Drug-coated balloon catheters for body lumens

Abstract

To provide various embodiments relating to drug-coated balloon catheters for treating a stricture in a body lumen and methods of using the same.SOLUTION: The invention relates to drug-coated balloon catheters 150 for treating a stricture in a body lumen and methods of using the same. 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.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 502,212, filed May 5, 2017, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] background Benign prostatic hyperplasia (BPH) is a noncancerous enlargement of the prostate gland that affects more than 50% of men over the age of 60. Before this age, the prostate gland is the size and shape of a walnut and weighs approximately 20 grams. BPH is considered a normal process. With age, the prostate gland gradually enlarges to more than twice its normal size. As the prostate gland grows, it compresses and narrows the urethra, causing prostatic urethral compression and urinary obstruction, making urination difficult or impossible.

[0003] 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 strictures experience moderate to severe complications such as lower urinary tract symptoms or urinary retention, recurrent urinary tract infections, and a high need for urethral procedures such as dilatation, urethrotomy, or urethroplasty.

[0004] Ureteral strictures of the upper urinary tract can be congenital or acquired. Congenital ureteral strictures are most commonly 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.

[0005] 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.

[0006] Biliary strictures occur when the bile duct becomes small or narrow. The bile duct is the tube that carries bile from the liver to the small intestine. When the bile duct narrows, 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.

[0007] 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 to alleviate the dysphagia.

[0008] Digestive strictures are narrowings of a section of the intestine that cause problems by slowing or blocking the movement of food through this area. Strictures can be 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.

[0009] 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 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 overinflation of the alveoli, or air sacs, in the lungs. This condition causes shortness of breath.

[0010] 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 excessively or respond too easily to stimuli. Asthma episodes or attacks narrow the airways, causing difficulty breathing. Asthma attacks can have a significant impact on a patient's life, limiting their participation in many activities. In severe cases, asthma attacks can be life-threatening. Currently, there is no known cure for asthma.

[0011] Chronic sinusitis is inflammation of the membranes lining one or more sinuses. Chronic sinusitis lasts for 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. Summary of the Invention

[0012] Summary of the Invention In various embodiments, the present invention provides a drug-coated balloon catheter for delivering a therapeutic agent to a target site of a stricture in a body cavity. The stricture in a body cavity may include benign prostatic hyperplasia (BPH), urethral stricture, ureteral stricture, prostate cancer, esophageal stricture, achalasia stricture, in-stent stricture, bile duct stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, and large intestinal stricture, asthma, and chronic obstructive pulmonary disease (COPD). The balloon catheter includes an elongated balloon having a main diameter. The balloon catheter also includes a coating layer covering the outer surface of the balloon, wherein the coating layer includes one or more water-soluble additives and an initial delivery amount of the therapeutic agent.

[0013] In various embodiments, the present invention provides a method for treating a stenosis of a body cavity. The method includes inserting a balloon catheter into a target site in the body cavity. Optionally, the method includes flushing the body cavity with water, saline solution, or an aqueous solution containing at least one water-soluble component before, during, or after inserting the balloon into the target site. The balloon catheter also 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 load of a therapeutic agent. The method includes contacting the coating layer with the wall of the body cavity at the target site and the balloon maintaining an inflated balloon diameter for the inflation period. Features (a) or (b) or (c) or (a) and (b) or (a) and (c) or (b) and (c) or (a) and (b) and (c) are present. (a) a ratio of inflated balloon diameter to normative body lumen diameter at the target site of about 1.0 to about 20; or (b) inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter to normative body lumen diameter at the target site, the nominal diameter of the balloon catheter being less than the inflated balloon diameter; or (d) a combination of (a), (b), and (c). The method includes deflating the balloon after the inflation period. The method also includes withdrawing the balloon catheter from the body lumen.

[0014] In various embodiments, the present invention provides a method for treating a stricture in a body cavity. The method includes inserting a scope, such as a cystoscope, into the body cavity. The method includes inserting a balloon catheter having a drug coating into the body cavity. The method includes inflating the balloon catheter to an initial pressure of 0.5 to 1.5 atmospheres and maintaining the initial pressure until the pressure stops decreasing. The method includes inflating the balloon to a next higher pressure at least 0.5 to 1.5 atmospheres above the initial pressure and maintaining the next higher pressure until the pressure in the balloon stops decreasing, repeating this process until the lumen expands to the desired diameter. The method includes maintaining the balloon inflated for 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to release the drug into the tissue and prevent bleeding. The method includes deflating the balloon catheter. The method also includes withdrawing the scope and balloon catheter from the body cavity.

[0015] Various embodiments of the present invention provide methods for treating a stenosis of a body cavity. The method includes inserting a flexible scope into the stenosis. The method also includes inserting a balloon catheter into the stenosis alongside the scope. The method also includes slowly inflating the balloon catheter to prevent balloon migration, such as by inflating it to an initial pressure of 0.5 to 1.5 atmospheres, maintaining the initial pressure until the pressure stops decreasing, inflating it to a pressure 0.5 to 1.5 atmospheres higher than the initial pressure, maintaining the increased pressure until the pressure inside the balloon stops decreasing, inflating it to a higher pressure until a tissue cavity is created, and maintaining the increased pressure until the pressure inside the balloon stops decreasing. The method also includes maintaining the balloon inflated for 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to release a drug into the tissue and prevent bleeding. The method also includes deflating the balloon catheter. The method also includes withdrawing the scope and balloon catheter assembly from the body cavity.

[0016] Various embodiments of the present invention are maxThe present invention provides a method for increasing the urinary stricture wall thickness. The method includes inserting a balloon catheter into a target site in a urinary stricture. The balloon catheter includes an elongate balloon and a coating layer covering the outer surface of the balloon. The coating layer includes one or more water-soluble additives and an initial drug load of a therapeutic agent. The method includes inflating the balloon for an inflation time until the coating layer contacts the wall of the urinary stricture. 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 normal lumen diameter at the target site is about 1.0 to about 20; or (b) inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, where the inflation ratio of the nominal diameter of the balloon catheter to normal lumen diameter at the target site is about 1.0 to about 20; or (c) inflation includes inflating to a pressure greater than the nominal pressure of the balloon catheter, where 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 includes deflating the balloon after the inflation time. The method includes withdrawing the balloon catheter from the urinary tract stricture. The method is max Increase the flow rate to a minimum of 15 mL / sec.

[0017] Various embodiments of the present invention provide methods for reducing International Prostate Symptom Score (IPSS). The method includes inserting a balloon catheter into a target site in a urinary stricture. The balloon catheter includes an elongate balloon and a coating layer covering the outer surface of the balloon. The coating layer includes one or more water-soluble additives and an initial drug load of a therapeutic agent. The method includes inflating the balloon for an inflation time until the coating layer contacts the wall of the urinary stricture. 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 normal lumen diameter at the target site of about 1.0 to about 20; or (b) inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, where the inflation ratio of the nominal diameter of the balloon catheter to the normal lumen diameter at the target site is about 1.0 to about 20; or (c) inflation includes inflating to a pressure greater than the nominal pressure of the balloon catheter, where 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 includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the urinary tract. The method reduces the IPSS to 14 or less.

[0018] Various embodiments of the present invention provide methods for forming a balloon. The methods include placing a tube containing balloon material into a balloon mold, where the balloon mold has a shape including a proximal cone, at least one body portion, at least one neck portion having a smaller diameter than the at least one body portion, at least one other body portion, and a distal cone. The methods include pressurizing the interior of the balloon material tube. The methods also include expanding the balloon material tube until it contacts the interior of the mold.

[0019] Various embodiments of the present invention provide methods for splitting an enlarged prostate or creating a commissurotomy for the treatment of benign prostatic hyperplasia. The method includes inserting a drug-coated balloon catheter-sheath assembly and a scope. The method includes aligning the scope and balloon catheter and positioning them near the external sphincter. The method optionally includes flushing the body cavity with water, saline solution, or an aqueous solution containing at least one water-soluble additive before, during, or after inserting the balloon into the target site. The method includes removing the sheath from over the balloon and slowly inflating it until the pressure decreases, prostate tissue is exposed, and a commissurotomy is performed. The method includes further increasing the pressure to the rated burst pressure to further expand the prostate. The method includes maintaining the balloon inflated for 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to release the drug into the tissue and prevent bleeding. The method includes deflating the balloon catheter and retracting the balloon into the sheath. The method also includes withdrawing the scope and balloon catheter assembly from the body cavity. Characteristic (a) or (b) or (c) or (a) and (b) or (a) and (c) or (b) and (c) or (a) and (b) and (c) or (a) and (b) and (c) are present: (a) the ratio of inflated balloon diameter to normal body lumen diameter at the target site is about 1.0 to about 20; or (b) inflation comprises inflating the balloon to at least as much as the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to normal body lumen diameter at the target site is about 1.0 to about 20; or (c) 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).

[0020] Various embodiments of the present invention provide methods for splitting an enlarged prostate or creating a commissurotomy for the treatment of benign prostatic hyperplasia. The method includes inserting an uncoated balloon catheter-sheath assembly and a scope. The method includes aligning the scope and balloon catheter and positioning them near the external sphincter. The method includes removing the sheath from over the balloon and slowly inflating it until the pressure decreases, the prostate tissue is exposed, and a commissurotomy is created. The method includes further increasing the pressure to the rated burst pressure to further expand the prostate. The method includes maintaining the balloon inflated for 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to prevent bleeding. The method includes deflating the uncoated balloon catheter and retracting the balloon into the sheath. The method includes withdrawing the scope and uncoated balloon catheter assembly from the body cavity. The method includes inserting a drug-coated balloon catheter-sheath assembly and a scope. The method includes aligning the scope and drug-coated balloon catheter and positioning them near the external sphincter. The method includes removing the sheath from over the drug-coated balloon and slowly inflating it to its rated burst pressure to further expand the prostate. The method includes maintaining the balloon inflated for 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to release the drug into the tissue and prevent bleeding. Characteristics (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 the inflated balloon diameter to the normal body lumen diameter at the target site is about 1.0 to about 20; or (b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, where the inflation ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; or (c) the inflation includes inflating to a pressure greater than the nominal pressure of the balloon catheter, where the nominal diameter of the balloon catheter is less than the inflated balloon diameter; or (d) a combination of (a), (b), and (c).

[0021] Various embodiments of the present invention provide methods for treating benign prostatic hyperplasia. The method includes inserting a balloon catheter into a target site in the prostate. 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 load of a therapeutic agent. The method includes inflating the balloon until the coating layer contacts the wall of the body cavity at the target site for an inflation time and the balloon achieves an inflated balloon diameter. 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 the inflated balloon diameter to the normal body lumen diameter at the target site of about 1.0 to about 20; or (b) inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, where the inflation ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; or (c) inflation includes inflating to a pressure greater than the nominal pressure of the balloon catheter, where 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 includes deflating the balloon after the inflation period. The method includes withdrawing the balloon catheter from the body lumen. The method separates the prostatic urethra and the prostate, achieving a voiding prostatic urethral diameter of at least 12 mm, and achieving an inflated diameter of the balloon catheter of at least 20 mm or at least 25 mm.

[0022] Various embodiments of the present invention provide a method for treating a urethral stricture, the method comprising inserting a balloon catheter into a target site in the urethra, the balloon catheter comprising a coating layer covering the outer surface of the balloon.wherein the coating layer comprises one or more water-soluble additives and an initial drug loading of a therapeutic agent, wherein the therapeutic agent is paclitaxel, docetaxel, taxol, analogs thereof, rapamycin, sirolimus, everolimus, tacrolimus, MTOR inhibitors, analogs thereof, and combinations thereof, and the water-soluble additives are N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide. Amides, Cerebrosides, Sphingomyelin, Galactocerebroside, Lactocerebroside, N-Acetyl-D-Sphingosine, N-Hexanoyl-D-Sphingosine, N-Octnoyl-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 Caprate Iodide, 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- The preferred water-soluble additive is at least one of 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 method optionally includes 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 includes inflating the balloon until the coating layer contacts the wall of the body cavity at the target site for an inflation time and the balloon achieves an inflated balloon diameter. Characteristic (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 the inflated balloon diameter to the normal body cavity diameter at the target site is about 1.0 to about 20; or (b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the normal body cavity diameter at the target site is about 1.0 to about 20; 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). The method includes deflating the balloon after the inflation time. The method includes withdrawing the balloon catheter from the body cavity. The method achieves a urethral diameter of at least 6.7 mm after dilation, with the balloon catheter having an inflated diameter of at least 7 mm.

[0023] Various embodiments of the present invention provide a balloon catheter for treating urethral strictures. 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 load of a therapeutic agent, wherein the therapeutic agent is paclitaxel, docetaxel, taxol, analogs thereof, rapamycin, sirolimus, everolimus, tacrolimus, an MTOR inhibitor, analogs thereof, or combinations thereof, and the water-soluble additive is 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-Octnoyl-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 Caproe 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-hydroxybenzoate) and at least one of N,N'-bis(hydroxymethyl)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.Characteristic (a) or (b) or (c) or (a) and (b) or (a) and (c) or (b) and (c) or (a) and (b) and (c) or (a) and (b) and (c) are present. (a) the ratio of inflated balloon diameter to normal body lumen diameter at the target site is about 1.0 to about 20; or (b) inflation comprises inflating the balloon to at least as much as the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to normal body lumen diameter at the target site is about 1.0 to about 20; or (c) 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). Post-procedure Q. max The inflated diameter of the balloon catheter is at least 7 mm.

[0024] BRIEF DESCRIPTION OF THE DRAWINGS The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present invention. [Brief explanation of the drawings]

[0025] [Figure 1] Figure 1A illustrates various embodiments of a balloon catheter having one neck, Figure 1B illustrates various embodiments of a balloon catheter having two necks, and Figure 1C illustrates various embodiments of a balloon catheter having three necks.

[0026] [Figure 2] Various embodiments of a two-necked drug-coated balloon catheter are illustrated, including a catheter shaft, a catheter tip, and a Tuohy Borst adapter (balloon catheters include fixed-wire, over-the-wire, and rapid-exchange balloon catheters, not shown in detail in FIG. 2).

[0027] [Figure 3]3 is a perspective view of one embodiment of a balloon catheter of the present invention (balloon catheters include fixed-wire, over-the-wire, and rapid exchange balloon catheters, not shown in detail in FIG. 3).

[0028] [Figure 4] 4A-4C are various embodiments of the distal portion of the balloon catheter of FIG. 3 taken along line AA showing example coating layers. DETAILED DESCRIPTION OF THE INVENTION

[0029] 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 will be understood that the exemplified subject matter is not intended to limit the claimed disclosed subject matter.

[0030] Throughout this specification, values ​​expressed in range format should be interpreted flexibly to include not only the numerical values ​​explicitly recited as limiting that range, but also all individual numerical values ​​or subranges within that range, as if each numerical value and subrange were explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the recited range. The term "about X to Y" has the same meaning as "about X to about Y" unless otherwise specified. Similarly, the term "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise specified.

[0031] As used herein, the terms "a," "an," and "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a non-exclusive "or" unless otherwise specified. The statement "at least one of A and B" has the same meaning as "A, B, or A and B." 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 located within or outside of a particular section.

[0032] 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 express claim language dictates that they should be used separately. For example, a claimed act of performing X and a claimed act of performing Y can be performed simultaneously in a single operation, and the resulting process falls within the literal scope of the claimed process.

[0033] 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.

[0034] 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%.

[0035] One aspect of various embodiments of the present invention is the delivery of therapeutic agents, such as paclitaxel, taxol, docetaxel, rapamycin, sirolimus, tacrolimus, everolimus, mTOR inhibitors or their analogs, to the wall of a body cavity to treat narrowing or stenosis.These drugs can be considered anti-inflammatory or anti-proliferative agents.Stenosis can be in the vascular lumen (e.g., vascular stenosis in coronary arteries or peripheral arteries) or in the non-vascular lumen.The drug can be a water-insoluble drug.

[0036] 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.

[0037] Causes of non-vascular luminal strictures and related non-vascular diseases such as benign prostatic hyperplasia (BPH), urethral strictures, ureteral strictures, prostate cancer, esophageal strictures, achalasia strictures, in-stent strictures, biliary strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, and large intestinal strictures, asthma, and chronic obstructive pulmonary disease (COPD) can include cancer and infection and inflammation caused by pathogens such as bacteria and viruses. Various embodiments of the present invention provide for the delivery of coating formulations to the strictures, including drugs and additives with properties that kill or inhibit bacteria and viruses.

[0038] The present invention provides a novel method for treating luminal stenosis to have long-term and sustained effects. The novel method opens the lumen and prevents, reduces, or minimizes restenosis and recurrent stenosis. The method includes delivering a therapeutic agent, such as an anti-inflammatory agent and an anti-proliferative agent (e.g., paclitaxel, taxol, docetaxel, rapamycin, sirolimus, tacrolimus, everolimus, mTOR inhibitors or analogs thereof), and one or more water-soluble additives to the target tissue.

[0039] An embodiment of the present invention provides a medical device coating formulation comprising a drug for treating a stenosis of a non-vascular body lumen and an additive that enhances absorption of the drug into the tissue of the body lumen. The additive may have antibacterial and antiviral properties. A balloon catheter includes a coating layer covering the outer surface of the balloon, wherein the coating layer includes one or more water-soluble additives and an initial drug load of an antiproliferative therapeutic agent.

[0040] Coating the outer surface of a balloon catheter with a layer containing, for example, a therapeutic agent and an additive is useful for solving coating-related problems. For example, the additive can have a hydrophilic portion and a drug-affinity portion. The drug-affinity portion can be hydrophobic and / or have affinity for the therapeutic agent through hydrogen bonding and / or van der Waals interactions. Surprisingly, additives in embodiments of the present invention, including a hydrophilic portion and a drug-affinity portion in combination with an antiproliferative therapeutic agent, form efficient drug-delivery coatings on medical devices without the use of oils or lipids, thereby avoiding the lipolysis dependency and other disadvantages of conventional oil-based coating formulations. Furthermore, additives in embodiments of the present invention promote rapid drug elution and excellent drug penetration into diseased tissues. Therefore, coatings in embodiments of the present invention increase the rate and / or extent of absorption of antiproliferative therapeutic agents into non-vascular diseased tissues or non-vascular body cavities. In embodiments of the present invention, the coated device delivers antiproliferative therapeutic agents to non-vascular tissues during extremely short indwelling times, such as within 10 minutes or even within 2 minutes, reducing restenosis and recurrence of stenosis in non-vascular body cavities.

[0041] Various embodiments of the present invention relate to a medical device for delivering a therapeutic agent to a stricture in a blood vessel or non-vascular body lumen, the device comprising a layer covering the 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 distally perforated drug infusion tube, a perforated balloon, a spaced double balloon, a porous balloon, or a permeable 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 having a diameter smaller than the main diameter, the at least one neck dividing the balloon into at least two sections, each having a diameter equal to or different from the main diameter. Furthermore, 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 through which blood is present. Non-vascular lumens include lumens through which blood is present. The balloon catheter shaft and balloon material may be composed of polyether-amide block copolymer, polyamide, nylon, or blends thereof.

[0042] In some embodiments, the additive is at least one of a surfactant and a compound. The coating layer covering the outer surface of the medical device can include one or more water-soluble additives. The coating layer covering 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).

[0043] The medical device may further comprise a dimethyl sulfoxide solvent layer, wherein the dimethyl sulfoxide solvent layer covers the exterior surface of the medical device.

[0044] The device releases the therapeutic agent and additives, delivering the therapeutic agent to the tissue in approximately 0.1 to 10 minutes. The therapeutic agent concentration in the layer is 1 to 20 μg / mm, measured when the balloon is inflated to its nominal diameter. 2 The concentration of the therapeutic agent in the layer can be 2 to 10 μg / mm 2 It could be.

[0045] 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.

[0046] The layer covering the exterior surface of the medical device can include a therapeutic agent and at least two additives, each of which includes a hydrophilic portion and a drug-affinity portion, wherein the drug-affinity portion is at least one of a hydrophobic portion, a portion having affinity for the therapeutic agent through hydrogen bonding, and a portion having affinity for the therapeutic agent through van der Waals interactions, and wherein each additive is soluble in a polar organic solvent and soluble in water. In some aspects of this embodiment, the polar organic solvent is selected from methanol, ethanol, isopropanol, acetone, dimethylformide, tetrahydrofuran, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, ethyl acetate, and chloroform, and mixtures of these polar organic solvents with water. In other aspects of this embodiment, the device further includes a top layer covering the layer covering the exterior surface of the medical device to reduce drug loss during transport through the body to the target tissue.

[0047] In some embodiments, the additive reduces the crystal size and particle number of the therapeutic agent, wherein the additive is water-soluble and the therapeutic agent is not water-soluble. The additive may have a fatty acid, ester, ether, or alcohol chain, wherein the fatty acid chain can directly insert into the lipid membrane structure of the tissue. The additive may penetrate and reorganize the lipid membrane structure of the tissue. The additive may have one or more functional groups that have affinity for the drug through hydrogen bonding and / or van der Waals interactions. In some embodiments, the additive may be at least one of a surfactant and a compound, wherein the compound has a molecular weight of 50 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.

[0048] Medical device coatings for drug delivery to non-vascular tissues or non-vascular stenosis can be prepared from a mixture. The coating can be prepared from a mixture including an organic phase with dispersed drug particles and an aqueous phase with a water-soluble additive. The water-soluble additive 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.

[0049] 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).

[0050] In certain embodiments, a method for treating a stricture in a non-vascular body lumen includes inserting a balloon catheter comprising a coating layer into the body stricture (wherein the stricture is one of 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, and sinus stricture, and wherein the coating layer comprises 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 load on the balloon catheter. In certain aspects of this embodiment, the additive enhances absorption of the drug into tissues of the non-vascular body lumen.

[0051] Some drugs for use in various embodiments that may be particularly suitable for the airways, sinuses, and other nasal passages are corticosteroids such as budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cotisone, betamethasone, triamcinolone acetonide, and the like.

[0052] Various embodiments relate to a method of treating a stenosis in a non-vascular body lumen, comprising flushing the lumen with water, saline solution, or an aqueous solution of an additive 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 to release the drug into the wall of the body lumen, deflating the balloon, and withdrawing the balloon catheter. A method for treating a stricture in a non-vascular body lumen comprises injecting water, 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, and large intestinal stricture, and bile duct stricture, and wherein the coating layer comprises a drug and an additive), inflating the balloon catheter to release the drug into the wall of the stricture in the non-vascular body lumen, deflating the balloon, and withdrawing the balloon catheter. In some embodiments of this embodiment, the additive enhances absorption of the drug into tissues of the non-vascular body lumen. In another aspect of this embodiment, the additive comprises a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion is at least one of a hydrophobic portion, a portion having affinity for the therapeutic agent through hydrogen bonding, and a portion having affinity for the therapeutic agent through van der Waals interactions. In another aspect of this embodiment, the drug is selected from paclitaxel, docetaxel, taxol and analogs thereof, and rapamycin, sirolimus, everolimus, tacrolimus and analogs thereof.In another aspect 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, polyglycerin 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 alkylphenols, 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 another aspect of this embodiment, the drug can be released into the airway wall before, during, or after an asthma attack. In yet another aspect of this embodiment, the drug can be released into the esophageal wall. In yet another aspect of this embodiment, the drug can be released into the sinus wall. In yet another aspect of this embodiment, the drug can be released into the bile duct wall. In yet another aspect of this embodiment, the drug can be released into the walls 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-vasostenotic portion within the stent.

