soluble additives and an initial drug load of a therapeutic agent. The method includes removing the second sheath from the urethra. The method includes inserting a cystoscope into the urethra with the drug-coated balloon catheter.The method includes using a cystoscope to visualize placement of the drug-coated balloon in the prostatic urethra. The method includes inflating the drug-coated balloon to contact the coating layer with the prostatic urethra. The method includes removing the cystoscope from the urethra. The method includes maintaining the drug-coated balloon in an inflated state for at least five minutes. The method includes deflating the drug-coated balloon. The method includes inserting a second sheath over the drug-coated balloon and pulling the drug-coated balloon into the second sheath. The method includes removing the second sheath containing the drug-coated balloon catheter from the urethra.

[0042] In various embodiments, the present invention provides a method of treating a radiation-induced stenosis. The method optionally includes predilating the radiation-induced stenosis with a predilatation balloon having a nominal diameter smaller than the balloon catheter and performing a stenotomy on the radiation-induced stenosis. The method optionally includes flushing the radiation-induced stenosis with water, a saline solution, or an aqueous solution comprising at least one water-soluble additive. The method includes inserting a balloon catheter into a target site in the radiation stenosis. The balloon catheter includes a balloon and a coating layer covering the outer surface of the balloon. The coating layer includes at least one water-soluble additive and a therapeutic agent with an initial drug loading of 1-6 micrograms of therapeutic agent per square millimeter of the balloon. The therapeutic agent is selected from paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, an mTOR inhibitor or analogs thereof, and combinations thereof.Water-soluble additives include N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lamellar ... N-Oleoyl-D-Sphingosine, N-Palmitoyl-D-Sphingosine, N-Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG 8 Caprylic / Capric Glyceride, PEG Caprylate, PEG 8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, 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, 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, and combinations thereof. A weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer is about 0.05-20. The method includes inflating the balloon until the coating layer contacts a wall of the radiation induced stenosis and the balloon achieves an inflated balloon diameter for an inflation period. The method includes deflating the balloon after the inflation period, wherein the inflation period is between 0.1 minutes and 10 minutes. The method includes withdrawing the balloon catheter from the radiation induced stenosis.The method optionally includes using a scope to visualize the insertion and placement of the drug coated balloon catheter at the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, and releasing the drug from the wall of the target site after the balloon is deflated, or any combination thereof. The stretch ratio at the treatment site is about 1.0 to about 40. Radiation induced strictures include urethral stricture, ureteral stricture, esophageal stricture, sinus stricture, gastric stricture, small intestinal stricture, colonic stricture, rectal stricture, large intestinal stricture, or bile duct stricture.

[0043] In various embodiments, the drug coating on the balloon catheter can prevent or reduce the occurrence of stenosis at the treatment site, can prevent or reduce the occurrence of cancer or malignancies at the treatment site, can treat BPH, or a combination thereof. [Brief description of the drawings]

[0044] Generally, the figures depict various embodiments of the invention by way of example, but not by way of limitation.

[0045] [Figure 1A] 1 shows a balloon catheter having one neck according to various embodiments.

[0046] [Figure 1B] 1 shows a two-neck balloon catheter according to various embodiments.

[0047] [Figure 1C] 1 shows a three neck balloon catheter according to various embodiments.

[0048] [Diagram 2] 2 shows a two-neck drug-coated balloon catheter including a catheter shaft, catheter tip, and Tuohy Borst adapter according to various embodiments (balloon catheters include fixed-wire, over-the-wire, and rapid exchange type balloon catheters not detailed in FIG. 2).

[0049] [Diagram 3] 3A-3C show perspective views of an embodiment of a balloon catheter of the present invention according to various embodiments (balloon catheters include fixed-wire, over-the-wire, and rapid exchange type balloon catheters not detailed in FIG. 3).

[0050] [Figure 4A] 4A-4D are cross-sectional views of various embodiments of the distal portion of the balloon catheter of FIG. 3 taken along line AA showing example coating layers according to various embodiments. [Figure 4B] 4A-4D are cross-sectional views of various embodiments of the distal portion of the balloon catheter of FIG. 3 taken along line AA showing example coating layers according to various embodiments. [Figure 4C] 4A-4D are cross-sectional views of various embodiments of the distal portion of the balloon catheter of FIG. 3 taken along line AA showing example coating layers according to various embodiments.

[0051] [Figure 5A] 1 illustrates a balloon catheter including an elongated rigid member according to various embodiments. [Figure 5B] 1 illustrates a balloon catheter including an elongated rigid member according to various embodiments. [Figure 5C] 1 illustrates a balloon catheter including an elongated rigid member according to various embodiments. [Figure 5D] 1 illustrates a balloon catheter including an elongated rigid member according to various embodiments.

[0052] [Figure 6] 1 illustrates an elongated rigid member that is a spring according to various embodiments.

[0053] [Figure 7A] 1 shows an over-the-wire catheter with a balloon having one neck according to various embodiments. [Figure 7B]1 shows an over-the-wire catheter with a balloon having one neck according to various embodiments. [Figure 7C] 1 shows an over-the-wire catheter with a balloon having one neck according to various embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] Detailed Description of the Invention Reference will now be made in further detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in some of the accompanying drawings. While the disclosed subject matter will be described in conjunction with numbered claims, it is understood that the illustrated subject matter is not intended to limit the disclosed subject matter to the claims.

[0055] Throughout this specification, values ​​expressed in range format should be interpreted flexibly to include not only the numerical values ​​explicitly recited as limiting the range, but also all individual numerical values ​​or subranges falling within the range as if each numerical value and subrange were explicitly recited. For example, the range "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 the 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 the range indicated. The description "about X to Y" has the same meaning as "about X to about Y" unless otherwise specified. Similarly, the description "about X, Y or about Z" has the same meaning as "about X, about Y or about Z" unless otherwise specified.

[0056] As used herein, the singular expressions "a," "an," and "an" are used to include one or more than one, unless the context clearly indicates 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." Furthermore, it should be understood that phraseology or terminology used herein and not otherwise defined is for purposes of description only and not of limitation. Any use of section headings is intended to aid in the reading of the text and should not be construed as limiting, and information associated with a section heading may be present within or outside of a particular section.

[0057] In the methods described herein, unless a temporal or operational order is explicitly stated, acts may be performed in any order without departing from the principles of the invention. Moreover, certain acts may be performed simultaneously unless a clear claim term dictates that they should be used separately. For example, a claimed act of performing X and a claimed act of performing Y may be performed simultaneously in one operation, and the resulting process falls within the literal scope of the claimed process.

[0058] As used herein, the term "about" allows for a degree of variability of a value or range, e.g., within 10%, within 5%, or within 1% of a stated value or the limits of a stated range, and includes the exact stated value or range.

[0059] 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%.

[0060] One aspect of various embodiments of the present invention is the delivery of therapeutic agents, such as paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, mTOR inhibitors or their analogues, to the wall of a body cavity to treat or prevent narrowing or stenosis.These drugs can be considered as anti-inflammatory or anti-proliferative agents.Stenosis can be in a vascular lumen (e.g., vascular stenosis in coronary or peripheral arteries) or in a non-vascular lumen.The drug can be a water-insoluble drug.

[0061] The antimicrobial properties of various fatty acids and monoglycerides of C8-C12 fatty acids have been studied for many years.Research has confirmed that both fatty acids and monoglycerides can inhibit the growth of many types of bacteria and viruses.The coating formulation of the present invention can contain various fatty acids and monoglycerides of C8-C12 fatty acids such as caprylic acid, monocaprylin, capric acid, monocapric acid, lauric acid and monolaurin as one of the additives for treating various diseases.

[0062] Benign prostatic hyperplasia (BPH), urethral stricture, ureteral stricture, prostate cancer, esophageal stricture, achalasia stricture, in-stent stricture, bile duct stricture, gastric stricture, small bowel stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, large bowel stricture, colorectal stricture, post-gastric bypass stricture, ileocolic stricture, gastrointestinal stricture, J-pouch stricture, bladder neck stricture (stricture), fibrostenosing eosinophilic esophagitis stricture, Crohn's disease (CD) and ulcerative colitis (UC) induced stricture, radiation induced stricture, endoscopy Causes of non-vascular lumen stenosis and related non-vascular diseases such as resection (EMR and ESD) induced stenosis, surgery related anastomotic stenosis, achalasia stenosis, gastrectomy induced stenosis and asthma and chronic obstructive pulmonary disease (COPD) may include cancer, infection and inflammation by pathogens such as bacteria and viruses, radiation therapy, laparoscopic gastrectomy, robotic assisted gastrectomy, EMR (endoscopic mucosal resection), ESD (endoscopic submucosal dissection), surgically formed anastomosis or inflammatory diseases. Various embodiments of the present invention provide for delivery of coating formulations to the stenosis that contain drugs and additives with properties that kill and block bacteria and viruses.

[0063] The present invention provides a novel method of treating luminal stenosis to have long-term and sustained effect.The novel method opens the lumen and prevents, reduces or minimizes restenosis and recurrent stenosis.The method includes delivering therapeutic agents such as anti-inflammatory and anti-proliferative agents (e.g., paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, mTOR inhibitors or their analogs) and one or more water-soluble additives to target tissue.

[0064] An embodiment of the present invention provides a medical device coating formulation comprising a drug for treating stenosis of a non-vascular body lumen and an additive that enhances absorption of the drug into tissues of the body lumen. The additive may have antibacterial and antiviral properties. A balloon catheter includes a coating layer covering an outer surface of the balloon, wherein the coating layer includes one or more water-soluble additives and an initial drug loading of an antiproliferative therapeutic agent.

[0065] Coating the outer surface of a balloon catheter with a layer including, for example, a therapeutic agent and an additive is useful for solving problems associated with the use of one or more therapeutic agents in a drug coating. For example, the additive may have a hydrophilic portion and a drug affinity portion. The drug affinity portion may be a hydrophobic portion and / or may have affinity for the therapeutic agent through hydrogen bonding and / or van der Waals interactions. Surprisingly, the additive in the embodiment of the present invention including a hydrophilic portion and a drug affinity portion in combination with an antiproliferative therapeutic agent forms an efficient drug delivery coating on a medical device without the use of oils and lipids, thereby avoiding the lipolysis dependency and other disadvantages of conventional oil-based coating formulations. Furthermore, the additive in the embodiment of the present invention promotes rapid drug elution and excellent penetration of the drug into diseased tissue. Thus, the coating in the embodiment of the present invention increases the rate and / or extent of absorption of the antiproliferative therapeutic agent into non-vascular diseased tissue or non-vascular body lumen. In the embodiment of the present invention, the coated device delivers the antiproliferative therapeutic agent to non-vascular tissue during a very short residence time of less than 10 minutes, less than 2 minutes, and reduces re-narrowing and recurrence of stenosis of non-vascular body lumen.

[0066] Various embodiments of the present invention relate to a medical device for delivering a therapeutic agent to a stenosis of a blood vessel or non-vascular body lumen, the device comprising a layer covering an outer surface of the medical device. The device is 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 spaced double balloon, a cutting balloon catheter, a scoring balloon catheter or an infusion catheter (e.g., a distal perforated drug infusion tube, a perforated balloon, a spaced double balloon, a porous balloon or a percolated balloon). The balloon catheter comprises an elongated balloon having a central section of a narrowed diameter. The balloon catheter comprises at least one neck on the balloon comprising a diameter smaller than the main diameter, the at least one neck dividing the balloon into at least two portions each having a diameter equal to or different from the main diameter. In some embodiments, the balloon catheter comprises a cylindrical balloon having no neck. Additionally, non-vascular lumens or non-vascular stenoses include the esophagus, airway, paranasal sinuses, trachea, colon, bile duct, stomach, small intestine, duodenum, jejunum, ileum, rectum, large intestine, urinary tract, prostate, urethra, ureter, and other non-vascular lumens. Vascular lumens include arteries, veins, or any lumen in which blood is present. Non-vascular lumens include lumens that are devoid of blood. The balloon catheter shaft and balloon material may be comprised of polyether-amide block copolymers, polyamides, nylon, polyethylene terephthalate, or combinations thereof. The balloon catheter shaft may include rigid materials such as stainless steel, polycarbonate, titanium, polyether ether ketone (PEEK), any other rigid biocompatible material, or combinations thereof.

[0067] In some embodiments, the additive is at least one of a surfactant and a compound.The coating layer that covers the outer surface of the medical device can include one or more water-soluble additives.The coating layer that covers the outer surface of the medical device can include one or more water-soluble additives (e.g., a water-soluble first additive, a water-soluble second additive and a water-soluble third additive).

[0068] The medical device may further include a dimethylsulfoxide solvent layer, where the dimethylsulfoxide solvent layer covers an exterior surface of the medical device.

[0069] The device releases the therapeutic agent and additives and can deliver the therapeutic agent to the tissue in approximately 0.1-10 minutes. The therapeutic agent concentration in the layer is 1-20 μg / mm, measured when the balloon is inflated to its nominal diameter. 2 The concentration of the therapeutic agent in the layer may be 2 to 10 μg / mm 2 It could be.

[0070] 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 water and ethanol solubility of at least 1 mg / mL, and the therapeutic agent can be water insoluble.

[0071] The layer covering the outer surface of the medical device may include a therapeutic agent and at least two additives, each of which includes a hydrophilic portion and a drug affinity portion, where the drug affinity portion is at least one of a hydrophobic portion, a portion having affinity for the therapeutic agent through hydrogen bonding, and a portion having affinity for the therapeutic agent through van der Waals interactions, where each additive is soluble in a polar organic solvent and soluble in water. In some aspects of this embodiment, the polar organic solvent is selected from methanol, ethanol, isopropanol, acetone, dimethylformamide, tetrahydrofuran, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, ethyl acetate, and chloroform, and mixtures of these polar organic solvents with water. In other aspects of this embodiment, the device further includes a top layer covering the surface of the layer covering the outer surface of the medical device to reduce drug loss during transport through the body to the target tissue.

[0072] In some embodiments, the additive reduces the crystal size and particle number of the therapeutic agent, where 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, where the fatty chain can be directly inserted into the lipid membrane structure of the tissue.The additive can penetrate and reorganize the lipid membrane structure of the tissue.The additive can have one or more functional groups that have affinity for the drug through hydrogen bonding and / or van der Waals interactions. In some embodiments, the additive may be at least one of a surfactant and a compound, where the compound 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 g / mol, 125 g / mol, 150 g / mol, 175 g / mol, 200 g / mol, 225 g / mol, 250 g / mol, 275 g / mol, 300 g / mol, 325 g / mol, 350 g / mol, 375 g / mol, 400 g / mol, 425 g / mol, 450 g / mol, 475 g / mol, 500 g / mol, 525 g / mol, 550 g / mol, 575 g / mol, 600 g / mol, 625 g / mol, 650 g / mol, 675 g / mol, 700 g / mol, 725 g / mol or less than or equal to 750 g / mol). The compound may have more than four hydroxyl groups. In some embodiments, the compound with more than four hydroxyl groups 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.

[0073] A medical device coating for delivering drugs to non-vascular tissue or non-vascular stenosis can be prepared from a mixture. The coating can be prepared from a mixture including an organic phase with drug particles dispersed therein and an aqueous phase with 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. Preparation of the mixture can include homogenization under high shear conditions and optionally pressure.

[0074] The coating layer covering the exterior surface of the medical device can consist essentially of a therapeutic agent and an additive. The coating layer covering the exterior surface of the medical device can consist essentially of a therapeutic agent, a water-soluble first additive, and a water-soluble second additive. The coating covering the exterior surface of the medical device can consist essentially of a therapeutic agent and one or more water-soluble additives (e.g., a water-soluble first additive, a water-soluble second additive, and a water-soluble third additive).

[0075] In certain embodiments, a method of treating a stricture in a non-vascular body lumen includes inserting a balloon catheter comprising the coating layer into a body stricture, wherein the stricture is a urethral stricture, benign prostatic hyperplasia (BPH) stricture, ureteral stricture, esophageal stricture, achalasia stricture, bile duct stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, in-stent stricture, large intestinal stricture, sinus stricture, colorectal stricture, post-gastric bypass stricture, ileocolic stricture, gastrointestinal stricture, J-pouch stricture, bladder neck stricture (e.g., stricture), fibrostenosis, or the like. the method includes treating one of chronic eosinophilic esophagitis strictures, Crohn's disease (CD) and ulcerative colitis (UC) induced strictures, radiation induced strictures, endoscopic resection (EMR and ESD) induced strictures, achalasia strictures, gastrectomy induced strictures and surgery related anastomotic strictures, where the coating layer comprises a drug and an additive), inflating the balloon catheter, releasing the drug into the wall of the stricture, deflating the balloon and withdrawing the balloon catheter, where the remaining drug can be about 1-70% of the total drug load of the balloon catheter. In some aspects of this embodiment, the additive increases absorption of the drug into tissues of the non-vascular body cavity.

[0076] Some drugs for use in various embodiments that may be particularly suitable for the airways, paranasal sinuses 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.

[0077] Various embodiments relate to a method of treating a stenosis in a non-vascular body lumen, comprising flushing the lumen with water, a saline solution, or an aqueous solution of an additive as described herein, inserting a balloon catheter including a coating layer into the body lumen (wherein the coating layer includes a drug and an additive), inflating the balloon catheter, releasing the drug into the wall of the body lumen, deflating the balloon, and withdrawing the balloon catheter. A method of treating a stricture in a non-vascular body lumen comprises injecting water, a saline solution or an aqueous solution comprising at least one of the additives described herein, inserting a balloon catheter comprising a coating layer into the stricture in the non-vascular body lumen (wherein the stricture in the non-vascular body lumen is one of urethral stricture, ureteral stricture, esophageal stricture, achalasia stricture, in-stent stricture, sinus stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, rectal stricture, large intestinal stricture, and bile duct stricture, where the coating layer comprises a drug and an additive), inflating the balloon catheter, releasing the drug into the wall of the stricture in the non-vascular body lumen, deflating the balloon, and withdrawing the balloon catheter. In some aspects of this embodiment, the additive increases absorption of the drug into the tissue of the non-vascular body lumen. In another aspect of this embodiment, the additive comprises a hydrophilic portion and a drug affinity portion, where the drug affinity portion is at least one of a hydrophobic portion, a portion having affinity for the therapeutic agent through hydrogen bonding, and a portion having affinity for the therapeutic agent through van der Waals interactions. In another aspect of this embodiment, the drug is selected from paclitaxel, docetaxel, taxol and analogs thereof, and rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus and analogs thereof.In other aspects of this embodiment, the additive is selected from PEG-fatty acids and PEG-fatty acid mono- and diesters, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerol fatty acids, propylene glycol fatty acid esters, sterols and derivatives thereof, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugars and derivatives thereof, polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, fat-soluble vitamins and salts thereof, water-soluble vitamins and amphiphilic derivatives thereof, amino acids and salts thereof, oligopeptides, peptides and proteins, and organic acids and esters and anhydrides thereof. In yet other aspects of this embodiment, the drug may be released into the airway wall before, during or after an asthma attack. In yet other aspects of this embodiment, the drug may be released into the esophageal wall. In yet other aspects of this embodiment, the drug may be released into the sinus wall. In yet other aspects of this embodiment, the drug may be released into the bile duct wall. In yet other aspects of this embodiment, the drug may be released into the wall of the urinary tract, prostate, urethra and ureter lumen. In yet another aspect of this embodiment, the drug can be released into the wall of the stomach, small intestine, duodenum, jejunum, ileum, colon, rectum or large intestine. In another aspect of this embodiment, the drug can be released into the wall of a non-vascular stenosis within the stent.

[0078] In various embodiments, the present invention provides a method of treating a body cavity, comprising inserting a balloon catheter, such as any of the balloon catheters described herein, into a target site in the body cavity. The method comprises inserting a balloon catheter of Figs. 1A, 1B, 1C, 2, 3, 5A-5D, or 7A-7C into a target site in the body cavity. The method may comprise inserting the balloon catheter and a scope together, or the balloon catheter within a lumen of the scope, into the target site in the body cavity. The scope may be an endoscope, enteroscope, colonoscope, sigmoidoscope, rectoscope, anoscope, nasoscope, bronchoscope, or cystoscope. The scope may be used to ensure that the balloon catheter is properly positioned within the target lumen. The method may comprise flushing the body cavity with water, a saline solution, or an aqueous solution comprising at least one water-soluble additive before, during, or after insertion of the balloon into the target site. The method may comprise inflating the balloon until the coating layer contacts the wall of the stricture in the body cavity at the target site and the balloon achieves an inflated balloon diameter for the inflation time. Features (a) or (b) or (c) or (a) and (b) or (a) and (c) or (b) and (c) or (a) and (b) and (c) are present. (a) the ratio of inflated balloon diameter to untreated 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 stretch ratio 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 comprises deflating the balloon after the inflation time. The method also comprises withdrawing the balloon catheter from the stenosis in the body lumen.

[0079] In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter at the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, the creation of the target site, the release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stenosis or target site.

[0080] In some embodiments, the balloon is expanded until the coating layer contacts the wall of the stenosis and the stenosis is expanded, and at the same time, the drug is transferred to the stenosis.In some embodiments, the balloon is expanded until the coating layer contacts the wall of the stenosis, and the expansion expands the diameter of the stenosis to increase, so that contact with the stenosis can provide full circumferential transfer of the drug to the wall of the stenosis.In some embodiments, the part of the balloon that contains the drug (e.g., in embodiments that include less than 100% of the surface area that is covered with the drug) can be in uniform contact with the stenosis.In other embodiments, the contact between various parts of the balloon surface and the stenosis is non-uniform.

[0081] The inflated diameter of the balloon may be any suitable diameter achieved during or throughout the inflation time such that a desired ratio of inflated balloon diameter to untreated diameter of the body cavity is achieved at the target site. The inflated diameter of the balloon is proportional to the pressure used to inflate the balloon during the inflation time. The inflation pressure may 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 label. In some embodiments, the inflation pressure may be the nominal pressure of the balloon, and the inflated diameter of the balloon may be approximately equal to the nominal diameter of the balloon or may be less than the nominal diameter of the balloon due to compression from the stenosis. In some embodiments, the inflation pressure of the balloon during the inflation time may be higher or lower than the nominal pressure, and the inflated diameter of the balloon may be correspondingly smaller or larger than the nominal diameter of the balloon.

[0082] In various embodiments, the present invention provides a method of treating a body cavity. The method includes 1) backloading a balloon catheter onto a scope (e.g., a cystoscope). The method includes 2) inserting the scope-balloon catheter assembly into the body cavity. The method includes 3) inflating the balloon to an initial pressure (e.g., 0.5 atm, 1 atm, or 1.5 atm) and maintaining the initial pressure for 1-2 minutes until the pressure does not drop. The method includes 4) inflating the balloon to the next higher pressure, 0.5 atm, 1 atm, or 1.5 atm above the previous pressure, and maintaining the higher pressure for 1-2 minutes until the pressure in the balloon does not drop. The method includes 5) repeating step 4) until luminal tissue, such as prostate tissue, is produced. The method includes 6) maintaining the balloon inflated for 1 minute to 7 days, or 1 minute to 1 day, or 1-10 minutes to release the drug into the tissue and prevent bleeding. The method includes 7) deflating the balloon catheter. The method includes 8) withdrawing the scope-balloon catheter assembly from the body cavity. In this embodiment, a scope may be used to ensure that the balloon catheter is properly positioned before and / or during inflation.

[0083] In various embodiments, the present invention provides a method for treating a body cavity. The method includes 1) inserting a flexible scope and a balloon catheter in a sheath into the body cavity while they are coexisting. The method includes 2) removing the sheath from over the balloon, inflating it to an initial pressure (e.g., 0.5 atm, 1 atm, or 1.5 atm), and maintaining the initial pressure for 1-2 minutes until the pressure stops dropping. The method includes 3) inflating it to the next higher pressure, which is 0.5 atm, 1 atm, or 1.5 atm higher than the previous pressure, and maintaining the higher pressure for 1-2 minutes until the pressure in the balloon stops dropping. The method includes 4) repeating step 3) until tissue of the body cavity is produced. The method includes 5) maintaining the balloon inflated for 1 minute to 7 days, 1 minute to 1 day, or 1-10 minutes to release the drug into the tissue and prevent bleeding. The method includes 6) deflating the balloon catheter. The method includes 7) pulling the balloon catheter back into the sheath. The method includes 8) withdrawing the scope and balloon catheter / sheath from the body cavity. In this embodiment, a scope may be used to ensure that the balloon is properly positioned before and / or during inflation.

[0084] In various embodiments, the present invention provides a method of treating a body cavity. The method includes 1) inserting a flexible scope into the body cavity. The method also includes 2) inserting a balloon catheter and a scope into the body cavity while they are coexisting. The method includes 3) inflating to an initial pressure (e.g., 0.5 atm, 1 atm, or 1.5 atm) and maintaining the initial pressure for 1-2 minutes until the pressure does not drop. The method includes 4) inflating to the next higher pressure, 0.5 atm, 1 atm, or 1.5 atm above the previous pressure, and maintaining the higher pressure for 1-2 minutes until the pressure in the balloon does not drop. The method includes 5) repeating step 4) until tissue of the body cavity is produced. The method includes 6) maintaining the balloon inflated for 1 minute to 7 days, 1 minute to 1 day, or 1-10 minutes to release the drug into the tissue and prevent bleeding. The method includes 7) deflating the balloon catheter. The method includes 8) withdrawing the scope and balloon catheter assembly from the body cavity. In this embodiment, a scope may be used to ensure that the balloon catheter is properly positioned before and / or during inflation.

[0085] In various embodiments, the present invention provides a method for treating a body cavity. The method includes 1) inserting a flexible scope into the body cavity and placing a guidewire. The method also includes 2) inserting a balloon catheter through the guidewire and co-locating the scope in the body cavity. The method includes 3) inflating to an initial pressure (e.g., 0.5 atm, 1 atm, or 1.5 atm) and maintaining the initial pressure for 1-2 minutes until the pressure does not drop. The method includes 4) inflating to the next higher pressure, which is 0.5 atm, 1 atm, or 1.5 atm higher than the previous pressure, and maintaining the higher pressure for 1-2 minutes until the pressure does not drop. The method includes 5) repeating steps 4) until the tissue of the body cavity is induced. The method includes 6) maintaining the balloon inflation for 1 minute to 7 days, 1 minute to 1 day, or 1-10 minutes to release the drug into the tissue and prevent bleeding. The method includes 7) deflating the balloon catheter. The method includes 8) withdrawing the scope, guidewire, and balloon catheter assembly from the body cavity. In this embodiment, the scope can be used to verify that the balloon catheter is properly positioned before and / or during inflation. In some embodiments, the method includes using the scope to visualize the insertion and placement of the drug-coated balloon catheter at the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method can include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stenosis or target site.

[0086] In various embodiments, the present invention provides a method for treating benign prostatic hyperplasia. The method includes 1) inserting a balloon catheter-sheath assembly and a scope (e.g., a cystoscope). The method includes 2) placing the proximal end of the scope and the balloon coexisting near the external sphincter. The method includes 3) removing the sheath from over the balloon, inflating it to an initial pressure (e.g., 0.5 atm, 1 atm, or 1.5 atm), and maintaining the initial pressure for 1-2 minutes until the pressure stops dropping. The method includes 4) inflating it to the next higher pressure, which is 0.5 atm, 1 atm, or 1.5 atm above the previous pressure, and maintaining the higher pressure for 1-2 minutes until the pressure in the balloon stops dropping. The method includes 5) repeating step 4) until prostatic tissue is produced and a commissural incision is formed. The method includes 6) maintaining the balloon inflated for 1 minute to 7 days, 1 minute to 1 day, or 1-10 minutes to release the drug into the tissue and prevent bleeding. The method includes 7) deflating the balloon catheter. The method includes 8) withdrawing the scope and balloon catheter assembly from the body cavity, wherein feature (a) or (b) or (c) or (a) and (b) or (a) and (c) or (b) and (c) or (a) and (b) and (c) are present: (a) a ratio of inflated balloon diameter to untreated body cavity diameter at the target site is about 1.0 to about 40; or (b) the inflation includes inflating the balloon to a pressure that is greater than or equal to a nominal pressure of the balloon catheter, and the stretch ratio at the target site is about 1.0 to about 40; or (c) the inflation includes inflating to a pressure that is greater than a 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).

[0087] Various embodiments of the present invention relate to a method of treating stenosis in a body lumen by delivering an effective amount of a therapeutic agent, such as an anti-inflammatory agent and an anti-proliferative agent (e.g., rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, paclitaxel, taxol, docetaxel or analogs thereof) to a target tissue. Stenosis in a body lumen includes vascular stenosis, non-vascular stenosis, urethral stenosis, ureteral stenosis, esophageal stenosis, achalasia stenosis, in-stent stenosis, sinus stenosis, bile duct stenosis, gastric stenosis, small intestinal stenosis, duodenal stenosis, jejunal stenosis, ileal stenosis, colonic stenosis, rectal stenosis and large intestinal stenosis. An embodiment of the present invention is a method of treating at least one of stenosis of vascular and non-vascular lumens, benign prostatic hyperplasia (BPH), urethral narrowing, prostate cancer, asthma and chronic obstructive pulmonary disease (COPD). Treatment is contemplated for a variety of animals, from premature birth infants to adults.

[0088] The drug of the coating of the balloon catheter can be released into the target body cavity. The continuous multi-lobed balloon with a neck having a small diameter mechanically fixes the balloon to the body cavity, thus preventing the balloon from slipping in the body cavity. If the balloon slips or moves away from the target diseased site, it may miss the target site and the healthy lumen may be damaged.

[0089] In various embodiments, the present invention has advantages, at least some of which are unexpected. For example, coating the outer surface of a balloon catheter with a layer containing a therapeutic agent and an additive having a hydrophilic portion and a drug affinity portion is useful for treating disorders disclosed herein. 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. Surprisingly, the additive in the embodiment of the present invention, which includes a hydrophilic portion and a drug affinity portion, in combination with the therapeutic agent, forms an efficient drug delivery coating on the medical device. Furthermore, the additive in the embodiment of the present invention can promote rapid drug elution and excellent penetration of the drug into the diseased tissue. Therefore, the coating in the embodiment of the present invention can provide an enhanced rate and / or extent of absorption of the therapeutic agent in the diseased tissue or body cavity. In the embodiment of the present invention, the coated device can deliver the therapeutic agent to the tissue with a very short residence time of 10 minutes or less (e.g., 2 minutes or less), and can reduce restenosis and recurrence of stenosis of the body cavity, such as compared to other balloon catheters lacking such necks or neck shapes.

[0090] In various embodiments, the balloon catheter of the present invention is compatible with a flexible or rigid scope that allows visualization of the treatment zone, allowing for more accurate and efficient placement than other balloon catheters. The scope can be an endoscope, enteroscope, colonoscope, sigmoidoscope, rectoscope, anoscope, nasoscope, bronchoscope, or cystoscope. In various embodiments, the balloon catheter of the present invention is self-searching because the neck of the balloon catheter directs the balloon catheter to the correct position during inflation (e.g., at the bladder neck, at the most distal neck of the balloon catheter), even if the balloon catheter is slightly out of position at the beginning of inflation.

[0091] Balloon catheter and method of using same In various embodiments, the present invention provides a balloon catheter for delivering a therapeutic agent to a target site in a body cavity. The balloon catheter may include an elongated balloon with multiple sections or a body and at least one neck with a diameter smaller than the main section. The balloon catheter may include an elongated balloon with a main diameter, such as multiple sections with a main diameter or with an average diameter equal to the main diameter. A multi-lobed balloon with a neck with a smaller diameter may mechanically fix the balloon to the body cavity and therefore prevent the balloon from slipping in the body cavity. If the balloon moves away from the target diseased site, it may become dislodged and the healthy lumen site may be damaged. The balloon catheter may include at least one neck on the balloon with a diameter smaller than the main diameter. The balloon catheter may also include a coating layer covering the outer surface of the balloon. The coating layer may include one or more water soluble additives and an initial drug loading of a therapeutic agent (e.g., paclitaxel, taxol, docetaxel, analogs thereof, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, analogs thereof, and combinations thereof).In the method of using the balloon catheter, feature (a) or (b) or (c) or (a) and (b) or (a) and (c) or (b) and (c) or (a) and (b) and (c) are present. (a) a ratio of inflated balloon diameter to untreated 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 that is at least as high as the nominal pressure of the balloon catheter, and the stretch ratio at the target site is about 1.0 to about 40; or (c) the inflation includes inflating to a pressure that is 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).

[0092] The major diameter of a balloon is the diameter of the main part of the balloon when the balloon is inflated. In some embodiments, the inflation pressure used to determine the major diameter can be any pressure that achieves tension in the balloon, excluding any folded or wrinkled areas of the balloon. The inflation pressure used to determine the major diameter can be a pressure such that the inflated balloon has a shape and size that corresponds to the desired shape and size of the balloon during the intended body cavity treatment. 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.

[0093] In some embodiments, the drug-coated balloon comprises two main parts with the same diameter at both ends, one neck with a smaller diameter between the two main parts, and two cones on the proximal and distal balloon bodies. The drug-coated balloon may comprise three main parts with the same diameter, two necks with a smaller diameter (where the three main parts and two necks are arranged alternately, and the necks are adjacent to the main parts with a larger diameter), and two cones on the proximal and distal balloon bodies. The drug-coated balloon may comprise four main parts with a larger diameter, three necks with a smaller diameter (where the four main parts and three necks with a larger diameter are arranged alternately, and the necks are adjacent to the main parts with a larger diameter), and two cones on the proximal and distal balloon bodies. The drug-coated balloon may comprise five main parts with a larger diameter, four necks with a smaller diameter (where the five main parts and four necks with a larger diameter are arranged alternately, and the necks are adjacent to the main parts with a larger diameter), and two cones on the proximal and distal balloon bodies. The balloon catheter includes at least one neck on the balloon that includes a diameter smaller than the balloon diameter of the main portion. The balloon catheter may include an elongated (e.g., cylindrical) balloon with multiple sections of various diameters. Features (a) or (b) or (c) or (a) and (b) or (a) and (c) or (b) and (c) or (a) and (b) and (c) are present. (a) the ratio of inflated balloon diameter to untreated body cavity 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 stretch ratio 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 multi-section balloon with a small neck increases the friction between the balloon and the body cavity, thus preventing the balloon from slipping in the body cavity.

[0094] The 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 therapeutic agent that is delivered to the prostatic tissue and prostatic urethra by balloon inflation. The balloon can be positioned in the prostate using a suitable method such as a separate location balloon in the bladder, a location balloon in the urethral bulb, a marker band on or below the balloon visible by fluoroscopy, or the catheter shaft can be scope (e.g., cystoscope) compatible to allow placement by direct visualization or the catheter can be with a scope. For example, several possible catheter designs allow direct visualization of the balloon during positioning and inflation. One design is cystoscope compatible, where the catheter is backloaded by a working channel. Once through the cystoscope, a Tuohy Borst adaptor and one-way stopcock can be connected to the catheter shaft to inflate the balloon. Other designs may include a multi-lumen catheter with a lumen in the center of the shaft that allows for a rigid cystoscope lens to be inserted and positioned next to the proximal end of the balloon.

[0095] In some embodiments, when treating the prostate, the balloon catheter is sized so that the catheter body is between the bladder neck sphincter (bladder outlet) and the external sphincter. In other embodiments, the catheter body is placed above the external sphincter and through the prostate, with one or more bodies passing through the bladder neck sphincter and secured to the bladder. In these embodiments, preferably, the neck region of the balloon catheter is aligned with the bladder neck. As described herein, a scope with visualization can be used to properly size and place the balloon catheter.

[0096] In certain embodiments where the balloon catheter includes a soft tip, Coude tip, etc., the tip may be used to aid in device insertion and tracking through the urethra, hi other embodiments, the balloon catheter includes a lumen or channel designed to allow insertion and tracking through the urethra to a target site or prostate.

[0097] Achalasia stricture is a rare disorder that makes it difficult for food and liquid to pass through the esophagus to the stomach. In some embodiments, when treating achalasia stricture, the balloon catheter shown in FIG. 1A should be sized so that the proximal body portion of the catheter is within the achalasia stricture and on the lower esophageal sphincter. In these embodiments, the neck region of the balloon catheter can be aligned with the lower esophageal sphincter neck. As described herein, a scope with visualization can be used to properly size and position the balloon catheter. In embodiments where the balloon catheter includes a soft tip, the tip can be inserted into the sphincter (e.g., the lower esophageal sphincter) or stomach to position the balloon catheter at the desired location.

[0098] Balloon catheters can relieve lower urinary tract symptoms (LUTS) due to BPH by direct expansion of prostate tissue. Prostate expansion with a balloon having an inflated balloon diameter to untreated lumen diameter ratio of 1.0-40 at the target site or a balloon having a stretch ratio of 1.0-40 at the target site can create a commissure incision in the natural plane separating the transverse sections at the fusion of the prostate. At the same time, drugs can be released from the coating into the prostate tissue, which can, for example, prevent prostate hypertrophy and re-narrowing of the newly formed orifice.

[0099] In various embodiments, during balloon inflation in the body lumen (e.g., during the practice of the methods of the invention), the nominal diameter of the balloon of the catheter (e.g., the diameter normally achieved at a nominal pressure) is such that the ratio of the nominal diameter of the balloon to the untreated diameter of the body lumen at the treatment location is between 1.0, 1.1, 1.2, 1.3, or 1.4 to 40 (e.g., between 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, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3. , 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 40 or any value therebetween) or any combination thereof. 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 of the stenosis may prevent the achievement of the nominal diameter or may restrict the inflation of the balloon, forming a "dog bone" shape. The nominal diameter of the balloon at the planned pressure (e.g., 2 atm, 3 atm, 6 atm or 9 atm) may be different if the diameter of the balloon for different diseases is different. For example, the nominal diameter of a urethral stricture balloon may be 6 mm, 8 mm, 10 mm, 12 mm and 14 mm at 6 atmospheres of inflation for 6 mm, 8 mm, 10 mm, 12 mm and 14 mm balloon catheters with 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm and 50 mm balloon lengths. The nominal diameter of a BPH stricture balloon may be 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm and 60 mm balloon catheter balloon lengths at 4 atmospheres, 5 atmospheres, 6 atmospheres, 8 atmospheres or 12 atmospheres of inflation. Table 1 shows examples of nominal balloon dimensions, nominal pressures and ratios of minimum balloon diameter to untreated lumen diameter for use in treating strictures of various diseases. The nominal pressure is the pressure required to bring the balloon to its labeled nominal diameter in an unconstrained pressure titration test. The nominal diameter is the desired diameter that the product is labeled with. Any physician can purchase a balloon and select a balloon for use by its nominal diameter.Rated burst pressure is the maximum pressure to which the balloon can be inflated with a high degree of confidence that it will not burst, and is a mandatory labeling for balloon catheters calculated from statistical analysis of the observed pressures at which the balloon bursts in an unrestrained pressure ramp test.

[0100] [Table 1]

[0101] In various embodiments, the balloon catheter can be sufficient to enable the balloon to have any suitable ratio of inflated balloon catheter diameter to untreated diameter of the body lumen at the treatment location at a planned pressure (e.g., nominal pressure), for example, from about 1 atmosphere (304 kPa) to about 30 atmospheres (3040 kPa) (e.g., less than about 1 atmosphere or less than, equal to, greater than or equal to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, or about 30 atmospheres).

[0102] Unless otherwise stated, the stretch ratio is defined herein as the ratio of the nominal diameter of the balloon to the untreated diameter of the body cavity in the area treated by the balloon catheter. The untreated diameter of the body cavity at the target site is the diameter before dilatation with the drug-coated balloon and also before any pre-dilatation method performed during the procedure (e.g., performed on the same day), such as before using pre-dilatation balloon or cutting techniques, e.g., DVIU or hot knife. The nominal diameter of the balloon for determining the stretch ratio is the diameter that the balloon achieves in an unconstrained environment at the nominal pressure. The untreated lumen diameter is the average diameter of the target site (e.g., the lumen or stricture, stricture or lesion at the target site). For the urinary tract, e.g., for strictures in the urethra, the untreated lumen diameter is the average diameter of the stricture location in the urethra before dilatation with the drug-coated balloon (and before any pre-dilatation or cutting, e.g., DVIU). For strictures in the urethra or prostatic urethra, the untreated lumen diameter of the target site is the untreated lumen diameter during urination (e.g., urination diameter) of the target site, especially when the untreated lumen diameter of the target site when not urinating is 0 or close to 0. For BPH and prostatic urethra, the untreated lumen diameter is the average diameter of the prostatic urethra at the treatment location. The inflated balloon diameter is the actual diameter of the balloon after inflation, which in some embodiments may be equal to, less than, or greater than the nominal diameter of the balloon. In various embodiments, the stretch ratio of the balloon catheter of the present invention makes it more effective in treating non-vascular lumens than other catheters. During the practice of the method of the present invention, the stretch ratio is selected to be any suitable ratio that achieves the desired ratio of actual inflated balloon diameter to untreated lumen diameter at the range of pressures used during the method.In various embodiments, the stretch ratio of the balloon is less than, equal to, or greater than about 1.0 to about 40 or about 4 to about 40 or about 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 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 or greater than about 40; such stretch ratios are less than, equal to, or greater than about 1.0 to about 40 or about 4 Pressures used for the inflation period may be the same, similar or different than a stretch ratio of up to about 40 or less than, equal to or greater than about 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 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, etc., may result in a desired ratio of inflated balloon diameter to untreated lumen diameter.