[0053] In various embodiments, the present invention provides a method for 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 includes inserting the balloon catheter of FIG. 1A, 1B, 1C, 2, or 3 into a target site in the body cavity. The method may include inserting the balloon catheter and a scope side-by-side or 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 include flushing the body cavity with water, saline solution, or an aqueous solution containing at least one water-soluble additive before, during, or after inserting the balloon into the target site. The method may include 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 the inflated balloon diameter for the inflation time. Feature (a) or (b) or (c) or (a) and (b) or (a) and (c) or (b) and (c) or (a) and (b) and (c) or (a) and (b) and (c) are present. (a) The ratio of the inflated balloon diameter to the normal body lumen diameter at the target site is about 1.0 to about 20; or (b) the inflation comprises inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; 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 includes deflating the balloon after the inflation period. The method also includes withdrawing the balloon catheter from the stenosis in the body lumen.

[0054] In some embodiments, the balloon is inflated until the coating layer contacts the wall of the stenosis and the stenosis is expanded, and at the same time, the drug moves to the stenosis.In some embodiments, the balloon is inflated until the coating layer contacts the wall of the stenosis, and the expansion causes the diameter of the stenosis to increase, so that contact with the stenosis can provide full circumferential movement of the drug to the wall of the stenosis.In some embodiments, the part of the balloon that contains the drug (for example, in embodiments where the surface area covered with the drug is less than 100%) can be in uniform contact with the stenosis.In other embodiments, the contact between various parts of the balloon surface and the stenosis is uneven.

[0055] The inflated diameter of the balloon can be any suitable diameter achieved during or throughout the inflation time so as to achieve a desired ratio of inflated balloon diameter to the normal diameter of the body lumen. The inflated diameter of the balloon is proportional to the pressure used to inflate the balloon during the inflation time. The inflation pressure can range from the nominal inflation pressure to the rated burst pressure. The nominal pressure is the pressure at the nominal diameter of the inflated balloon catheter. The nominal diameter is the diameter at the nominal pressure of the balloon catheter and is specified on the product label. In some embodiments, the inflation pressure can be the nominal pressure of the balloon, and the inflated diameter of the balloon can be approximately equal to the nominal diameter of the balloon or can be less than the nominal diameter of the balloon due to pressure from the stenosis. In some embodiments, the inflation pressure of the balloon during the inflation time can be higher or lower than the nominal pressure, and the inflated diameter of the balloon can be correspondingly smaller or larger than the nominal diameter of the balloon.

[0056] In various embodiments, the present invention provides a method for 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 atmospheres, 1 atmosphere, or 1.5 atmospheres) and maintaining the initial pressure for 1 to 2 minutes until the pressure stops decreasing. The method includes: 4) inflating the balloon to a next higher pressure, 0.5 atmospheres, 1 atmosphere, or 1.5 atmospheres above the previous pressure, and maintaining the higher pressure for 1 to 2 minutes until the pressure in the balloon stops decreasing. The method includes: 5) repeating step 4) until luminal tissue, such as prostate tissue, is produced. The method includes: 6) maintaining the balloon inflation for 1 minute to 7 days, or 1 minute to 1 day, or 1 to 10 minutes to release a 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.

[0057] In various embodiments, the present invention provides a method for treating a body cavity. The method includes: 1) lining up a flexible scope and a balloon catheter within a sheath and inserting them into the body cavity. The method includes: 2) removing the sheath from over the balloon, inflating it to an initial pressure (e.g., 0.5 atmospheres, 1 atmosphere, or 1.5 atmospheres), and maintaining the initial pressure for 1 to 2 minutes until the pressure stops decreasing. The method includes: 3) inflating it to the next higher pressure, increased by 0.5 atmospheres, 1 atmosphere, or 1.5 atmospheres, and maintaining the higher pressure for 1 to 2 minutes until the pressure in the balloon stops decreasing. The method includes: 4) repeating step 3) until the tissue of the body cavity is irrigated. The method includes: 5) maintaining the inflation of the balloon for 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to release the drug into the tissue and prevent bleeding. The method includes: 6) deflating the balloon catheter. The method includes: 7) retracting the balloon catheter 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.

[0058] 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. The method also includes: 2) inserting a balloon catheter and a scope side-by-side into the body cavity. The method includes: 3) inflating to an initial pressure (e.g., 0.5 atmospheres, 1 atmosphere, or 1.5 atmospheres) and maintaining the initial pressure for 1 to 2 minutes until the pressure stops decreasing. The method includes: 4) inflating to a next higher pressure, 0.5 atmospheres, 1 atmosphere, or 1.5 atmospheres above the previous pressure, and maintaining the higher pressure for 1 to 2 minutes until the pressure in the balloon stops decreasing. The method includes: 5) repeating step 4) until the tissue of the body cavity is irrigated. The method includes: 6) maintaining the balloon inflation for 1 minute to 7 days, 1 minute to 1 day, or 1 to 10 minutes to release the drug into the tissue and prevent bleeding. The method includes: 7) 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.

[0059] 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) lining up the scope and balloon catheter and positioning them 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 atmospheres, 1 atmosphere, or 1.5 atmospheres), and maintaining the initial pressure for 1 to 2 minutes until the pressure stops decreasing. The method includes: 4) inflating it to the next higher pressure, increased by 0.5 atmospheres, 1 atmosphere, or 1.5 atmospheres, and maintaining the higher pressure for 1 to 2 minutes until the pressure in the balloon stops decreasing. The method includes: 5) repeating step 4) until prostate tissue is developed 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 to 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) the ratio of the inflated balloon diameter to the normal body cavity diameter at the target site is about 1.0 to about 20; or (b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the normal body cavity diameter at the target site is about 1.0 to about 20; 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).

[0060] Various embodiments of the present invention relate to methods for treating strictures in body lumens by delivering an effective amount of a therapeutic agent, such as an anti-inflammatory agent and an anti-proliferative agent (e.g., rapamycin, sirolimus, everolimus, tacrolimus, paclitaxel, taxol, docetaxel, or analogs thereof), to a target tissue. Strictures in body lumens include vascular strictures, non-vascular strictures, urethral strictures, ureteral strictures, esophageal strictures, achalasia strictures, in-stent strictures, sinus strictures, biliary strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, and large intestinal strictures. An embodiment of the present invention is a method for treating at least one of strictures 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 weight infants to adults.

[0061] The drug coating on the balloon catheter can be released into the target body cavity. The multi-lobed balloon with a small-diameter neck mechanically fixes the balloon to the body cavity, thus preventing the balloon from slipping through the body cavity. If the balloon slips or moves away from the target diseased area, it may miss the target area and damage the healthy lumen.

[0062] In various embodiments, the present invention has advantages, 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 the disorders disclosed herein. The drug-affinity portion is hydrophobic and / or has affinity for the therapeutic agent through hydrogen bonding and / or van der Waals interactions. Surprisingly, the additive in embodiments of the present invention, comprising a hydrophilic portion and a drug-affinity portion, in combination with a therapeutic agent, forms an efficient drug-delivery coating on the medical device. Furthermore, the additive in embodiments of the present invention can promote rapid drug elution and excellent drug penetration into diseased tissue. Therefore, the coating in embodiments of the present invention can provide enhanced rate and / or extent of absorption of the therapeutic agent in the affected tissue or body cavity. In embodiments of the present invention, the coated device can deliver a therapeutic agent to tissue with an extremely short dwell time of 10 minutes or less (e.g., 2 minutes or less) and can reduce restenosis and recurrence of stenosis in the body cavity, for example, compared to other balloon catheters lacking such a neck or neck shape.

[0063] In various embodiments, the balloon catheters of the present invention are compatible with flexible or rigid scopes that allow visualization of the treatment zone, allowing for more precise 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 catheters of the present invention are self-finding because the neck of the balloon catheter directs the balloon catheter to the appropriate 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 misaligned at the beginning of inflation.

[0064] 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 having multiple segments or a body and at least one neck with a smaller diameter than the main segment. The balloon catheter may include an elongated balloon having a major diameter, such as multiple segments with a major diameter or an average diameter equal to the major diameter. A multi-lobed balloon with a smaller-diameter neck mechanically secures the balloon to the body cavity and thus prevents the balloon from slipping within the body cavity. If the balloon moves away from the target diseased site, it may become dislodged, potentially damaging a healthy lumen site. The balloon catheter may also 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 load of a therapeutic agent (e.g., paclitaxel, taxol, docetaxel, analogs thereof, rapamycin, sirolimus, everolimus, tacrolimus, analogs thereof, and combinations thereof). A method of using a balloon catheter, wherein characteristics (a) or (b) or (c) or (a) and (b) or (a) and (c) or (b) and (c) or (a) and (b) and (c) or (a) and (b) and (c) are present: (a) the ratio of inflated balloon diameter to normal body lumen diameter at the target site is about 1.0 to about 20; or (b) inflation comprises inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to normal body lumen diameter at the target site is about 1.0 to about 20; or (c) 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).

[0065] The major diameter of a balloon is the diameter of the main portion 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 on the balloon, excluding any folded or wrinkled areas of the balloon. The inflation pressure used to determine the major diameter can be a pressure that causes the inflated balloon to have a shape and size that corresponds to the desired shape and size of the balloon during the intended treatment of the body cavity. 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.

[0066] In some embodiments, the drug-coated balloon comprises two main sections of the same diameter at both ends, one neck of a smaller diameter between the two main sections, and two cones on the proximal and distal balloon bodies. The drug-coated balloon may comprise three main sections of the same diameter, two necks of a smaller diameter (where the three main sections and two necks are alternately arranged, with the necks adjacent to the main section with a larger diameter), and two cones on the proximal and distal balloon bodies. The drug-coated balloon may comprise four main sections of a larger diameter, three necks of a smaller diameter (where the four main sections and three necks of a larger diameter are alternately arranged, with the necks adjacent to the main section with a larger diameter), and two cones on the proximal and distal balloon bodies. The drug-coated balloon may comprise five main sections of a larger diameter, four necks of a smaller diameter (where the five main sections and four necks of a larger diameter are alternately arranged, with the necks adjacent to the main section 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 having a diameter smaller than the diameter of the balloon at the main portion. The balloon catheter may include an elongated (e.g., cylindrical) balloon with multiple sections of varying diameters. Features (a) or (b) or (c) or (a) and (b) or (a) and (c) or (b) and (c) or (a) and (b) and (c) are present. (a) The ratio of the inflated balloon diameter to the normal body lumen diameter at the target site is about 1.0 to about 20; or (b) inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the stretch ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; or (c) 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-segment 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.

[0067] A drug-coated balloon catheter can be a medical device for treating benign prostatic hyperplasia (BPH). The balloon catheter can dilate the prostatic urethra and can include a catheter shaft for insertion into the urethra and a compliant, semi-compliant, or non-compliant balloon for inflation in the prostatic urethra. The balloon can be coated with a therapeutic agent that is delivered to the prostatic tissue and prostatic urethra upon balloon inflation. The balloon can be positioned within the prostate using any suitable method, such as a separate location balloon in the bladder, a location balloon in the urethral bulb, etc., or the catheter shaft can be compatible with a scope (e.g., a cystoscope) to allow placement under direct visualization, or the catheter can be aligned with a scope. For example, several possible catheter designs allow direct visualization of the balloon during positioning and inflation. One design is cystoscope-compatible, and the catheter is backloaded through a working channel. Once through the cystoscope, a Tuohy Borst adapter 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 the insertion of a rigid cystoscope lens and placement next to the proximal end of the balloon.

[0068] In some embodiments, when treating the prostate, the balloon catheter is sized so that the catheter body is located 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, the neck region of the balloon catheter preferably fits over the bladder 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, a coude tip, or the like, the tip can be inserted into the internal urethral sphincter (e.g., the bladder neck sphincter) to aid in positioning the balloon catheter at the desired location.

[0069] Balloon catheters can alleviate lower urinary tract symptoms (LUTS) associated with BPH by directly expanding the prostate tissue. Prostate expansion with a balloon having a ratio of inflated balloon diameter to normal lumen diameter at the target site of 1.0-20 or a balloon having a nominal balloon diameter to normal lumen diameter at the target site expansion ratio of 1.0-20 can create a commissural incision in the natural plane, separating the transverse sections at the fused portions of the prostate. Simultaneously, drugs can be released from the coating into the prostate tissue, which can, for example, prevent prostate enlargement and re-narrowing of the newly formed orifice.

[0070] In various embodiments, during balloon inflation in a body lumen (e.g., during the practice of a method of the invention), the nominal diameter of the catheter balloon (e.g., the diameter normally achieved at a nominal pressure) is any suitable ratio such that the ratio of the nominal diameter of the balloon to the normal diameter of the body lumen at the treatment location is less than, equal to, greater than, or greater than about 1.01 to about 20, or about 1.01 to about 15, or about 1.2 to about 10, or about 1.31 to about 8, or about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20. In certain embodiments, the inflated diameter of the balloon at the target site during inflation to a nominal pressure is equal to the nominal diameter; however, during actual use, a portion of the stenosis may prevent the nominal diameter from being achieved or may restrict the inflation of the balloon, forming a "dog bone" shape. The nominal balloon diameter at a predetermined pressure (e.g., 2 atmospheres, 3 atmospheres, 6 atmospheres, or 9 atmospheres) may vary depending on the diameter of the balloon for various diseases. For example, the nominal diameter of a urethral stricture balloon may be 6 mm, 8 mm, 10 mm, 12 mm, or 14 mm when inflated to 6 atmospheres for a 6-, 8-, 10-, 12-, or 14-mm balloon catheter. The nominal diameter of a BPH stricture balloon may be 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, or 60-mm balloon catheter with a nominal pressure inflation of 2 atmospheres, 3 atmospheres, 4 atmospheres, 6 atmospheres, or 9 atmospheres. Table 1 shows examples of nominal balloon dimensions, nominal pressures, and ratios of minimum balloon diameter to normal lumen diameter for use in treating strictures in various diseases. Nominal pressure is the pressure required to bring the balloon to its labeled nominal diameter in an unconstrained pressure ramp test. Nominal diameter is the desired diameter for which the product is labeled. Every physician purchases balloons and selects balloons for use by their 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 requirement for balloon catheters, calculated from statistical analysis of the pressures observed when the balloon bursts in an unconstrained pressure ramp test.

[0071] [Table 1]

[0072] In various embodiments, the balloon catheter can be sufficient to allow the balloon to have any suitable ratio of inflated balloon catheter diameter to the normal diameter of the body lumen at the treatment location at a predetermined pressure (e.g., a 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 greater than about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28 atmospheres, or about 30 atmospheres).

[0073] Unless otherwise specified, the stretch ratio is defined as the ratio of the nominal diameter of the balloon to the normal diameter of the body lumen in the area treated by the balloon catheter. The nominal diameter of the balloon is the diameter achieved in an unconstrained environment at the nominal pressure. The normal lumen diameter is the average diameter of the healthy lumens adjacent to the stenosis, stricture, or lesion, proximal and distal to the luminal stricture, stricture, or lesion. For the urinary tract, e.g., the urethra and prostatic urethra, the normal lumen diameter is the average diameter of the voiding urethra of the healthy lumens distal and proximal to the obstruction. For all lumens, if the average diameter distal to the distal and proximal healthy tissue is not available, the normal lumen diameter is the diameter of the biological material flowing through it when the lumen is healthy. The inflated balloon diameter is the actual diameter of the balloon after inflation, which in some embodiments is equal to, less than, or greater than the nominal diameter of the balloon. In various embodiments, the stretch ratio of the balloon catheters of the present invention makes them more effective at treating non-vascular lumens than other catheters. During the practice of the methods of the present invention, the stretch ratio can be selected to be any suitable ratio that achieves the desired ratio of actual inflated balloon diameter to normal lumen diameter over the range of pressures used during the method.In various embodiments, the stretch ratio of the balloon can be less than, equal to, greater than, or greater than about 1.01 to about 20, 1.31 to 20, or about 1.01 to about 15, or about 1.1 to about 10, 1.2 to 10, 1.3 to 10, 1.31 to 10, 1.4 to 10, 1.5 to 10, 1.6 to 10, 1.7 to 10, 1.8 to 10, 2 to 10, 2.2 to 10, 2.5 to 10, 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, 12, 14, 16, 18, or about 20; such stretch ratios may be the same, similar, or different. The pressure used during the possible inflation time can result in a desired ratio of inflated balloon diameter to normal lumen diameter of less than, equal to, greater than, or greater than about 1.01 to about 20, 1.31 to 20, or about 1.01 to about 15, or about 1.1 to about 10, 1.2 to 10, 1.3 to 10, 1.31 to 10, 1.4 to 10, 1.5 to 10, 1.6 to 10, 1.7 to 10, 1.8 to 10, 2 to 10, 2.2 to 10, 2.5 to 10, 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, 12, 14, 16, 18, or about 20.

[0074] In various embodiments, the method includes measuring the stenosis of a body cavity to be treated. The distal and proximal healthy tissue diameters and the length of the stenosis can be evaluated to select a drug-coated balloon to be used. The physician selects a balloon based on the normal diameter stenosis of the body cavity and achieving a stretch ratio of the balloon's nominal diameter to the normal diameter stenosis of the body cavity of 1.0 to 20, or 1.1 to 15, or 1.2 to 10, or 1.3 to 1.8. The physician can then inflate the balloon to at least the nominal pressure, and in some cases, can inflate the balloon above the nominal pressure, up to the balloon's rated burst pressure. The range of pressures used during the inflation period can be referred to as the working pressure range of the drug-coated balloon. In some cases, the method can include exceeding the balloon's rated burst pressure. Since the balloon's nominal diameter is determined without any restraint, the inflated diameter of the balloon passing through the stenosis can be approximately the same as, less than, or greater than the nominal diameter. At or above the burst pressure, the inflated diameter of the balloon may be less than, equal to, or greater than the nominal diameter. For example, a body cavity stenosis may be measured to have a normal 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 10 atmospheres, and in some cases to more than 10 atmospheres to achieve the desired inflated balloon diameter during the procedure.

[0075] In various embodiments, the balloon catheter has one or more necks separating one or more sections, and the shape of at least one neck or one or more necks of the balloon catheter of the present invention allows the balloon catheter to remain in place during the procedure more consistently and efficiently to dilate stenoses and deliver drugs compared to other balloon catheters lacking such a neck or neck shape.

[0076] 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, aligning them near the external sphincter. Live video feed from the scope can be used to position the balloon at the external sphincter. The balloon can be positioned adjacent to the external sphincter and within the prostatic urethra. Balloon inflation, drug release, and balloon deflation can be visualized by the scope.

[0077] 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. Live video feed from the cystoscope can be used to position the external sphincter. The balloon can be positioned adjacent to the external sphincter and within the prostatic urethra.

[0078] In some embodiments, when treating the prostate, it is preferable to position the proximal balloon waist at the external sphincter to prevent the external sphincter from expanding. When the balloon waist is at the external sphincter, it is also preferable to size the balloon so that the balloon neck (e.g., the most distal balloon neck) fits over the bladder neck. This positioning provides retention to prevent the balloon from slipping during inflation. If the balloon neck cannot be aligned with the bladder neck, it may be preferable to inflate the balloon slowly to allow the prostate to accommodate as the balloon expands.

[0079] Once properly positioned, the balloon is inflated, such as 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 slide proximally into the bladder and vice versa. While single- or multi-necked balloon configurations prevent balloon migration by aligning the most distal neck with the bladder neck, in unusual circumstances, such as with an enlarged middle lobe (e.g., approximately 10-15% of cases), the balloon neck 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 approximately 0.5-1 atmospheres per minute may prevent balloon migration. As the tissue accommodates, the balloon pressure correspondingly decreases, allowing additional fluid to be inserted into the balloon without inserting pressure. When the pressure is stable for approximately 1-2 minutes, the pressure may be increased in 0.5 or 1 atmosphere increments and maintained in a similar manner. The pressure can be increased continuously, allowing 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 period of approximately 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.

[0080] In some embodiments, when treating the prostate, it may be desirable to pre-dilatate the stricture. In this embodiment, the pre-dilatation catheter may be shorter and / or smaller in diameter than the drug-coated balloon treatment catheter. In this scenario, the pre-dilatation catheter is placed with the proximal waist of the balloon at the external sphincter, aligning the neck region with the bladder neck. The balloon is slowly inflated as described herein to help the prostate accommodate while preventing 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 BPH is properly pre-dilated, it is not necessary to align the balloon neck with the bladder neck, as the balloon is less likely to slip than in a non-pre-dilatation lumen.

[0081] 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, wherein the balloon body includes at least two larger-diameter sections and at least one smaller-diameter neck section, wherein the larger-diameter sections and neck sections are arranged alternately and adjacently. The elongated balloon is generally cylindrical in shape except for any neck sections of the balloon, any tapered sections (e.g., cones) between the neck section and the main diameter section, and any tapered or sharp sections at the longitudinal ends 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, or polygonal (e.g., pentagonal, hexagonal, heptagonal, octagonal, etc.), or a combination thereof. The diameter of a non-cylindrical balloon is the largest dimension perpendicular to the longitudinal direction.

[0082] The balloon can be formed from any suitable material, such as a non-compliant or semi-compliant biocompatible material. In some embodiments, the balloon can be manufactured by blow molding to achieve the desired geometry. In some embodiments, the balloon can comprise a material that does not interact with the drug coating, such as nylon (e.g., any 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.

[0083] The balloon may have any suitable size. The balloon may be designed to fit within the prostatic urethra, with the distal section of the balloon being positioned within the bladder. The main diameter and nominal balloon diameter can be selected from 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, e.g., 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 less than, equal to, greater than, or greater than about 50 mm; the main diameter can be an independent range from any of these ranges or specific dimensions. The balloon can have a length of about 20 mm to about 160 mm, 40 mm to about 80 mm, or less than about 20 mm or 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 less than, equal to, greater than, or greater than about 80 mm. Balloon length and diameter can be selected based on the patient's specific prostate anatomy.

[0084] The balloon may include at least one neck. A neck is a portion of the balloon having a diameter smaller than the balloon's nominal main diameter. The neck diameter may be less than, equal to, greater than, or greater than about 5 mm to about 35 mm, 10 mm to about 35 mm, or about 5 mm or less, or about 6 mm, 8 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 about 35 mm. 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 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 main balloon section. In some embodiments, where the main balloon section has a nominal diameter of 35 to 40 mm, the neck has a diameter of 15 to 20 mm. In some embodiments, if the neck diameter is too close to the main diameter, the ability of the balloon to prevent slippage may be reduced.