[0103] In various embodiments, the method includes measuring the lumen stenosis 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 selects the balloon based on the untreated diameter of the lumen stenosis and the achievement of a stretch ratio of 1.0-40 or 4-40. The physician can then inflate the balloon to at least the nominal pressure, and in some cases, the balloon can be inflated beyond the nominal pressure to the rated burst pressure of the balloon. The range of pressures used during the inflation time can be nominalized as the working pressure range of the drug-coated balloon. In some cases, the method can include exceeding the rated burst pressure of the balloon. Since the nominal diameter of the balloon has been determined without any restraint, the inflated diameter of the balloon at the treatment site passing through the stenosis can be about the same as, less than, or greater than the nominal diameter. At, above, or below the burst pressure, the inflated diameter of the balloon can be less than, equal to, or greater than the nominal diameter. For example, the lumen stenosis can be measured to have an untreated diameter of 10 mm. A physician may select a 14 mm nominal diameter drug-coated balloon with a nominal pressure of 6 atmospheres and a rated burst pressure of 10 atmospheres. The stretch ratio is 1.4. The physician will inflate the balloon to at least 6 atmospheres, in some cases to 8 atmospheres or 10 atmospheres, and in some cases beyond 10 atmospheres to achieve the desired inflated balloon diameter during the procedure.

[0104] In various embodiments, the balloon catheter has one or more necks separating one or more sections, and at least one neck or the shape of the neck of the balloon catheter of the present invention allows the balloon catheter to remain in a fixed position during a procedure to dilate a stenosis and deliver a drug more consistently and efficiently than other balloon catheters lacking such a neck or neck shape.

[0105] In various embodiments, the balloon catheter can be assembled with a sheath. The catheter assembly and a scope (e.g., a cystoscope) are transurethrally positioned into the prostatic urethra, together near the external sphincter. Live video feed from the scope can be used to position the external sphincter. The balloon can be positioned adjacent to the external sphincter and within the prostatic urethra. Balloon expansion, drug release, and balloon deflation can be visualized by the scope.

[0106] In various embodiments, the balloon catheter can be assembled with the cystoscope by backloading the shaft through the working channel and connecting a Tuohy Borst and one-way stopcock to the proximal end. The cystoscope-catheter assembly is inserted transurethrally into the prostatic urethra. Using live video feed from the cystoscope, it can be positioned at the external sphincter. The balloon can be positioned adjacent to the external sphincter and within the prostatic urethra.

[0107] In some embodiments, when treating the prostate, it is preferable to place the proximal balloon waist at the external sphincter so that the external sphincter does not expand. It is also preferable to size the balloon so that the balloon neck (e.g., the most distal balloon neck) fits the bladder neck when the balloon waist is at the external sphincter. This positioning provides retention so that the balloon does not slip during inflation. If the balloon neck cannot be aligned with the bladder neck, it may be preferable to inflate the balloon slowly so that the prostate can accommodate as the balloon inflates.

[0108] Once properly positioned, the balloon is inflated, such as by using an inflation device equipped with a pressure gauge. The balloon may be inflated slowly to allow the prostate tissue to accommodate and reduce the tendency of the balloon to slip proximally and reverse distally into the bladder. Although the single-neck or multi-neck configuration of the balloon prevents balloon migration by aligning the most distal neck with the bladder neck, in unusual circumstances, such as with an enlarged middle lobe (e.g., about 10-15% of cases), the neck of the balloon may not align with the bladder neck during inflation and additional techniques to further prevent balloon migration may be useful. In some instances, inflation at a rate of about 0.5-1 atm / min may prevent balloon migration. As the tissue accommodates, the balloon pressure correspondingly decreases, allowing for the introduction of additional fluid into the balloon without increasing pressure. When the pressure is stable for about 1-2 minutes, the pressure may be increased in 0.5 or 1 atm increments and maintained in a similar manner. The pressure can be increased continuously, and this method of pressure increase allows the pressure to stabilize after pressure reduction and continue to increase until commissurotomy or division is achieved. Alternatively, very slow inflation can prevent balloon movement until commissurotomy or prostate division is achieved. Once commissurotomy or prostatic urethra and prostate division are observed and confirmed by video feed from the scope, mechanical decompression can be achieved. The balloon can be left inflated for a time period of about 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to allow migration of the drug from the coating into the tissue. Once the procedure is complete, the balloon can be deflated and the catheter and scope can be removed from the patient's body cavity.

[0109] In some embodiments, when treating the prostate, pre-dilatation of the stricture may be desired. In this embodiment, the pre-dilatation catheter may be shorter and / or narrower in diameter than the drug-coated balloon treatment catheter and may be devoid of drug coating. In this scenario, the pre-dilatation catheter is placed at the proximal waist of the balloon in the external sphincter, lining the neck region with the bladder neck. The balloon is slowly inflated as described herein to help create the prostate while protecting against balloon slippage. Once inflated, the pre-dilatation balloon is deflated 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 has been properly pre-dilated, there is no need to align the balloon neck with the bladder neck, since the balloon will not tend to be as slippery as in non-pre-dilatation cavities. In some embodiments, other strictures described herein may be pre-dilated with a non-drug-coated balloon catheter before treatment with the drug-coated balloon.

[0110] The drug-coated balloon catheter may include an elongated balloon body with multiple sections, two cones at the distal and proximal ends of the balloon body, an inflation lumen and a wire lumen, where the balloon body includes at least two larger diameter sections and at least one smaller diameter neck section, where the larger diameter sections and neck sections are arranged alternately and adjacently. The elongated balloon is generally cylindrical in shape, except for any neck section of the balloon, any tapered section (e.g., cone) between the neck section and the main diameter section, and any tapered section or sharp section at the longitudinal end of the balloon. The elongated balloon may have any suitable profile perpendicular to the longitudinal direction of the balloon, such as annular (e.g., cylindrical balloon), oval, curvilinear, asymmetrical, or polygonal (e.g., pentagonal, hexagonal, heptagonal, octagonal, etc.), or combinations thereof. The diameters listed for non-cylindrical balloons are the maximum size perpendicular to the longitudinal direction or the average size perpendicular to the longitudinal direction.

[0111] The balloon may be formed from a suitable material, such as a non-compliant or semi-compliant biocompatible material. In some embodiments, the balloon may be manufactured by blow molding to achieve a desired geometry. In some embodiments, the balloon may comprise a material that does not interact with the drug coating or a material such as nylon (e.g., a suitable nylon such as nylon 6,6 or nylon 12), polyether block amide (PEBA), polyethylene terephthalate (PET), polyvinyl chloride (PVC), polyester, polyurethane, derivatives thereof, or combinations thereof.

[0112] The balloon may be of any suitable size and may be designed to fit within the prostatic urethra, with a distal section of the balloon being positioned within the bladder. The main diameter and nominal balloon diameter can be selected from the ranges 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, at least 30 mm, such as about 5 mm or less or about 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, 30 mm, 32 mm, 34 mm, 36 mm, 38 mm, 40 mm, 41 mm, 42 mm, 43 mm, 44 mm, 45 mm, 46 mm, 47 mm, 48 mm, 49 mm, or about 50 mm or more; the main diameter can be an independent range from any of these ranges or specific dimensions. The balloon may have a length of about 20 mm to about 160 mm, 40 mm to about 80 mm, or less than about 20 mm, or less than, equal to, or greater than about 22 mm, 24 mm, 26 mm, 28 mm, 30 mm, 32 mm, 34 mm, 36 mm, 38 mm, 40 mm, 42 mm, 44 mm, 46 mm, 48 mm, 50 mm, 52 mm, 54 mm, 56 mm, 58 mm, 60 mm, 62 mm, 64 mm, 66 mm, 68 mm, 70 mm, 72 mm, 74 mm, 76 mm, 78 mm, or about 80 mm or greater. Balloon length and diameter may be selected based on the patient's unique prostate anatomy.

[0113] The balloon may include at least one neck. A neck is a portion of the balloon that has a diameter smaller than the main nominal diameter of the balloon. The neck diameter may be about 2 mm to about 35 mm, about 5 mm to about 35 mm, 10 mm to about 35 mm, or about 2 mm or less, about 3 mm, 4 mm, 5 mm, 6 mm, 8 mm, 9 mm, 10 mm, 12 mm, 14 mm, 16 mm, 18 mm, 20 mm, 22 mm, 24 mm, 26 mm, 28 mm, 30 mm, 32 mm, 34 mm, or less than, equal to, greater than, or about 35 mm or more. At least one neck can independently have a diameter of about 5% to about 99% of the main diameter, e.g., about 20% to about 99% or less than about 5% or less than, equal to, greater than, or greater than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or about 99%. In some embodiments, the neck diameter is 35% to 75% of the diameter of the balloon main section. In some embodiments, where the balloon main section has a nominal diameter of 30 to 40 mm, the neck has a diameter of 12 to 20 mm. In some embodiments, if the neck diameter is too close to the main section diameter, the ability to prevent balloon slippage may be reduced. In some embodiments, the balloon neck can be directly bonded to the catheter shaft, which may provide separation between adjacent lobes. In one embodiment, separation between adjacent balloon lobes can be achieved by individually bonding two adjacent balloons in close proximity to the catheter such that the distance separating the two balloons is less than, equal to, or greater than 0 mm or 1 mm, 2, 3, 4, 5, 6, 7, 8, 9, or about 10 mm or more.

[0114] The neck can be a rigid or semi-rigid neck such that the diameter of the neck (e.g., the portion of the neck having the neck diameter) remains substantially stationary during balloon inflation. The neck can comprise a substantially inelastic (e.g., non-compliant or minimally non-compliant) portion of the balloon, a reinforced portion of the balloon, or a combination thereof. The neck can comprise an inelastic material wrapped around the circumference of the neck, such as a suture or a monofilament or multifilament of such material, such as nylon, polyamide, aromatic polyamide, ultra-high molecular weight polyethylene (UHMWPE), polyester, aromatic polyester, polyethylene terephthalate (PET), or a combination thereof.

[0115] In some embodiments, the balloon neck is semi-compliant and may be inflated at a different rate than the main balloon body. The neck compliance may be greater than, equal to, or less than the compliance of the balloon body. Table 2 shows example measurements of a balloon having a neck that expands more than the balloon body. The neck diameter expansion rate may be greater than the body diameter expansion rate in the test pressure range of 1-5 atmospheres. The neck diameter expansion rate may be in the range of 1.1-10 times the body diameter (main diameter), for example, in the range of 2-6 times the main diameter, in the test pressure range of 1-5 atmospheres. The neck diameter expansion rate is 12.38% / atm. The body diameter expansion rate is 2.4% / atm. The difference in expansion rates is 9.98% / atm. Table 3 shows example measurements of a balloon having a neck that expands less than the balloon body when inflated at 2-4 atmospheres. The neck diameter expansion rate may be less than the body diameter expansion rate in the test pressure range of 2-4 atmospheres.

[0116] [Table 2]

[0117] [Table 3]

[0118] The neck may create a wedge of tissue between the larger diameter portions of the balloon that can keep the balloon in place. The larger portion of the balloon cannot cross the tissue barrier created at the neck, and therefore, a balloon with a neck prevents, reduces, or minimizes balloon migration during inflation. Balloon necks can be located at various positions along the balloon, can be more or less than two in number (e.g., 1, 2, 3, 4 or more), and can vary in diameter. Neck placement can be designed to promote maximum increase in traction while still maintaining treatment efficacy.

[0119] The neck may have a central narrow portion having a minimum diameter at the neck and a variable diameter, including adjacent portions between the central narrow portion and the portion of the balloon having the main diameter. References to the diameter of the neck herein refer to the diameter of the central narrow portion having the minimum diameter, and not the tapered portion, unless otherwise specified. The tapered portion of the balloon may be rigid, flexible (e.g., elastic), or a combination thereof. The neck may be any suitable length, e.g., less than or equal to about 1% to about 50% of the balloon length, or less than or equal to about 1%, or less than or equal to about 2%, 4%, 6%, 8%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, or about 50%, as measured including the central narrow portion and the tapered portion adjacent thereto (e.g., cone). The diameter of the molecule may be greater than or equal to, or between about 0.5 mm and about 40 mm, or less than or equal to, or about 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 12 mm, 14 mm, 16 mm, 18 mm, 20 mm, 22 mm, 24 mm, 26 mm, 28 mm, 30 mm, 32 mm, 34 mm, 36 mm, 38 mm, or less than, equal to, or greater than about 40 mm.

[0120] In some embodiments, the balloon may include one neck and no other neck, such that the balloon includes two portions separated by one neck. The one neck may have any suitable location on the balloon, such as approximately in the middle of the balloon length or offset relative to the balloon length. The one neck may be offset relative to the balloon length and may be at the distal end of the balloon. An embodiment of a balloon including one neck offset relative to the balloon length is illustrated in FIG. 1A.

[0121] In some embodiments, the balloon may include two necks, and the other neck is absent, such that the balloon includes three lobes separated by the two necks. The two necks may have approximately the same diameter, or one of the necks may have a smaller diameter than the other neck. The two necks may be located symmetrically or asymmetrically with respect to the center of the balloon length. The three segments may have approximately equal lengths or different lengths. FIG. 1B describes an embodiment of a balloon catheter having two necks and three segments, where the necks are located symmetrically with respect to approximately the center of the balloon length, and where the three segments of the balloon have approximately the same length. In use, the distal neck (e.g., the neck at the distal end of the balloon catheter that is inserted into the body first) can fix and position the balloon at the bladder neck, while the proximal neck can be located at the prostatic urethra. In some embodiments, the distal segment of the balloon catheter may be free of a therapeutic agent.

[0122] In some embodiments, the balloon may include three necks, with no other necks, such that the balloon includes four portions separated by the three necks. The three necks may be arranged in any suitable manner along the length of the balloon. The four portions formed by the three necks may have equal or different lengths. The three necks may 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. FIG. 1C shows an embodiment of a balloon catheter having three necks and four portions, each having approximately equal lengths, where two of the necks have equal diameters that are smaller than the diameters of the other necks.

[0123] The balloon catheter may be a fixed-wire balloon catheter. The outer shaft may be coupled to the proximal balloon neck, the distal end of the tapered wire may be coupled to the distal neck of the balloon, and the proximal end of the wire and the outer shaft may be coupled to a hub (e.g., a valve, connector, or adapter) at the proximal end of the balloon catheter. The balloon catheter may be a movable-wire catheter. The outer shaft may be coupled to the proximal balloon neck, the distal end of the tapered wire may be coupled to the distal neck of the balloon, and the proximal end of the wire is free to move relative to the hub at the proximal end of the balloon catheter. The balloon catheter may be an over-the-wire balloon catheter. The balloon catheter may be a rapid-exchange balloon catheter. The balloon catheter may include a catheter shaft at the longitudinal end of the balloon (e.g., the proximal end of the balloon inserted into the body after the distal end is inserted), the catheter shaft including an internal lumen for delivering air, liquid, or a combination thereof to the balloon interior. The catheter shaft may comprise a thermoplastic material that thermally bonds (e.g., heats or melts) to the balloon, such as a high durometer material, such as a material similar or identical to the balloon material, such as polyurethane, polyamide, nylon (e.g., nylon 6,6 or nylon 12), polyether block amide (PEBA), or a combination thereof. In some embodiments, the catheter shaft may be a scope (e.g., a cystoscope). The high durometer material may help prevent, reduce, or minimize breakage and may allow for pushability and mobility. The catheter shaft outer diameter may be sized to allow the working channel of a standard cystoscope to pass through, or with a diameter small enough to fit the cystoscope within the body cavity. It may include a fluid connection between the inner lumen and the interior of the balloon, such as a hole in the catheter shaft below the balloon attachment point to allow the balloon to be inflated by injection of a medium through the inner lumen.

[0124] In some embodiments, the balloon may be inflated through a single inflation channel or lumen that communicates with the proximal catheter and inflates the entire body and neck of the balloon simultaneously. In some embodiments, the balloon may be inflated through separate channels or lumens that communicate with different portions of the balloon, such that one lumen is the proximal body of the balloon, a second lumen is the neck, and a third lumen is the distal body of the balloon. Any suitable combination of inflation lumens or channels and communication locations within the balloon may be used to create one or more pressures appropriate for carrying out the present methods.

[0125] In some embodiments, the catheter shaft may include an elongated, rigid element, such as a rod, mandrel, or wire, disposed longitudinally in the catheter shaft. Figures 5A-5D depict a balloon catheter including an elongated, rigid element, a core wire 505. Figure 5A depicts an embodiment of an inflated balloon, and Figure 5B depicts the balloon in a non-inflated state. At the proximal end of the shaft, the core wire 505 is attached to the catheter shaft 501 under strain relief 508. The core wire 505 is inflated distally in the catheter shaft 501. In some embodiments, the catheter shaft is made of 72D PEBA polymer. The shaft 501 is made of a material that exhibits a certain degree of elasticity under tension. Under the balloon 503, the core wire 505 is covered with a hypotube 510. The hypotube 510 provides lateral strength to the core wire 505 to prevent it from bending when the balloon 503 is inflated. Near the distal end of the catheter, the hypotube 510 and corewire 505 are coupled to the tip 502. A tip extrusion 506 places the tip 502 in communication with the hypotube 510 and corewire 505. The space between the shaft 501 and corewire 505 is the inflation lumen of the balloon 503, and the interior of the balloon 503 is in fluid communication with the luer hub 507. Although this embodiment may be used with any suitable balloon of the present invention, Figures 5A and 5B show a balloon 503 having one neck with polyethylene fibers 504 used for neck reinforcement. Figure 5C illustrates a cross-section of the deflated balloon of Figure 5A illustrating the balloon 504, hypotube 510, and corewire 505. Figure 5D illustrates a cross-section of Figure 5B showing the shaft 501 and corewire 505.

[0126] The elongated, rigid element may have a cross-sectional profile that is cylindrical, tapered, rectangular, hexagonal or other shape, and may be made of metal or a non-metallic material that is relatively incompressible. The elongated element may run from the proximal side of the balloon to the distal side of the balloon or from a location proximal to the proximal side of the balloon to the distal side of the balloon. The elongated element may be free-floating within the central lumen of the catheter shaft, located in a dedicated lumen of a multi-lumen catheter shaft, or located longitudinally outside the main catheter shaft. The elongated element may be fixed at one, two or more points along the catheter shaft. The elongated element may be thermally fused directly to the catheter shaft, adhesively or chemically bonded to the catheter shaft, stretched or crimped to one or more portions of the catheter, overmolded, or fixed in any other suitable manner. The elongated element may be reinforced along its entire length or along certain portions to prevent buckling; for example, the elongated metallic element may be wire reinforced. The reinforcement may be constructed using any hard material such as stainless steel, Nitinol (i.e., nickel-titanium alloy), steel, tungsten, iridium, superalloys (e.g., containing elements such as nickel (Ni), chromium (Cr), aluminum (Al), titanium (Ti), tungsten (W), niobium (Nb), tantalum (Ta), or cobalt (Co)), PEEK, or combinations thereof, and may have any suitable cross-sectional shape. In certain embodiments, the reinforcement may be a tube having a cylindrical, rectangular, hexagonal, or any suitable outer profile. The elongated elements may be positioned inside the reinforcement tube or along the outside of the reinforcement tube as shown in FIG. 5C.

[0127] As shown in Figures 5A and 5B, the catheter has a balloon length adjustment mechanism that stretches and lengthens the balloon when in a deflated state, providing the balloon with a small cross-sectional deflated profile for tracking through the body lumen and removal after treatment. When the balloon is inflated, the length adjustment mechanism shortens the overall length of the balloon, allowing it to be inflated to a predetermined inflated diameter and length of the balloon (e.g., created during a molding or forming process). In some embodiments, the force generated by the balloon inflation can be returned from the distal end of the balloon, for example, to the elongated metal component via a balloon bond, or through a connection between the catheter tip and the elongated metal component, through the catheter shaft by an elongated rigid metal element, to the catheter shaft proximal to the balloon, via a connection between the proximal end of the balloon or the catheter shaft proximal to the proximal end of the balloon. This transmission of force to the catheter shaft allows the catheter shaft material to act as a spring, operating in the elastic region of the catheter shaft material's stress-strain curve. When the catheter shaft is elongated under tension due to balloon inflation, energy can be stored in the catheter shaft material during balloon inflation and released by pushing the catheter shaft against the elongated metal element during contraction to stretch the balloon. In some embodiments, a spring disposed longitudinally along the catheter shaft can be used to store and release the force of the balloon length adjustment mechanism. FIG. 6 describes an embodiment of a spring 600 that can be used as an alternative to the core wire 505 in FIGS. 5A-5D. Referring to FIG. 6, the spring 600 has a spring portion 601 and a wire portion 602. In some embodiments, the spring portion 601 can be located at the proximal end of the catheter shaft. The spring can be located intraluminally in the catheter shaft, extraluminally, but within the catheter shaft, or outside the catheter shaft. The spring can be within the balloon or away from the balloon, such as proximal to the balloon proximal end, or a combination thereof.The elongated length of the deflated balloon compared to the length of the inflated balloon can be about 0.1 mm longer to about 100 mm longer or about 0.1 mm longer, 0.2 mm, 0.4 mm, 0.6 mm, 0.8 mm, 1 mm, 1.5 mm, 1 mm, 2.5 mm, 3 mm, 4 mm, 5 mm, 6 mm, 8 mm, 10 mm, 12 mm, 15 mm, 20 mm, 25 mm, 30 mm, 40 mm, 50 mm, 60 mm, 70 mm, 80 mm, 90 mm or less than, equal to or greater than about 100 mm longer. The catheter shaft can include a variety of materials, such as polyamide, nylon (e.g., nylon 6,6 or nylon 12), polyether block amide (PEBA) (e.g., 35D PEBA, 55D PEBA or 72D PEBA), polyurethane, silicone, rubber, other thermoplastic polymers or combinations thereof, to achieve the desired amount of force in the balloon stretching. The catheter shaft may be uniform in composition or may include a combination of materials distributed along one or more portions of the catheter shaft to create a desired stretching force. Different materials may result in different elastic tensions and different forces applied to the elongated, rigid metal element for balloon stretching. The catheter shaft may be an extruded catheter shaft.