[0085] The neck can be rigid or semi-rigid, such that the diameter of the neck (e.g., the portion of the neck having the neck diameter) remains substantially constant 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, e.g., nylon, polyamide, aromatic polyamide, ultra-high molecular weight polyethylene (UHMWPE), polyester, aromatic polyester, polyethylene terephthalate (PET), or a combination thereof.

[0086] In some embodiments, the balloon neck is semi-compliant and can expand at a different rate than the main balloon body. The neck compliance can 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 expansion rate of the neck diameter can be greater than the expansion rate of the main body diameter over a test pressure range of 1 to 5 atmospheres. The expansion rate of the neck diameter can be in the range of 1.1 to 10 times the main body diameter (main diameter), e.g., in the range of 2 to 6 times the main diameter, over a test pressure range of 1 to 5 atmospheres. The expansion rate of the neck diameter is 12.38% / atmosphere. The expansion rate of the main diameter is 2.4% / atmosphere. The difference in expansion rates is 9.98% / atmosphere. Table 3 shows example measurements of a balloon having a neck that expands less than the balloon body when inflated at 2 to 4 atmospheres. The expansion rate of the neck diameter can be less than the expansion rate of the main body diameter over a test pressure range of 2 to 4 atmospheres.

[0087] [Table 2]

[0088] [Table 3]

[0089] The neck can create a wedge of tissue between the larger diameter portions of the balloon, which can maintain the balloon in place. The larger portion of the balloon cannot overcome the tissue barrier created by the neck, and therefore, a balloon with a neck prevents, reduces, or minimizes balloon migration during inflation. Balloon necks can be positioned at various locations 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 traction while still maintaining treatment efficacy.

[0090] The neck may have a central narrowed portion having a minimum diameter at the neck and various diameters, including adjacent portions between the central narrowed 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 narrowed portion having the minimum diameter, 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., about 1% to about 50% of the balloon length, or less than or equal to about 1%, or 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 less than or equal to about 50% of the balloon length, as measured including the central narrowed portion and the adjacent tapered portion (e.g., cone). , greater than or greater than about 0.5 mm to about 40 mm or less than about 0.5 mm 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, greater than or greater than about 40 mm.

[0091] In some embodiments, the balloon may include one neck and no other neck, such that the balloon includes two main sections separated by a neck. The one neck may have any suitable location on the balloon, such as approximately midway along the length of the balloon or offset along the length of the balloon. The one neck may be offset along the length of the balloon and may be at the distal end of the balloon. An embodiment of a balloon including one neck offset along the length of the balloon is illustrated in FIG. 1A.

[0092] In some embodiments, the balloon may include two necks, with no other neck, 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 positioned symmetrically or asymmetrically relative to the center of the balloon length. The three sections may have approximately equal or different lengths. FIG. 1B illustrates an embodiment of a balloon catheter having two necks and three sections, where the necks are positioned symmetrically relative to approximately the center of the balloon length and where the three sections of the balloon have approximately the same length. During use, the distal neck (e.g., the neck at the distal end of the balloon catheter that is inserted first into the body) can secure and position the balloon at the bladder neck, while the proximal neck can be positioned at the prostatic urethra. In some embodiments, the distal section of the balloon catheter may be free of a therapeutic agent.

[0093] In some embodiments, the balloon may include three necks, with no other necks, such that the balloon includes four sections separated by the three necks. The three necks may be arranged in any suitable manner along the length of the balloon. The four sections 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. Figure 1C shows an embodiment of a balloon catheter having three necks and four sections, each having approximately equal lengths, where two of the necks have equal diameters that are smaller than the diameters of the other necks.

[0094] The balloon catheter can be a fixed-wire balloon catheter. The outer shaft can be connected to the proximal balloon neck, the distal end of the tapered wire can be connected to the distal neck of the balloon, and the proximal ends of the wire and outer shaft can be connected to a hub (e.g., a valve, connector, or adapter) at the proximal end of the balloon catheter. The balloon catheter can be a movable-wire catheter. The outer shaft can be connected to the proximal balloon neck, the distal end of the tapered wire can be connected to the distal neck of the balloon, and the proximal end of the wire can move freely relative to the hub at the proximal end of the balloon catheter. The balloon catheter can be an over-the-wire balloon catheter. The balloon catheter can be a rapid-exchange balloon catheter. The balloon catheter can 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), and the catheter shaft can include an internal lumen for delivering air, liquid, or a combination thereof into the balloon. The catheter shaft may comprise a thermoplastic material that thermally bonds (e.g., by heating or melting) to the balloon, such as a high-durometer material similar to or identical to the balloon material, such as 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 shattering and allow for pushability and maneuverability. The outer diameter of the catheter shaft may be sized to allow passage through the working channel of a standard cystoscope. The catheter shaft may include a fluid connection between the interior of the balloon and an internal lumen, such as a hole in the catheter shaft below the balloon attachment point to allow inflation of the balloon by injecting a medium through the internal lumen.

[0095] In various embodiments, the catheter shaft can 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 tissue healing into the new position. The drug-coated balloon can be used not only for inflation and drug delivery, but also as a Foley catheter.

[0096] The end (e.g., the proximal end) of the catheter shaft that remains outside the body can 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 can prevent backflow of fluid or air from the balloon (e.g., when closed or at all times). The hub can include any suitable valve, such as a Tuohy Borst adapter. A Tuohy Borst adapter is a compression-sealing device that can 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 can control fluid overflow into the balloon and can be connected to an inflation device with a standard luer.

[0097] The balloon catheter may include a catheter tip at the longitudinal end of the balloon, which is 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 that is overcoated on the catheter shaft or adhesively bonded to the shaft. For example, the Coude tip may be made of Pebax®. (登録商標) Alternatively, it may be made from liquid silicone rubber.

[0098] Figure 2 shows an embodiment of a balloon catheter, including a 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 any of a number of other drugs or biologics that would promote improvement of BPH symptoms. During use, only the proximal two sections of the balloon are coated with the drug, since the distal section resides within the bladder.

[0099] The balloon catheter may include an inflation device including a pressure gauge or pressure sensor, which is fluidly connected to a catheter shaft that is connected to the balloon catheter.

[0100] The balloons shown in Figures 1A, 1B, 1C, and 2 are blown 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 tube of balloon material 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, and the like. (登録商標) The balloon material can be any of polyurethanes, polyurethanes, and block copolymers of polyethers and polyesters. The tubing and mold are heated to a temperature above the glass transition temperature of the balloon material tubing and pressurized with gas, air, fluid, etc., causing the tubing material to take the shape of the mold. The formed balloon is then cooled, trimmed, and then ready to be bonded to a catheter.

[0101] After the balloon is attached to the catheter, the balloon is inflated at low pressure, and a neck reinforcement is bonded to the neck region. The neck reinforcement is used to control 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 monofilament or multifilament of such materials, including elements contained in superalloys including 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 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 using two or more points of glue or adhesive.

[0102] The balloon's main sections can be formed with the same or similar diameters. In some embodiments, the diameters of the various main sections can differ from each other by up to 30% when measured at the balloon's nominal diameter. In Figures 1A, 1B, 1C, and 2, the balloon's main sections are depicted with equal diameters, i.e., the diameter of each main section is constant. In practice, at high pressures, the diameter of the main section may sag slightly, with the central section of the main section having a slightly larger diameter than the ends of the main section near the balloon cone and / or near the neck.

[0103] In embodiments in which the balloon has a neck and a trunk, as shown in Figures 1A, 1B, 1C, and 2, and in which the balloon does not have any neck, as shown in Figure 3, after the balloon catheter is assembled, the balloon may be coated with at least one water-soluble additive and drug described herein. In some embodiments in which 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 coating the balloon. The catheter is then packaged, sterilized, and labeled as known in the art.

[0104] Embodiments of the present invention relate to balloon catheters having rapid drug-releasing coatings and methods of manufacturing such coated devices. The therapeutic agent in embodiments of 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 goal of embodiments 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.

[0105] The drug coating may cover any suitable percentage of the balloon's outer 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 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or less than, equal to, greater than, or greater than about 100%.

[0106] 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, PEG8 Caprylic / Capric Glyceride, PEG Caprylate, PEG8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, Monolaurin, Monocaprin, Monocaprylin, Monomyris The present invention may include water-soluble additives such as those selected from the group consisting of thiamin, thiamin monophosphate ... 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.

[0107] In various embodiments, the present invention provides methods 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) the ratio of the inflated balloon diameter to the normal body lumen diameter at the target site is about 1.0 to about 20; or (b) the inflation comprises inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, wherein the inflation ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; or (c) the inflation comprises inflating to a pressure greater than the nominal pressure of the balloon catheter, wherein 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 inflation. The method may include withdrawing the balloon catheter from the stenosis in the body lumen.

[0108] Various embodiments provide a method for treating benign prostatic hyperplasia (BPH) stricture, urethral stricture, ureteral stricture, prostate cancer, esophageal stricture, bile duct stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, and large intestinal stricture, asthma, or chronic obstructive pulmonary disease (COPD).The method is a method for treating strictures in body cavities, such as urethral stricture, benign prostatic hyperplasia (BPH) stricture, ureteral stricture, esophageal stricture, sinus stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, and large intestinal stricture, and bile duct stricture.The stricture in body cavities can be benign prostatic hyperplasia (BPH) stricture, urethral stricture, or esophageal stricture. The method may be a method of treating benign prostatic hyperplasia, prostate cancer, or a combination thereof, wherein the body cavity is the prostate.

[0109] The method may include 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.

[0110] The body cavity can be the prostate, and wherein 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.

[0111] The body cavity may be the prostate, the balloon may have multiple sections divided by one or more necks, and balloon catheter insertion may include positioning one section of the balloon catheter in the prostate and a second section of the balloon catheter in the bladder.

[0112] The insertion can include positioning at least one neck of the balloon at the bladder neck. The at least one neck of the balloon catheter can be a distal neck, and the insertion can include positioning the distal neck at the bladder neck. The balloon catheter can include a proximal neck, and the insertion can include positioning the proximal neck at the prostatic urethra.

[0113] 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.

[0114] 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 Atmospheres may be increased at any suitable rate (e.g., time periods during which pressure drops due to tissue production can be excluded and pressure can be maintained during these times), such as less than, equal to, greater than, or greater than about 10 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.

[0115] Dilation may include monitoring the pressure within the balloon, such as with a pressure gauge. During stenosis creation, which may involve reducing the pressure, dilation may include stabilizing the pressure within the balloon, allowing the stabilized pressure within the balloon to stabilize for a period of time during tissue production, and then resuming increasing the pressure within the balloon until the desired dilated diameter is achieved. The stabilization time can be any 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.

[0116] As shown in FIG. 3 , in one embodiment, the medical device is a balloon catheter. The balloon catheter can be any suitable catheter for the desired use, including conventional balloon catheters known to those skilled in the art. For example, balloon catheter 10 can include an expandable, inflatable balloon 12 at the distal end of catheter 10, a handle assembly 16 at the proximal end of catheter 10, and an elongated flexible member 14 extending between the proximal and distal ends. Handle assembly 16 can 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). Flexible member 14 can 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 inflation medium and pass such medium to balloon 12 for inflation. The balloon catheter can be a rapid exchange or over-the-wire catheter and can be fabricated from any suitable biocompatible material. The material of the balloon 12 is polyester, polyamide, nylon 12, nylon 11, polyamide 12, polyether-polyamide block copolymer, Pebax (登録商標) , polyurethanes, and block copolymers of polyether and polyester.

[0117] In one embodiment, the present invention provides a balloon catheter for delivering a therapeutic agent to tissue, such as vascular or non-vascular tissue. The device includes a layer applied to the outer surface of the balloon catheter. The layer includes a therapeutic agent and one or more additives. The additives can be any suitable additive. A layer can include one additive, or a layer can include more than one additive, such as a water-soluble first additive and a water-soluble second additive. For example, as shown in the embodiment depicted in FIG. 4A, balloon 12 is coated with layer 20 including a therapeutic agent and an additive. In one 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 one embodiment, the device can optionally include an adhesive layer. For example, as shown in the embodiment depicted in FIG. 4B, balloon 12 is coated with adhesive layer 22. Layer 24 including a therapeutic agent and an additive covers the adhesive layer. The adhesive layer, a separate layer underlying the drug coating layer, improves adhesion of the drug coating layer to the outer surface of the medical device and protects the coating integrity. For example, if the drug and additive have different adhesion properties to the medical device, 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. Furthermore, the adhesive layer can function to promote rapid release of the coating layer components from the device surface upon contact with tissue at the target site. In other embodiments, the device can include a top layer. For example, as shown in the embodiment depicted in FIG. 4C, balloon 12 is coated with adhesive layer 22, layer 26 containing a therapeutic agent and additives overlying the adhesive layer, and top layer 28. The top layer can prevent loss of the drug layer prior to contact with the target tissue, for example, during delivery of balloon 12 to the therapeutic intervention site or during the first moment of inflation of balloon 12 before coating layer 20 is pressed into direct contact with the target tissue.

[0118] Embodiments of the present invention relate to the treatment of strictures in body lumens by delivery of an effective amount of a therapeutic agent, such as an anti-inflammatory agent and an anti-proliferative agent (e.g., rapamycin, paclitaxel or analogs thereof). Strictures in body lumens include vascular strictures, urethral strictures, ureteral strictures, esophageal strictures, achalasia strictures, in-stent strictures, sinus strictures, gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, and large intestinal strictures and bile duct strictures. ... The present invention relates to a method for treating at least one of vascular stenosis, benign prostatic hyperplasia (BPH), urethral problems, prostate cancer, asthma, and chronic obstructive pulmonary disease (COPD). In an embodiment, the method includes delivering a therapeutic agent, such as an anti-inflammatory agent and an anti-proliferative agent (e.g., rapamycin, paclitaxel, or an analog thereof), from a coated medical device, such as a balloon catheter. The therapeutic agent can be coated onto the medical device alone or together with one or more additives.

[0119] In certain embodiments, the present invention relates to a method for treating a stricture in a body cavity, comprising inserting a balloon catheter comprising a coating layer into the stricture (wherein the stricture is one 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, and bile duct stricture, wherein the coating layer comprises 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 to 70% of the total drug load on the balloon catheter, and wherein the drug in the wall of the body cavity can be about 0.1 to 25% of the total drug load on the balloon catheter. In certain aspects of this embodiment, the additive enhances absorption of the drug into the tissue of the stricture in the body cavity.

[0120] In one embodiment, the present invention relates to a method for 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 lumen, and wherein the coating layer comprises a drug and an additive), inflating the balloon catheter to release 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 to 70% of the total drug load on the balloon catheter, and wherein the drug in the wall of the body cavity can be about 0.1 to 25% of the total drug load on the balloon catheter. In some aspects of this embodiment, the additive enhances absorption of the drug into tissues in the body cavity. In another aspect of this embodiment, the additive comprises a hydrophilic moiety and a drug affinity moiety, wherein the drug affinity moiety is at least one of a hydrophobic moiety, a moiety having affinity for the therapeutic agent through hydrogen bonding, and a moiety having affinity for the therapeutic agent through van der Waals interactions.

[0121] In one embodiment, the present invention relates to a balloon catheter for delivering a therapeutic agent to a target site of a stricture in a body cavity, the balloon catheter comprising 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, docetaxel, taxol, analogs thereof, rapamycin, sirolimus, everolimus, tacrolimus, analogs thereof, and combinations thereof, and 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-octnoyl-D-sphingosine, N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG-caprylic / capric diglyceride, PEG-8 caprylic / capric glyceride Lysine, 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, xanthan gum, monophosphate In some embodiments, the hydroxybenzoates are selected from the group consisting of inosin, 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.

[0122] In some embodiments of the balloon catheter, one or more water-soluble additives facilitate rapid release of the therapeutic agent from the balloon, whereby rapid release includes a residual amount of the therapeutic agent remaining in the balloon after the balloon is inflated at the target site in the body cavity for an inflation time of about 0.1 to 10 minutes and then removed from the body cavity.

[0123] 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 greater 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 about 0.05 or less, or 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 less than, equal to, greater than, or greater 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 about 0.05 or less, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20.

[0124] In one embodiment, the present invention relates to a method for treating a stricture 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 a balloon catheter into a target site of a stenosis in a body cavity (the balloon catheter includes a balloon and a coating layer covering the outer surface of the balloon, the coating layer including 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, everolimus, tacrolimus, analogs thereof, and combinations thereof, and the water-soluble additive is 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-oct ... 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, Mono Nocaprin, 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 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), 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 to 10 minutes), and withdrawing the balloon catheter from the stenosis in the body cavity. The dilatation balloon catheter diameter may have a ratio of dilatation balloon diameter to normal diameter of the treated body lumen of about 1.0 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or less than about 1.0, or less than, equal to, greater than, or greater than about 1.01, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20; The stretch ratio of the balloon nominal diameter to the normal diameter of the body lumen at the treatment site can be about 1.0 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or less than about 1.0, or less than, equal to, greater than, or greater than about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20. Optionally, inflation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0125] The balloon may have a residual drug amount thereon after withdrawal of about 90 wt%, 88 wt%, 86 wt%, 84 wt%, 82 wt%, 80 wt%, 78 wt%, 76 wt%, 74 wt%, 72 wt%, 70 wt%, 68 wt%, 66 wt%, 64 wt%, 62 wt%, 60 wt%, 58 wt%, 56 wt%, 54 wt%, 52 wt%, 50 wt%, 48 wt%, 46 wt%, 44 wt%, 42 wt%, 40 wt%, 38 wt%, 3 Any suitable residual drug amount may remain after withdrawal, such as less than, equal to, or greater than 6 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%.

[0126] In certain embodiments, the present invention relates to a method for treating at least one of benign prostatic hyperplasia and prostate cancer, the method comprising: flushing the prostate with water, saline solution, or an aqueous solution comprising at least one water-soluble additive; 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, wherein 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 prostate 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 minutes to 10 minutes); and withdrawing the balloon catheter from the prostate. The ratio of the inflated balloon diameter to the normal diameter of the body lumen may be about 1.0 to about 20, or about 1.01 to about 15, or less than about 1.01, or about 1.01, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or less than, equal to, greater than, or greater than about 20, and the balloon nominal diameter The stretch ratio to the normal diameter of the body lumen at the treatment location can be about 1.0 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or less than about 1.0, or less than, equal to, greater than, or greater than about 1.01, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20. Optionally, inflation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0127] In certain embodiments, the present invention relates to a method for treating a urethral stricture, the method comprising: flushing the urethral stricture with water, 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 the 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 to 20); inflating the balloon until the coating layer contacts the urethral stricture 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 urethral stricture. The ratio of the inflated balloon diameter to the normal diameter of the urethra at the location of the stricture may be less than, equal to, greater than, or greater than about 1.0 to about 20, or about 1.01 to about 15, or less than about 1.01, or about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20, and the balloon nominal diameter The stretch ratio to the normal diameter of the body lumen at the treatment location can be less than, equal to, greater than, or greater than about 1.0 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or less than about 1.0, or about 1.01, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20. After dilation, the diameter of the urethral stricture can be less than, equal to, greater than, or greater than 6.7 mm or greater, e.g., from about 6.7 mm to about 50 mm, or from about 6.7 mm to about 20 mm, or from 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. Optionally, dilation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0128] In certain embodiments, the present invention relates to a method for treating an esophageal stricture, such as an achalasia stricture, comprising: optionally flushing the esophageal stricture with water, saline solution, or an aqueous solution comprising at least one water-soluble additive before, during, or after balloon catheter insertion; and inserting the balloon catheter into a target site in the esophageal stricture, the balloon catheter comprising a balloon and a coating layer covering the exterior surface of the balloon, wherein the coating layer comprises at least one water-soluble second additive and a coating layer having a diameter of 1 mm or less than 1 mm of the nominal diameter of the balloon. 2 the coating layer contains an initial drug load of a therapeutic agent of 1 to 6 μg per coating layer, 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 to 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 to 10 minutes); and withdrawing the balloon catheter from the esophageal stricture. The ratio of the balloon diameter to the normal diameter of the esophagus at the stricture location may be about 1.0 to about 20, or about 1.01 to about 20, or less than about 1.01, or about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or less than, equal to, greater than, or greater than about 20; The stretch ratio of the normal diameter of the esophagus at the stricture location can be less than, equal to, greater than, or greater than about 1.0 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or less than about 1.0, or about 1.01, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20. In some embodiments, the balloon catheter properties are equal to or similar to those shown in Table 4 and have a growth rate that slows at high pressures. 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.

[0129] [Table 4]

[0130] In certain embodiments, the present invention relates to a method for treating an esophageal stricture, such as an achalasia stricture, comprising: optionally flushing the esophageal stricture with water, saline solution, or an aqueous solution comprising at least one water-soluble additive before, during, or after balloon catheter insertion; inserting the balloon catheter into a target site in the esophageal stricture, the balloon catheter comprising a balloon and a coating layer covering the exterior surface of the balloon, wherein the coating layer comprises at least one water-soluble second additive and a coating layer having a diameter of 1 mm or less than 1 mm of the nominal diameter of the balloon; 2the coating layer comprises an initial drug loading of 1 to 6 μg of therapeutic agent per coating layer, 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 to 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 ratio of the inflated balloon diameter to the normal diameter of the esophagus at the location of the stenosis may be about 1.0 to about 20, or about 1.01 to about 20, or about 1.31 to 20, or less than about 1.01, or about 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or less than, equal to, greater than, or greater than about 20, and the balloon nominal diameter The stretch ratio to the normal diameter of the esophagus at the stenosis site can be about 1.0 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or about 1.31 to 20, or less than about 1.0, or about 1.01, 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or less than, equal to, greater than, or greater than about 20. Optionally, inflation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter. In some embodiments, the balloon catheter has properties equal to or similar to those shown in Table 5, which are single-balloon catheters capable of achieving a wide range of balloon diameters at relatively high working pressures compared to conventional compliant balloons. The balloons in Table 5 have unique properties, with three balloon diameter increments at three incremental inflation pressures. The nominal inflated diameter is the diameter at Stage I. The diameter increases by approximately 0.5 to 4 mm, preferably 0.75 to 3 mm, and most preferably 0.9 to 2 mm with each stage of pressure increase. For example, a balloon with a diameter of 15 mm at Pressure I (3 atmospheres) will have a diameter of 16.5 mm at Pressure II (4.5 atmospheres) and a diameter of 18 mm at Pressure III (7 atmospheres).

[0131] [Table 5]

[0132] In one embodiment, the present invention relates to a method for treating a gastrointestinal stricture, wherein the gastrointestinal stricture includes a gastric stricture, a small intestinal stricture, a duodenal stricture, a jejunal stricture, an ileal stricture, a colonic stricture, a rectal stricture, and a large intestinal stricture and 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 the outer surface of the balloon, wherein the coating layer comprises at least one water-soluble second additive and a coating layer covering the outer surface of the balloon, the coating layer comprising at least one water-soluble second additive and a coating layer covering the outer surface of the balloon, the coating layer being greater than 1 mm in diameter. 2the coating layer comprises an initial drug loading of 1 to 6 μg of therapeutic agent per coating layer, 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 to 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 period (wherein the inflation period is 0.1 to 10 minutes), and withdrawing the balloon catheter from the esophageal stricture. The dilatation balloon catheter diameter may be such that the ratio of the balloon diameter to the normal diameter of the esophagus at the location of the stenosis is about 1.0 to about 20, or about 1.31 to about 20, or about 1.01 to about 15, or less than about 1.01, or about 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or less than, equal to, greater than, or greater than about 20; The stretch ratio of the nominal diameter to the normal diameter of the esophagus at the stenosis may be about 1.0 to about 20, or about 1.31 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or less than about 1.0, or less than, equal to, greater than, or greater than about 1.01, 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20. Optionally, inflation may include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter. In some embodiments, the balloon catheter is similar to or equal to those shown in Tables 4 and 5, having a slow growth rate at high pressure and a single balloon catheter capable of achieving a wide range of balloon diameters at high working pressures.