[0128] The catheter shaft, balloon, or combination thereof may have single or multiple markings along their length to aid in positioning and alignment with certain anatomical structures. The markings may have any suitable orientation, such as circumferential or longitudinal along the catheter shaft or balloon. The catheter shaft or balloon markings may be used to aid in positioning the balloon in the treatment area, indicating that the balloon has been fully retrieved into the sheath or positioned in the device within the patient's anatomy. The catheter shaft markings may be visible using an endoscope, cystoscope, or with the naked eye, or the markings may include radiologically distinguishable elements, such as radiopaque materials. The markings may be made by thermally bonding a polymer to the catheter shaft surface with a distinguishable color, by pad printing, laser marking, or any other method. Figures 5A and 5B show an embodiment of a balloon recapture mark 509 and a positioning mark 511. The balloon recapture mark 509 may be used when the balloon catheter has a sheath covering the balloon. The mark 509 may be located just proximal to the proximal end of the sheath when it covers the balloon. After the user advances the catheter to the desired location, removes the sheath, and inflates the balloon, the user may wish to later advance the sheath so that the balloon is covered for removal. In this case, after deflation, the user advances the sheath distally until the recapture mark 509 is visible. The positioning mark 511 may be used to assist the user in positioning the catheter within the body cavity. For example, when the one-neck balloon shown in FIGS. 5A and 5B is used for BPH treatment, the positioning mark may be located just proximal to the proximal end of the balloon, just proximal to the external sphincter. In various embodiments, the user can see the mark 511 through the scope, and when the mark is just proximal to the external sphincter, the user can confirm that the balloon is properly positioned.

[0129] In various embodiments, the catheter shaft may have a separate lumen that allows urine to pass from the bladder through the catheter shaft and out through the exterior portion of the device. This embodiment allows the drug-coated balloon catheter to remain in place for a period of time, such as 0.1 to about 7 days, while preventing bleeding and allowing the tissue to heal into a new configuration. The drug-coated balloon may be used not only for expansion and drug delivery, but also as a Foley catheter or urinary catheter.

[0130] The end (e.g., the proximal end) of the catheter shaft that remains outside the body may include a hub (e.g., a valve, connector, or adapter) that provides a connection to the internal lumen of the catheter shaft. During inflation, the hub may prevent backflow of fluid or air from the balloon (e.g., when closed or at all times). The hub may include a suitable valve, such as a Tuohy Borst adapter. A Tuohy Borst adapter is a compression sealing device that may be placed onto the catheter shaft and tightened to provide a fluid-tight / air-tight connection to the internal lumen of the catheter shaft. A one-way stopcock may control fluid overflow into the balloon and may be connected to an inflation device by a standard luer.

[0131] The proximal side of the catheter shaft may include a hub or any other attachment manifold for injecting fluids, air or other gases through the catheter to connect and inflate a balloon, allow passage of a guidewire, allow catheterization, or any other suitable connection to the catheter shaft. Connection to the hub or attachment manifold may be via any suitable connection or connections, such as a single female or male Luer hub or a Luer manifold having multiple channels. The hub or manifold may be made of any suitable material, such as polycarbonate, acrylonitrile butadiene styrene, nylon, Pebax, etc. (登録商標)The hub may be made of any suitable biocompatible material, such as cellulose, silicone, any other moldable polymeric material, or a combination thereof. The hub may be attached to the catheter in any suitable manner, such as using an adhesive (e.g., cyanoacrylate adhesive, silicone adhesive, epoxy, any other adhesive suitable for the substrate, or a combination thereof) or using chemical bonding. The hub or manifold may be overmolded onto the catheter shaft for direct fusion to the catheter shaft. The catheter shaft may have a strain relief element at the catheter shaft to hub or manifold connection. The strain relief element may help prevent kinking. The strain relief element may include polyolefin, PET, FEP, other heat shrinkable materials, or a combination thereof. The strain relief element may be heat shrink. The strain relief element may be a soft molded material that interfaces with the hub (e.g., the strain relief element may be glued to the hub).

[0132] The balloon catheter may include a catheter tip at the longitudinal end of the balloon, the distal end that is first inserted into the body. The catheter tip may facilitate passage of the balloon through the urethra. The tip may be an atraumatic tip that helps prevent damage during insertion into the urethra. The tip may be a Coude atraumatic tip. The atraumatic Coude tip is designed to facilitate passage of the catheter through bends in the male urethra while preventing damage to the urethral wall during insertion. The tip may be a low durometer biocompatible material overcoated on the catheter shaft or adhesively bonded to the shaft. For example, the Coude tip may be a Pebax tip. (登録商標) Or it may be made from liquid silicone rubber.

[0133] In some embodiments, the catheter may include an insertion sheath that covers the balloon (e.g., a coated and folded / pleated balloon) during insertion and may be completely removed from the body during the procedure. The sheath may be designed in combination with an obturator or dilator to facilitate reinsertion of the sheath into the body cavity. The sheath may include one material or more than one material. The sheath may have a layered structure in which several layers of different materials are combined to make the sheath or may be formed by simple extrusion or co-extrusion. In some embodiments, the sheath may include an inner layer including a fluoropolymer such as PTFE or FEP, a central reinforcing layer including braided or spiraled wire filaments such as stainless steel, nitinol, PEEK or other materials, and a cellulose acylate. (登録商標) The obturator includes an outer layer comprising a polymer such as nylon, polyurethane or other thermoplastic material. The durometer of the outer sheath material and the pitch of the braided or spiral reinforcement can be uniform or vary along the length of the sheath. The obturator can be an extruded tube or molded to a specific geometry and can include 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 be tapered, radiused or some combination to facilitate passage through the body cavity. The sheath and obturator can have a hub connection attached by overmolding, crimping, crimping or adhesive bonding to allow them to be attached to one another. Alternatively, the obturator can be expanded proximally to create grasping features and an interference connection with the sheath. After the procedure, the obturator and sheath can be inserted proximally of the balloon through the body cavity. Once in position, the obturator can be separated from the sheath and the sheath can be placed over the deflated balloon to facilitate removal of the balloon catheter.

[0134] FIG. 2 shows an embodiment of a balloon catheter including the catheter shaft, catheter tip, and Tuohy Borst adapter / plug assembly. All materials may be biocompatible. The balloon is coated with a paclitaxel solution, but may be coated with other drugs or biologics that may promote improvement of BPH symptoms. In use, only the proximal two sections of the balloon are coated with drug, since the distal section is within the bladder.

[0135] The balloon catheter may include an inflation device, including a pressure gauge or pressure sensor, that is fluidly connected to a catheter shaft that is connected to the balloon catheter.

[0136] The balloons shown in Figures 1A, 1B, 1C and 2 are blow molded in a mold that includes a body and a neck. A tube of balloon material is poured into the mold of the desired shape. The balloon material tube may be pre-stretched. The balloon mold has a shape corresponding to the balloon shown in Figures 1A, 1B, 1C or 2. It includes a proximal cone, at least one body, at least one neck, at least one or more body portions and a distal cone. Balloon materials include polyester, polyamide, nylon 12, nylon 11, polyamide 12, block copolymers of polyether and polyamide, Pebax, etc. (登録商標) The balloon material may be any of the following: polyurethane, and block copolymers of polyether and polyester. The tube and mold are heated to a temperature above the glass transition temperature of the tube of balloon material and pressurized with gas, air, fluid, etc., causing the material in the tube to take the shape of the mold. The formed balloon is then cooled, trimmed, and then bonded to a catheter.

[0137] In some embodiments, the balloon is inflated at low pressure and a neck reinforcement is bonded to one or more neck regions. The neck reinforcement is used to control the neck expansion during balloon inflation. The neck can be a substantially inelastic portion of the balloon, a reinforced portion of the balloon, or a combination thereof. The neck can include an inelastic material wrapped around the circumference of the neck, such as a suture or a monofilament or multifilament of such material, such as steel, stainless steel, nitinol, tungsten, aluminum, copper, silver, gold, platinum, iridium, nickel (Ni), chromium (Cr), aluminum (Al), titanium (Ti), molybdenum (Mo), tungsten (W), niobium (Nb), tantalum (Ta) and superalloys including cobalt (Co), nylon, polyamide, aromatic polyamide, ultra-high molecular weight polyethylene (UHMWPE), polyester, aromatic polyester, polyethylene terephthalate (PET), or combinations thereof. In some embodiments, the polymeric material is in the form of a thread or fiber that is wrapped around the neck multiple times and then held in place by a continuous bead of glue or adhesive, two or more points of glue or adhesive, thermal welding, bonding by post-plasma treatment adhesively, or adhesive bonding to an adhesive layer. An adhesive layer, which is a separate layer applied to the balloon prior to the fiber bonding process, can improve adhesion of the fiber adhesive or glue to the outer surface of one or more of the balloon necks.

[0138] The balloon body parts can be formed with the same or similar diameter. In some embodiments, the diameters of the various body parts can differ from each other by up to 30% when measured at the balloon nominal diameter. In Figures 1A, 1B, 1C and 2, the balloon body parts are depicted with equal diameters, i.e., the diameter of each body part is constant. In practice, at high pressure, the diameter of the body part may sag slightly, and the diameter of the central part of the body part may be slightly larger than the diameter of the end of the body part near the balloon cone and / or near the neck part.

[0139] In the embodiments shown in Figures 1A, 1B, 1C and 2, where the balloon has a neck and a trunk, and in Figure 3, where the balloon has no neck, after the balloon catheter is assembled, the balloon may be coated with at least one water soluble additive and drug as described herein. In some embodiments where the balloon has multiple trunks, the distal trunk may not be coated. The balloon may be coated by the methods described herein. If a sheath is used, it is placed over the balloon after the balloon is coated. The catheter is then packaged, sterilized and labeled as known in the art.

[0140] The present invention relates to balloon catheters having rapid drug release coatings and methods of making such coated devices. The therapeutic agent in the present invention does not require delayed or prolonged release, instead, for example, the therapeutic agent and additives are released in a very short time to provide a therapeutic effect upon contact with tissue. The objective of the present invention is to promote rapid and efficient uptake of the drug by the target tissue during temporary device placement at the target site.

[0141] The drug coating may cover a 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 nominal pressure, excluding the neck and end cone), such as about 1% to about 100%, or about 50% to about 100%, about 80% to about 100%, or less than about 10% or less than, equal to, greater than or equal to 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or about 100%.

[0142] The drug coatings are N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauro ... N-Oleoyl-D-Sphingosine, N-Palmitoyl-D-Sphingosine, N-Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG 8 Caprylic / Capric Glyceride, PEG Caprylate, PEG 8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, Monolaurin, Monocaprin, Monocaprylin, Monomyris In some embodiments, the present invention may include water soluble additives such as those selected from the group consisting of glycerol, monopalmitolein, monoolein, 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, and combinations thereof. The water soluble additives may 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 additives may include a second water soluble additive that is a compound having one or more moieties that are hydroxyl, amine, carbonyl, carboxyl, or ester, such as sorbitol, sorbitan, xylitol, gluconolactone, or a combination thereof.The drug coating may include both a first water-soluble additive and a second water-soluble additive. In some embodiments, the distal end of the balloon may be free of a therapeutic agent.

[0143] In various embodiments, the present invention provides a method of treating a body cavity. The body cavity can be a vascular body cavity or a non-vascular body cavity. The method can include inserting a balloon catheter (e.g., any embodiment of a balloon catheter described herein) into a target site in the body cavity. The method can include inflating the balloon until (e.g., at least until) the coating layer contacts a wall of a stenosis in the body cavity at the target site and the balloon achieves an inflated balloon diameter for the inflation time. Features (a) or (b) or (c) or (a) and (b) or (a) and (c) or (b) and (c) or (a) and (b) and (c) are present. (a) a ratio of inflated balloon diameter to untreated body lumen diameter at the target site is about 1.0 to about 40; or (b) the inflation comprises inflating the balloon to at least as much as a nominal pressure of the balloon catheter, and the stretch ratio 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 may include deflating the balloon after the inflation period. The method may include withdrawing the balloon catheter from the stenosis in the body lumen.

[0144] Various embodiments provide methods of treating benign prostatic hyperplasia (BPH) strictures, urethral strictures, ureteral strictures, prostate cancer, esophageal strictures, bile duct strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, large intestinal strictures, colorectal strictures, post-gastric bypass strictures, ileocolic strictures, gastrointestinal strictures, colonic J-pouch strictures, bladder neck strictures (e.g., strictures), fibrostenosing 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, or chronic obstructive pulmonary disease (COPD). The method is a method for treating strictures in a body cavity, such as urethral strictures, benign prostatic hyperplasia (BPH) strictures, ureteral strictures, esophageal strictures, sinus strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, large intestinal strictures, and bile duct strictures. The strictures in a body cavity can be benign prostatic hyperplasia (BPH) strictures, urethral structure, or esophageal strictures. The method can be a method for treating benign prostatic hyperplasia, prostate cancer, or a combination thereof, where the body cavity is the prostate.

[0145] The method may include flushing the body cavity with water, a saline solution, or an aqueous solution containing at least one water soluble additive before, during, or after insertion of the balloon into the target site.

[0146] The body cavity can be the prostate, where inserting the balloon catheter includes positioning the balloon catheter in the prostate using a scope (e.g., flexible or rigid, such as a cystoscope). The balloon catheter can include a scope, and the method can include using video feed from the scope to position the balloon catheter at the target site. The method can include using video feed from the scope to position the balloon catheter at the target site.

[0147] The body cavity can be the prostate, the balloon can have multiple sections divided by one or more necks, and balloon catheter insertion can include positioning one section of the balloon catheter in the prostate and positioning a second section of the balloon catheter in the bladder.

[0148] The insertion may include positioning at least one neck of the balloon at the bladder neck. The at least one neck of the balloon catheter may be a distal neck and the insertion may include positioning the distal neck at the bladder neck. The balloon catheter may include a proximal neck and the insertion may include positioning the proximal neck at the prostatic urethra.

[0149] The swelling time can be any suitable swelling time such as about 0.1 minutes to about 10 minutes, about 0.5 minutes to about 2 minutes, or about 0.1 minutes or less, or about 0.2 minutes, 0.3 minutes, 0.4 minutes, 0.5 minutes, 0.6 minutes, 0.7 minutes, 0.8 minutes, 0.9 minutes, 1 minute, 1.1 minutes, 1.2 minutes, 1.3 minutes, 1.4 minutes, 1.5 minutes, 1.6 minutes, 1.8 minutes, 2 minutes, 2.2 minutes, 2.4 minutes, 2.6 minutes, 2.8 minutes, 3 minutes, 3.5 minutes, 4 minutes, 4.5 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or about 10 minutes or more.

[0150] Inflation is about 0.1 atmospheres / minute to about 10 atmospheres / minute, or about 0.5 to about 1.5 atmospheres / minute, or about 0.1 atmospheres / minute or less, or about 0.2 atmospheres / minute, 0.3 atmospheres / minute, 0.4 atmospheres / minute, 0.5 atmospheres / minute, 0.6 atmospheres / minute, 0.7 atmospheres / minute, 0.8 atmospheres / minute, 0.9 atmospheres / minute, 1 atmosphere / minute, 1.1 atmospheres / minute, 1.2 atmospheres / minute, 1.3 atmospheres / minute, 1.4 atmospheres / minute, 1.5 atmospheres / minute, 1.6 atmospheres / minute, 1.8 atmospheres / minute, 2 atmospheres / minute, 2.2 Atmospheres / minute, 2.4 atmospheres / minute, 2.6 atmospheres / minute, 2.8 atmospheres / minute, 3 atmospheres / minute, 3.5 atmospheres / minute, 4 atmospheres / minute, 4.5 atmospheres / minute, 5 atmospheres / minute, 6 atmospheres / minute, 7 atmospheres / minute, 8 atmospheres / minute, 9 atmospheres / minute or about 10 atmospheres / minute or less, equal to, greater than or equal to 10 atmospheres / minute (e.g., times when pressure drops due to tissue production can be excluded and pressure can be maintained during these times).

[0151] Inflation may include monitoring the pressure within the balloon, such as with a pressure gauge. During stenosis creation, which may involve reducing the pressure, inflation may include stabilizing the pressure within the balloon, stabilizing the stabilized pressure within the balloon for a time during tissue creation, and then resuming an increase in the pressure within the balloon until the desired inflated diameter is achieved. The stabilization time may be a suitable time, such as about 0.1 minutes to about 10 minutes, about 0.5 minutes to about 2 minutes, or about 0.1 minutes or less, or about 0.2 minutes, 0.3 minutes, 0.4 minutes, 0.5 minutes, 0.6 minutes, 0.7 minutes, 0.8 minutes, 0.9 minutes, 1 minute, 1.1 minutes, 1.2 minutes, 1.3 minutes, 1.4 minutes, 1.5 minutes, 1.6 minutes, 1.8 minutes, 2 minutes, 2.2 minutes, 2.4 minutes, 2.6 minutes, 2.8 minutes, 3 minutes, 3.5 minutes, 4 minutes, 4.5 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or about 10 minutes or more.

[0152] As shown in FIG. 3, in one embodiment, the medical device is a balloon catheter. The balloon catheter may be any suitable catheter for the desired use, including conventional balloon catheters known to those of skill in the art. For example, the balloon catheter 10 may include an expandable, inflatable balloon 12 at a distal end of the catheter 10, a handle assembly 16 at a proximal end of the catheter 10, and an elongated flexible member 14 extending between the proximal and distal ends. The handle assembly 16 may be connected to and / or receive one or more suitable medical devices, such as a source of inflation medium (e.g., air, saline, or contrast medium). The flexible member 14 may be a tube made of a suitable biocompatible material and have one or more lumens therein. At least one of the lumens is configured to receive the inflation medium and pass such medium to the balloon 12 for inflation. The balloon catheter may be a rapid exchange or over-the-wire catheter and is manufactured from a suitable biocompatible material. The material of the balloon 12 may be polyester, polyamide, nylon 12, nylon 11, polyamide 12, block copolymer of polyether and polyamide, Pebax, etc. (登録商標) , polyurethanes, and block copolymers of polyether and polyester.

[0153] In an 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 balloon catheter outer surface. The layer includes a therapeutic agent and one or more additives. The additives can be any suitable additive. The layer can include one additive or the layer can include more than one additive, such as a water-soluble first additive and a water-soluble second additive. For example, as shown in the embodiment depicted in FIG. 4A, the balloon 12 is coated with a layer 20 including a therapeutic agent and an additive. In an embodiment, the layer consists essentially of the therapeutic agent and the additive, e.g., the layer includes only the therapeutic agent and the additive, without any other substantially significant components. In an embodiment, the device can optionally include an adhesive layer. For example, as shown in the embodiment depicted in FIG. 4B, the balloon 12 is coated with an adhesive layer 22. A layer 24 including a therapeutic agent and an additive covers the adhesive layer. The adhesive layer, another layer underneath the drug coating layer, improves the attachment of the drug coating layer to the outer surface of the medical device and protects the coating integrity. For example, if the attachment to the medical device is different for the drug and additive, the adhesive layer can prevent differential loss of the components during transport to the target site for therapeutic intervention and maintain the drug to additive ratio in the coating. Additionally, the adhesive layer can function to facilitate 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. 4C, the balloon 12 is coated with an adhesive layer 22, a layer 26 containing a therapeutic agent and additives overlying the adhesive layer, and a top layer 28. The top layer can prevent loss of the drug layer prior to contact with the target tissue, for example, during transport of the balloon 12 to the therapeutic intervention site or during the first moment of expansion of the balloon 12 before the coating layer 20 is pressed into direct contact with the target tissue.