[0133] In various embodiments, the drug-coated balloon catheter used to treat esophageal strictures, achalasia strictures, and gastrointestinal strictures (including gastric strictures, small intestinal strictures, duodenal strictures, jejunal strictures, ileal strictures, colonic strictures, rectal strictures, and large intestinal strictures and bile duct strictures) has a catheter design that is a fixed wire, wire-guided, over-the-wire catheter, or rapid exchange design catheter.

[0134] In certain embodiments, the present invention relates to a method for treating a sinus stenosis, the method comprising flushing the sinus stenosis with water, saline solution, or an aqueous solution comprising at least one water-soluble additive; 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, wherein the coating layer comprises at least one water-soluble additive and a thickness of at least 1 mm for a nominal diameter of the balloon; 2The therapeutic agent comprises an initial drug loading dose of 1 to 6 μg of therapeutic agent per capsule, wherein the therapeutic agent is selected from budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cortisone, betamethasone, triamcinolone acetonide, and combinations thereof, and the water-soluble additive is 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-Octnoyl-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 Caproe 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(hydroxybenzoate) 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 selected from the group consisting of (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, 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 sinus stenosis at the target site and the balloon achieves its 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 sinus stenosis.

[0135] In some embodiments, it may be desirable to pre-dilatate a target area of ​​a body cavity, such as the prostate, before using a 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 that of 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, it may be desirable to directly dilate a target area of ​​a body cavity without pre-dilatation.

[0136] Embodiments of the present invention relate to balloon catheters having rapid drug-releasing coatings and methods of manufacturing such coated devices. The therapeutic agent in embodiments of 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 goal of embodiments 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.

[0137] 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 have any suitable length, such as about 10 to 20 mm. The necks can divide the balloon symmetrically, or some balloon body portions can be longer than others. The balloon nominal diameter ranges from 6 to 45 mm and the working length is 20 to 160 mm.

[0138] FIG. 1A illustrates a balloon having one neck in one embodiment. 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, secured, or otherwise attached to a catheter shaft (not shown). During inflation, waists 101 and 107 do not expand because they are connected to the catheter shaft. FIG. 1B illustrates a balloon having two necks in one embodiment. 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, secured, or otherwise attached to a catheter shaft. During inflation, waists 121 and 129 do not expand because they are connected to the catheter shaft. While necks 124 and 126 are shown as having the same diameter when inflated, they can be the same or different diameters with the same or different compliances. In one embodiment, FIG. 1C shows a balloon having three necks. 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. Once assembled into a balloon catheter, waists 141 and 151 are connected, secured, or otherwise attached to the catheter shaft, as known to those skilled in the art. During inflation, waists 141 and 151 do not expand because they are connected to the catheter shaft. Although necks 144, 146 and 148 are shown as having different diameters in the expanded state, they may be the same or different diameters with the same or different compliances.

[0139] As shown in FIG. 2 , in some embodiments, the medical device is a balloon catheter, fixed-wire balloon catheter, movable-wire catheter, over-the-wire balloon catheter, or rapid-exchange balloon catheter, including conventional balloon catheters known to those skilled in the art. For example, balloon catheter 150 may include an expandable, inflatable balloon at the distal end of catheter 150, a handle assembly 160 at the proximal end of catheter 150, an elongated flexible member 164 extending from the proximal end to the distal end, and an atraumatic coupe tip 163. Handle assembly 160 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). 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 inflation medium and pass such medium through balloon 162 for inflation thereof. The balloon catheter may be a fixed wire, 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, and others. (登録商標) , polyurethane, and block copolymers of polyether and polyester. In one embodiment, Figure 2 shows a balloon having two necks. Balloon 162 has waist 151, cone 152, first body portion 153, first neck 154, second body portion 155, second neck 156, third body portion 157, cone 158, and waist 159. When assembled into a balloon catheter, waists 151 and 159 are connected, secured, etc., to the catheter shaft as known to those skilled in the art. During inflation, waists 151 and 159 do not expand because they are connected to the catheter shaft. While necks 154 and 156 are shown as having the same diameter when inflated, they can be the same or different diameters with the same or different compliances.

[0140] As shown in FIG. 3 , in one embodiment, the medical device is a balloon catheter. The balloon catheter can be any suitable catheter for the desired use, including conventional balloon catheters known to those skilled in the art, including fixed-wire balloon catheters, movable-wire catheters, over-the-wire balloon catheters, and rapid-exchange balloon catheters. For example, the balloon catheter 10 can include an expandable, inflatable balloon 12 at the distal end of the catheter 10, a handle assembly 16 at the proximal end of the catheter 10, and an elongated flexible member 14 extending between the proximal and distal ends. The handle assembly 16 can be connected 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 inflation medium and pass such medium through the balloon 12 for inflation thereof. The balloon catheter can be a rapid-exchange or over-the-wire catheter and can be fabricated from any suitable biocompatible material. The material of the balloon 12 is polyester, polyamide, nylon 12, nylon 11, polyamide 12, polyether-polyamide block copolymer, Pebax (登録商標) , polyurethanes, and block copolymers of polyether and polyester.

[0141] In one embodiment, the present invention provides a medical device for delivering a therapeutic agent to diseased tissue or a 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. A layer can include one additive, or a layer can include more than one additive, such as a first water-soluble additive and a second water-soluble additive. For example, as shown in the embodiment depicted in FIG. 4A, balloon 12 is coated with layer 20 including a therapeutic agent and an additive. In one 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 one embodiment, the device can optionally include an adhesive layer. For example, as shown in the embodiment depicted in FIG. 4B, balloon 12 is coated with adhesive layer 22. Layer 24 including a therapeutic agent and an additive covers the adhesive layer. The adhesive layer, a separate layer underlying the drug coating layer, improves adhesion of the drug coating layer to the outer surface of the medical device and protects the integrity of the coating. For example, if the drug and additives adhere differently to the medical device, 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. Furthermore, the adhesive layer can function to promote rapid release of the coating layer components from the device surface upon contact with tissue at the target site. In other embodiments, the device can include a top layer. The top layer can reduce loss of the drug layer prior to contact with the target tissue, for example, during delivery of the balloon 12 to the therapeutic intervention site or during the first moment of inflation of the balloon 12 before the coating layer 20 is pressed into direct contact with the target tissue.

[0142] Embodiments of the present invention relate to the treatment of strictures of non-vascular body lumens by delivering an effective amount of a therapeutic agent, such as an anti-inflammatory agent and an anti-proliferative agent (e.g., rapamycin, sirolimus, everolimus, tacrolimus, paclitaxel, taxol, docetaxel or analogs thereof). Strictures of non-vascular body lumens include 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, and large intestinal 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). In various embodiments, the methods include delivering therapeutic agents such as anti-inflammatory and anti-proliferative agents (e.g., rapamycin, sirolimus, everolimus, tacrolimus, paclitaxel, taxol, docetaxel, or analogs thereof) via a coated balloon catheter. The anti-inflammatory and anti-proliferative agents may be coated onto the medical device alone or in combination with one or more additives.

[0143] A method for treating a stenosis in a non-vascular body cavity includes inserting a balloon catheter including a coating layer into the body cavity (wherein the coating layer includes a drug and an additive), inflating the balloon catheter to release the drug into the wall of the non-vascular body cavity, deflating the balloon, and withdrawing the balloon catheter, wherein the remaining drug can be about 1-70% of the total drug load on the balloon catheter, and wherein the drug in the wall of the body cavity can be about 0.1-25% of the total drug load on the balloon catheter. The method can include flushing the body cavity with water, 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 tissues of the non-vascular body cavity. In another aspect of this embodiment, the additive includes a hydrophilic moiety and a drug-affinity moiety, wherein the drug-affinity moiety is at least one of a hydrophobic moiety, a moiety having affinity for a therapeutic agent through hydrogen bonding, and a moiety having affinity for a therapeutic agent through van der Waals interactions.

[0144] A balloon catheter for delivering a therapeutic agent to a target site in a non-vascular body lumen can include a coating layer covering the outer surface of the balloon, wherein the coating layer includes an initial drug load of the therapeutic agent and one or more water-soluble additives, wherein the therapeutic agent is selected from paclitaxel, taxol, docetaxel, analogs thereof, rapamycin, sirolimus, everolimus, analogs thereof, and combinations thereof, and the water-soluble additives are N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octyl-D-gluconamide ... Noyl-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, PE G8 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 The compound is selected from the group consisting of tetrahydrofuran, ...

[0145] The non-vascular body cavity can be one of the esophagus, airway, sinuses, trachea, colon, bile duct, stomach, small intestine, duodenum, jejunum, ileum, rectum, large intestine, urinary tract, prostate, urethra, ureter, and other non-vascular lumens.

[0146] 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 10 minutes and subsequently removed from the non-vascular lumen.

[0147] 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 greater 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 about 0.05 or less, or 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, equal to, greater than, or greater 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 about 0.05 or less, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20.

[0148] The initial drug loading was 1 mm 2 per external surface area of ​​the nominal diameter of the balloon) of therapeutic agent, the residual drug amount can be less than, equal to, greater than, or greater than 1 μg to 20 μg, or about 2 to about 6 μg, or about 1 μg or less, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 μg. The residual drug amount can be 70% or less of the initial drug load.

[0149] A method for treating a stenosis in a non-vascular body lumen includes flushing the non-vascular body lumen with water, saline solution, or an aqueous solution containing 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 including a balloon and a coating layer covering the exterior surface of the balloon, the coating layer including at least one water-soluble additive and an initial drug load of a therapeutic agent, the therapeutic agent being selected from paclitaxel, taxol, docetaxel, analogs thereof, rapamycin, sirolimus, everolimus, analogs thereof, and combinations thereof, and 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-heterocyclic amine, N-hydroxybenzoate ... Xanoyl-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, Monocapron Glyceryl acetate, 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 inflating the balloon until the coating layer contacts the wall of the stenosis in a non-vascular body lumen 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 to 10 minutes), and withdrawing the balloon catheter from the stenosis in a 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 normal diameter of the target site of the body lumen can be about 1.01 to about 20, and the stretch ratio of the balloon nominal diameter to the normal diameter of the body lumen at the treatment location can be about 1.0 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or less than about 1.0, or less than, equal to, greater than, or greater than about 1.01, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20. Optionally, inflation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0150] The balloon may have a residual drug amount thereon after withdrawal. Any 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%.

[0151] 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 greater 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 about 0.05 or less, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20.

[0152] In various embodiments, the coating layer can include one or more water-soluble additives and an initial drug load of a therapeutic agent, wherein the therapeutic agent is selected from paclitaxel, paclitaxel analogs, rapamycin, rapamycin analogs, and combinations thereof, and the water-soluble additive is N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, or the like. Erin, 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, Monocaprylate Glyceryl Caprate, 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-Hydroxyethylhexyl)benzylparaben, (2-Hydroxyethyl ... 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.

[0153] A method for treating at least one of benign prostatic hyperplasia and prostate cancer can include flushing the prostate with water, saline solution, or an aqueous solution containing at least one water-soluble additive, and inserting a balloon catheter into a target site in the prostate, the balloon catheter including a balloon and a coating layer covering the exterior surface of the balloon. The method can include inflating the balloon until the coating layer contacts the wall of the benign prostatic hyperplasia or prostate 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 minutes to 10 minutes), and withdrawing the balloon catheter from the prostate. The ratio of the inflated balloon diameter to the normal lumen diameter at the target site can be about 1.01 to about 20, or about 1.31 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or greater than about 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20, and the ... nominal balloon diameter to the normal lumen diameter at the treatment site can be about 1.01 to about 20, or about 1.31 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or greater than about 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20, and the ratio of the nominal balloon diameter to the treatment site The stretch ratio to the normal diameter of the body lumen at this point can be less than, equal to, greater than, or above about 1.0 to about 20, or about 1.31 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or less than about 1.0, or about 1.01, 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 or less. Optionally, inflation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0154] A method for treating a urethral stricture includes flushing the urethral stricture 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 urethral stricture (the balloon catheter includes a balloon and a coating layer covering the exterior surface of the balloon, wherein the coating layer includes 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 to 20); inflating the balloon until the coating layer contacts the urethral stricture at the target site and 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 minutes to 10 minutes); and withdrawing the balloon catheter from the urethral stricture. The ratio of the inflated balloon diameter to the normal diameter of the body lumen at the site of the urethral stricture can be about 1.01 to about 20, or about 1.31 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or greater than about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20, and the ... nominal balloon diameter to the treatment location can be about 1.01 to about 20, or about 1.31 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or greater than about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20, and the ratio of the nominal balloon diameter to the treatment location can be The stretch ratio of the normal diameter of the body cavity at this point may be less than, equal to, greater than, or greater than about 1.0 to about 20, or about 1.31 to about 20, or about 1.1 to about 15, or about 1.2 to about 10, or less than about 1.0, or about 1.01, 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20. After dilation, the diameter of the urethral stricture can be less than, equal to, greater than, or greater than 6.7 mm or greater, e.g., from about 6.7 mm to about 50 mm, or from about 6.7 mm to about 20 mm, or from 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. Optionally, dilation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0155] In some embodiments, the balloon has a residual drug amount thereon after withdrawal that is less than 70% of the initial drug load.

[0156] A method for treating an esophageal stricture includes flushing the esophageal stricture with water, saline solution, or an aqueous solution containing at least one water-soluble additive, and inserting a balloon catheter into a target site in the esophageal stricture, the balloon catheter including a balloon and a coating layer covering the exterior surface of the balloon, wherein the coating layer contains at least one water-soluble second additive and a coating layer covering the exterior surface of the balloon. 2The therapeutic agent comprises an initial drug loading of 1 to 6 μg of therapeutic agent per capsule, wherein the therapeutic agent is selected from paclitaxel, taxol, docetaxel, rapamycin, sirolimus, tacrolimus, everolimus, an mTOR inhibitor or analog thereof, and combinations thereof, and the water-soluble additive is N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactosamine, or the like. Cerebroside, Lactocerebroside, N-Acetyl-D-Sphingosine, N-Hexanoyl-D-Sphingosine, N-Octnoyl-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, The coating layer is selected from the group consisting of erythritol 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, 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 0.0.1 to 10 minutes), 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 to 10 minutes), and withdrawing the balloon catheter from the esophageal stricture. The ratio of the inflated balloon diameter to the normal diameter of the esophagus at the stricture location can be about 1.01 to about 20, 1.31 to 20, or about 1.1 to about 15, or about 1.3 to about 10, or about 1.31 to 10, or about or greater than about 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20, and the ratio of the inflated balloon diameter to the normal diameter of the esophagus at the stricture location can be about 1.01 to about 20, 1.31 to 20, or about 1.1 to about 15, or about 1.3 to about 10, or about 1.31 to 10, or greater than about 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20. The stretch ratio of the normal diameter of the body lumen can be less than, equal to, greater than, or greater than about 1.0 to about 20, 1.31 to 20, or about 1.1 to about 15, or about 1.2 to about 10, or about 1.3 to 10, or about 1.31 to 10, or less than about 1.0, or about 1.01, 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20. Optionally, inflation can include inflation to a pressure equal to or greater than the nominal pressure of the balloon catheter.

[0157] A method for treating a sinus stenosis includes flushing the sinus stenosis with water, saline solution, or an aqueous solution containing at least one water-soluble additive, and inserting a balloon catheter into a target site in the sinus stenosis, the balloon catheter including a balloon and a coating layer covering an exterior surface of the balloon, wherein the coating layer contains at least one water-soluble additive and a coating layer covering the exterior surface of the balloon. 2The therapeutic agent comprises an initial drug loading dose of 1 to 6 μg of the therapeutic agent per capsule, the therapeutic agent being selected from budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cotisone, betamethasone, triamcinolone acetonide, and combinations thereof, and the water-soluble additive is N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucamine, N-octanoyl-N-methylglutamine, C6-sodium glutamate, C6-hydroxybenzo ... Ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octonoyl-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(hydroxypropyl)urea 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 selected from the group consisting of dimethyl 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, and05-20), inflating the balloon until the coating layer contacts the wall of the sinus stenosis at the target site and the balloon achieves its 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 sinus stenosis.

[0158] additives In various embodiments, the additive may have two portions: one hydrophilic portion and the other a drug-affinity portion. The drug-affinity portion has affinity for the therapeutic agent through hydrophobic moieties and / or hydrogen bonding and / or van der Waals interactions. The drug-affinity portion of the additive may bind lipophilic drugs, such as rapamycin or paclitaxel. The hydrophilic portion accelerates diffusion and increases the drug's penetration into tissues. It may facilitate drug migration off the medical device during deployment at the target site by preventing hydrophobic drug molecules from aggregating with each other and the device, increasing drug solubility in interstitial spaces, and / or accelerating drug migration through the polar end groups to the lipid bilayer of the target tissue cell membrane. The additive of the present invention has two portions that function together to prevent premature release of the drug from the device surface before device deployment at the target site, while promoting rapid drug release from the device surface and uptake by the target tissue (by accelerating the drug's contact with tissues for which it has a high affinity) during deployment.

[0159] In embodiments of the present invention, the therapeutic agent is rapidly released and easily absorbed after the medical device comes into contact with tissue. For example, some embodiments of the device of the present invention include a drug-coated balloon catheter that delivers a therapeutic agent, such as a lipophilic antiproliferative drug (e.g., paclitaxel or rapamycin), to nonvascular tissues by simple, direct pressure contact at high drug concentrations during nonvascular balloon expansion. The lipophilic drug is retained in the target tissue at the delivery site, where it prevents hyperplasia and restenosis while still allowing epithelialization. In these embodiments, the coating formulation of the present invention not only promotes rapid drug release from the balloon surface and drug transport to the target tissue during deployment, but also prevents the drug from diffusing out of the device and the device from rupturing during the initial phase of balloon expansion before the drug reaches the target site via transport through complex body structures and before the drug coating is forced into direct contact with the surface of the body lumen.

[0160] In some embodiments, the additive has a drug affinity moiety and a hydrophilic moiety. The drug affinity moiety is a hydrophobic moiety that has affinity for therapeutic agents through hydrogen bonding and / or van der Waals interactions. The drug affinity moiety may include aliphatic and aromatic organic hydrocarbon compounds such as benzene, toluene, and alkanes. These moieties are not water-soluble. They can bind to both hydrophobic drugs and lipids in cell membranes, which share structural similarities. The drug affinity moiety may contain functional groups capable of forming hydrogen bonds with the drug and itself. The hydrophilic moiety may include hydroxyl groups, amine groups, amide groups, carbonyl groups, carboxylic acids and anhydrides, ethyl oxide, ethyl glycol, polyethylene glycol, ascorbic acid, amino acids, amino alcohols, glucose, sucrose, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic salts, and substituted molecules thereof. One or more hydroxyl groups, carboxyl groups, acid groups, amide groups or amine groups can be advantageous, for example, because they can easily replace the water molecules hydrogen-bonded to polar end groups and surface proteins of cell membranes, thereby eliminating 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 placement and for their rapid transfer from medical devices to target tissues.

[0161] The additives of the present invention can be surfactants and compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties. Surfactants include ionic, nonionic, aliphatic, and aromatic surfactants. The compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties can be selected from amino alcohols, hydroxyl carboxylic acids and anhydrides, ethyl oxide, ethyl glycol, amino acids, peptides, proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, and substituted molecules thereof.

[0162] As is well known in the art, the terms "hydrophilic" and "hydrophobic" are relative terms. To function as an additive in exemplary embodiments of the present invention, a compound contains a polar or charged hydrophilic portion and a non-polar hydrophobic (lipophilic) portion.

[0163] A commonly used empirical parameter in medicinal chemistry to characterize the relative hydrophilicity and hydrophobicity of a pharmaceutical compound is the partition coefficient P, e.g., P = ([solute] octanol / [solute] water), which is the concentration ratio of a non-ionized compound in the two phases of a mixture of two immiscible solvents, usually octanol and water. A compound with a high log P is more hydrophobic, while a compound with a low log P is more hydrophilic. Lipinski's law indicates that a pharmaceutical compound with a log P < 5 may be more membrane-permeable. For purposes of certain embodiments of the present invention, for example, an additive has a log P smaller than the log P of the drug being formulated (e.g., paclitaxel has a log P of 7.4). The greater the difference between the log P of the drug and the additive, the more likely it is that the drug will phase separate. For example, if the log P of the additive is much smaller than that of the drug, the additive can facilitate the release of the drug into the aqueous environment from the device surface, to which the drug would otherwise be intimately attached, thereby facilitating drug delivery to tissues during short placement at the intervention site. In some embodiments of the invention, the log P of the additive is negative. In other embodiments, the log P of the additive is less than the log P of the drug. The octanol-water partition coefficient, P, or log P, of a compound is useful for measuring relative hydrophilicity and hydrophobicity, but is only a rough guide as to the definition of an additive suitable for use in embodiments of the invention.

[0164] 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 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.

[0165] 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, as well as combinations of surfactants and other additives, are also within the scope of various embodiments of the present invention. Surfactants often contain 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.

[0166] An empirical parameter commonly used to characterize 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, while the HLB scale is generally considered inapplicable to anionic, cationic, or amphoteric compounds. Similarly, hydrophobic surfactants are compounds with HLB values ​​less than about 10. In some embodiments of the present invention, high HLB values ​​are utilized because increased hydrophilicity can promote hydrophobic drug release from the surface of a device. In some embodiments, the HLB of the surfactant additive is greater than 10. The additive HLB can be greater than 14. Alternatively, surfactants with low HLB values ​​can be used, for example, in a top coat over a drug layer with a superhydrophilic additive to prevent drug loss prior to device placement at the target site.

[0167] The HLB value of surfactants is generally only a rough guideline that can be 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, HLB value can be used as a guideline to identify surfactants that have suitable hydrophilicity or hydrophobicity for use in embodiments of the present invention, as described herein.

[0168] 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.

[0169] Polyethylene glycol fatty acid diesters are also suitable for use as surfactants in the compositions of this invention. Hydrophilic surfactants include PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, and PEG-32 dioleate. HLB values ​​range from 5 to 15.

[0170] In general, mixtures of surfactants, including mixtures of two or more commercially available surfactants and mixtures of a surfactant with 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.

[0171] 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.

[0172] Alcohol-oil transesterification products Many surfactants with varying degrees of hydrophobicity or hydrophilicity can be produced by the reaction of alcohols or polyalcohols with various natural and / or hydrogenated oils. The oils most commonly 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 transesterification surfactants, hydrophilic surfactants include PEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT), and PEG-40 hydrogenated castor oil (Cremophor RH 40). 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).