[0154] An embodiment of the present invention relates to the treatment of stenosis in a body lumen by delivery of an effective amount of a therapeutic agent, such as an anti-inflammatory and anti-proliferative agent (e.g., paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, an mTOR inhibitor or analogs thereof or combinations thereof). Stenosis in a body lumen includes vascular stenosis, urethral stenosis, ureteral stenosis, esophageal stenosis, achalasia stenosis, in-stent stenosis, sinus stenosis, gastric stenosis, small intestinal stenosis, duodenal stenosis, jejunal stenosis, ileal stenosis, colonic stenosis, rectal stenosis, large intestinal stenosis and bile duct stenosis. An embodiment of the present invention relates to a method for treating at least one of vascular stenosis, benign prostatic hyperplasia (BPH), urethral problems, prostate cancer, colorectal stenosis, post-gastric bypass stenosis, ileocolic stenosis, digestive stenosis, J-pouch stenosis, bladder neck stenosis (e.g., stricture), fibrostenosing eosinophilic esophagitis stenosis, Crohn's disease (CD) and ulcerative colitis (UC)-induced stenosis, radiation-induced stenosis, endoscopic resection (EMR and ESD)-induced stenosis, surgery-related anastomotic stenosis, achalasia stenosis, gastrectomy-induced stenosis, asthma, and chronic obstructive pulmonary disease (COPD). According to an embodiment, the method includes delivery of a therapeutic agent, such as an anti-inflammatory and anti-proliferative agent (e.g., rapamycin, paclitaxel, or analogs thereof), by a coated medical device, such as a balloon catheter. The therapeutic agent can be coated on the medical device alone or with one or more additives.

[0155] In certain embodiments, the present invention provides a method of treating a stricture in a body lumen, comprising inserting a balloon catheter comprising a coating layer into the stricture, wherein the stricture is selected from the group consisting of urethral stricture, ureteral stricture, esophageal stricture, sinus stricture, achalasia stricture, in-stent stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, large intestinal stricture, colorectal stricture, post-gastric bypass stricture, ileocolic stricture, gastrointestinal stricture, colonic J-pouch stricture, bladder neck stricture (e.g., stricture), fibrostenosing eosinophilic esophagitis stricture, Crohn's disease (CD) and ulcerative colitis (UC) induced stricture. the coating layer comprises one of a drug and an additive, inflating the balloon catheter to release the drug into the wall of the stricture, deflating the balloon; and withdrawing the balloon catheter, wherein the remaining drug can be about 1-70% of the total drug loaded in the balloon catheter, and wherein the drug in the wall of the body cavity can be about 0.1-25% of the total drug loaded in the balloon catheter. In some aspects of this embodiment, the additive can enhance drug absorption into the tissue of the stricture in the body cavity.

[0156] In certain embodiments, the present invention relates to a method of treating a stricture in a body cavity, comprising inserting a balloon catheter comprising a coating layer into a body cavity, wherein the body cavity is one of the esophagus, airway, paranasal sinuses, trachea, colon, bile duct, stomach, small intestine, duodenum, jejunum, ileum, rectum, large intestine, urinary tract, prostate, urethra, ureter, and other cavities, and wherein the coating layer comprises a drug and an additive, inflating the balloon catheter, releasing the drug into the wall of the body cavity, deflating the balloon, and withdrawing the balloon catheter, wherein the remaining drug can be about 1-70% of the total drug load of the balloon catheter, and wherein the drug in the wall of the body cavity can be about 0.1-25% of the total drug load of the balloon catheter. In certain aspects of this embodiment, the additive increases the absorption of the drug into tissues in the body cavity. In another aspect of this embodiment, the additive comprises a hydrophilic portion and a drug affinity portion, where the drug affinity portion is at least one of a hydrophobic portion, a portion having affinity for the therapeutic agent through hydrogen bonding, and a portion having affinity for the therapeutic agent through van der Waals interactions.

[0157] In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a target site of a stenosis in a body lumen, the balloon catheter comprising a coating layer covering an outer surface of the balloon, wherein the coating layer comprises an initial drug loading amount of the therapeutic agent and one or more water soluble additives, the therapeutic agent being selected from paclitaxel, docetaxel, taxol, analogs thereof, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, analogs thereof, and combinations thereof, and the water soluble additives being N-acetylglucosamine, N-octyl-D- ... N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG caprylic / capric diglyceride, PEG8 caprylic / capric Glycerides, PEG caprylate, PEG 8 caprylate, PEG caprate, PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monocaproate, monolaurin, monocaprin, monocaprylin, monomyristin, monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, monophosphate Selected from xanthosine, 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, and combinations thereof.

[0158] In some embodiments of the balloon catheter, the one or more water soluble additives facilitate rapid release of the therapeutic agent from the balloon, whereby rapid release includes the residual drug amount of the therapeutic agent that remains in the balloon after the balloon is inflated at a target site in a body cavity for an inflation time of about 0.1 minutes to 10 minutes and then removed from the body cavity.

[0159] In certain embodiments of the balloon catheter, the weight ratio 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 less than, equal to, greater than or equal to about 0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about 3, about 2 to about 6, or less than about 0.05 or less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20. In certain embodiments of the balloon catheter, the weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer (e.g., relative to the total weight of the first and second water soluble additives or the first, second and third water soluble additives in the coating layer) is about 0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about 3, about 2 to about 6, or less than about 0.05 or less than, equal to, greater than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20.

[0160] In one embodiment, the present invention relates to a method of treating a stenosis in a body cavity, the method comprising flushing the body cavity with water, a saline solution, or an aqueous solution comprising at least one water-soluble additive. and inserting the balloon catheter into a target site of a stenosis in a body cavity, the balloon catheter comprising a balloon and a coating layer covering an exterior surface of the balloon, the coating layer comprising at least one water soluble additive and an initial drug load of a therapeutic agent, the therapeutic agent being selected from paclitaxel, docetaxel, taxol, analogs thereof, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, analogs thereof and combinations thereof, the water soluble additive being N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl- D-Sphingosine, N-Lauroyl-D-Sphingosine, N-Palmitoyl-D-Sphingosine, N-Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG 8 Caprylic / Capric Glyceride, PEG Caprylate, PEG 8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, 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, caffeine, allantoin, (2-hydroxyethyl)urea, N,and a combination thereof), inflating the balloon until the coating layer contacts a wall of the stenosis in the body cavity at the target site and the balloon achieves an inflated balloon diameter for the inflation time, deflating the balloon after the inflation time (wherein the inflation time is 0.1 minutes to 10 minutes), and withdrawing the balloon catheter from the stenosis in the body cavity. The dilated balloon catheter diameter can be such that the ratio of the dilated balloon diameter to the untreated diameter of the treated body lumen can be from about 1.0 to about 40 or from about 4 to about 40, and the stretch ratio at the treatment site can be from about 1.0 to about 40 or from about 4 to about 40. Optionally, the dilation can include dilation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0161] The balloon may have a residual amount of drug thereon after withdrawal. A suitable residual drug amount may remain after withdrawal, such as less than, equal to, or greater than about 0 wt%, 36 wt%, 34 wt%, 32 wt%, 30 wt%, 28 wt%, 26 wt%, 24 wt%, 22 wt%, 20 wt%, 18 wt%, 16 wt%, 14 wt%, 12 wt%, 10 wt%, 8 wt%, 6 wt%, 4 wt%, 3 wt%, 2 wt%, 1 wt%, or about 0 wt%.

[0162] In one embodiment, the present invention relates to a method of treating at least one of benign prostatic hyperplasia and prostatic 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 of the prostate (the balloon catheter comprises a balloon and a coating layer covering the outer surface of the balloon, the coating layer may comprise one or more water-soluble additives and an initial drug loading amount of a therapeutic agent), inflating the balloon until the coating layer contacts the wall of the benign prostatic hyperplasia or prostatic cancer at the target site and the balloon achieves an inflated balloon diameter, deflating the balloon after the inflation time (wherein the inflation time is 0.1 min to 10), and withdrawing the balloon catheter from the prostate. The ratio of the inflated balloon diameter to the untreated diameter of the body cavity may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment site may be about 1.0 to about 40 or about 4 to about 40. Optionally, the inflation may include inflation to a pressure equal to or higher than the nominal pressure of the balloon catheter.

[0163] In one embodiment, the present invention relates to a method of treating a urethral stricture, the method comprising: flushing the urethral stricture with water, a saline solution or an aqueous solution comprising at least one water-soluble additive; inserting a balloon catheter into a target site of the urethral stricture (the balloon catheter comprises a balloon and a coating layer covering an outer surface of the balloon, wherein the coating layer comprises at least one water-soluble additive and an initial drug loading amount of a therapeutic agent, and wherein the weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water-soluble additives in the coating layer is about 0.05-20); contacting the coating layer with the urethral stricture at the target site; inflating the balloon until the balloon achieves an inflated balloon diameter for an inflation time; deflating the balloon after the inflation time (wherein the inflation time is 0.1 min-10); and withdrawing the balloon catheter from the urethral stricture. The ratio of the inflated balloon diameter to the untreated diameter of the urethra at the stricture location may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment location may be about 1.0 to about 40 or about 4 to about 40. After dilation, the diameter of the urethral stricture can be less than, equal to, greater than, or about 50 mm, e.g., about 6.7 mm to about 50 mm, or about 6.7 mm to about 20 mm, or about 6.7 mm, 6.8 mm, 6.9 mm, 7.0 mm, 7.2 mm, 7.4 mm, 7.6 mm, 7.8 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or about 50 mm or more. Optionally, dilation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0164] In certain embodiments, the present invention relates to a method of treating an esophageal stricture, such as an achalasia stricture, comprising: optionally flushing the esophageal stricture with water, a saline solution, or an aqueous solution comprising at least one water soluble additive before, during, or after balloon catheter insertion; and inserting a balloon catheter into a target site in the esophageal stricture, the balloon catheter comprising a balloon and a coating layer covering an exterior surface of the balloon, the coating layer comprising at least one water soluble second additive and a coating layer having a thickness of less than 1 mm at the nominal diameter of the balloon.2 the coating layer comprises an initial drug loading of a therapeutic agent of 1-6 μg of therapeutic agent per coating layer, the weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer being about 0.05-20, inflating the balloon until the coating layer contacts the wall of the esophageal stricture at the target site and the balloon achieves an inflated balloon diameter, deflating the balloon after the inflation time (wherein the inflation time is 0.1 min-10 min), and withdrawing the balloon catheter from the esophageal stricture. The ratio of the balloon diameter to the untreated diameter of the esophagus at the stricture location may be about 1.0-40 or about 4-40, and the stretch ratio at the treatment location may be about 1.0-40 or about 4-40. In some embodiments, the balloon catheter properties are equal to or similar to those shown in Table 4, and have a growth rate that is delayed at high pressure. Compliance is the percent change in balloon diameter from nominal diameter to rated burst pressure (RBP) diameter, calculated as diameter@RBP-diameter@nominal pressure) / diameter@nominal pressure)*100%. Optionally, inflation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0165] [Table 4]

[0166] In certain embodiments, the present invention relates to a method of treating an esophageal stricture, such as an achalasia stricture, comprising: optionally flushing the esophageal stricture with water, a saline solution, or an aqueous solution comprising at least one water soluble additive before, during, or after balloon catheter insertion; and inserting a balloon catheter into a target site in the esophageal stricture, the balloon catheter comprising a balloon and a coating layer covering an exterior surface of the balloon, the coating layer comprising at least one water soluble second additive and a thickness of less than 1 mm at the nominal diameter of the balloon. 2The method includes inflating the balloon until the coating layer contacts the wall of the esophageal stricture at the target site and the balloon achieves an inflated balloon diameter, deflating the balloon after the inflation time (wherein the inflation time is 0.1 min to 10 min), and withdrawing the balloon catheter from the esophageal stricture. The ratio of the inflated balloon diameter to the untreated diameter of the esophagus at the stricture location may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment location may be about 1.0 to about 40 or about 4 to about 40. Optionally, the inflation may include inflation to a pressure equal to or higher than the nominal pressure of the balloon catheter. In one embodiment, the properties of the balloon catheter are equal to or similar to those shown in Table 5, and are a single balloon catheter with the ability to achieve a wide range of balloon diameters at relatively high working pressures compared to conventional compliant balloons. The balloons in Table 5 have the unique property that there are three balloon diameter increments at three increasing inflation pressures. The nominal inflated diameter is the diameter at stage I. The diameter increases by about 0.5-4 mm, preferably 0.75-3 mm, and most preferably 0.9-2 mm with each 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).

[0167] [Table 5]

[0168] In one embodiment, the present invention relates to a method of treating a gastrointestinal stricture, the gastrointestinal stricture comprising 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, or a bile duct stricture, the method comprising flushing the gastrointestinal stricture with water, a saline solution, or an aqueous solution comprising at least one water soluble additive, and inserting a balloon catheter into a target site in the gastrointestinal stricture, the balloon catheter comprising a balloon and a coating layer covering an exterior surface of the balloon, the coating layer comprising at least one water soluble second additive and a coating layer having a diameter of less than 1 mm at a nominal diameter of the balloon. 2 the coating layer comprises an initial drug loading of therapeutic agent of 1-6 μg therapeutic agent per coating layer, wherein the weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer is about 0.05-20, inflating the balloon until the coating layer contacts the wall of the esophageal stricture at the target site and the balloon achieves an inflated balloon diameter, deflating the balloon after the inflation time (wherein the inflation time is 0.1 minutes to 10 minutes), and withdrawing the balloon catheter from the esophageal stricture. The inflated balloon catheter diameter is such that the ratio of the balloon diameter to the untreated diameter of the esophagus at the location of the stricture may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment location may be about 1.0 to about 40 or about 4 to about 40. Optionally, the inflation may include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter. In one embodiment, the balloon catheter is the same or similar to those shown in Tables 4 and 5, with a single balloon catheter having a delayed growth rate at high pressure and the ability to achieve a wide range of balloon diameters at high working pressures.

[0169] In various embodiments, the drug coated balloon catheters used in the treatment of esophageal strictures, achalasia strictures, gastrointestinal strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, large intestinal strictures, colorectal strictures, post-gastric bypass strictures, ileocolic strictures, gastrointestinal strictures including J-pouch strictures, bladder neck strictures (e.g., strictures), fibrostenosing 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 and bile duct strictures have a catheter design that is a fixed wire, wire-guided, over-the-wire catheter or a rapid exchange design catheter.

[0170] In one embodiment, the present invention relates to a method of treating a sinus stenosis, the method comprising flushing the sinus stenosis with water, a saline solution, or an aqueous solution comprising at least one water-soluble additive, and inserting a balloon catheter into a target site in the sinus stenosis, the balloon catheter comprising a balloon and a coating layer covering an exterior surface of the balloon, the coating layer comprising at least one water-soluble additive and a thickness of less than 1 mm at the nominal diameter of the balloon. 2The therapeutic agent includes an initial drug loading dose of 1 to 6 μg of therapeutic agent per injection, and the therapeutic agent may be budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cortisone, betamethasone, triamcinolone acetonide, paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, ebetoxin, cyclosporine ... The water-soluble additive is selected from N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-gluconamide, N-acetylglucosamine ... -Sphingosine, N-Octanoyl-D-Sphingosine, N-Lauroyl-D-Sphingosine, N-Palmitoyl-D-Sphingosine, N-Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG 8 Caprylic / Capric Glyceride, PEG Caprylate, PEG 8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate aryl, 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, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerol ethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5, 12-crown-4 and combinations thereof, wherein the weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water-soluble additives in the coating layer is about 0.05-20), inflating the balloon until the coating layer contacts the wall of the sinus stenosis at the target site and the balloon achieves an inflated balloon diameter, deflating the balloon after the inflation time (wherein the inflation time is 0.1 min-10), and withdrawing the balloon catheter from the sinus stenosis.

[0171] In some embodiments, it may be desired to pre-dilatate the target area of ​​the body cavity, such as the prostatic urethra or any other target area, before using the drug-coated balloon. In some embodiments, the pre-dilatation balloon is selected to have a nominal diameter that is slightly shorter and / or slightly smaller than the treatment balloon. If the pre-dilatation balloon is shorter than the treatment balloon, the entire pre-dilatation zone or area is likely to be treated by the treatment balloon. In some embodiments, the pre-dilatation balloon may be substantially the same size as the treatment balloon, such that the nominal diameter and length of the pre-dilatation balloon substantially matches the treatment balloon. In some embodiments, it is desired to directly treat the target area of ​​the body cavity without pre-dilatation. In some embodiments, the method includes inserting and positioning the pre-dilatation balloon catheter into the target area, using a scope to visualize the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, the creation of the target area, or any combination thereof.

[0172] The present invention relates to balloon catheters having rapid drug release coatings and methods of making such coated devices. The therapeutic agent in the present invention does not require delayed or prolonged release, instead, for example, the therapeutic agent and additives are released in a very short time to provide a therapeutic effect upon contact with tissue. The objective of the present invention is to promote rapid and efficient uptake of the drug by the target tissue during temporary device placement at the target site.

[0173] In various embodiments, the balloon catheter can have one or more (e.g., two) necks along the body of the balloon. The necks can have a nominal diameter smaller than the nominal diameter of the balloon body (e.g., 1.5 to 2.5 times smaller) and can be of any suitable length, such as about 10 to 20 mm long. The necks can divide the balloon symmetrically or some balloon bodies can be longer than others. The nominal balloon diameter ranges from 6 to 45 mm and the working length is 20 to 160 mm.

[0174] In FIG. 1A, in one embodiment, a balloon with one neck is shown. Balloon 100 has waist 101, cone 102, first body portion 103, neck 104, second body portion 105, cone 106, and waist 107. When assembled into a balloon catheter as known to those skilled in the art, waists 101 and 107 are connected or secured, etc., to a catheter shaft (not shown). During inflation, waists 101 and 107 do not expand because they are connected to the catheter shaft. Sections 102, 103, 104, 105, and 106 can all be inflated simultaneously through a single inflation point in communication with the catheter shaft and an external luer hub. In FIG. 1B, in one embodiment, a balloon with two necks is shown. Balloon 120 has waist 121, cone 122, first body portion 123, first neck 124, second body portion 125, second neck 126, third body portion 127, cone 128, and waist 129. When assembled into a balloon catheter as known to those skilled in the art, waists 121 and 129 are connected or secured, etc., to the catheter shaft. During inflation, waists 121 and 129 do not expand because they are connected to the catheter shaft. Sections 122, 123, 124, 125, 126, 127, and 128 can all be simultaneously inflated through a single inflation point in communication with the catheter shaft and an external luer hub. Although necks 124 and 126 are shown as being the same diameter in the current inflation state, they can be the same or different diameters with the same or different compliance. In FIG. 1C, in one embodiment, a balloon having three necks is shown. Balloon 140 has waist 141, cone 142, first body portion 143, first neck 144, second body portion 145, second neck 146, third body portion 147, third neck 148, fourth body portion 149, cone 150, and waist 151. When assembled into a balloon catheter as known to one of ordinary skill in the art, waists 141 and 151 are connected, secured, etc. to the catheter shaft. During inflation, waists 141 and 151 do not expand because they are connected to the catheter shaft.Sections 142, 143, 144, 145, 146, 147, 148, 149 and 150 may all be simultaneously inflated through a single inflation point in communication with the catheter shaft and external luer hub. Although necks 144, 146 and 148 are shown having different diameters in the present expanded state, they may be the same or different diameters with the same or different compliance.

[0175] As shown in FIG. 2, in one embodiment, the medical device is a balloon catheter, a fixed wire balloon catheter, a movable wire catheter, an over-the-wire balloon catheter, a rapid exchange balloon catheter, including conventional balloon catheters known to those skilled in the art. For example, the balloon catheter 160 may include an expandable, inflatable balloon 162 at the distal end of the catheter 160, a handle assembly 161 at the proximal end of the catheter 160, an elongated flexible member 164 extending from the proximal end to the distal end, and an atraumatic Coude tip 163 at the distal end. The handle assembly 161 may be connected to and / or receive one or more suitable medical devices, such as a source of inflation medium (e.g., air, water, saline, or contrast medium). The flexible member 164 may be made of a suitable biocompatible material and may be a tube having one or more lumens therein. At least one of the lumens is configured to receive an inflation medium and pass such medium through the balloon 162 for inflation thereof. The balloon catheter may be a fixed wire or rapid exchange or over-the-wire catheter and may be made from any suitable biocompatible material. Materials for the balloon 162 include polyester, polyamide, nylon 12, nylon 11, polyamide 12, block copolymers of polyether and polyamide, Pebax, etc. (登録商標), polyurethane, and block copolymers of polyether and polyester. In FIG. 2, in one embodiment, a balloon having two necks is shown. Balloon 162 has waist 165, cone 166, first body section 167, first neck 168, second body section 169, second neck 170, third body section 171, cone 172, and waist 173. When assembled into a balloon catheter as known to those skilled in the art, waists 165 and 173 are connected or secured, etc., to the catheter shaft. During inflation, waists 165 and 173 do not expand because they are connected to the catheter shaft. Sections 166, 167, 168, 169, 170, 171, and 172 may all be simultaneously inflated through a single inflation point in communication with the catheter shaft and external luer hub. Although necks 168 and 170 are shown as being the same diameter in the present inflation state, they may be the same or different diameters with the same or different compliance.

[0176] As shown in FIG. 3, in one embodiment, the medical device is a balloon catheter. The balloon catheter can be any suitable catheter for a desired use, including fixed wire balloon catheters, movable wire catheters, over-the-wire balloon catheters, rapid exchange balloon catheters, including conventional balloon catheters known to those skilled in the art. For example, the balloon catheter 10 can include an expandable, inflatable balloon 12 at a distal end of the catheter 10, a handle assembly 16 at a proximal end of the catheter 10, and an elongated flexible member 14 extending between the proximal and distal ends. The handle assembly 16 can be connected to and / or receive one or more suitable medical devices, such as a source of inflation medium (e.g., air, saline, or contrast medium). The flexible member 14 can be made of a suitable biocompatible material and can be a tube having one or more lumens therein. At least one of the lumens is configured to receive an inflation medium and pass such medium through the balloon 12 for inflation thereof. The balloon catheter 10 can be a rapid exchange or over-the-wire catheter and can be manufactured from any suitable biocompatible material. The material of the balloon 12 may be polyester, polyamide, nylon 12, nylon 11, polyamide 12, block copolymer of polyether and polyamide, Pebax, etc. (登録商標) , polyurethanes, and block copolymers of polyether and polyester.

[0177] As shown in Figures 7A-7C, in one embodiment, the medical device is an over-the-wire balloon catheter or a rapid exchange type balloon catheter. Figure 7A shows a side view. Figure 7B illustrates a cross-sectional view of the shaft in Figure 7A. Figure 7C illustrates a cross-sectional view of the balloon in Figure 7A. The balloon catheter 700 can include an expandable, inflatable balloon at a distal end of the catheter 700. The balloon 711 can have a proximal cone portion 706, a first body portion 707, a neck portion 708, a second body portion 709, and a distal cone portion 710. The balloon catheter 700 can have a handle or luer assembly 705 in communication with a channel 704 for inflating the balloon 711 and allowing for guidewire placement through a channel 703. The handle assembly 705 can connect to and / or receive one or more suitable medical devices, such as a source of inflation media (e.g., air, water, saline, or contrast media). Flexible members 701 and 702 are made of suitable biocompatible materials and may be tubes having one or more lumens therein. An outer flexible member or extrusion 701 is disposed over the top of flexible member or extrusion 702 and terminates at the proximal balloon bond. An inner flexible member or extrusion 702 runs the entire length of balloon catheter 700 under balloon 711 and terminates at a flexible radiused tip at the distal end of the catheter. Materials for balloon 711 include polyester, polyamide, nylon 12, nylon 11, polyamide 12, block copolymers of polyether and polyamide, Pebax, etc. (登録商標) , polyurethane, block copolymers of polyether and polyester, or combinations thereof.

[0178] In an embodiment, the present invention provides a medical device for delivering a therapeutic agent to diseased tissue or stenosis, such as vascular or non-vascular tissue. The device includes a layer applied to the outer surface of a balloon catheter. The layer includes a therapeutic agent and one or more additives. The additives can be any suitable additive. The layer can include one additive or the layer can include more than one additive, such as a water-soluble first additive and a water-soluble second additive. For example, as shown in the embodiment depicted in FIG. 4A, the balloon 12 is coated with a layer 20 including a therapeutic agent and an additive. In an embodiment, the layer consists essentially of the therapeutic agent and the additive, e.g., the layer includes only the therapeutic agent and the additive, without any other substantially significant components. In an embodiment, the device can optionally include an adhesive layer. For example, as shown in the embodiment depicted in FIG. 4B, the balloon 12 is coated with an adhesive layer 22. A layer 24 including a therapeutic agent and an additive covers the adhesive layer. The adhesive layer, another layer underneath the drug coating layer, improves the attachment of the drug coating layer to the outer surface of the medical device and protects the integrity of the coating. For example, if the attachment to the medical device is different for the drug and additive, the adhesive layer can prevent differential loss of the components and maintain the drug-to-additive ratio in the coating during delivery to the target site for therapeutic intervention. Additionally, the adhesive layer can function to facilitate 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. The top layer can reduce loss of the drug layer prior to contacting the target tissue, for example during delivery of the balloon 12 to the therapeutic intervention site or during the first moment of expansion of the balloon 12 before the coating layer 20 is pressed into direct contact with the target tissue.

[0179] An embodiment of the present invention relates to the treatment of stenosis in non-vascular body lumens by delivery of an effective amount of a therapeutic agent, such as an anti-inflammatory and anti-proliferative agent (e.g., rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, paclitaxel, taxol, docetaxel or analogs thereof). Stenosis of non-vascular body lumens includes urethral strictures, ureteral strictures, esophageal strictures, sinus strictures, achalasia strictures, in-stent strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, large intestinal strictures, colorectal strictures, post-gastric bypass strictures, ileocolic strictures, gastrointestinal strictures, J-pouch strictures, bladder neck strictures (e.g., strictures), fibrostenosing 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 and bile duct strictures.Embodiments of the present invention relate to methods of treating at least one of benign prostatic hyperplasia (BPH), prostate cancer, asthma, and chronic obstructive pulmonary disease (COPD). According to various embodiments, the methods include delivery of a therapeutic agent, such as an anti-inflammatory and anti-proliferative agent (e.g., rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, paclitaxel, taxol, docetaxel or analogs thereof) via a coated balloon catheter. The anti-inflammatory and anti-proliferative agent may be coated onto the medical device alone or with one or more additives.

[0180] A method of treating a stenosis in a non-vascular body cavity includes inserting a balloon catheter including a coating layer into the body cavity, where the coating layer includes a drug and an additive, inflating the balloon catheter, releasing the drug into the wall of the non-vascular body cavity, deflating the balloon, and withdrawing the balloon catheter, where the remaining drug can be about 1-70% of the total drug load of the balloon catheter, where the drug in the wall of the body cavity can be about 0.1-25% of the total drug load of the balloon catheter. The method can include flushing the body cavity with water, a saline solution, or an aqueous solution including at least one water-soluble additive before, during, or after insertion of the balloon into the target site. In one aspect of this embodiment, the additive enhances absorption of the drug into the tissue of the non-vascular body cavity. In another aspect of this embodiment, the additive includes a hydrophilic portion and a drug affinity portion, where the drug affinity portion is at least one of a hydrophobic portion, a portion having affinity for the therapeutic agent through hydrogen bonding, and a portion having affinity for the therapeutic agent through van der Waals interactions.

[0181] A balloon catheter for delivering a therapeutic agent to a target site in a non-vascular body lumen can include a coating layer covering an outer surface of the balloon, wherein the coating layer comprises an initial drug load of the therapeutic agent and one or more water soluble additives, the therapeutic agent being selected from paclitaxel, taxol, docetaxel, analogs thereof, rapamycin, sirolimus, zotarolimus, everolimus and analogs thereof, and combinations thereof, and the water soluble additives being N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-Octanoyl-N-Methylglutamine, C6-Ceramide, Dihydro-C6-Ceramide, Cerebroside, Sphingomyelin, Galactocerebroside, Lactocerebroside, N-Acetyl-D-Sphingosine, N-Hexanoyl-D-Sphingosine, N-Octanoyl-D-Sphingosine, N-Lauroyl-D-Sphingosine, N-Palmitoyl-D-Sphingosine, N-Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG8 Caprylic / Capric Glyceride, PEG Caprylate , PEG8 caprylate, PEG caprate, PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monocaproate, 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, The aryl ethers are selected from phenanthritol, 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, and combinations thereof.

[0182] The non-vascular body cavity can be one of the esophagus, airway, paranasal sinuses, trachea, colon, bile duct, stomach, small intestine, duodenum, jejunum, ileum, rectum, large intestine, urinary tract, prostate, urethra, ureters, and other non-vascular lumens.

[0183] In some embodiments, the one or more water soluble additives can facilitate rapid release of the therapeutic agent from the balloon, where rapid release includes the residual drug amount 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 time of about 0.1 minutes to about 10 minutes and subsequently removed from the non-vascular lumen.

[0184] 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 less than, equal to, greater than or equal to about 0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about 3, about 2 to about 6, or less than about 0.05 or less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20. The weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer (e.g., relative to the total weight of the first and second water soluble additives or the first, second and third water soluble additives in the coating layer) can be less than about 0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about 3, about 2 to about 6, or less than about 0.05 or less than, equal to, greater than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20.

[0185] The initial drug loading was 1 mm 2 per (i.e., per external surface area of ​​the nominal diameter of the balloon) of therapeutic agent may be less than, equal to, greater than, or greater than about 1 μg to 20 μg, or about 2 to about 6 μg, or less than about 1 μg, or less than about 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, 10 μg, 12 μg, 14 μg, 16 μg, 18 μg, or less than about 20 μg. The amount of residual drug may be 70% or less of the initial drug load.

[0186] A method of treating a stenosis in a non-vascular body lumen includes flushing the non-vascular body lumen with water, a saline solution, or an aqueous solution comprising at least one water soluble additive, and inserting a balloon catheter into a target site of the stenosis in the non-vascular body lumen, the balloon catheter comprising a balloon and a coating layer covering an exterior surface of the balloon, the coating layer comprising at least one water soluble additive and an initial drug loading amount of a therapeutic agent, the therapeutic agent being selected from paclitaxel, taxol, docetaxel, analogs thereof, rapamycin, sirolimus, zotarolimus, everolimus and analogs thereof, and combinations thereof, the water soluble additive being selected from N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, glyceryl-2-phosphate dehydrogenase ... N-Hexanoyl-D-Sphingosine, N-Octanoyl-D-Sphingosine, N-Lauroyl-D-Sphingosine, N-Palmitoyl-D-Sphingosine, N-Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG 8 Caprylic / Capric Glyceride, PEG Caprylate, PEG 8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Monocapric Acid Glyceryl stearate, 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, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerol ethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5, 12-crown-4 and combinations thereof) and inflating the balloon until the coating layer contacts the wall of the stenosis in the non-vascular body lumen at the target site and the balloon achieves an inflated balloon diameter for the inflation time, and after the inflation time, deflating the balloon (wherein the inflation time is 0.1 minutes to 10 minutes), and withdrawing the balloon catheter from the stenosis in the non-vascular body lumen. In one embodiment, the balloon diameter is 10 mm at a nominal inflation pressure of 6 atmospheres. The ratio of the inflated balloon diameter to the untreated diameter at the target site of the body cavity may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment site may be about 1.0 to about 40 or about 4 to about 40. Optionally, the inflation may include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0187] The balloon may have a residual drug amount thereon after withdrawal. A suitable residual drug amount may remain after withdrawal, for example, greater than, equal to or less than about 70 wt%, 65 wt%, 60 wt%, 55 wt%, 50 wt%, 45 wt%, 40 wt%, 35 wt%, 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 5 wt%, or about 0 wt%.

[0188] 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 less than, equal to, greater than or equal to about 0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about 3, about 2 to about 6, or less than about 0.05 or less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20.

[0189] In various embodiments, the coating layer may include one or more water soluble additives and an initial drug loading of a therapeutic agent, the therapeutic agent being selected from paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, mTOR inhibitors, analogs thereof, and combinations thereof, and the water soluble additives being N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihybrid. D-C6-Ceramide, Cerebroside, Sphingomyelin, Galactocerebroside, Lactocerebroside, N-Acetyl-D-Sphingosine, N-Hexanoyl-D-Sphingosine, N-Octanoyl-D-Sphingosine, N-Lauroyl-D-Sphingosine, N-Palmitoyl-D-Sphingosine, N-Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG 8 Caprylic / Capric Glyceride, PEG Caprylate, PEG 8 Caprylate, PEG Caprate , PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monocaproate, 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, caffeine, allantoin In some embodiments, the aryl ethers are selected from the group consisting of aryl ethers, (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, and combinations thereof.

[0190] In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter at the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stenosis or target site.

[0191] The method for treating at least one of benign prostatic hyperplasia and prostatic cancer may include, optionally, flushing the prostate with water, a saline solution, or an aqueous solution containing at least one water-soluble additive; inserting a balloon catheter including a balloon and a coating layer covering the outer surface of the balloon into a target site in the prostate; and positioning the balloon body within the prostate and over the external urethral sphincter such that the balloon neck is at the bladder neck when the balloon is inflated. The method may include inflating the balloon until the coating layer contacts the wall of the benign prostatic hyperplasia or prostatic cancer at the target site, enlarging the prostatic division, creating a commissure incision, and the balloon achieves the inflated balloon diameter for the inflation period; deflating the balloon after the inflation period, which is 0.1 minutes to 10 minutes; and withdrawing the balloon catheter from the prostate. The ratio of the inflated balloon diameter to the untreated lumen diameter of the target site may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment site may be about 1.0 to about 40 or about 4 to about 40. Optionally, inflation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter. In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter at the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after balloon deflation, or any combination thereof. The method can include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stenosis or target site.

[0192] A method of treating an achalasia stricture may include optionally flushing the achalasia stricture with water, a saline solution, or an aqueous solution containing at least one water-soluble additive; inserting a balloon catheter including a balloon and a coating layer covering the outer surface of the balloon into a target site in the esophagus; positioning the balloon body in the esophagus and on the esophageal sphincter such that the balloon neck is at the lower esophageal sphincter when the balloon is inflated and the distal segment of the balloon is at the top of the stomach. The method may include inflating the balloon until the coating layer contacts the wall of the achalasia stricture at the target site and achieves an inflated balloon diameter for the inflation period; deflating the balloon after the inflation period, which may be 0.1 minutes to 10 minutes; and withdrawing the balloon catheter from the esophagus. The ratio of inflated balloon diameter to untreated lumen diameter at the target site may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment site may be about 1.0 to about 40 or about 4 to about 40. In some cases, the achalasia stricture may be pre-dilated with a balloon without a coating layer, which may be smaller than the nominal diameter of the treatment balloon. Optionally, the dilation may include dilating to a pressure equal to or exceeding the nominal pressure of the balloon catheter. The balloon catheter may include one or more necks as shown in Figures 1A-1C and 2. In various embodiments, the neck of the balloon may be positioned at the lower esophageal sphincter with one or more balloon lobes distal to the neck in the stomach and one or more balloon lobes proximal to the neck in the esophagus.

[0193] A method of treating a urethral stricture includes flushing the urethral stricture with water, a saline solution, or an aqueous solution comprising at least one water-soluble additive; inserting a balloon catheter comprising a balloon and a coating layer covering an outer surface of the balloon into a target site at the urethral stricture, wherein the coating layer comprises at least one water-soluble additive and an initial drug loading amount of a therapeutic agent; and a weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water-soluble additives in the coating layer is about 0.05-20; 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; deflating the balloon after an inflation period that is 0.1 minutes to 10 minutes; and withdrawing the balloon catheter from the urethral stricture. The ratio of the inflated balloon diameter to the untreated diameter of the body lumen at the site of the urethral stricture may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment site may be about 1.0 to about 40 or about 4 to about 40. After dilation, the diameter of the urethral stricture can be 6.7 mm or more, e.g., from about 6.7 mm to about 50 mm, or from about 6.7 mm to about 20 mm, or about 6.7 mm, 6.8 mm, 6.9 mm, 7.0 mm, 7.2 mm, 7.4 mm, 7.6 mm, 7.8 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or less than, equal to, greater than, or about 50 mm or more. Optionally, dilation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0194] In some embodiments, the balloon has a residual drug load after withdrawal that is less than 70% of the initial drug load.

[0195] A method of treating an esophageal stricture may include optionally flushing the esophageal stricture with water, a saline solution, or an aqueous solution comprising at least one water soluble additive; inserting a balloon catheter comprising a balloon and a coating layer covering an exterior surface of the balloon to a target site in the esophageal stricture, wherein the coating layer comprises at least one water soluble second additive and a therapeutic agent, the therapeutic agent being at an initial drug loading of 1-6 micrograms of therapeutic agent per square millimeter of the balloon; the therapeutic agent is selected from paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, an mTOR inhibitor or analogs thereof, and combinations thereof;Water-soluble additives include N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N -Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG8 Caprylic / Capric Glyceride, PEG Caprylate, PEG8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, Monolaurin, Monocaprin, Monocaprylin, Monomyristin, Monopalmitolein, Monoolein, Creatine, Creatinine, Agmatine, Citrulline, Guanidine, Sucralose, Aspartate , 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, trimethylol propane and wherein the weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer is about 0.05 to 20; 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; deflating the balloon after the inflation period, which is 0.1 minutes to 10 minutes;and withdrawing the balloon catheter from the esophageal stricture. The ratio of inflated balloon diameter to untreated diameter of the esophagus at the location of the stricture may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment location may be about 1.0 to about 40 or about 4 to about 40. In some cases where severe strictures are present, it may not be possible to inflate the balloon to the untreated lumen diameter, and the balloon may achieve an expansion ratio of 0.7, 0.8, 0.9 or more. Optionally, the inflation may include inflation to a pressure equal to or exceeding the nominal pressure of the balloon catheter;

[0196] Eosinophilic esophagitis (EoE) is a chronic inflammatory disease. Symptoms of the disease include dysphagia and food impaction, which often result in esophageal stricture or narrowing. Repeated endoscopic dilatation of esophageal fibrostenosing eosinophilic esophagitis strictures using bougies and balloon catheters is required to treat the esophageal strictures of EoE.

[0197] A method of treating an esophageal stricture in eosinophilic esophagitis includes optionally flushing the esophageal stricture with water, a saline solution, or an aqueous solution comprising at least one water soluble additive; inserting a balloon catheter comprising a balloon and a coating layer covering an exterior surface of the balloon to a target site in the esophageal stricture, wherein the coating layer comprises at least one water soluble additive and a therapeutic agent at an initial drug loading of 1-6 micrograms of therapeutic agent per square millimeter of the balloon; the therapeutic agent is selected from paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, an mTOR inhibitor or analogs thereof, and combinations thereof;Water-soluble additives include N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N -Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG8 Caprylic / Capric Glyceride, PEG Caprylate, PEG8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, Monolaurin, Monocaprin, Monocaprylin, Monomyristin, Monopalmitolein, Monoolein, Creatine, Creatinine, Agmatine, Citrulline, Guanidine, Sucralose, Aspartate , 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, trimethylol propane and wherein the weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer is about 0.05 to 20; 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; deflating the balloon after the inflation period, which is 0.1 minutes to 10 minutes;and withdrawing the balloon catheter from the esophageal stricture of eosinophilic esophagitis. The ratio of inflated balloon diameter to untreated diameter of the esophagus at the location of the stricture may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment location may be about 1.0 to about 40 or about 4 to about 40. In some cases where severe strictures are present, it may not be possible to inflate the balloon to the untreated lumen diameter, and the balloon may achieve an expansion ratio of 0.7, 0.8, 0.9 or more. In some cases, the esophageal stricture may be predilated with a balloon without a coating layer, which may be smaller than the nominal diameter of the treatment balloon. Optionally, the inflation may include inflation to a pressure equal to or exceeding the nominal pressure of the balloon catheter.;

[0198] Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC). CD- and UC-induced strictures are common complications of inflammatory bowel disease (IBD) and its associated surgeries. Stenosis rates can range from 34% to 70% over time. A portion of strictures are refractory or recurrent. Using prior art techniques, repeated endoscopic dilation is necessary to treat refractory or recurrent strictures.