[0173] Polyglycerol fatty acids Polyglycerol esters of fatty acids are also suitable surfactants for use in embodiments of the present invention. Among 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- and dioleate (CaproI). TM PEG 860), Polyglycerol-10 Stearate, Polyglycerol-10 Laurate, Polyglycerol-10 Myristate, Polyglycerol-10 Palmitate, Polyglycerol-10 Linoleate, Polyglycerol-6 Stearate, Polyglycerol-6 Laurate, Polyglycerol-6 Myristate, Polyglycerol-6 Palmitate, and Polyglycerol-6 Linoleate. Polyglycerol polyricinoleate (Polymuls) is also a surfactant.

[0174] 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).

[0175] 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).

[0176] Polyethylene glycol sorbitan fatty acid ester A variety of PEG-sorbitan fatty acid esters are available and suitable for use as surfactants in embodiments of the present invention. Among PEG-sorbitan fatty acid esters, surfactants include PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitan monooleate (Tween-80). In some embodiments, laurate esters are used because they have shorter lipid chains compared to oleate esters, which increases drug absorption.

[0177] 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).

[0178] sugars and their 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.

[0179] 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.

[0180] 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 various 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(CHO) a (C3H6O) b (C2H4O) aH, where "a" and "b" refer to the number of polyoxyethylene and polyoxypropylene units, respectively.

[0181] 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.

[0182] 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.

[0183] Sorbitan monopalmitate, an amphiphilic derivative of vitamin C (with vitamin C activity), can serve two important functions in solubilized systems. First, it possesses effective polar groups that can modulate the microenvironment. These polar groups are the same ones that make vitamin C itself (ascorbic acid) the most water-soluble organic solid compound available; ascorbic acid is soluble in water at approximately 30 wt / wt% (e.g., very close to the solubility of sodium chloride). Second, as the pH increases, it converts a fraction of the ascorbyl palmitate to more soluble salts, such as sodium ascorbyl palmitate.

[0184] Ionic surfactants Ionic surfactants, including cationic, anionic, and amphoteric surfactants, are suitable hydrophilic surfactants for use in embodiments of the present invention. Ionic surfactants include quaternary ammonium salts, fatty acid salts, and bile salts. Specific examples of ionic surfactants include benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, docetyitrimethylammonium bromide, sodium docetyi sulfate, dialkylmethylbenzylammonium chloride, edrophonium chloride, domiphen bromide, dialkyl esters of sodium sulfonosuccinate, dioctyl sodium sulfosuccinate, sodium cholate, and sodium taurocholate. They are soluble in both organic solvents (e.g., ethanol, acetone, and toluene) and water. They are particularly useful for medical device coatings because they simplify the preparation and coating process and have good adhesive properties. Water-insoluble drugs are generally soluble in organic solvents.

[0185] Some of the surfactants described herein are highly stable under heat. They survive ethylene oxide sterilization. They do not react with drugs such as paclitaxel or rapamycin during sterilization. Hydroxyl, ester, and amide groups are utilized because they are less likely to react with drugs, while amine and acid groups react with paclitaxel or rapamycin during sterilization. Furthermore, the addition of surfactants improves the integrity and quality of the coating layer, preventing particles from shedding during handling. When formulated with paclitaxel, the surfactants described herein promote rapid release and elution of paclitaxel during extremely short indwell times of 0.2 to 10 minutes at the target site while protecting against premature drug release during the device delivery process. Experimental results demonstrate unexpectedly high drug absorption by tissue at the target site.

[0186] Compounds containing one or more of the following moieties: hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester Compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties include creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin, (2-hydroxyethyl)urea, N,N'-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritol propoxylate / ethoxylate, glycerol ethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crown 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.

[0187] Compounds containing one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties include amino alcohols, hydroxyl carboxylic acids, esters, anhydrides, hydroxyl ketones, hydroxyl lactones, hydroxyl esters, sugar phosphates, sugar sulfates, ethyl oxides, ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol, polyalcohols, phosphates, sulfates, organic acids, esters, salts, vitamins, combinations of amino alcohols and organic acids, and substituted molecules thereof. Hydrophilic compounds containing one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties with molecular weights of less than 5,000 to 10,000 are utilized in some embodiments. In other embodiments, the molecular weight of the additive containing one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties is less than 1,000 to 5,000, or less than 750 to 1,000, or less than 750. In these embodiments, the molecular weight of the additive must be smaller than that of the drug to be delivered. Additionally, the molecular weight of the additive must be greater than 80, as molecules with molecular weights less than 80 volatilize very easily and do not remain in the coating of the medical device. Small molecules can diffuse rapidly; 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.

[0188] In some embodiments, for example, in the case of high molecular weight additives, additives with more than four hydroxyl groups are used. 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 four hydroxyl groups, their hydrophilicity increases, which is necessary for relatively large molecules to release the drug quickly. The increased hydrophilicity helps the coating dissolve from the balloon, accelerates drug release, and promotes drug migration through the water barrier and the polar head of the lipid bilayer to penetrate into tissues. In some embodiments, hydroxyl groups are used 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 four 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, and all of them 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 the improvement of compatibility of water-insoluble drugs and hydrophilic additives, and the improvement of tissue uptake and absorption of drugs.

[0189] Some of the compounds described herein that contain one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties are highly stable under heat. They survive ethylene oxide sterilization 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, and react with paclitaxel. When the compounds described herein are formulated with paclitaxel, a topcoat layer can be advantageous to protect against premature drug loss during the device delivery process prior to deployment at the target site, as hydrophilic small molecules sometimes release the drug too easily. The compounds described herein rapidly release the drug 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, for example, hydroxylactone additives such as riboflavin lactone and gluconolactone.

[0190] Fat-soluble vitamins and their salts Vitamins A, D, E, and K, in their various forms and most of their provitamin forms, are considered fat-soluble vitamins, and in addition, several other vitamins and vitamin sources or closely related compounds are also fat-soluble and 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 them useful as additives in embodiments of the present invention.

[0191] The following 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, methylolriboflavin, 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.

[0192] Water-soluble vitamins and their amphiphilic derivatives Vitamins B, C, U, pantothenic acid, folic acid, and some 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 form amphiphilic forms with relatively high octanol-water partition coefficients and polar groups. Similarly, such compounds can have low toxicity and a high benefit-to-risk ratio, making them useful as additives in embodiments of the present invention. Their salts can also be useful as additives in the present invention. Examples of water-soluble vitamins and derivatives include, 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.

[0193] Compounds containing amino or other basic groups 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 on vitamins, such as hydroxyl groups, to form bonds, such as ester bonds. Derivatives of water-soluble vitamins bearing acidic groups can be reacted with hydrophobic-group-containing reactants, such as stearylamine or riboflavin, to produce compounds useful in embodiments of the present invention, for example. Attachment of a palmitate chain to vitamin C results in ascorbyl palmitate.

[0194] 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.

[0195] 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. For purposes of this description, we interpret "low-solubility amino acids" to mean amino acids with 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.

[0196] 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 create additional additives useful in embodiments of the invention.

[0197] Catecholamines such as dopamine, levodopa, carbidopa and DOPA are also useful as additives.

[0198] 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 in the study.

[0199] Proteins are also useful as additives in embodiments of the present invention. Serum albumin, for example, is a useful additive because it is water-soluble and contains a significant hydrophobic moiety that binds to drugs. Paclitaxel is 89%-98% protein-bound, primarily to albumin (97%), after intravenous infusion in humans, while 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.

[0200] Other useful proteins include, but are not limited to, other albumins, immunoglobulins, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, vitronectin, fibrinogen, lipase, and the like.

[0201] Organic acids and their esters and anhydrides Examples include acetic acid and anhydride, benzoic acid and anhydride, diethylenetriaminepentaacetic dianhydride, ethylenediaminetetraacetic dianhydride, maleic acid and anhydride, succinic acid and anhydride, diglycolic anhydride, glutaric anhydride, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic aspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and 2-pyrrolidone.

[0202] These esters and anhydrides are soluble in organic solvents such as ethanol, acetone, methyl ethyl ketone, and ethyl acetate. Water-insoluble drugs can be dissolved in organic solvents using these esters and anhydrides, then easily coated onto 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 the device to the wall of the body cavity.

[0203] others Compounds having one or more hydroxyl, amine, carbonyl, carboxyl or ester moieties of In some embodiments, additives 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 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(propylene glycol), poly(propylene glycol) oligomers, block copolymers and derivatives of polyethylene glycol and polypropylene glycol, and combinations thereof.

[0204] Combinations of additives may also be useful for purposes of the present invention. Some embodiments include a combination or mixture of two additives, for example, a first additive comprising a surfactant and a second additive comprising a compound having one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties.

[0205] Combinations or mixtures of surfactants and small water-soluble molecules (compounds with one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties) have advantages. Formulations containing a mixture of two additives and a water-insoluble drug are sometimes superior to mixtures containing either additive alone. Hydrophobic drugs bind poorly to extremely water-soluble small molecules than surfactants. They are phase-separated from small water-soluble molecules, which can lead to suboptimal coating uniformity and integrity. Water-insoluble drugs have a higher log P than both surfactants and small water-soluble molecules. However, the log P of surfactants is generally higher than that of compounds with one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties. Surfactants have a relatively high log P (usually above 0), while water-soluble molecules have a low log P (e.g., below 0). Some surfactants, when used as additives in embodiments of the present invention, adhere so strongly to water-insoluble drugs and the surface of the medical device that the drug cannot be rapidly released from the surface of the medical device at the target site. On the other hand, some water-soluble small molecules (containing one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties) adhere poorly to medical devices, resulting in drug release in the serum before reaching the target site, e.g., during transport of a coated balloon catheter to the intervention target site. Surprisingly, by adjusting the concentration ratio of small hydrophilic molecules and surfactants in the formulation, the inventors discovered that coating stability during transport and rapid drug release upon expansion and pressing against the tissue of the lumen wall at the intervention target site are sometimes superior to formulations containing either additive alone. Furthermore, the presence of surfactants improves the miscibility and compatibility of water-insoluble drugs with highly water-soluble molecules. Surfactants also improve coating uniformity and integrity by providing better adhesion to drugs and small molecules. The long-chain hydrophobic portion of the surfactant binds tightly to the drug, while the hydrophilic portion of the surfactant binds to water-soluble small molecules.

[0206] The surfactants in the mixture or combination include all of the surfactants described herein for use in embodiments of the present invention. The surfactants in the mixture include PEG sorbitan fatty esters; PEG omega-3 fatty esters, ethers and alcohols; glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty esters, PEG fatty esters and alcohols, sugar fatty esters, PEG sugar esters, Tween 20, Tween 40, Tween 60, p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglycerol laurate, polyglyceryl oleate, polyglycerol myristate, polyglycerol palmitate, polyglycerol-6 laurate, polyglyceryl-6 oleate, polyglycerol-6 myristate, polyglycerol-6 palmitate, polyglycerol-10 laurate, polyglyceryl-10 oleate, polyglycerol-10 myristate, polyglycerol-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, Tween 20, Tween 40, Tween 60, Tween 80, Octoxynol, Octoxynol-9, Nonoxynol, Tyloxapol, Sucrose Monopalmitate, Sucrose Monolaurate, Decanoyl-N-methylglucamide, n-Decyl-β-D-glucopyranoside, n-Decyl-β-D-maltopyranoside, n-Dodecyl-β-D-glucopyranoside, n-Dodecyl-β-D-maltoside, Heptanonyl-N-methylglucamide The alkyl esters may be selected from n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside and derivatives thereof.

[0207] Embodiments of compounds having one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties in a mixture or combination can include any compound having one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties described herein for use in embodiments of the present invention. In various embodiments, the compound having one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties in the mixture has at least one hydroxyl group. In some embodiments, for example, in the case of high molecular weight additives, additives having more than four hydroxyl groups are utilized. In some embodiments, compounds having more than four hydroxyl groups have a melting point of 120°C or less. Large molecules diffuse slowly. If the molecular weight of the additive or compound is high, for example, if the molecular weight is greater than 800, greater than 1000, greater than 1200, greater than 1500, or greater than 2000, the large molecule may dissolve at the surface of the medical device too slowly to release the drug within two minutes. If these large molecules have more than four hydroxyl groups, the hydrophilic properties are increased, which is necessary for relatively large molecules to release the drug quickly. The increased hydrophilicity aids in eluting the coating from the balloon, accelerating drug release and facilitating drug transport through the water barrier and the polar head groups of the lipid bilayer into 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.

[0208] The compounds having one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties in the mixture are L-ascorbic acid and its salts, D-glucoscorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, riboic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic 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, vanillin, methylparaben, propylparaben, xylitol, 2-ethoxyethanol, sugar, galactose, gluco sugar, ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose, fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, salts of any of the organic acids and amines described herein, polyglycidol, glycerol, mulglycerol, Glycerol, galactitol, monolaurin, monocaprin, monocaprylin, monomyristin, monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin, (2-hydroxyethyl)urea, N,The copolymer is selected from 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, di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol) oligomers, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol) and penta(propylene glycol), poly(propylene glycol) oligomers, block copolymers and derivatives of polyethylene glycol and polypropylene glycol, and combinations thereof.

[0209] A mixture or combination of surfactants and water-soluble small molecules offers the benefits of both additives. Water-insoluble drugs are often incompatible with highly water-soluble compounds, and surfactants improve compatibility. Surfactants also improve coating quality, uniformity, and integrity, preventing particles from falling off the balloon during handling. Surfactants reduce drug loss during delivery to the target site. Water-soluble compounds improve drug release from the balloon and drug absorption in tissue. Experimentally, the combination has been surprisingly effective in preventing drug release during delivery and achieving high drug levels in tissues after an extremely short 0.2-2 minute indwelling. Furthermore, in animal studies, it effectively reduced stenosis and delayed lumen loss.

[0210] Some mixtures or combinations of surfactants and water-soluble small molecules are extremely stable under heat. They survive ethylene oxide sterilization and do not react with the water-insoluble drugs paclitaxel or rapamycin during sterilization. In some embodiments, hydroxyl, ester, and amide groups are utilized because they are less likely to react with therapeutic agents such as paclitaxel or rapamycin. Occasionally, amine and acid groups react with paclitaxel and are not stable under ethylene oxide sterilization, heating, and aging. When the mixtures or combinations described herein are formulated with paclitaxel, a topcoat layer may be advantageous to protect the drug layer from premature drug loss from the device.

[0211] Examples of additives include p-isononylphenoxypolyglycidol, PEG glyceryl oleate, PEG glyceryl stearate, polyglycerol laurate, polyglyceryl oleate, polyglycerol myristate, polyglycerol palmitate, polyglycerol-6 laurate, polyglyceryl-6 oleate, polyglycerol-6 myristate, polyglycerol-6 palmitate, polyglycerol-10 laurate, polyglyceryl-10 oleate, polyglycerol-10 myristate, polyglycerol-10 palmitate, PEG sorbitan, Sucrose monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, Octoxynol, Octoxynol-9, Nonoxynol, Tyloxapol, Sucrose monopalmitate, Sucrose monolaurate, Decanoyl-N-methylglucamide, n-Decyl-β-D-glucopyranoside, n-Decyl-β-D-maltopyranoside, n-Dodecyl-β-D-glucopyranoside, n-Dodecyl-β-D-maltoside, Heptanonyl-N-methylglucamide, n-Heptyl-β-D-glucopyranoside Glucoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cysteine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid and methionine (amino acids), cetotiamine, cyclotiamine, dexpanthenol, niacinamide, nicotinamide citric acid and its salts, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K7 and vitamin U (vitamins); albumin, immunoglobulins, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, vitronectin, fibrinogen, lipase, benzalkonium chloride, benzethonium chlorideDocetyltrimethylammonium bromide, sodium docetyI sulfate, dialkylmethylbenzylammonium chloride and dialkyl ester of sodium sulfonosuccinate, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone Ton, mannonic acid lactone, riboic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin, methylparaben, propylparaben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, Tiletamine, ketamine, propofol, lactic acid, acetic acid, salts of all organic acids and organic amines, polyglycidol, glycerol, multiglycerol, galactitol, monolaurin, monocaprin, monocaprylin, monomyristin, monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine, theobromine, theophylline, adenine, uracil, uridine, guanine, thymine, thymidine, xanthine, xanthosine, xanthosine monophosphate, cuff Ethylene, 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, di(ethylene glycol), tri(ethylene glycol),Examples of additives include tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol) oligomers, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol) and penta(propylene glycol), poly(propylene glycol) oligomers, block copolymers and derivatives of polyethylene glycol and polypropylene glycol, and combinations thereof (compounds having one or more hydroxyl, amino, carbonyl, carboxyl, or ester moieties). Some of these additives are water-soluble and organic solvent-soluble. They have good adhesive properties and adhere to the surface of polyamide medical devices such as balloon catheters. They may therefore be used in the adhesive layer, top layer, and / or drug layer in embodiments of the present invention. Aromatic and aliphatic groups increase the solubility of water-insoluble drugs in the coating solution, and alcohol and acid polar groups accelerate drug penetration into tissues.

[0212] In other embodiments of the present invention, additives include hydroxyl ketones, hydroxyl lactones, hydroxyl acids, hydroxyl esters, and hydroxyl amides. Examples include gluconolactone, D-glucoheptono-1,4-lactone, glucoctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, erythronic acid lactone, riboic acid lactone, glucuronic acid, gluconic acid, gentisic acid, lactobionic acid, lactic acid, acetaminophen, vanillic acid, sinapic acid, hydroxybenzoic acid, methylparaben, propylparaben, and derivatives thereof.

[0213] From a structural perspective, these additives share structural similarities and are compatible with water-insoluble drugs (e.g., paclitaxel and rapamycin). They often contain double bonds, such as C=C, C=N, or C=O, in aromatic or aliphatic structures. These additives also contain amine, alcohol, ester, amide, anhydride, carboxylic acid, and / or hydroxyl groups. They can form hydrogen bonds and / or van der Waals interactions with drugs. They are also useful as top layers in coatings. Compounds containing one or more hydroxyl, carboxyl, or amine groups are particularly useful as additives, for example, because they can facilitate drug release from device surfaces and readily displace water adjacent to polar head groups and surface proteins in cell membranes, thereby eliminating this barrier to hydrophobic drug permeability. They accelerate the transfer of hydrophobic drugs from the balloon into the lipid layers of cell membranes and tissues, for which they have a very high affinity. They can also transport or accelerate the transfer of drugs from the balloon into more aqueous environments, such as non-vascular tissue interstitial spaces that have been damaged by, for example, balloon angioplasty or stent expansion. Additives such as polyglycerol fatty esters, ascorbic acid esters of fatty acids, sugar esters, alcohols, and fatty acid ethers can be integrated into the lipid structure of target tissue membranes and have fatty chains that carry drugs to the lipid structure. Some amino acids, vitamins, and organic acids have aromatic C=N groups and amino, hydroxyl, and carboxylic acid elements in their structures. They have structural moieties that can bind or complex with hydrophobic drugs such as paclitaxel or rapamycin, and also have structural moieties that facilitate tissue penetration by removing the barrier between the hydrophobic drug and the lipid structure of cell membranes.

[0214] For example, isononylphenyl polyglycidol (Olin-10 G and Surfactant-10G), PEG glyceryl monooleate, sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitan monostearate, polyglycerol-10 oleate, polyglycerol-10 laurate, polyglycerol-10 palmitate, and polyglycerol-10 stearate all have more than four hydroxyl groups in their hydrophilic moieties. These hydroxyl groups have excellent affinity for the walls of body cavities and can replace hydrogen-bonded water molecules. At the same time, they contain long chains of fatty acids, alcohols, ethers, and esters that can complex with hydrophobic drugs and become integrated into and form part of the lipid structure of cell membranes. This deformation or relaxation of the lipid membrane of target cells can further accelerate the penetration of hydrophobic drugs into tissues.

[0215] Other examples include L-ascorbic acid, thiamine, maleic acid, niacinamide, and 2-pyrrolidone-5-carboxylic acid, all of which have extremely high aqueous and ethanol solubilities and low molecular weights and sizes. They also contain structural elements including aromatic C=N, amino, hydroxyl, and carboxylic acid groups. These structures are highly compatible with paclitaxel and rapamycin, potentially increasing the aqueous solubility of these water-insoluble drugs and accelerating their absorption into tissues. However, they often exhibit poor adhesion to the surface of medical devices. Therefore, they are often used in combination with other additives in the drug and top layers, where they are useful for enhancing drug absorption. Vitamins D2 and D3 are particularly useful, especially when used in combination with paclitaxel, because they have antirestenotic effects and reduce thrombosis.

[0216] In embodiments of the present invention, the additive is soluble in aqueous solvents and soluble in organic solvents. Extremely hydrophobic compounds that lack a sufficient hydrophilic moiety and are insoluble in aqueous solvents, such as the dye Sudan Red, are not useful as additives in these embodiments. Sudan Red is also genotoxic.

[0217] In some embodiments, the concentration density of the at least one therapeutic agent applied to the surface of the medical device is about 1-20 μg / mm 2 or approximately 2 to 6 μg / mm 2 or approximately 0.5 μg / mm 2 Less than or equal to about 1 μg / mm 2 , 2 μg / mm 2 , 3 μg / mm 2 , 4 μg / mm 2 , 5 μg / mm 2 , 6 μg / mm 2 , 7 μg / mm 2 , 8 μg / mm 2 , 9 μg / mm 2 , 10 μg / mm 2 , 12 μg / mm 2 , 14 μg / mm 2 , 16 μg / mm 2 , 18 μg / mm 2 or approximately 20 μg / mm 2 If the medical device is a balloon, these measurements are calculated at the nominal diameter. In some embodiments, the concentration of at least one additive applied to the surface of the medical device is about 0.5 to 20 μg / mm 2 or approximately 2 to 6 μg / mm 2 or approximately 0.5 μg / mm 2 Less than or equal to about 1 μg / mm 2 , 2 μg / mm 2 , 3 μg / mm 2 , 4 μg / mm 2 , 5 μg / mm 2 , 6 μg / mm 2 , 7 μg / mm 2 , 8 μg / mm 2 , 9 μg / mm 2 , 10 μg / mm 2 , 12 μg / mm 2 , 14 μg / mm 2 , 16 μg / mm 2 , 18 μg / mm 2 or approximately 20 μg / mm 2In embodiments of the present invention, the weight ratio of additive to drug in the coating layer can be about 20 to 0.05, about 10 to 0.1, or about 5 to 0.15.

[0218] The relative amounts of therapeutic agent and additive in the coating layer may vary depending on the applicable environment. The optimal amount of additive may depend, for example, on the particular therapeutic agent and additive selected, the critical micelle concentration of the surface modifier if it forms micelles, the hydrophilic-lipophilic balance (HLB) of the surfactant or the octanol-water partition coefficient (P) of the additive, the melting point of the additive, the aqueous solubility of the additive and / or therapeutic agent, the surface tension of an aqueous solution of the surface modifier, etc.

[0219] Other considerations further inform the selection of specific proportions of the various additives. These considerations may include the degree of biotolerability of the additives and the desired dose of therapeutic agent to be provided.

[0220] therapeutic agent The therapeutic agent that can be used in embodiments of the present invention can be any drug or biologically active substance. The therapeutic agent can be a hydrophobic therapeutic agent, an antiproliferative therapeutic agent, an anti-inflammatory agent, or a combination thereof. The drug can be in various physical states, such as molecular distribution, crystalline form, or cluster form. Examples of drugs that are particularly useful in embodiments of the present invention include lipophilic, substantially water-insoluble drugs, such as paclitaxel, rapamycin, daunorubicin, doxorubicin, rapachone, vitamins D2 and D3, and analogs and derivatives thereof. These drugs are particularly suitable for use in coating balloon catheters used to treat vasculature tissue. Therapeutic agents, such as antiproliferative agents, such as paclitaxel, taxol, docetaxel, rapamycin, sirolimus, tacrolimus, everolimus, mTOR inhibitors (i.e., a group of drugs that inhibit the mechanistic target of rapamycin) or their analogs, can be delivered to the wall of a body cavity to treat narrowing or stenosis.

[0221] Other drugs that may be useful in embodiments of the present invention include, but are not limited to, glucocorticoids (e.g., dexamethasone, betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisense agents, anticancer agents, antiproliferative agents, oligonucleotides, and more generally, antiplatelet agents, anticoagulants, antimitotic agents, antioxidants, antimetabolites, antichemotactic agents, anti-inflammatory agents, and combinations thereof.

[0222] Some drugs that may be useful in various embodiments, particularly for respiratory tract, paranasal sinuses, and other nasal cavity, as well as urethral applications, are corticosteroids such as budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone, mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cotisone, betamethasone, triamcinolone acetonide, etc. Some other suitable drugs are terbutaline, albuterol, ipratropium, pirbuterol, epinephrine, salmeterol, levalbuterol, formoterol, etc., and the drug may be a bronchodilator or a vasoconstrictor.

[0223] Also useful in embodiments of the invention are polynucleotides, antisense, RNAi or siRNA, which inhibit, for example, inflammation and / or smooth muscle cell or fibroblast proliferation.

[0224] Antiplatelet agents may include drugs such as aspirin and dipyridamole. Aspirin is classified as an analgesic, antipyretic, anti-inflammatory, and antiplatelet drug. Dipyridamole is a drug similar to aspirin in that it has antiplatelet properties. Dipyridamole is also classified as a coronary vasodilator. Anticoagulants for use in embodiments of the present invention may include drugs such as heparin, protamine, hirudin, and tick anticoagulant protein. Antioxidants may include probucol. Antiproliferative agents include drugs such as amlodipine and doxazosin. Mitotic inhibitors and antimetabolites that may be used in embodiments of the present invention may include drugs such as methotrexate, azathioprine, vincristine, vinblastine, 5-fluorouracil, adriamycin, and mutamycin. Antibiotics for use in embodiments of the present invention include penicillin, cefoxitin, oxacillin, tobramycin, and gentamicin. Antioxidants suitable for use in embodiments of the present invention include probucol. Furthermore, genes or nucleic acids, or portions thereof, may be used as therapeutic agents in embodiments of the present invention. Additionally, collagen synthesis inhibitors, such as tranilast, may be used as therapeutic agents in embodiments of the present invention.

[0225] For example, photosensitizing agents for photodynamic or radiotherapy, including various porphyrin compounds such as porfimers, are also useful as drugs in embodiments of the present invention.

[0226] Drugs for use in embodiments of the present invention include everolimus, somatostatin, tacrolimus, roxithromycin, zunaymycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, Nimustine, carmustine, lomustine, cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan, ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, temozolomide, thiotepa, daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine-5'-dihydrogen phosphate , cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole, exemestane, letrozole, formestane, aminoglutethimide, adriamycin, azithromycin, spiramycin, cepharanthine, SMC proliferation inhibition Agent-2w, epothilone A and B, mitoxantrone, azathioprine, mycophenolate mofetil, c-myc-antisense, b-myc-antisense, betulinic acid, camptothecin, lapachol, beta-lapachone, podophyllotoxin, betulin, podophyllinic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b, lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab, daclizumab, selectin (cytokine antagonist),CETP inhibitors, cadherins, cytokinin inhibitors, COX-2 inhibitors, NFkB, angiopeptins, ciprofloxacin, camptothecin, fluoroblastine, monoclonal antibodies inhibiting muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one, scopoletin, colchicine, NO donors such as pentaerythritol tetranitrate and syndnoeimine, S-nitroso derivatives, tamoxifen, staurosporine, beta-estradiol, α-estradiol, estriol, estrone, ethinylestradiol, fosfestrol, medroxyprogesterone, estradiol cypionate, estradiol benzoate, tranilast, camebacaurine and applied in the treatment of cancer. Other terpenoids used include verapamil, tyrosine kinase inhibitors (tyrphostin), cyclosporin A, 6-α-hydroxy-paclitaxel, baccatin, taxotere and other macrocyclic oligomers of carbon suboxides (MCS) and their derivatives, mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, gold sodium thiomalate, oxaceprol, celecoxib, β-sitosterol, ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, escin, ellipticine, D-24851 (Calbiochem), colcemid, cytochalasins A-E, indanocine, nocodazole, S 100 proteins, bacitracin, vitronectin receptor antagonists, azelastine, guanylyl cyclase stimulator tissue inhibitor of metalloproteinases-1 and -2, free nucleic acids, nucleic acids incorporated into viral transmitters, DNA and RNA fragments, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotides, VEGF inhibitors, IGF-1, antibiotics such as cefadroxil, cefazolin, cefaclor, cefotaxime, tobramycin, gentamicin,Penicillins, e.g., dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotic agents, e.g., argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulfated and N-reacetylated heparin, tissue plasminogen activator, GpIIb / IIIa platelet membrane receptor, factor Xa inhibitor antibodies, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin phosphorus, urokinase, vasodilators such as dipyridamole, trapidil, nitroprusside, PDGF antagonists such as triazolopyrimidines and suramin, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thiol protease inhibitors, prostacyclin, vapiprost, interferon alpha, beta and gamma, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators such as p65 NF-kB or BcI-xL antisense oligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, boswellic acid and its derivatives, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone, mutamycin, procainamide, retinoic acid, quinidine, disopyramide, flecainide, propafenone, sotalol, amiodarone, natural and synthetic steroids, such as bryophylline A, inotodiol, makiroside A, galactoside, mansonin, strebrosides, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances (NSAIDS) such as fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone and other antivirals such as acyclovir, ganciclovir and zidovudine, antifungals such as clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprotozoals such as chloroquine, mefloquine, quinine, and also natural terpenoids such as hypocaesculin, barringtogenol-C21-angelate,14-Dehydroagrostistatin, agroskerin, agrostistatin, 17-hydroxyagrostistatin, obatodiolide, 4,7-oxycycloanisomelic acid, baccarinoids B1, B2, B3 and B7, tubeimoside, bruceanol A, B and C, bruceantinoside C, yadandiolide N and P, isodeoxyelephantopine, tomenfantopine A and B, coronarin A, B, C and D, ursolic acid, hyptatic acid A, zeolin, iso-isoiridogermanal, meitenfoliol, efsanthin A, exisanin A and B, longicaulin B, scurponeatin C, cambounin, leucamenin A and B, 13,18-dehydro-6-α-senecioyloxychaparin, taxamaylin A and B, regenirol, triptolide, as well as cymarin, apocymarin, aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, chelibrine chloride, cicutoxin, cinococrine, bombrestatin A and B, kudraisoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-beta-hi Droxypregnadiene-3,20-dione, bilobol, ginkgolic acid, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, glycoside 1a, podophyllotoxin, justicidin A and B, lareatin, malotellin, malottochromanol, isobutyrylmalotochromanol, macilloside A, marcantin A, maytansine, lycoricidin, margetin, pancreastatin, liriodenine, bisparthenolidine, oxosinthunin, aristolactam-AII, bisparthenolidine, perimethicone Procoside A, Galakinoside, Ursolic Acid, Deoxysolospermine, Psycholvin, Ricin A, Sanguinarine, Manuwum Acid, Methylsorbifolin, Sphaceliachromene, Stizophylline, Mansonine, Strebroside, Akagerin, Dihydrousambalensin, Hydroxyusambalin, Strychnopentamine, Strychnophylline, Usambalin, Usambalensin, Berberine, Liriodenine, Oxosinsonin, Daphnoretin, Lariciresinol, Methoxylariciresinol, Syringaresinol, Umbelliferone, Afromosone,Also included are active agents selected from the group consisting of acetyl vismion B, desacetyl vismion A, and vismion A and B.

[0227] Combinations of drugs can also be used in embodiments of the present invention. Some combinations, such as paclitaxel and rapamycin, paclitaxel and active vitamin D, paclitaxel and rapachone, rapamycin and active vitamin D, and rapamycin and rapachone, have additive effects due to different mechanisms. Due to the additive effects, the drug doses can be reduced as well. These combinations can reduce complications caused by the use of high drug doses.

[0228] solvent Examples of solvents for producing the coating layer include one or a combination of the following: (a) water, (b) alkanes such as hexane, octane, cyclohexane, and heptane, (c) aromatic solvents such as benzene, toluene, and xylene, (d) alcohols such as ethanol, propanol, and isopropanol, diethylamide, ethylene glycol monoethyl ether, transcutol, and benzyl alcohol, (e) ethers such as dioxane, dimethyl ether, and tetrahydrofuran, (f) esters / acetates such as ethyl acetate and isobutyl acetate, (g) ketones such as acetone, acetonitrile, diethyl ketone, and methyl ethyl ketone, and (h) mixtures of water and organic solvents such as water / ethanol, water / acetone, water / methanol, and water / tetrahydrofuran. The solvent in the top coating layer can be, for example, methanol, ethanol, and acetone.

[0229] Organic solvents such as short chain alcohols, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, dimethyl sulfoxide, and the like are particularly useful solvents in embodiments of the present invention because these organic solvents generally disrupt colloidal aggregation and co-solubilize all of the components in the coating solution.

[0230] The therapeutic agent and one or more additives may be dispersed, solubilized, or otherwise mixed in the solvent. The weight percentage of the drug and additives in the solvent may range from 0.1 to 80% by weight or from 2 to 20% by weight.

[0231] Various embodiments provide a method for preparing a balloon catheter. First, a coating solution or suspension is prepared containing at least one solvent, at least one therapeutic agent, and at least one additive. In at least one embodiment, the coating solution or suspension contains only these three components. The content of the therapeutic agent in the coating solution can be 0.5 to 50 wt % based on the total weight of the solution. The content of the additive in the coating solution can be about 0.1 wt % to about 45 wt %, about 0.2 wt % to about 40 wt %, about 0.3 to about 15 wt %, or about 0.1 wt % or less, or about 0.2 wt %, 0.3 wt %, 0.4 wt %, 0.5 wt %, 0.6 wt %, 0.8 wt %, 1 wt %, 2 wt %, 3 wt %, or less, based on the total weight of the solution. The solvent content can be less than, equal to, greater than, or equal to 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 12 wt%, 14 wt%, 16 wt%, 18 wt%, 20 wt%, 22 wt%, 24 wt%, 26 wt%, 28 wt%, 30 wt%, 35 wt%, 40 wt%, or about 45 wt%. The amount of solvent used depends on the coating process and viscosity. It affects the uniformity of the drug-excipient coating, but is subject to evaporation.

[0232] In other embodiments, more than one solvent, more than one therapeutic agent, and / or more than one additive may be used in the coating solution.

[0233] In other embodiments, a therapeutic agent, an additive, and a polymeric material may be used in a coating solution for a balloon catheter, where the therapeutic agent is not encapsulated in polymer particles.

[0234] Various techniques can be used to apply the coating solution to the medical device, such as casting, fixed-volume liquid dispensing, metering (e.g., dispensing a fixed amount of coating solution volumetrically onto the balloon), spinning, spraying, dipping, inkjet printing, electrostatic techniques, and combinations of these methods. The balloon may be at least partially inflated during application of the coating solution. Metering can be performed in any suitable manner, such as by pumping the liquid coating solution from a reservoir to a nozzle proximal to the balloon surface (e.g., the surface of an at least partially inflated balloon). The nozzle dispenses liquid therefrom, which can be immediately transferred to the exterior of the balloon due to its proximity to the nozzle (e.g., the nozzle is close to the balloon such that liquid exiting the nozzle can contact and be transferred to the exterior of the balloon before forming droplets of liquid exiting the nozzle). The nozzle can dispense liquid to the exterior of the balloon with substantially no loss of liquid. The balloon can rotate about its longitudinal axis during liquid dispensing from the nozzle. The nozzle can move during dispensing to follow the exterior of the balloon parallel to the balloon's longitudinal axis. In some embodiments, the balloon can be rotated about its longitudinal axis during dispensing, and the nozzle can be moved along the longitudinal axis of the balloon (e.g., similar to the movement of a wood chisel on a cylindrical piece of wood turning on a lathe), so that substantially the entire balloon surface is coated with the coating solution.

[0235] The choice of application technique depends primarily on the viscosity and surface tension of the solution. In certain embodiments of the invention, metering may be utilized to facilitate control of the thickness of the coating layer and the uniformity of the therapeutic agent concentration applied to the medical device.

[0236] In one embodiment of the invention, the balloon is inflated or partially inflated and the coating solution is metered onto the inflated balloon while the balloon is inflated and rotated along its longitudinal axis. The balloon is then dried and then deflated, folded, and placed into a sheath.

[0237] The described embodiments of application devices, fixtures, and metering techniques are examples. Any suitable metering or other technique may be used to coat the balloon catheter.

[0238] After coating the medical device with the coating solution, the coated balloon is dried to evaporate the solvent in the coating solution, thereby forming a coating matrix containing the therapeutic agent on the balloon. One example of a drying technique is to place the coated balloon in an oven at about 20°C or higher for about 24 hours. Any other suitable method of drying the coating solution may be used. The time, temperature, and relative humidity may vary depending on the particular additives and therapeutic agent.

[0239] An embodiment of the present invention relates to a method for treating benign prostatic hyperplasia. The method includes inserting a medical device containing a coating into the prostatic urethra. The coating layer includes a therapeutic agent and an additive. In this embodiment, the medical device can be configured with at least an expandable portion. Some examples of such devices include balloon catheters, fixed-wire balloon catheters, over-the-wire balloon catheters, rapid exchange catheters, perfusion balloon catheters, infusion catheters (e.g., distally perforated drug infusion catheters, perforated balloons, spaced double balloons, porous and leaching balloons, cutting balloon catheters), spaced double balloons, cutting balloon catheters, scoring balloon catheters, self-expanding and balloon-expandable stents, guide catheters, guidewires, embolic protection devices, and various imaging devices.

[0240] As described herein, one example of a medical device particularly useful in the present invention is a coated balloon catheter. A balloon catheter generally comprises a long, narrow, hollow tube with a tiny, deflated balloon attached. In an embodiment of the present invention, the balloon is coated with a drug solution. The balloon is then guided through the stenosis in a non-vascular body lumen to the blockage, occlusion, or other tissue requiring a therapeutic agent. Once in the appropriate position, the balloon is inflated and contacted with the wall of the stenosis and / or blockage or occlusion in the non-vascular body lumen. Rapid delivery of the drug to the target tissue and promotion of absorption are goals of embodiments of the present invention. In various embodiments, it may be advantageous to efficiently deliver the drug to the tissue in as short a time as possible while the device is positioned at the target site. The therapeutic agent may be released into such tissue, e.g., the lumen wall, within about 0.1 to 30 minutes, e.g., about 0.1 to 10 minutes, about 0.2 to 2 minutes, or about 0.1 to 1 minute of balloon inflation time, during which the drug coating is pressed into contact with the diseased non-vascular tissue.

[0241] Given that therapeutically effective amounts of drug may be delivered, for example, to the prostate, by practice of embodiments of the present invention, the need for stents may in some cases be eliminated, eliminating the associated complications of fracture and dripping.

[0242] Balloon catheters can be used to treat non-vascular tissues / diseases, either alone or in combination with other methods and medical devices for the treatment of non-vascular structures, such as direct vision intraurethrotomy (DVIU) for strictures and transurethral resection of the prostate (TURP) for BPH. DVIU is a method used to open urethral strictures. Specifically, DVIU is a method in which a relaxing incision is made in the stricture to create a urethral lumen. DVIU can be achieved using a cold knife (urethrotome) or a hot knife (electrode). A cutter is inserted into the body and advanced through the urethra to the narrowed area. After the relaxing incision is made, balloon dilation using the coated balloon of an embodiment of the present invention can be performed. Furthermore, stent placement can be performed afterwards or simultaneously with the inflation of the coated balloon described herein. In other embodiments, balloon dilation using the coated balloon of an embodiment of the present invention can be performed within an indwelling stent. For TURP, the medical device commonly used is a hot knife (electrode) or a laser. In either case, the device is introduced into the body and advanced through the urethra to the area of ​​narrowing. After the prostate tissue is removed, balloon dilation using the coated balloon of an embodiment of the present invention can be performed. Additionally, stent placement can be performed after or simultaneously with inflation of the coated balloon described herein. In other embodiments, self-expanding stents coated with the therapeutic agents and additives of the present invention can be delivered to and placed into body lumen strictures, including 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.

[0243] preparation Various embodiments of the present invention provide methods for forming a balloon. The methods may include placing a tube containing balloon material into a balloon mold having any suitable shape, such as a balloon mold having a shape including a proximal cone, at least one body portion, at least one neck portion having a smaller diameter than the at least one body portion, at least one other body portion, and a distal cone. The methods may include pressurizing the interior of the balloon material tube. The methods may also include expanding the balloon material tube until it contacts the interior of the mold.

[0244] Various embodiments of the present invention provide methods for forming a balloon and then deflating it to a large diameter range. The method includes placing a tube containing balloon material into a balloon mold, where the balloon mold has a shape including a proximal cone, at least one body portion, and a distal cone. The method includes pressurizing the interior of the balloon material tube. The method includes inflating the balloon material tube at a pressure of 200-400 psi and a temperature of 100-200°C until it contacts the interior of the mold. The formed balloon is then deflated by slowly cooling the balloon at a lower temperature than during the formation process at a low inflation pressure for a specified period of time, preferably 1-30 psi and 70-90°C for 3-30 seconds. Once deflated, the balloon can be attached to a catheter shaft and coated with a drug. In embodiments of the present invention, any of the manufacturing techniques, methods for treating body cavities, or balloons described in the following patents can be used: U.S. Patents 7,163,522 and 7,108,826, which are incorporated herein by reference in their entireties.

[0245] The medical devices and coating layers of embodiments of the present invention can be prepared by various methods. For example, a coating solution can be prepared by dispersing, dissolving, diffusing, or otherwise mixing all of the components, such as the therapeutic agent, additive, and solvent, together at the same time. Alternatively, the coating solution can be prepared by sequentially adding each component based on solubility or some other parameter. For example, the coating solution can be prepared by first adding the therapeutic agent to the solvent and then adding the additive. Alternatively, the additive can be added to the solvent first, and the therapeutic agent can be added later. If the solvent used does not sufficiently dissolve the drug, it is useful to first add the additive to the solvent and then add the drug, as the additive increases the drug's solubility in the solvent.

[0246] International Prostate Symptom Score (IPSS) and Q max Q maxQ is a measure of the maximum urine flow rate obtained during urodynamic testing. It is the maximum volumetric flow rate of urine during urination. It is a measure of the amount of urine voided in a specific time (per second or per minute). It can be measured by uroflowmetry. max indicates the maximum flow velocity. Q max is used as an indicator for diagnosing an enlarged prostate or other urinary tract obstruction or stricture. max may indicate an enlarged prostate gland compressing the urethra or a urethral stricture partially obstructing the urethra.

[0247] Using the present invention, for example, the balloon shown in FIG. 3, a patient with a urethral stricture can max A person with a urethral stricture may experience an increase in max After treatment with the balloon of the present invention (measurements are usually taken 14 to 30 days after treatment), Q max is expected to increase to 9-52 mL / sec or at least 15 mL / sec, or in some embodiments at least 20 mL / sec, or in some embodiments, to less than, equal to, greater than, or greater than about 8 mL / sec, 9 mL / sec, 10 mL / sec, 11 mL / sec, 12 mL / sec, 13 mL / sec, 14 mL / sec, 15 mL / sec, 16 mL / sec, 17 mL / sec, 18 mL / sec, 19 mL / sec, 20 mL / sec, 22 mL / sec, 24 mL / sec, 26 mL / sec, 28 mL / sec, 30 mL / sec, 35 mL / sec, 40 mL / sec, 45 mL / sec, or about 50 mL / sec. max In one embodiment, after 6 months, max may also be less than, equal to, greater than, or greater than 15 mL / sec, 20 mL / sec or more, or in the range of 6 to 50 mL / sec, or about 8 mL / sec, 9 mL / sec, 10 mL / sec, 11 mL / sec, 12 mL / sec, 13 mL / sec, 14 mL / sec, 15 mL / sec, 16 mL / sec, 17 mL / sec, 18 mL / sec, 19 mL / sec, 20 mL / sec, 22 mL / sec, 24 mL / sec, 26 mL / sec, 28 mL / sec, 30 mL / sec, 35 mL / sec, 40 mL / sec, 45 mL / sec, or about 50 mL / sec. maxmay also be less than, equal to, greater than or equal to 15 mL / sec, greater than 20 mL / sec, or in the range of 6 to 50 mL / sec, 9 to 32 mL / sec, about 8 mL / sec, 9 mL / sec, 10 mL / sec, 11 mL / sec, 12 mL / sec, 13 mL / sec, 14 mL / sec, 15 mL / sec, 16 mL / sec, 17 mL / sec, 18 mL / sec, 19 mL / sec, 20 mL / sec, 22 mL / sec, 24 mL / sec, 26 mL / sec, 28 mL / sec, 30 mL / sec, 35 mL / sec, 40 mL / sec, 45 mL / sec or about 50 mL / sec.