[0199] A method for treating inflammatory bowel strictures in Crohn's disease (CD) and ulcerative colitis (UC) comprises optionally flushing the inflammatory bowel stricture with water, a saline solution, or an aqueous solution comprising at least one water soluble additive; inserting a balloon catheter into a target site for inflammatory bowel stricture treatment, the balloon catheter comprising a balloon and a coating layer covering an outer surface of the balloon, wherein the coating layer comprises at least one water soluble additive and a therapeutic agent, the initial drug loading being between 1 and 6 micrograms of therapeutic agent per square millimeter of the balloon; the therapeutic agent being selected from paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, an mTOR inhibitor or analogs thereof, and combinations thereof;Water-soluble additives include N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N -Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG8 Caprylic / Capric Glyceride, PEG Caprylate, PEG8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, Monolaurin, Monocaprin, Monocaprylin, Monomyristin, Monopalmitolein, Monoolein, Creatine, Creatinine, Agmatine, Citrulline, Guanidine, Sucralose, Aspartate , hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerol ethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5, 12-crown-4 and combinations thereof; and a weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer is about 0.05 to 20; inflating the balloon until the coating layer contacts the wall of the inflammatory bowel stricture at the target site and achieves an inflated balloon diameter for an inflation period; deflating the balloon after the inflation period, which is 0.1 minutes to 10 minutes;and withdrawing the balloon catheter from the inflammatory bowel stricture. The ratio of inflated balloon diameter to untreated diameter of the inflammatory bowel at the location of the stricture may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment location may be about 1.0 to about 40 or about 4 to about 40. In some cases where severe strictures are present, it may not be possible to inflate the balloon to the untreated lumen diameter, and the balloon may achieve an expansion ratio of 0.7, 0.8, 0.9 or more. In some cases, the stricture may be pre-dilated with a balloon without a coating layer, which may be smaller than the nominal diameter of the treatment balloon. Optionally, the inflation may include inflation to a pressure equal to or exceeding the nominal pressure of the balloon catheter. Inflammatory bowel stenosis in Crohn's disease (CD) and ulcerative colitis (UC) includes small intestinal stenosis, duodenal stenosis, jejunal stenosis, ileal stenosis, colonic stenosis, rectal stenosis, large intestinal stenosis, colorectal stenosis, post-gastric bypass stenosis, ileocolic stenosis, digestive stenosis and J-pouch colonic stenosis. Although balloon dilation has been shown to be a safe and effective non-surgical method for treating inflammatory bowel stenosis in Crohn's disease (CD) and ulcerative colitis (UC), problems remain. Stenosis may be refractory or recurrent stenosis, requiring repeated balloon dilation using techniques in the prior art. In another embodiment, the method for treating inflammatory bowel stenosis in Crohn's disease (CD) and ulcerative colitis (UC) includes performing a stricture incision before drug-coated balloon inflation. Stenosis incision may include endoscopic mucosal resection, endoscopic submucosal dissection, needle knife electrodissection and electrocautery. In some embodiments, the method includes using a scope to visualize the insertion and placement of a drug-coated balloon catheter at the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, the creation of the target site, the release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stenosis or target site;

[0200] A method of treating radiation induced stenosis includes optionally flushing the radiation induced stenosis with water, a saline solution, or an aqueous solution comprising at least one water soluble additive; inserting a balloon catheter comprising a balloon and a coating layer covering an outer surface of the balloon into a target site in the radiation stenosis, wherein the coating layer comprises at least one water soluble additive and a therapeutic agent at an initial drug loading of 1-6 micrograms of therapeutic agent per square millimeter of balloon; the therapeutic agent is selected from paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, an mTOR inhibitor or analogs thereof, and combinations thereof;Water-soluble additives include N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N -Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG8 Caprylic / Capric Glyceride, PEG Caprylate, PEG8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, Monolaurin, Monocaprin, Monocaprylin, Monomyristin, Monopalmitolein, Monoolein, Creatine, Creatinine, Agmatine, Citrulline, Guanidine, Sucralose, Aspartate , 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, the weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer is about 0.05 to 20; inflating the balloon until the coating layer contacts the wall of the radiation induced stenosis at the target site and achieves an inflated balloon diameter for an inflation period; deflating the balloon after the inflation period, which is 0.1 minutes to 10 minutes;and withdrawing the balloon catheter from the radiation-induced stenosis. The ratio of inflated balloon diameter to untreated diameter of the radiation lumen at the location of the stenosis may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment location may be about 1.0 to about 40 or about 4 to about 40. In some cases, the radiation-induced stenosis may be pre-dilated with a balloon without a coating layer, which may be smaller than the nominal diameter of the treatment balloon. Optionally, the dilation may include dilatation to a pressure equal to or exceeding the nominal pressure of the balloon catheter. Radiation-induced stenosis includes any stenosis induced by radiation injury from the treatment of cancer. Radiation stenosis may include urethral stenosis, ureteral stenosis, esophageal stenosis, paranasal sinus stenosis, gastric stenosis, small intestinal stenosis, colonic stenosis, rectal stenosis, large intestinal stenosis, and bile duct stenosis. In another embodiment, the method of treating a radiation stenosis includes performing a stricture resection prior to drug-coated balloon dilation. Stricture dissection may include urethrotomy, endoscopic mucosal resection, endoscopic submucosal dissection, needle knife electrodissection, transurethral internal urethrotomy (DVIU) and electrocautery. In some embodiments, the method includes using a scope to visualize the insertion and placement of a drug-coated balloon catheter into the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after balloon deflation, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stricture or target site;

[0201] A method of treating a surgical anastomotic stenosis may include optionally flushing the surgical anastomotic stenosis with water, a saline solution, or an aqueous solution containing at least one water soluble additive; inserting a balloon catheter comprising a balloon and a coating layer covering an outer surface of the balloon into a target site at the surgical anastomotic stenosis, wherein the coating layer comprises at least one water soluble additive and a therapeutic agent at an initial drug loading of 1 to 6 micrograms of therapeutic agent per square millimeter of the balloon; the therapeutic agent being selected from the group consisting of paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacro ... , everolimus, mTOR inhibitors or analogs thereof and combinations thereof; the water soluble additive is selected from N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-Palmitoyl-D-Sphingosine, N-Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG 8 Caprylic / Capric Glyceride, PEG Caprylate, PEG 8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, Monolaurin, Monocaprin, Monocaprylin, Monomyristin, Monopalmitolein, Monoolein, Creatine, Creatinine, Agmatine, Citrulline, Guanidine, Sucralose, Aspartame Thame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerol ethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate, pentaerythritol,dipentaerythritol, crown ether, 18-crown-6, 15-crown-5, 12-crown-4 and combinations thereof; and the weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer is about 0.05-20; inflating the balloon until the coating layer contacts the wall of the surgical anastomotic stenosis at the target site and achieves an inflated balloon diameter for an inflation period; deflating the balloon after an inflation period of 0.1 minutes to 10 minutes; and withdrawing the balloon catheter from the surgical anastomotic stenosis. The ratio of inflated balloon diameter to untreated diameter of the body lumen at the location of the stenosis may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment location may be about 1.0 to about 40 or about 4 to about 40. In some cases where severe stenosis is present, it may not be possible to inflate the balloon to the untreated lumen diameter, and the balloon may achieve an expansion ratio of 0.7, 0.8, 0.9 or more. In some cases, the anastomotic stricture may be pre-dilated with a balloon without a coating layer, which may be smaller than the nominal diameter of the treatment balloon. Optionally, the dilation may include dilating to a pressure equal to or exceeding the nominal pressure of the balloon catheter. Surgical anastomotic stricture includes any stricture of a surgical connection between two strictures of a body that carries fluid. Surgical anastomosis is a surgical technique used to create a new connection between two strictures of a body that carries fluid. Anastomotic stricture is a common complication of various surgical procedures. These strictures are mostly fibrotic and difficult to manage. Anastomotic strictures include esophageal strictures, bile duct strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, large intestinal strictures, colorectal strictures, post-gastric bypass strictures, ileocolic strictures, gastrointestinal strictures, urethral strictures, ureteral strictures, J-pouch strictures, and bladder neck strictures (strictures). Balloon dilation has been shown to be a safe and effective non-surgical method of managing surgical anastomotic strictures. Anastomotic strictures may be refractory or recurrent strictures that require repeated balloon dilation using techniques from the prior art. In other embodiments, the method of treating surgical anastomotic strictures includes performing a stricture incision prior to drug-coated balloon dilation. The stricture incision may be performed using techniques such as urethrotomy, endoscopic mucosal resection, endoscopic submucosal dissection, needle knife electrodissection,It may include transurethral intraurethral incision (DVIU) and electrocautery. In some embodiments, the method includes using a scope to visualize the insertion and placement of a drug-coated balloon catheter into the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stricture or target site.

[0202] Bladder neck stenosis (stricture or contracture) is a recognized complication of many treatments for prostate cancer. Resistant bladder neck stenosis is relatively rare overall; however, it is associated with significant morbidity and often involves complications and requires multiple interventions that affect quality of life. These bladder neck stenosis lesions are often complications following prostate cancer treatments, including radical prostatectomy (RP), radiation therapy, cryotherapy, and high intensity focused ultrasound (HIFU), and may develop following prostate procedures or due to other conditions.

[0203] A method of treating bladder neck stenosis (stricture or contracture) includes optionally flushing the bladder neck stenosis with water, a saline solution, or an aqueous solution comprising at least one water soluble additive; inserting a balloon catheter comprising a balloon and a coating layer covering an outer surface of the balloon to a target site in the bladder neck stenosis, wherein the coating layer comprises at least one water soluble additive and a therapeutic agent at an initial drug loading of 1-6 micrograms of therapeutic agent per square millimeter of balloon; the therapeutic agent is selected from paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, an mTOR inhibitor or analogs thereof, and combinations thereof;Water-soluble additives include N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N -Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG8 Caprylic / Capric Glyceride, PEG Caprylate, PEG8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, Monolaurin, Monocaprin, Monocaprylin, Monomyristin, Monopalmitolein, Monoolein, Creatine, Creatinine, Agmatine, Citrulline, Guanidine, Sucralose, Aspartate , hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerol ethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5, 12-crown-4 and combinations thereof; and a weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer is about 0.05 to 20; inflating the balloon until the coating layer contacts the wall of the bladder neck stenosis at the target site and achieves an inflated balloon diameter for an inflation period; deflating the balloon after the inflation period, which is 0.1 minutes to 10 minutes;The balloon catheter is then withdrawn from the bladder neck containing stenosis. The ratio of inflated balloon diameter to untreated diameter of the bladder neck at the location of the stenosis may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment location may be about 1.0 to about 40 or about 4 to about 40. In some cases where severe stenosis is present, it may not be possible to inflate the balloon to the untreated lumen diameter, and the balloon may achieve an expansion ratio of 0.7, 0.8, 0.9 or more. In some cases, the stenosis may be pre-dilated with a balloon without a coating layer, which may be smaller than the nominal diameter of the treatment balloon. Optionally, the inflation may include inflation to a pressure equal to or exceeding the nominal pressure of the balloon catheter. Bladder neck stenosis includes any narrowing of the surgical connection between the bladder and the prostate or urethral lumen. Bladder neck stenosis is a common complication of various surgical procedures, including radical prostatectomy (RP), radiation therapy, cryotherapy, and high intensity focused ultrasound (HIFU). These strictures are mostly fibrotic and difficult to manage. Bladder neck stenosis may be refractory or recurrent stenosis requiring repeated balloon dilation using prior art techniques. In another embodiment, the method of treating bladder neck stenosis includes performing a stricture dissection prior to drug-coated balloon dilation. The stricture dissection may include urethrotomy, endoscopic mucosal resection, endoscopic submucosal dissection, needle knife electrodissection, transurethral internal urethrotomy (DVIU) and electrocautery.;

[0204] EMR (endoscopic mucosal resection) and ESD (endoscopic submucosal dissection) in the treatment of various stages of cancer and Barrett's esophagus. Needle knife, EMR (endoscopic mucosal resection) and ESD (endoscopic submucosal dissection) are used to treat early stage superficial cancer. Cancer includes esophageal cancer, bile duct cancer, gastric cancer, small intestine cancer, duodenal cancer, jejunal cancer, ileal cancer, colon cancer, rectal cancer, colorectal cancer, ileocolonic cancer and gastrointestinal cancer. EMR (endoscopic mucosal resection) and ESD (endoscopic submucosal dissection) are used to treat advanced Barrett's esophagus disease. EMR and ESD are feasible techniques in terms of clinical efficacy and safety; however, recurrence of malignant tumors and refractory strictures has been shown in some patients. The local recurrence rate of treated cancer ranges from 2 to 20% depending on the type and stage of cancer and the number of follow-ups. The recurrence rate of stricture or stricture is about 26% to 70%. Repeated endoscopic balloon dilation is necessary for the treatment of refractory or recurrent stenosis or strictures using the techniques of the prior art.In various embodiments, the present invention reduces the recurrence of malignant tumors or cancers using drug-coated balloon dilation after EMR (endoscopic mucosal resection) and ESD (endoscopic submucosal dissection).In various embodiments, the present invention reduces the need for repeated balloon dilation of stenosis using drug-coated balloon dilation after EMR (endoscopic mucosal resection) or ESD (endoscopic submucosal dissection).

[0205] Methods are provided for reducing stenosis and cancer recurrence following needle knife, EMR (endoscopic mucosal resection) and ESD (endoscopic submucosal dissection) surgical procedures. The methods include performing endoscopic resection of a cancerous region of a body cavity using needle knife, EMR (endoscopic mucosal resection) and ESD (endoscopic submucosal dissection); optionally flushing the resected body cavity with water, saline solution or an aqueous solution containing at least one water-soluble additive; inserting a balloon catheter comprising a balloon and a coating layer covering the outer surface of the balloon into a target site in the resected body cavity, wherein the coating layer comprises at least one water-soluble second additive and a therapeutic agent with an initial drug loading of 1-6 micrograms of therapeutic agent per square millimeter of the balloon; the therapeutic agent is selected from paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, an mTOR inhibitor or analogs thereof and combinations thereof;Water-soluble additives include N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N- Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG8 Caprylic / Capric Glyceride, PEG Caprylate, PEG8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, 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, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerol ethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate, xylates, pentaerythritol, dipentaerythritol, crown ethers, 18-crown-6, 15-crown-5, 12-crown-4 and combinations thereof; and a weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer is about 0.05 to 20; inflating the balloon until the coating layer contacts the wall of the body cavity undergoing resection at the target site and achieves an inflated balloon diameter for an inflation period; deflating the balloon after the inflation period, which is 0.1 minutes to 10 minutes;and withdrawing the balloon catheter from the body cavity that underwent the ablation. The ratio of the inflated balloon diameter to the untreated diameter of the body cavity may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment location may be about 1.0 to about 40 or about 4 to about 40. In some cases, the stenosis may be pre-dilated with a balloon without a coating layer that may be smaller than the nominal diameter of the treatment balloon. Optionally, the dilation may include dilating to a pressure equal to or exceeding the nominal pressure of the balloon catheter. The length of the drug-coated balloon is longer than the length of the body cavity that underwent the ablation, and therefore the ablation area is completely covered with the drug formulation after balloon dilation. The length of the drug-coated balloon is 1 to 2 mm longer than the length of the body cavity that underwent the ablation. Two drug-coated balloons may be used to cover a lesion of greater length. The cancer may include esophageal cancer, bile duct cancer, stomach cancer, small intestine cancer, duodenal cancer, jejunal cancer, ileal cancer, colon cancer, rectal cancer, colorectal cancer, ileocolonic cancer, and gastrointestinal cancer, especially those in the early stages of cancer. The recurrence of cancer and strictures may increase as the area and depth of the body cavity resection increases. In some embodiments, the method includes using a scope to visualize the insertion and placement of a drug-coated balloon catheter into the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after balloon deflation, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope before inserting the balloon catheter into the stricture or target site.;

[0206] A method for reducing recurrence of strictures, colonic polyps or Barrett's esophagus following needle knife, EMR (endoscopic mucosal resection) and ESD (endoscopic submucosal dissection) surgical procedures includes first performing an endoscopic resection of a colonic polyp or Barrett's area of ​​a body cavity using needle knife, EMR (endoscopic mucosal resection) or ESD (endoscopic submucosal dissection); optionally flushing the resected body cavity with water, saline solution or an aqueous solution containing at least one water soluble additive; inserting a balloon catheter comprising a balloon and a coating layer covering an outer surface of the balloon into a target site in the resected body cavity, wherein the coating layer comprises at least one water soluble second additive and a therapeutic agent with an initial drug loading of 1-6 micrograms of therapeutic agent per square millimeter of the balloon; the therapeutic agent is selected from paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, an mTOR inhibitor or analogs thereof and combinations thereof;Water-soluble additives include N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N- Oleoyl-D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG8 Caprylic / Capric Glyceride, PEG Caprylate, PEG8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, 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, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerol ethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate, xylates, pentaerythritol, dipentaerythritol, crown ethers, 18-crown-6, 15-crown-5, 12-crown-4 and combinations thereof; and a weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer is about 0.05 to 20; inflating the balloon until the coating layer contacts the wall of the body cavity undergoing resection at the target site and achieves an inflated balloon diameter for an inflation period; deflating the balloon after the inflation period, which is 0.1 minutes to 10 minutes;and withdrawing the balloon catheter from the resected body cavity. The ratio of inflated balloon diameter to untreated diameter of the body cavity may be about 1.0 to about 40 or about 4 to about 40, and the stretch ratio at the treatment location may be about 1.0 to about 40 or about 4 to about 40. If severe stenosis is present, it may not be possible to inflate the balloon to the untreated lumen diameter, and the balloon may achieve an expansion ratio of 0.7, 0.8, 0.9 or more. In some cases, the stenosis may be pre-dilated with a balloon without a coating layer, which may be smaller than the nominal diameter of the treatment balloon. Optionally, the dilation may include dilating to a pressure equal to or exceeding the nominal pressure of the balloon catheter. The length of the drug-coated balloon is longer than the length of the resected body cavity, and therefore the resected area is completely covered with the drug formulation after balloon dilation. The length of the drug-coated balloon is 1 to 2 mm longer than the length of the resected body cavity. Recurrence of polyps or Barrett's esophagus and strictures may increase as the resection area and depth of the body cavity increase.;

[0207] A method of treating a sinus stenosis includes flushing the sinus stenosis with water, a saline solution, or an aqueous solution comprising at least one water soluble additive; inserting a balloon catheter comprising a balloon and a coating layer covering an exterior surface of the balloon into a target site in the sinus stenosis, wherein the coating layer comprises at least one water soluble additive and a therapeutic agent at an initial drug loading of 1-6 micrograms of therapeutic agent per square millimeter of the balloon; the therapeutic agent is selected from budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cortisone, betamethasone, triamcinolone acetonide, paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, an mTOR inhibitor, analogs thereof, and combinations thereof;The water-soluble additives are N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octanoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N-oleoyl- D-Sphingosine, PEG Caprylic / Capric Diglyceride, PEG 8 Caprylic / Capric Glyceride, PEG Caprylate, PEG 8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, Monolaurin, Monocaprin, Monocaprylin, Monomyristin, Monopalmitolein, Monoolein, Creatine, Creatinine, Agmatine, Citrulline, Guanidine, Sucralose, Aspartame, Hypoxanthine, Theobromine amine, 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, the weight ratio of the therapeutic agent in the coating layer to the total weight of the one or more water soluble additives in the coating layer is about 0.05 to 20; inflating the balloon until the coating layer contacts the wall of the sinus stenosis at the target site and achieves an inflated balloon diameter for an inflation period; deflating the balloon after the inflation period, which is 0.1 minutes to 10 minutes; and withdrawing the balloon catheter from the sinus stenosis.

[0208] In some embodiments, the method includes using a scope to visualize the insertion and placement of the drug-coated balloon catheter at the target site, the inflation and deflation steps, the increase in diameter during balloon inflation, the decrease in diameter during balloon deflation, securing the target site, the release of drug from the wall of the target site after the balloon is deflated, or any combination thereof. The method may include flushing the target site with water or saline solution through the scope prior to inserting the balloon catheter into the stenosis or target site.

[0209] additives In various embodiments, the additive may have two parts. One part is hydrophilic and the other part is a drug affinity part. The drug affinity part has affinity for the therapeutic agent by hydrophobic part and / or hydrogen bond and / or van der Waals interaction. The drug affinity part of the additive may bind lipophilic drugs such as paclitaxel, taxol, docetaxel, rapamycin, sirolimus, zotarolimus, tacrolimus, everolimus, mTOR inhibitors or their analogs and combinations. The hydrophilic part may accelerate diffusion and increase the penetration of the drug into tissue. It may promote the movement of the drug off the medical device during placement at the target site by preventing hydrophobic drug molecules from aggregating with each other and the device, increasing the drug solubility in the interstitial space, and / or accelerating the drug to move through the lumen to the lipid bilayer of the cell membrane of the target tissue by polar end groups. The additive of an embodiment of the present invention has two parts that function together to prevent premature release of the drug from the device surface prior to device deployment at the target site, while promoting rapid release of the drug from the device surface during deployment and uptake by the target tissue (by accelerating the drug's contact with tissues for which it has a high affinity).

[0210] In the embodiments of the present invention, the therapeutic agent is released quickly after the medical device contacts tissue and is easily absorbed. For example, some embodiments of the device of the present invention include a drug-coated balloon catheter that delivers therapeutic agents such as lipophilic antiproliferative drugs (e.g., paclitaxel or rapamycin) to nonvascular tissues by simple direct pressure contact at high drug concentration during nonvascular balloon expansion. The lipophilic drug is retained in the target tissue at the delivery site, for example, where it prevents hyperplasia and restenosis while still allowing epithelialization. In these embodiments, the coating formulation of the present invention not only promotes the rapid release of drug from the balloon surface during deployment and the movement of drug to the target tissue, but also prevents the drug from being expelled from the device and the device from bursting during the initial phase of balloon expansion before the drug reaches the target site via transport through complex internal structures and the drug coating is pressed into direct contact with the surface of the body cavity.

[0211] In some embodiments, the additive has a drug affinity portion and a hydrophilic portion. The drug affinity portion is a hydrophobic portion and has affinity for the therapeutic agent through hydrogen bonds and / or van der Waals interactions. The drug affinity portion may 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 and lipids of cell membranes that share structural similarities. The drug affinity portion may include functional groups that can form hydrogen bonds with the drug and with itself. The hydrophilic portion may include hydroxyl groups, amine groups, amide groups, carbonyl groups, carboxylic acids and anhydrides, ethyl oxides, ethyl glycols, polyethylene glycols, ascorbic acid, amino acids, amino alcohols, glucose, sucrose, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic salts, and substituted molecules thereof, and the like. One or more hydroxyl, carboxyl, acid, amide or amine groups can be advantageous, for example, because they can easily displace the water molecules that are hydrogen-bonded to polar end group moieties and surface proteins of cell membranes, and function to remove this barrier between hydrophobic drugs and cell membrane lipids.These moieties can dissolve in water and polar solvents.The additive of the present invention has components that bind to drugs and release them during both placement and their rapid transfer from medical device to target tissue.

[0212] The additive of the present invention can be a surfactant and a compound having one or more of hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties. The surfactant includes ionic, non-ionic, aliphatic and aromatic surfactants. The compound having one or more of hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties is selected from amino alcohols, hydroxyl carboxylic acids and anhydrides, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins and substituted molecules thereof.