[0248] Using the present invention, for example, the balloon shown in Figures 1A, 1B, 1C, or 2, patients with benign prostatic hyperplasia can undergo Q max People with BPH may experience an increase in max After treatment with the balloon of the present invention, in various embodiments, Q max is at least 16 mL / sec, and may be increased to a range of 4 to 35 mL / sec or to less than, equal to, greater than, or greater than about 8 mL / sec, 9 mL / sec, 10 mL / sec, 11 mL / sec, 12 mL / sec, 13 mL / sec, 14 mL / sec, 15 mL / sec, 16 mL / sec, 17 mL / sec, 18 mL / sec, 19 mL / sec, 20 mL / sec, 22 mL / sec, 24 mL / sec, 26 mL / sec, 28 mL / sec, 30 mL / sec, 35 mL / sec, 40 mL / sec, 45 mL / sec, or about 50 mL / sec. max It has been shown to have long-term effects on max is at least greater than 16 mL / sec, or in some embodiments, can be in the range of 16 to 32 mL / sec or less than, equal to, greater than, or greater than about 8 mL / sec, 9 mL / sec, 10 mL / sec, 11 mL / sec, 12 mL / sec, 13 mL / sec, 14 mL / sec, 15 mL / sec, 16 mL / sec, 17 mL / sec, 18 mL / sec, 19 mL / sec, 20 mL / sec, 22 mL / sec, 24 mL / sec, 26 mL / sec, up to 28 mL / sec, 30 mL / sec, 35 mL / sec, 40 mL / sec, 45 mL / sec, or about 50 mL / sec. maxmay be at least greater than 16 mL / sec, or in some embodiments, in the range of 16 to 30 mL / sec, or less than, equal to, greater than, or greater than about 8 mL / sec, 9 mL / sec, 10 mL / sec, 11 mL / sec, 12 mL / sec, 13 mL / sec, 14 mL / sec, 15 mL / sec, 16 mL / sec, 17 mL / sec, 18 mL / sec, 19 mL / sec, 20 mL / sec, 22 mL / sec, 24 mL / sec, 26 mL / sec, 28 mL / sec, 30 mL / sec, 35 mL / sec, 40 mL / sec, 45 mL / sec, or about 50 mL / sec. These advantages distinguish the present invention from prior art devices and methods.

[0249] The International Prostate Symptom Score (IPSS) is a validated patient-reported outcome measure (PROM) scoring system. Urologists worldwide recognize it and use it to screen for and diagnose benign prostatic hyperplasia (BPH) and to monitor symptoms and guide decisions about how to manage the disease. The IPSS consists of eight questions: seven about disease symptoms and one about the patient's quality of life. For the symptom questionnaire, patients are asked to select the rating that best describes their condition. The scale ranges from 0 to 5, with 5 representing the most symptomatic disease. The seven symptom scores are combined to obtain an overall score with a maximum possible score of 35. Responses to the quality of life questionnaire are scored on a scale of 0 to 6. These scoring systems allow for classification of scores as follows: a score of 7 or less indicates mild symptoms; a score of 8 to 19 indicates moderate symptoms; and a score of 20 to 35 indicates severe symptoms.

[0250] Using the balloon of the present invention, such as that shown in FIG. 3, patients with urethral strictures may experience a decrease in IPSS. Typical IPSS values ​​for individuals with urethral strictures range from 15 to 35. Following treatment with a balloon of the present invention, the IPSS is expected to be less than, equal to, greater than, or greater than 14, or in some embodiments, in the range of 0-13, 4-13, 0-11, or 0 or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or about 14. This treatment has been shown to have a long-term effect on IPSS. After six months, the IPSS is still less than 14, and in some embodiments, in the range of 0-13, 1-13, 0-11, or 0, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or about 14. After 12 months, the IPSS can still be up to less than 14 or 0-7 or 0 or less than, equal to, greater than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or about 14. These advantages distinguish the present invention from prior art devices and methods.

[0251] Using the balloon catheter of the present invention, such as that shown in Figures 1A, 1B, 1C, or 2, patients with benign prostatic hyperplasia may experience a decrease in IPSS. Typical IPSS values ​​for individuals with BPH range from 15 to 35. After treatment with a balloon of the present invention, the IPSS may be up to 14, or, in some embodiments, in the range of 4 to 13, or less than, equal to, greater than, or equal to 0 or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or less than, equal to, greater than, or equal to 14. This treatment may have a long-term effect on the IPSS. After six months, the IPSS may still be up to 14, or, in some embodiments, in the range of 1 to 13, or less than, equal to, greater than, or equal to 0 or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or less than, equal to, greater than, or equal to 14. After 12 months, the IPSS may still be below a maximum of 14 or in some embodiments in the range of 1 to 14, or 0 or less than, equal to, greater than, or greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or about 14. These advantages distinguish the present invention from prior art devices and methods.

[0252] Desired Q maxTo achieve an increase or decrease in IPSS, in some embodiments, a balloon coated with a therapeutic agent, such as an antiproliferative or anti-inflammatory drug, and one or more water-soluble additives, as described herein, is placed in the area of ​​the urethral stricture or in the prostate. For strictures, the balloon is then inflated to a diameter 1.0 to 20 times larger, e.g., about 1.2 to 3 times larger, than the native urethra (e.g., the normal diameter of the treated urethra). For BPH treatment, the balloon is inflated to a diameter about 1.0 to 20 times larger or about 1.2 to 10 times larger than the native (non-diseased) prostatic urethra. That is, the ratio of the balloon diameter at the urethral stricture treatment site to the normal diameter of the body cavity may be 1.2 to 3 and 1.2 to 10 for BPH treatment, and the stretch ratio may be the same or different. The balloon may remain inflated for 0.1 to 10 minutes to deliver the drug to the urethra. In some embodiments, a scope, such as a cystoscope, may be used to assist in balloon placement. In some embodiments, the balloon catheter shaft may be located within the lumen of the scope, and in other embodiments, it may be positioned alongside the scope. In some embodiments, the stricture or prostate may be pre-dilated with a non-drug-coated balloon before treatment with the drug-coated balloon. In some embodiments, the pre-dilation balloon is slightly shorter than the treatment balloon to ensure that the entire pre-dilated area of ​​the urethra or prostate is subsequently treated with the drug-coated balloon. In some embodiments, the lumen and / or the drug-coated balloon is flushed or soaked with water, saline, urine, or an aqueous solution containing at least one water-soluble additive before inserting the drug-coated balloon. The drug-coated balloon may be covered with a sheath to protect the coating during delivery to the treatment site. The sheath may be removed from the balloon before inflating the balloon.

[0253] While various embodiments have been specifically illustrated and described herein, it is recognized that modifications and variations of the present invention are encompassed by the above teachings and are within the purview of the following claims without departing from the spirit and intended scope of the present invention.

[0254] Except as otherwise indicated in the operating examples, all numbers expressing quantities of elements in layers, reaction conditions, and the like used in the specification and claims are to be understood as being prefaced in all instances with the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. [Example]

[0255] Various embodiments of the present invention may be better understood by reference to the following examples, which are provided for illustrative purposes only and are not intended to be limiting of the invention.

[0256] Throughout the examples, unless otherwise specified, the stretch ratio was calculated as the ratio of the nominal balloon diameter at the treatment location to the normal diameter of the body lumen. The normal diameter of the body lumen at the treatment location is the normal diameter of the body lumen at the treatment location, which can be calculated as the average diameter of the luminal stenosis or stenosis or healthy tissue adjacent to the stenosis, stenosis, or lesion proximal and distal to the stenosis or lesion. The inflated balloon diameter was approximately the same as the nominal balloon diameter at the pressure used during inflation, within 10% of the nominal balloon diameter.

[0257] Part I Example I-1. Preparation of coating solution Formulation 1: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG-8 caprylic / capric acid glyceride, and 2-6 ml ethanol were mixed.

[0258] Formulation 2: 50–150 mg (0.06–0.18 mmole) paclitaxel, 25–300 mg PEG-8 caprylic / capric acid glyceride, 25–300 mg uracil, and 2–6 ml ethanol were mixed.

[0259] Formulation 3: 50–150 mg (0.06–0.18 mmole) paclitaxel, 25–300 mg PEG-8 caprylic / capric acid glyceride, 25–300 mg uridine, and 2–6 ml ethanol were mixed.

[0260] Formulation 4: 50–150 mg (0.06–0.18 mmole) paclitaxel, 25–300 mg PEG-8 caprylic / capric acid glyceride, 25–300 mg sucralose, and 2–6 ml ethanol were mixed.

[0261] Formulation 4a: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8 caprylic / capric acid glyceride, 25-300 mg sucralose, and 2-6 ml ethanol were mixed in a 1:1:1 mass ratio of paclitaxel:PEG8 caprylic / capric acid glyceride:sucralose.

[0262] Formulation 4b: 50–150 mg (0.06–0.18 mmole) paclitaxel, 25–300 mg PEG8 caprylic / capric acid glyceride, 25–300 mg sucralose, and 2–6 ml ethanol were mixed in a mass ratio of paclitaxel:PEG8 caprylic / capric acid glyceride:sucralose of 1:1:2.

[0263] Formulation 5: 50–150 mg (0.06–0.18 mmole) paclitaxel, 25–300 mg PEG-8 caprylic / capric acid glyceride, 25–300 mg creatinine, and 2–6 ml ethanol were mixed.

[0264] Formulation 6: 50–150 mg (0.06–0.18 mmole) paclitaxel, 25–300 mg PEG-6 caprylic / capric acid glyceride, 25–300 mg uracil, and 2–6 ml ethanol were mixed.

[0265] Formulation 7: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg C6-ceramide, and 2-6 ml ethanol were mixed.

[0266] Formulation 8: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg monolaurin, 25-300 mg sucralose, and 2-6 ml ethanol were mixed.

[0267] Formulation 9: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg sucralose, and 2-6 ml ethanol were mixed.

[0268] Formulation 10: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG-8 monocaprylate / caprate, and 1-6 ml ethanol were mixed.

[0269] Formulation 11: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG-8 monocaprylate / caprate, 25-300 mg sucralose, and 1-6 ml ethanol were mixed.

[0270] Formulation 12: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg thymidine, and 1-6 ml (96 / 4 v / v) THF / water were mixed.

[0271] Formulation 13: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg uridine, and 1-6 ml (96 / 4 v / v) THF / water were mixed.

[0272] Formulation 14: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg caffeine, and 1-6 ml (96 / 4 v / v) THF / water were mixed.

[0273] Formulation 15: 50-150 mg (0.06-0.18 mmol) paclitaxel, 25-300 mg 18-crown 6, and 1-6 ml ethanol were mixed.

[0274] Formulation 16: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg 18-crown 6, and 1-6 ml ethanol were mixed.

[0275] Formulation 17: 50–150 mg (0.06–0.18 mmole) paclitaxel, 10–100 mg 18-crown 6, 10–100 mg pentaerythritol ethoxylate (15 / 4), and 1–6 ml ethanol were mixed.

[0276] Formulation 18: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg pentaerythritol ethoxylate (15 / 4) and 1-6 ml ethanol were mixed.

[0277] Formulation 19: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg trimethylpropane ethoxylate (Mw approximately 1014) and 1-6 ml ethanol were mixed.

[0278] Formulation 20: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg pentaerythritol ethoxylate (3 / 4) and 1-6 ml ethanol were mixed.

[0279] Formulation 21: 50-150 mg (0.06-0.18 mmol) paclitaxel, 25-300 mg 15-crown 5, and 1-6 ml ethanol were mixed.

[0280] Formulation 22: 25-100 mg (0.03-0.12 mmole) paclitaxel, 25-300 mg thymidine, and 1-6 ml (90 / 10 v / v) THF / water were mixed.

[0281] Formulation 23: 50–150 mg (0.06–0.18 mmole) paclitaxel, 5–75 mg pentaerythritol ethoxylate (15 / 4), 10–200 mg pentaerythritol ethoxylate (3 / 4), and 1–6 ml ethanol were mixed.

[0282] Formulation 24: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg trimethylpropane ethoxylate (Mw approximately 170) and 1-6 ml ethanol were mixed.

[0283] Example I-2. Preclinical trials 1 & 2 sample preparation Twenty-one balloon catheters (12 with a diameter of 4 mm and a length of 40 mm, 6 with a diameter of 8 mm and a length of 40 mm, and 3 with a diameter of 20 mm and a length of 50 mm) were inflated to a pressure of 1-2 atmospheres and wiped with ethanol tissue to clean the balloon surface. The balloons were then inflated to a pressure of 1-2 atmospheres and wiped with ethanol tissue to clean the balloon surface. 2 The balloons were coated using various formulations (1-6) from Example I-1, using enough coating solution to achieve 2-4 μg paclitaxel per balloon. The balloons were then dried, folded, sheathed, packaged in Tyvek pouches, and ethylene oxide sterilized in preparation for animal testing.

[0284] Example I-3. Preclinical trials 1 & 2 Treatment Male dogs were used in this study. A baseline urethrogram was taken to measure the internal diameter of the urethral treatment site before drug-coated balloon treatment. The drug-coated balloon catheters prepared in Example I-2 were used in a non-overlapping procedure in the pelvic, bulbar, and distal urethras immediately proximal to the os baculum. The os baculum urethra was not treated. The treatment site diameter was approximately 3.5 to 4.5 mm. The balloon catheters were selected so that the stretch ratio of the prostatic urethra balloon was approximately 4 to 10. For the anterior urethra, the balloon catheters were selected so that the stretch ratio was approximately 1.8 to 2.3. Approximately 5 mL of saline was used to flush the urethra before catheter insertion. An 18- to 20-mm nominal diameter balloon was inflated in the prostatic urethra, and an 8-mm nominal diameter balloon was inflated in the anterior urethra. The 18- to 20-mm nominal diameter balloon was inflated to 4 atmospheres at the treatment site for 10 minutes to release the drug and additives, then deflated and withdrawn from the dog. The 8-mm nominal diameter balloons were inflated to 12 atmospheres at the treatment site for 10 minutes to release the drug and additives, then deflated and withdrawn from the dog. The stretch ratios of the inflated 20-mm nominal diameter balloons ranged from 4.4 to 6.3. The stretch ratios of the inflated 8-mm nominal diameter balloons ranged from 2.0 to 2.5. The amount of residual drug in the treated urethral tissue of sacrificed animals was measured 4 hours and 1 day later to analyze the residual drug remaining in the balloons after use.

[0285] The drug-coated balloon catheters prepared in Example I-2 were inserted into the left ureter and urethra of female pigs. The 4 mm nominal diameter balloon was inflated to 14 atmospheres in the ureter, and the 8 mm balloon was inflated to 12 atmospheres in the urethra. The balloons were inflated at the treatment site for 10 minutes to release the drug and additives, then deflated and withdrawn from the pig. The stretch ratio of the 4 mm nominal diameter balloon was 2 to 2.5. The stretch ratio of the 8 mm nominal diameter balloon was 2.0 to 2.5. The drug concentrations in the urethral and prostate tissues of sacrificed animals were measured after 4 hours. The residual drug remaining in the balloons after use was analyzed.

[0286] Example I-4. Preclinical trials 1 & 2: Tissue and balloon residual drug content The dog tissue drug concentration from the prostatic urethra sample of Example I-3 using Formulation 4a was 0.4 μg / g at 4 hours. The dog tissue drug concentration from the prostate sample of Example I-3 using Formulation 4a was 0.367 μg / g at 4 hours. The dog tissue drug concentration from the pelvic urethra sample of Example I-3 using Formulation 4b was 11.7 μg / g at 4 hours. The dog tissue drug concentration from the bulbar urethra sample of Example I-3 using Formulation 4a was 25.2 μg / g at 4 hours. The dog tissue drug concentration from the prostatic urethra sample of Example I-3 using Formulation 4a was 0.586 μg / g on Day 1. The dog tissue drug concentration from the prostate sample of Example I-3 using Formulation 4a was 0.429 μg / g on Day 1. Dog tissue drug concentrations from pelvic urethra samples in Example I-3 using Formulation 4b were 26.6 μg / g on Day 1. Dog tissue drug concentrations from distal urethra samples in Example I-3 using Formulation 4a were 2.04 μg / g on Day 1. The remaining balloon content as a percentage of the original drug load from samples in Example I-3 using Formulation 4a ranged from 45 to 87%.

[0287] The remaining balloon content as a percentage of the original drug load from the samples of Example I-3 using Formulation 4b ranged from 83-85%.

[0288] At 4 hours, the proximal (Formulation 4b) right ureteral porcine tissue drug concentration from the sample in Example I-3 was 17.3 μg / g. At 4 hours, the sow urethra (Formulation 4a) drug concentration was 66.9 μg / g. The remaining balloon content as a percent of the original drug load from the samples in Example I-3 ranged from 6 to 58%. The average remaining balloon content for Formulation 4a was 52.8%. The average remaining balloon content for Formulation 4b was 64.7%.

[0289] Example I-5. Preclinical trial 3 Sample preparation Twenty-three balloon catheters (12 8 mm diameter and 40 mm length, 6 10 mm diameter and 40 mm length, 4 12 mm diameter and 30 mm length, and 3 10 mm diameter and 30 mm length) were inflated to 50% of their nominal inflation pressure and wiped with ethanol tissue to clean the balloon surface. The balloons were then inflated to within 1 mm of the balloon surface. 2 The balloons were coated with various formulations (1-6) from Example I-1 using sufficient coating solution to achieve 2 μg paclitaxel per balloon. The balloons were then dried, folded, sheathed, packaged in Tyvek pouches, and ethylene oxide sterilized in preparation for animal testing.

[0290] Example I-6. Preclinical Trial 3 Treatment Male dogs were used in this study. Baseline retrograde urethrograms were taken to measure the internal diameter of the urethral treatment site before drug-coated balloon treatment. The drug-coated balloon catheters prepared in Example I-5 were used in non-overlapping procedures in the prostate, pelvic, bulbar, and distal urethra just proximal to the os baculum. The os baculum urethra was not treated. Treatment site diameters ranged from approximately 2.1 to 8.5 mm. Balloon catheters were selected to plan a prostatic urethral balloon (ratio of balloon nominal diameter to normal diameter of target site) of approximately 1.7 to 3.4. For the anterior urethra, balloon catheters were selected to achieve a stretch ratio of approximately 1.8 to 2.3. Prior to catheter insertion, approximately 5 mL of saline was used to flush the urethra. A 12 mm nominal diameter balloon was inflated in the prostatic urethra, and 8 and 10 mm nominal diameter balloons were inflated in the anterior urethra. The 12-mm nominal diameter balloon was inflated to 9 atmospheres at the treatment site for 10 minutes to release the drug and additives, then deflated and withdrawn from the dog. The 8-mm nominal diameter balloon was inflated to 10 atmospheres at the treatment site for 10 minutes to release the drug and additives, then deflated and withdrawn from the dog. The stretch ratio for the 12-mm nominal diameter balloon was 2.0 to 3.0. The stretch ratio for the 8-mm and 10-mm nominal diameter balloons was 1.3 to 3.0. The amount of drug in the treated urethral tissue of sacrificed animals was measured 1 and 7 days later, and the residual drug remaining in the balloon after use was analyzed.

[0291] Example I-7. Preclinical trial 3: Residual drug content in tissue and balloon Dog tissue drug concentrations from the samples of Example I-6 ranged from 4 to 176 μg / g on Day 1 and from 0.003 to 23 μg / g on Day 7. The remaining balloon content as a percentage of the original drug load from the samples of Example I-6 ranged from 5 to 98%.

[0292] Example I-8. Preclinical trial 4 Sample preparation One hundred and eight balloon catheters (42 8 mm diameter and 20 mm length, 27 10 mm diameter and 40 mm length, 25 12 mm diameter and 40 mm length, 5 8 mm diameter and 55 mm length, and 9 12 mm diameter and 55 mm length) were inflated to 50% of their nominal inflation pressure and wiped with ethanol tissue to clean the balloon surface. The balloons were then divided into two groups; one group had 1 mm of the balloon surface and 2 mm of the balloon surface. 2 The other group was coated using formulation 1 and formulation 4 from Example I-1 with a coating solution sufficient to achieve 2 μg paclitaxel per mm of the balloon surface. 2 The balloons were coated using the same formulation from Example I-1 with sufficient coating solution to achieve 4 μg paclitaxel per balloon. The balloons were then dried, folded, sheathed, packaged in Tyvek pouches, and ethylene oxide sterilized in preparation for animal testing.

[0293] Example I-9. Preclinical trial 4 Treatment Male dogs were used for this study. Baseline retrograde urethrograms were taken to measure the internal diameter of the urethral treatment site before drug-coated balloon treatment. The drug-coated balloon catheters prepared in Example I-8 were used in non-overlapping procedures in the prostate, pelvic, bulbar, and distal urethra just proximal to the os baculum. The os baculum urethra was not treated. Treatment site diameters were approximately 2.6 to 7.7 mm. Balloon catheters were selected so that the prostatic urethral balloon stretch ratio was planned to be approximately 2 to 4. For the anterior urethra, balloon catheters were selected so that the stretch ratio was approximately 1.8 to 2.3. Approximately 5 mL of saline was used to flush the urethra before catheter insertion. 8- and 12-mm nominal diameter balloons were inflated in the prostatic urethra, and an 8-mm nominal diameter balloon was inflated in the anterior urethra. The prostatic urethral balloon was inflated at 6 to 9 atmospheres for 10 minutes to release the drug and additives, then deflated and withdrawn from the dog. An 8-mm nominal diameter balloon was inflated to 10 atmospheres at the treatment site for 10 minutes to release the drug and additives, then deflated and withdrawn from the dog. The stretch ratios for the prostatic urethral balloons were 2.0-5, 10, 15, or 20. The stretch ratios for the anterior urethral balloons were 1.1, 1.2, 1.3, 1.4, or 1.5-1.75, 2.0, 2.25, 2.50, 2.75, or 3.0. Treated urethral tissue from sacrificed animals was measured for urethral diameter and drug content after 1, 7, and 28 days to analyze residual drug remaining in the balloon after use. On day 28, samples were taken for histological evaluation, comparing the drug-coated balloon tissue with the flattened, older balloon, and untreated tissue.

[0294] Example I-10. Preclinical study 4 Pharmacokinetics, balloon residual drug content, and urethral lumen expansion The dog tissue mean drug concentrations from the samples of Example I-9 were 582 μg / g on Day 1, 0.347 μg / g on Day 7, and 4 μg / g on Day 28. The dog tissue mean drug concentrations from one sample of the 2 μg / g and 4 μg / g dose density formulations of Example I-9 were 20.34 μg / g and 0.73 μg / g, respectively, on Day 28. The dog tissue mean drug concentrations from four samples of the 2 μg / g and 4 μg / g dose density formulations of Example I-9 were 0.01 μg / g and 1.20 μg / g, respectively, on Day 28. The remaining balloon content as a percentage of the original drug load from the samples of Example I-9 ranged from 0 to 60%. The mean remaining balloon content as a percentage of the original drug load from one sample of the 2 μg / g and 4 μg / g dose density formulations was 11.5% and 2.4%, respectively. The mean residual balloon content as a percentage of the original drug load from the four samples of the 2 μg / g and 4 μg / g dose density formulations was 12.2% and 19.9%, respectively. The mean urethral increase at day 28, calculated as the treatment site urethral diameter minus the urethral diameter at treatment, ranged from 1.6 mm to minus 4.4 mm. Histological examination of the samples showed no differences between drug-coated balloon-treated, flat balloon-treated, and untreated tissue.

[0295] Example I-11. Preclinical trial 5 Sample preparation Forty balloon catheters (20 with a diameter of 6 mm and a length of 20 mm, and 20 with a diameter of 8 mm and a length of 20 mm) were inflated to 50% of their nominal inflation pressure and wiped with ethanol tissue to clean the balloon surface. The balloons were then divided into two groups; one group had a 1 mm diameter and 20 mm length. 2 The other group was coated with the various formulations (1-6) of Example I-1 using a coating solution sufficient to achieve 3.5 μg paclitaxel per 1 mm of the balloon surface. 2 The balloons were coated with various formulations (1-6) from Example I-1 using a coating solution sufficient to achieve 10 μg paclitaxel per balloon. The balloons were then dried, folded, sheathed, packaged in Tyvek pouches, and ethylene oxide sterilized in preparation for animal testing.