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

[0214] An empirical parameter commonly used in medicinal chemistry to characterize the relative hydrophilicity and hydrophobicity of pharmaceutical compounds is the partition coefficient P, e.g., P=([solute]octanol / [solute]water), which is the concentration ratio of a non-ionized compound in two phases of a mixture of two immiscible solvents, usually octanol and water. Compounds with high logP are more hydrophobic, and compounds with low logP are more hydrophilic. Lipinski's law indicates that pharmaceutical compounds with logP<5 may be more membrane permeable. For the purposes of certain embodiments of the present invention, for example, the additive has a logP smaller than the logP of the drug to be formulated (for example, the logP of paclitaxel is 7.4). The greater the difference between the logP of the drug and the additive, the greater the phase separation of the drug may be promoted. For example, if the logP of the additive is much smaller than the logP of the drug, the additive can promote the release of the drug into the aqueous environment from the device surface to which the drug would otherwise be intimately attached, thereby promoting drug delivery to tissue during short placement at the intervention site. In some embodiments of the invention, the logP of the additive is negative. In other embodiments, the logP of the additive is less than the logP of the drug. The octanol-water partition coefficient P or logP of a compound is useful for measuring the relative hydrophilicity and hydrophobicity, but is only a rough guide as to the definition of a suitable additive for use in embodiments of the invention.

[0215] Suitable additives that may be used in embodiments of the present invention include, but are not limited to, organic and inorganic pharmaceutical recipients, natural products and their 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 being useful in the present invention are provided for illustrative purposes only and are not intended to be comprehensive. Many other additives may be useful for purposes of the present invention.

[0216] Surfactants The surfactant may be any surfactant suitable for use in pharmaceutical compositions. Such surfactants may be anionic, cationic, amphoteric 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 and form part of the lipid structure, while other components of the surfactant loosen the lipid structure and facilitate drug penetration and absorption. The contrast agent iopromide does not have these properties.

[0217] A commonly used empirical parameter for characterizing the relative hydrophilicity and hydrophobicity of surfactants is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with low HLB values ​​are more hydrophobic and have greater solubility in oil, while surfactants with high HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Using HLB values ​​as a rough guide, hydrophilic surfactants are generally compounds with HLB values ​​greater than about 10, with the HLB scale generally considered inapplicable to anionic, cationic or amphoteric compounds. Similarly, hydrophobic surfactants are compounds with HLB values ​​less than about 10. In certain embodiments of the present invention, high HLB values ​​are utilized because increased hydrophilicity can promote hydrophobic drug release from the surface of the device. In certain embodiments, the HLB of the surfactant additive is greater than 10. The additive HLB can be greater than 14. Alternatively, surfactants with low HLB can be used to prevent drug loss prior to device placement at the target site, for example in a top coat covering a drug layer with a superhydrophilic additive.

[0218] The HLB value of surfactant is generally only a rough guideline used to enable the formulation of, for example, industrial, pharmaceutical and cosmetic emulsions.It has been reported that for many important surfactants, including some polyethoxylated surfactants, the HLB value can vary as much as about 8 HLB units depending on the experimental method selected for determining the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)).With these difficulties in mind, using the HLB value as a guideline, surfactants can be identified as having suitable hydrophilicity or hydrophobicity for use in the embodiments of the present invention, as described herein.

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

[0220] Polyethylene glycol fatty acid diesters are also suitable for use as surfactants in the compositions of the present 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] In general, mixtures of surfactants, including mixtures of two or more commercially available surfactants, and mixtures of a surfactant and one or more other additives, are also useful in embodiments of the present invention.Several PEG-fatty acid esters are commercially available as mixtures of mono- and diesters.

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

[0223] Alcohol-oil transesterification products Many surfactants with varying degrees of hydrophobicity or hydrophilicity can be produced by the reaction of alcohols or polyalcohols with a variety of natural and / or hydrogenated oils. 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 glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol and pentaerythritol. Among these alcohol-oil ester-transfer surfactants, the hydrophilic surfactants are PEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT TM 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), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic / capric glyceride (Labrasol) and PEG-6 caprylic / capric glyceride (Softigen 767). For example, hydrophobic surfactants in this group include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil TM M 2125 CS), PEG-6 almond oil (Labrafil TM M 1966 CS), PEG-6 apricot kernel oil (Labrafil TM M 1944 CS), PEG-6 olive oil (Labrafil TM M 1980 CS), PEG-6 peanut oil (Labrafil TM M 1969 CS), PEG-6 hydrogenated palm kernel oil (Labrafil TM M 2130 BS), PEG-6 palm kernel oil (Labrafil TM M 2130 CS), PEG-6 triolein (Labrafil TM b M 2735 CS), PEG-8 corn oil (Labrafil TMWL 2609 BS), PEG-20 corn glycerides (Crovol M40) and PEG-20 almond glycerides (Crovol A40).

[0224] Polyglyceryl Fatty Acids Polyglycerol esters of fatty acids are also suitable surfactants for use in the present embodiment. Among the polyglycerol fatty acid esters, hydrophobic surfactants include polyglycerol oleate (Plurol Oleique), polyglycerol-2 dioleate (Nikkol DGDO), polyglycerol-10 trioleate, polyglycerol stearate, polyglycerol laurate, polyglycerol myristate, polyglycerol palmitate, and polyglycerol linoleate. Hydrophilic surfactants include polyglycerol-10 laurate (Nikkol Decaglyn 1-L), polyglycerol-10 oleate (Nikkol Decaglyn 1-O), and polyglycerol-10 mono, dioleate (CaproI). TM Polyglycerol polyglycerol oleate (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 group, hydrophobic surfactants include propylene glycol monolaurate (Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propylene glycol monooleate (Myverol P-06), propylene glycol dicaprylate / dicaprate (Captex TM200) and propylene glycol dioctanoate (Captex TM 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 group 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 the PEG-sorbitan fatty acid esters, the surfactants include PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitan monooleate (Tween-80). In some embodiments, laurate esters are used because they have shorter lipid chains compared to oleate esters, which increases drug absorption.

[0228] Polyethylene glycol alkyl ether Ethers of polyethylene glycols and alkyl alcohols are suitable surfactants for use in embodiments of the present invention. The ethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij 30).

[0229] Sugar and its derivatives Sugar derivatives are suitable surfactants for use in embodiments of the present invention. Surfactants in this group 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, heptanonyl-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.

[0230] 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, nonoxynol, and the like.

[0231] Polyoxyethylene-Polyoxypropylene (POE-POP) Block Copolymer POE-POP block copolymers are a unique group of polymeric surfactants. The unique structure of the surfactants, with well-defined ratios and positions of hydrophilic POE and hydrophobic POP moieties, provides a wide range of surfactants suitable for use in embodiments of the present invention. These surfactants are available under a variety of trade names, including the Synperonic PE series (ICI); Pluronic TM 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(C 2 H 4 O) a (C 3 H 6 O)b (C 2 H 4 O) a H, where "a" and "b" refer to the number of polyoxyethylene and polyoxypropylene units, respectively.

[0232] Hydrophilic surfactants in this group include poloxamers 108, 188, 217, 238, 288, 338, and 407. Hydrophobic surfactants in this group include poloxamers 124, 182, 183, 212, 331, and 335.

[0233] 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.

[0234] Sorbitan monopalmitate, an amphiphilic derivative of vitamin C (with vitamin C activity), may serve two important functions in solubilized systems. First, it has effective polar groups that can modulate the microenvironment. These polar groups are the same groups that make vitamin C itself (ascorbic acid) the most water-soluble organic solid compound available, with ascorbic acid being soluble in water at about 30 wt / wt% (e.g., very close to the solubility of sodium chloride). Second, it converts a fraction of the ascorbyl palmitate to more soluble salts, such as sodium ascorbyl palmitate, when the pH is increased.

[0235] Ionic Surfactants Ionic surfactants, including cationic, anionic and amphoteric surfactants, are suitable hydrophilic surfactants for use in the embodiments of the present invention. Ionic surfactants include quaternary ammonium salts, fatty acid salts and bile salts. Specifically, ionic surfactants include benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, docetylitrimethylammonium bromide, sodium docetylsulfate, dialkylmethylbenzylammonium chloride, edrophonium chloride, domiphen bromide, dialkyl esters of sodium sulfonosuccinic acid, dioctyl sodium sulfosuccinate, sodium cholate and sodium taurocholate. They are soluble in both organic solvents (e.g. ethanol, acetone and toluene) and water. This is particularly useful for medical device coating, as it simplifies the preparation and coating process and has good adhesive properties. Water-insoluble drugs are generally soluble in organic solvents.

[0236] Some of the surfactants described herein are extremely 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 utilized because they are less likely to react with drugs, while amine and acid groups react with paclitaxel or rapamycin during sterilization. Additionally, the addition of surfactants improves the integrity and quality of the coating layer so that particles do not fall off during handling. When formulated with paclitaxel, the surfactants described herein protect against premature release of the drug during the device delivery process while promoting rapid release and elution of paclitaxel during extremely short retention times of 0.2 to 10 minutes at the target site in experimental studies. Drug absorption by tissues at the target site is unexpectedly high in experimental studies.

[0237] A chemical compound that has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties Compounds having one or more of a hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moiety 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-Acetylglucosamine, N-Octyl-D-gluconamide, C6-ceramide, Dihydro-C6-ceramide, Cerebroside, Sphingomyelin, Galactocerebroside, Lactocerebroside, N-Acetyl-D-sphingosine, N-Hexanoyl-D-sphingosine, N-Octanoyl-D-sphingosine, N-Lauroyl-D-sphingosine, N-Palmitoyl-D-sphingosine, N-Oleoyl-D-sphingosine Gosine, PEG caprylic / capric diglyceride, PEG 8 caprylic / capric glyceride, PEG caprylate, PEG 8 caprylate (e.g., Labrasol®), PEG caprate, PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monocaproate, monolaurin, monocaprin, monocaprylin, monomyristin, monopalmitolein, and monoolein.

[0238] Compounds having one or more of a hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moiety include amino alcohols, hydroxyl carboxylic acids, esters, anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids and substituted molecules thereof. Compounds having one or more of a hydrophilic hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moiety with a molecular weight of less than 5,000-10,000 are utilized in certain embodiments. In other embodiments, the molecular weight of the additive having one or more of a hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moiety is less than 1000-5,000 or less than 750-1,000 or less than 750. In these embodiments, the molecular weight of the additive must be less than the drug to be delivered. Additionally, the molecular weight of the additive must be higher than 80, as molecules with molecular weights below 80 volatilize very easily and do not remain in the coating of the medical device. Small molecules can diffuse quickly; as such, they can be easily released from the delivery balloon, accelerating the release of the drug, and can diffuse away from the drug when it binds to the tissue of the body cavity.

[0239] In some embodiments, for example, in the case of high molecular weight additives, additives with more than 4 hydroxyl groups are utilized. Large molecules diffuse slowly. If the molecular weight of the additive or compound is high, for example, if the molecular weight is more than 800, more than 1000, more than 1200, more than 1500, or more than 2000, the large molecule may dissolve on the surface of the medical device too slowly to release the drug within 2 minutes. If these large molecules have more than 4 hydroxyl groups, the hydrophilic nature increases, which is necessary for relatively large molecules to release the drug quickly. The increased hydrophilicity helps the coating to dissolve from the balloon, accelerates the release of the drug, and promotes drug migration through the water barrier and the polar head of the lipid bilayer to penetrate the tissue. In some embodiments, hydroxyl groups are utilized as hydrophilic moieties because they are less likely to react with water-insoluble drugs such as paclitaxel or rapamycin. In some embodiments, compounds with more than 4 hydroxyl groups have a melting point of 120°C or less. In some embodiments, compounds with more than four hydroxyl groups have three adjacent hydroxyl groups, all of which are in the configuration on one side of the molecule.For example, sorbitol and xylitol have three adjacent hydroxyl groups, all of which are in the configuration on one side of the molecule, while galactitol does not.This difference affects the physical properties of isomers, such as melting temperature.The configuration of three adjacent hydroxyl groups can enhance drug binding.This leads to improved compatibility of water-insoluble drugs and hydrophilic additives and improved tissue uptake and absorption of drugs.

[0240] Some of the compounds described herein that have one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties are extremely stable under heating. They survive ethylene oxide sterilization and do not react with the water-insoluble drugs paclitaxel or rapamycin during sterilization. On the other hand, L-ascorbic acid and its salts and diethanolamine do not necessarily survive such sterilization and react with paclitaxel. Therefore, different sterilization methods are used for L-ascorbic acid and diethanolamine. For example, hydroxyl, ester and amide groups are used because they are less likely to react with therapeutic agents such as paclitaxel or rapamycin. Occasionally, amine and acid groups react with paclitaxel, for example, experimentally, benzoic acid, gentisic acid, diethanolamine and ascorbic acid are not stable under ethylene oxide sterilization, heating and aging processes and react with paclitaxel. When the compounds described herein are formulated with paclitaxel, a topcoat layer may be advantageous to protect against premature drug loss during the device delivery process prior to deployment at the target site, as sometimes hydrophilic small molecules release the drug too easily. The compounds described herein release the drug rapidly from the balloon during deployment at the target site. Surprisingly, even if some drug is lost during delivery of the device to the target site, experimental drug absorption by tissue is unexpectedly high when the coating contains these additives, e.g., additive hydroxylactones such as ribonucleic acid lactone and gluconolactone, after only 0.2-10 minutes of deployment.

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

[0242] 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 is water-soluble at physiological pH, but 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 by well-known chemical reactions with hydrophilic molecules.

[0243] Water-soluble vitamins and their amphiphilic derivatives Vitamins B, C, U, pantothenic acid, folic acid and some of the menadione related vitamins / provitamins are considered water-soluble vitamins in most of their various forms. They can also be conjugated or complexed with hydrophobic moieties or polyvalent ions to make them amphiphilic forms with relatively high octanol-water partition coefficients and polar groups. Similarly, such compounds can be of low toxicity and high benefit-to-risk ratios, 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, but are not limited to, 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.

[0244] Compounds in which an amino or other basic group is present can be easily modified by simple acid-base reactions with hydrophobic group-containing acids such as fatty acids (especially lauric, oleic, myristic, palmitic, stearic or 2-ethylhexanoic acids), low solubility amino acids, benzoic, salicylic or acidic fat-soluble vitamins (e.g. riboflavin). Other compounds can be obtained by reacting such acids with other groups of vitamins, such as hydroxyl groups, to form bonds such as ester bonds. Derivatives of water-soluble vitamins with acidic groups can be reacted with hydrophobic group-containing reactants such as stearylamine or riboflavin to produce compounds that are useful, for example, in embodiments of the present invention. Attachment of a palmitate chain to vitamin C results in ascorbyl palmitate.

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

[0246] Certain amino acids, in zwitterionic form and / or salt form 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 present description, we interpret "low solubility amino acids" to mean amino acids that have a solubility of less than about 4% (40 mg / mL) in unbuffered water. These include cysteine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine.

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

[0248] Catecholamines such as dopamine, levodopa, carbidopa and DOPA are also useful as additives.

[0249] Oligopeptides, peptides and proteins Oligopeptides and peptides are useful as additives because hydrophobic and hydrophilic amino acids can be readily attached and various sequences of amino acids can maximize tissue penetration by the drug under test.

[0250] Proteins are also useful as additives in embodiments of the invention. Serum albumin, for example, is a useful additive because it is water soluble and contains significant hydrophobic moieties that bind to the drug; paclitaxel is 89%-98% protein bound after human intravenous infusion, primarily to (97%) albumin, and rapamycin is 92% protein bound. Furthermore, paclitaxel solubility in PBS increases more than 20-fold with the addition of BSA. Albumin is naturally present in serum at high concentrations and is therefore extremely safe for human use.

[0251] Other useful proteins include, but are not limited to, other albumins, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobulins, a-2-macroglobulin, fibronectin, vitronectin, fibrinogen, lipase, and the like.

[0252] 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, aspartic oxalate, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and 2-pyrrolidone.

[0253] These esters and anhydrides are soluble in organic solvents such as ethanol, acetone, methyl ethyl ketone, ethyl acetate, etc. Water-insoluble drugs can be dissolved in organic solvents using these esters and anhydrides, then easily coated on medical devices, and then hydrolyzed under high pH conditions. The hydrolyzed anhydrides or esters are acids or alcohols, which are water-soluble and can efficiently transport drugs from devices to the walls of body cavities.

[0254] Other chemical compounds that have one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties Additives in some embodiments include amino alcohols, alcohols, amines, acids, amides and hydroxyl acids of both cyclic and straight chain aliphatic and aromatic groups. Examples include L-ascorbic acid and its salts, D-glucoscorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, gluconic acid, hydroxyl ketones, hydroxyl lactones, gluconolactone, glucoheptonolactone, glucooctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, riboic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, Acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, 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 Examples of suitable glycerols include, but are not limited to, glycerol, fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, salts of any of the organic acids and amines described herein, polyglycidol, glycerol, multiglycerols (e.g., compounds having multiple hydroxyl, amino, carbonyl, carboxyl or ester moieties), galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol) oligomers, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol and penta(pro...

Claims

1. A balloon catheter for the treatment, prevention, or reduction of stenosis and / or cancer recurrence in nonvascular cavities or for the treatment of benign prostatic hyperplasia (BPH), A long, thin balloon; A coating layer covering the outer surface of a balloon, wherein the coating layer contains one or more water-soluble additives and an initial drug load of a therapeutic agent; Catheter shaft; and A length adjustment mechanism for extending and stretching a balloon while it is deflated, wherein the length adjustment mechanism includes an elongated rigid element from the distal end of the elongated balloon to at least the proximal end of the elongated balloon, and as the balloon inflates, force is transmitted proximal to the elongated rigid element, and the distal end of the elongated rigid element is mechanically coupled to the distal end of the elongated balloon, such that energy during balloon inflation is stored in the catheter shaft, and the proximal end of the elongated rigid element is coupled to the catheter shaft at the proximal end of the elongated balloon or proximal to the proximal end of the elongated balloon, wherein the stored energy is used to extend the balloon when it is deflated. A balloon catheter, including one.

2. The balloon catheter according to claim 1, wherein the catheter shaft operates within the elastic region of the stress-strain curve of the catheter shaft material when energy is stored in the catheter shaft during balloon inflation.

3. The balloon catheter according to claim 1, wherein an elongated rigid element is positioned inside or outside a reinforcing tube that is continuous or discontinuous along the length of the elongated rigid element.

4. The balloon catheter according to claim 1, wherein the distal end of a long, rigid element is connected to a catheter tip.

5. The balloon catheter according to claim 1, wherein the balloon catheter includes an elastic member coupled to the proximal end of an elongated rigid element such that as the elongated rigid element moves proximal, force is stored in the elastic member, and as the force is released from the elastic member, force is applied distally from the elastic member to the elongated rigid element.

6. The balloon catheter according to claim 1, wherein the elongated length of the deflated balloon is approximately 0.1 mm to approximately 100 mm longer than the length of the inflated balloon.

7. The balloon catheter according to claim 1, wherein the therapeutic agent is selected from paclitaxel, docetaxel, taxol, their analogues, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, mTOR inhibitors, their analogues, and combinations thereof.

8. Water-soluble additives include N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine, and N-lauroyl- D-sphingosine, N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG caprylic / capric diglyceride, PEG-8 caprylic / capric glyceride, PEG caprylate, PEG-8 caprylate, PEG caprate, PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monocaproate, monolaurin, monocaprin, monocaprylin, monomyristate, mo A balloon catheter according to claim 1, selected from nopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerol ethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof.

9. The balloon catheter according to claim 1, wherein the water-soluble additive is selected from pentaerythritol ethoxylate, pentaerythritol propoxylate, and combinations thereof.

10. The balloon catheter according to claim 1, wherein the balloon catheter is for the treatment of cancer-induced nonvascular stenosis at a target site in a nonvascular body cavity.

11. The balloon catheter according to claim 1, wherein the balloon catheter is for the treatment of radiation-induced nonvascular stenosis at a target site in a nonvascular body cavity.

12. The balloon catheter according to claim 1, wherein the balloon catheter is for the treatment of benign prostatic hyperplasia (BPH), and is configured to be positioned at a target site including the prostatic urethra.

13. The balloon catheter according to claim 1, wherein the balloon catheter is for treating urethral strictures which are trauma-induced, idiopathic, and / or iatrogenic.

14. The balloon catheter according to claim 1, wherein the balloon catheter is covered with a sheath, and the balloon catheter is used to deliver a therapeutic agent to a target site in a non-vascular body cavity after the body cavity has been flushed with water, saline solution, or an aqueous solution containing at least one water-soluble additive.

15. The balloon catheter according to claim 1, wherein the balloon catheter is fitted to a scope for placement of the balloon catheter in a non-vascular body lumen and for visualization of balloon inflation, balloon deflation, target site yielding, release of therapeutic agent into the wall of the target site, or any combination thereof.

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