[0296] Example I-12. Preclinical trial 5 Treatment For this study, sows were used to allow easy access to the ureter. Before drug-coated balloon treatment, baseline ureterograms and urethrograms were taken, and the internal diameters of the ureter and urethral treatment sites were measured before treatment. The treatment site diameter was approximately 4.0 to 6.0 mm. For the urethra, a balloon catheter was selected so that the stretch ratio was approximately 1.8 to 2.3. The drug-coated balloon catheter prepared in Example I-11 was used for non-overlapping treatments. Control experiments were conducted to test two method parameters: the balloon for urethral stretching, inflation time, and product design characteristics; and drug dose density. The amount of drug in the treated urethral tissue of sacrificed animals was measured one day later, and the residual drug remaining in the balloon after use was analyzed.

[0297] Example I-13. Preclinical trial 5: Remaining drug content in balloon and tissue drug content The porcine tissue mean drug concentration from the samples of Example I-12 was 12.5 μg / g on Day 1. The remaining balloon content as a percentage of the original drug load from the samples of Example I-12 ranged from 1 to 52%.

[0298] Example I-14. Preclinical trial 6 Sample preparation Eighty-seven balloon catheters (37 with a diameter of 12 mm and a length of 20 mm, and 50 with a diameter of 8 mm and a length of 20 mm) were inflated to 50% of their nominal inflation pressure and wiped with ethanol tissue to clean the balloon surface. The balloons were then divided into two groups; one group had a balloon surface 1 mm 2 The other group was coated with the various formulations (1-6) of Example I-1 using a coating solution sufficient to achieve 3.5 μg paclitaxel per 1 mm of the balloon surface. 2 The balloons were coated with various formulations (1-6) from Example I-1 using a coating solution sufficient to achieve 10 μg paclitaxel per balloon. The balloons were then dried, folded, sheathed, packaged in Tyvek pouches, and ethylene oxide sterilized in preparation for animal testing.

[0299] Example I-15. Preclinical trial 6 Treatment For this study, casted male pigs were used. Before drug-coated balloon treatment, a baseline urethrogram was taken to measure the internal diameter of the urethral treatment site before treatment. The drug-coated balloon catheters prepared in Example I-14 were used in non-overlapping treatments. Before inflation, 5-10 mL of saline was used to flush the urethra. Control experiments were conducted to examine the effects of dual inflation and drug dose density on the amount of drug in the treated urethral tissue. Tissue drug content was measured after 1 and 28 days to analyze the residual drug remaining in the balloon after use. Histology samples were taken on day 28 to compare the two different drug dose density catheter groups.

[0300] Example I-16. Preclinical trial 5: Residual drug content in balloon and tissue drug content Pig tissue mean drug concentrations from the samples of Example I-14 were 83 ng / g on Day 1 and 2.5 ng / g on Day 28. The remaining balloon content as a percentage of the original drug load from the samples of Example I-14 ranged from 19 to 73%.

[0301] Example I-17. Preclinical trial 7 Sample preparation Fifty-seven balloon catheters (43 with a diameter of 8 mm and a length of 20 mm, and 14 with a diameter of 20 mm and a length of 60 mm) were inflated to 50% of their nominal inflation pressure and wiped with ethanol tissue to clean the balloon surface. 2 The balloons were coated using the various formulations (1-6) in Example I-1, using a coating solution sufficient to achieve 3.5 μg paclitaxel per balloon. The balloons were then dried, folded, sheathed, packaged in Tyvek pouches, and ethylene oxide sterilized in preparation for animal testing.

[0302] Example I-18. Preclinical trial 7 Treatment Male dogs were used for this study. These procedures were performed under direct visualization using a 2.4 mm external diameter endoscope. The endoscope utilized constant saline irrigation to wash away any obstructions from the field of view, thus ensuring constant flushing of the treatment zone. The first stage of the procedure involved the use of cutting balloons (balloon catheters with blades running longitudinally along the length of the balloon) in the prostatic, mid, and distal urethras. Next, an uncoated balloon was used to dilate the treatment site where the cutting balloon was used. A baseline urethrogram was then taken to measure the internal diameter of the urethral treatment site before drug-coated balloon treatment. Finally, the drug-coated balloon catheter prepared in Example I-17 and an uncoated balloon catheter (as a control) were used. A 20 mm nominal diameter balloon was used in the prostatic urethra, and an 8 mm nominal diameter balloon was used in the anterior urethra. The prostatic urethral balloon was inflated to 4-5 atmospheres at the treatment site for 2 minutes to release the drug and additives, then deflated and withdrawn from the dog. An 8-mm nominal diameter balloon was inflated to 10 atmospheres at the treatment site for 2 minutes to release the drug and additives, then deflated and withdrawn from the dog. The stretch ratios for the prostatic urethral balloons ranged from 2.9 to 9.7. The stretch ratios for the anterior urethral balloons ranged from 1.5 to 2.8. Tissue drug content was measured after 3, 7, and 28 days to analyze residual drug remaining in the balloons after use. Histology samples were taken on days 3 and 28 to compare direct drug-coated balloon treatment with cutting-balloon pretreatment followed by drug-coated balloon treatment.

[0303] Example I-19. Preclinical Study 7 Pharmacokinetics, Balloon Residual Drug Content, Lumen Gain, and Histology Dog tissue mean drug concentrations from the samples of Example I-18 were 100 μg / g on Day 3, 62 μg / g on Day 7, and 33 μg / g on Day 28. The remaining balloon content as a percentage of the original drug load from the samples of Example I-18 ranged from 2 to 50%.

[0304] Example I-20. Preclinical trial 8 Sample preparation Thirty-nine balloon catheters (8 mm diameter and 30 mm length) were inflated to 3 atmospheres and wiped with ethanol tissue to clean the balloon surface. 2 The balloons were coated using formulations 18, 19, and 23 from Example I-1 with sufficient coating solution to achieve 2.5 μg paclitaxel per balloon. The balloons were then dried, folded, sheathed, packaged in Tyvek pouches, and ethylene oxide sterilized in preparation for animal testing.

[0305] Example I-21. Preclinical Trial 8 Treatment Male dogs were used for this study. A baseline urethrogram was taken to measure the internal diameter of the urethral treatment site before drug-coated balloon treatment. The treatment site diameter was approximately 3.5 to 4.5 mm. The balloon catheter was selected so that the stretch ratio of the anterior urethral balloon was approximately 1.8 to 2.3. The drug-coated balloon catheter 0 prepared in Example I-2 was used in a non-overlapping procedure in the pelvic, bulbar, and distal urethra just proximal to the os baculum. The os baculum urethra was not treated. Prior to catheter insertion, approximately 5 mL of saline was used to flush the urethra. An 8 mm nominal diameter balloon was inflated to 12 atmospheres at the treatment site for 2 minutes to release the drug and additives, then deflated and withdrawn from the dog. The stretch ratio of the anterior urethral balloon was approximately 2.0 to 2.5. Tissue drug content was measured one day later, and residual drug remaining in the balloon after use was analyzed.

[0306] Example I-22. Preclinical trial 8: Tissue drug content and balloon residual drug content Dog tissue drug concentrations from pelvic urethral samples of Example I-21 were 0.305 μg / g, 1.17 μg / g, 17.3 μg / g, and 33.4 μg / g on Day 1. Dog tissue drug concentrations from bulbar urethral samples of Example I-21 were 0.28 μg / g, 4.31 μg / g, 44.5 μg / g, and 57.8 μg / g on Day 1. Dog tissue drug concentrations from distal urethral samples of Example I-21 were 7.37 μg / g, 38.9 μg / g, 238 μg / g, and 268 μg / g on Day 1. The mean drug concentrations from Formulations 18, 19, and 23 were 6.5 μg / g, 33.6 μg / g, and 137.7 μg / g, respectively, on Day 1. The remaining balloon content as a percentage of the original drug load from the samples of Example I-21 ranged from 20.4 to 81.7%. The mean remaining balloon content as a percentage of the original drug load from Formulations 18, 19, and 23 was 57.7%, 68.7%, and 51.9%, respectively.

[0307] Example I-23. Benchtop Drug Release Test Sample Preparation Forty-nine balloon catheters (31 with a diameter of 8 mm and a length of 30 mm, 6 with a diameter of 10 mm and a length of 20 mm, and 13 with a diameter of 12 mm and a length of 20 mm) were inflated to 3 atmospheres and wiped with ethanol tissue to clean the balloon surface. 2 The balloons were coated using various formulations (1-34) from Example I-1 with sufficient coating solution to achieve 2.5 μg or 3.5 μg paclitaxel per balloon. The balloons were then dried, folded, sheathed, packaged in Tyvek pouches, and ethylene oxide sterilized in preparation for bench testing.

[0308] Example I-24. Tabletop drug release test A benchtop drug release device was developed consisting of a 10-inch long x 2-inch diameter cylindrical container placed in a temperature-controlled water bath. The cylindrical container was filled with 0.9% saline and maintained at 37°C for testing. An 8 French (i.e., 3 French = 1 mm) x 13 cm long introducer sheath was used to pierce the top of the cylindrical container and serve as a conduit for passing the balloon catheter sample into the cylindrical container. The samples developed in Example I-22 were individually placed into the cylindrical container, immersed therein for 1 minute, then inflated to 10 atmospheres for 1 minute and then withdrawn. The remaining drug on the balloon was analyzed to determine how much drug had been released. The amount of drug released during this test ranged from 37% to 97%.

[0309] Part II Example II-1. Bench Testing Using Pig Urethra The purpose of this experiment was to evaluate whether the necked balloon design was able to prevent migration during inflation in an anatomical model.

[0310] Intact boar bladders and urethras were obtained from a local research facility. Balloon catheters were inserted into the bladder using a 20 mm diameter x 80 mm length 7233 Pebax (登録商標) The balloon was constructed from a 10-French catheter. Two balloon necks were created on the balloon using UHMWPE sutures. The balloon was tied off with sutures at the desired locations to prevent balloon inflation, thereby creating the necks. The necks were symmetrically positioned along the length of the balloon, dividing the 80 mm length into three approximately 20 mm body sections. The necks were sized to be 10 mm long and approximately 8 mm in diameter. The necks were measured from one large body section to the adjacent large body section. The balloon was attached to a 10 French catheter shaft, crimped / folded, and placed in a sheath for ease of insertion.

[0311] Intact porcine urethras and bladders were placed in a 37°C water bath to mimic body temperature. A balloon catheter was inserted through the urethra and positioned so that the distal end of the balloon was at the bladder neck. The balloon was inflated until urethral division was visible or to a maximum rated burst pressure (RBP) of 6 atm. The balloon was deflated immediately after confirmation of urethral division. Inflation rates were varied between samples using 0.5 atm / min, 1.0 atm / min, and 2.0 atm / min. Total inflation time ranged from 3 to 10 min depending on inflation rate.

[0312] The necked balloon in this study was able to prevent balloon migration during inflation. The stretch ratio of inflated balloon diameter to normal prostatic urethral diameter was approximately 3.0-3.5. Furthermore, this study demonstrated that inflation rate plays a role in balloon migration. By inflating the balloon at a slower rate, forcing the tissue to relax and prepare, balloon migration into the bladder was further minimized. Rates of 0.5 atm / min and 1.0 atm / min resulted in less balloon migration during inflation.

[0313] Part III. Testing of drug-coated balloons in urethral strictures in human subjects The following examples include embodiments of the use of medical devices having drug coatings within the scope of the present invention. Although the following examples are believed to embody the present invention, they should not be construed as limitations of the present invention.

[0314] Material: 3.5 μg paclitaxel / mm 2 Drug-coated balloon catheters with dose densities of 6 mm, 8 mm, 10 mm, 12 mm, and 14 mm were used to treat human subjects with stenotic disease in clinical trials. The drug-coated balloon catheters had nominal diameters of 6 mm, 8 mm, 10 mm, 12 mm, and 14 mm and lengths of 30 mm and 50 mm, with a nominal pressure of 6 atmospheres. The paclitaxel (PTX) dose per balloon size can be seen in Table 6.

[0315] [Table 6]

[0316] The drug-coated balloon catheters had a dual-lumen shaft design with a single inflatable balloon. One lumen was sized to accommodate a 0.038" guidewire lumen. The other lumen was an inflation port lumen, allowing the balloon to be inflated with a mixture of saline and contrast fluid. The drug-coated balloon catheters had a connecting tube with two Luer-type connections; one connection was compatible with an inflation syringe, and the other allowed the guidewire to protrude from the connecting tube, allowing the balloon catheter to slide freely over the guidewire. The 6 mm and 8 mm drug-coated balloon catheters had a rated burst pressure of 12 atmospheres. The 10 mm, 12 mm, and 14 mm drug-coated balloon catheters had a rated burst pressure of 10 atmospheres. The balloons were made of polyamide.

[0317] Uroflow measurement (Q max Uroflow measurement is performed by urinating into a special urine bottle, toilet, or disposable device with a built-in measuring device. Parameter Q max is the maximum flow rate measured during the uroflowmetry test. This method was used before treatment (baseline) and at subsequent 1-, 3-, 6-, and 12-month visits to demonstrate the durability of treatment.

[0318] International Prostate Symptom Score (IPSS). The IPSS is based on responses to eight questions - seven about disease symptoms and one about the patient's quality of life: 1) Residual urination: How often did you feel like your bladder wasn't emptying? 2) Frequency: How often did you have to urinate less than every two hours? 3) Intermittency: How often did you stop and start urination multiple times? 4) Urgency: How often did you have difficulty holding your bladder? 5) Weak stream: How often did you have a weak urination force? 6) Straining: How often did you strain to start urination? 7) Nocturia: How many times did you typically wake up during the night to urinate? 8) Quality of life due to urinary symptoms: How would you feel if you had to live with your current urinary condition for the rest of your life? Although the IPSS was developed for BPH, it can be applied to other bladder outlet obstructive disorders, such as strictures, to determine whether obstructive symptoms improve after medical treatment. For the symptom questionnaire, patients are asked to choose the rating that best describes their condition. The scale ranges from 0 to 5, with 5 representing the most symptomatic disease. The seven symptom scores are combined to obtain an overall score with a maximum possible of 35 points. Responses to the quality of life questionnaire are scored on a scale of 0 to 6. These scoring systems allow scores to be classified as follows: a score of 7 or less indicates mild symptoms; a score of 8 to 19 indicates moderate symptoms; and a score of 20 to 35 indicates severe symptoms. This questionnaire was administered before treatment (baseline) and at subsequent visits at 1, 3, 6, and 12 months to demonstrate the sustainability of treatment.

[0319] Example III-1. Human Clinical Subject A Treated with an Uncoated Pre-dilatation Balloon Followed by an 8mm Nominal Diameter Drug-Coated Balloon Catheter Subject A had a 1.5 cm long x 2.5 mm diameter stricture in the anterior urethra, specifically in the bulbar portion of the anterior urethra. This was determined by performing a retrograde urethrogram. Human clinical subjects had a baseline Q maxThe patient had a maximum urine flow rate of 4.0 mL / s and a baseline IPSS score of 25. First, a cystoscope was inserted into the urethra. A guidewire was then inserted into the working channel of the cystoscope. A pre-dilatation balloon with a nominal diameter of 7 mm and a length of 20 mm was then inserted over the guidewire into the urethra, positioned so that the balloon spanned the stricture. The pre-dilatation balloon was inflated to 14 atmospheres using a syringe equipped with a pressure gauge. The syringe contained a mixture of saline and contrast medium. Fluoroscopy images were obtained to ensure uniform inflation of the balloon. Once this was confirmed, the balloon was deflated and withdrawn from the urethra. Next, a drug-coated balloon with a nominal diameter of 8 mm and a length of 30 mm was inserted into the urethra over the guidewire. The drug-coated balloon was positioned so that the balloon body completely covered the pre-dilatation stricture area. The drug-coated balloon was held in place for at least 1 minute before inflation to allow the coating to hydrate. The drug-coated balloon was then inflated with a mixture of saline and contrast medium using a syringe equipped with a pressure gauge. The balloon was inflated to 11 atmospheres to achieve a dilated diameter of 8.5 mm and maintained at this inflation pressure for 5 minutes. The balloon was then deflated and withdrawn from the human subject. The stretch ratio of the 8 mm nominal diameter drug-coated balloon was 1.1-1.4. The diameter of the dilated stricture was 7 mm after dilation. Residual drug remaining in the balloon was analyzed after use. The residual amount of paclitaxel remaining in the balloon was 158 μg (6% of the initial drug load). Human clinical subjects were followed up at 14, 30, 90, 180, and 365 days for peak urinary flow rate and IPSS score measurements. Additionally, the urethral diameter of the human clinical subjects was assessed at 6 months by visual inspection and by passing a flexible cystoscope through the previously treated area to determine whether the urethra was larger than 16 French (5.3 mm). The human clinical subjects had maximum urinary flow rates of 50.0 mL / sec, 44.0 mL / sec, 35.0 mL / sec, and 32.0 mL / sec at the 14-, 90-, 180-, and 365-day follow-up visits, respectively. The human clinical subjects had IPSSs of 6, 4, and 2 at the 30-, 90-, and 180-day follow-up visits, respectively. The human clinical subjects had urethral diameters greater than 16 French (5.3 mm) at 6 months.

[0320] Example III-2. Human Clinical Subject B Treated with an Uncoated Pre-dilatation Balloon Followed by a 10mm Nominal Diameter Drug-Coated Balloon Catheter Subject B had a 1.5 cm long x 2.0 mm diameter stricture in the anterior urethra, specifically in the bulbar portion of the anterior urethra. This was determined by performing a retrograde urethrogram. Human clinical subjects had a baseline Q maxThe patient had a maximum urine flow rate of 2.0 mL / s and a baseline IPSS score of 24. First, a cystoscope was inserted into the urethra. A guidewire was then inserted into the working channel of the cystoscope. A pre-dilatation balloon with a nominal diameter of 10 mm and a length of 20 mm was then inserted over the guidewire into the urethra, positioned so that the balloon spanned the stricture. The pre-dilatation balloon was inflated to 20 atmospheres using a syringe equipped with a pressure gauge. The syringe contained a mixture of saline and contrast medium. Fluoroscopy images were obtained to ensure uniform inflation of the balloon. Once this was confirmed, the balloon was deflated and withdrawn from the urethra. Next, a drug-coated balloon with a nominal diameter of 10 mm and a length of 30 mm was inserted into the urethra over the guidewire. The drug-coated balloon was positioned so that the balloon body completely covered the pre-dilatation stricture area. The drug-coated balloon was held in place for at least 1 minute before inflation to allow the coating to hydrate. The drug-coated balloon was then inflated with a mixture of saline and contrast medium using a syringe equipped with a pressure gauge. The balloon was inflated to 10 atmospheres for 5 minutes. The balloon was then deflated and withdrawn from the human subject. The stretch ...

Claims

1. A drug-coated balloon catheter for delivering a therapeutic agent to a target site of a body cavity stricture, the balloon catheter comprising: an elongated balloon having a major diameter; and A balloon catheter comprising a coating layer covering the outer surface of the balloon, wherein the coating layer comprises one or more water-soluble additives and an initial drug load of a therapeutic agent.

2. 2. The balloon catheter of claim 1, wherein the balloon includes at least one neck portion having a diameter smaller than the main diameter when the balloon is inflated, the at least one neck portion dividing the balloon into at least two main portions each having a constant diameter.

3. 3. The balloon catheter of claim 2, wherein the major diameter is at least 13 mm, or at least 15 mm, or at least 20 mm, or at least 30 mm, or at least 35 mm.

4. 3. The balloon catheter of claim 2, wherein the diameter of the at least two main portions is the same as the main diameter of the elongated balloon or the at least one neck portion has a diameter that is about 5% to about 99% of the diameter of at least one of the at least two main portions.

5. 3. The balloon catheter of claim 2, wherein at least one neck independently has a diameter that is from about 5 mm to about 35 mm.

6. The balloon catheter of claim 2 , wherein at least one neck is substantially stationary during balloon inflation.

7. 3. The balloon catheter of claim 2, wherein at least one neck comprises a substantially inelastic portion of the balloon, a reinforced portion of the balloon, or a combination thereof.

8. 3. The balloon catheter of claim 2, wherein at least one neck includes an inelastic material around a circumference of the neck.

9. 9. The balloon catheter of claim 8, wherein the inelastic material comprises ultra-high molecular weight polyethylene, nylon, polyamide, or a combination thereof.

10. 10. The balloon catheter of claim 1, wherein the elongated balloon has a length of about 20 mm to about 160 mm.

11. 3. The balloon catheter of claim 2, wherein the diameter of the at least two main portions is from about 5 mm to about 45 mm.

12. 3. The balloon catheter of claim 2, wherein the at least one neck is about 1% to about 50% of the balloon length.

13. 3. The balloon catheter of claim 2, wherein the at least one neck is one neck and the balloon has no other necks.

14. 3. The balloon catheter of claim 2, wherein the at least one neck is two necks and the balloon has no other necks.

15. 15. The balloon catheter of claim 14, wherein the two necks have approximately the same diameter.

16. 15. The balloon catheter of claim 14, wherein one of the two necks has a smaller diameter than the other neck.

17. 15. The balloon catheter of claim 14, wherein the two necks are located symmetrically about the center of the balloon length.

18. 15. The balloon catheter of claim 14, wherein the balloon catheter comprises three sections separated by two necks.

19. 3. The balloon catheter of claim 2, wherein the at least one neck is three necks, and wherein the balloon has no other necks.

20. 20. The balloon catheter of claim 19, wherein the three necks are arranged to provide four main sections spaced apart by the three necks.

21. 10. The balloon catheter of claim 1, further comprising a catheter shaft on a longitudinal end of the balloon, the catheter shaft comprising an internal lumen for delivery of gas, liquid, or a combination thereof, to the interior of the balloon.

22. The balloon catheter of claim 1 , comprising an atraumatic coupe tip.

23. 2. The balloon catheter of claim 1, wherein the therapeutic agent is selected from paclitaxel, docetaxel, taxol, analogs thereof, rapamycin, sirolimus, everolimus, tacrolimus, mTOR inhibitors, analogs thereof, and combinations thereof.

24. 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, PEG 8 Caprylic / Capric Glyceride, PEG Caprylate, PEG 8 Caprylate, PEG Caprate, PEG Caproate, Glyceryl Monocaprylate, Glyceryl Monocaprate, Glyceryl Monocaproate, Monolaurin, Monocaprin, Monocaprylin, Monomyristin, Monopal 24. The balloon catheter according to claim 1, wherein the hydroxybenzoate is selected from the group consisting of mitolein, 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.

25. 25. The balloon catheter of claim 24, wherein the water-soluble additive is selected from pentaerythritol ethoxylates and pentaerythritol propoxylates and combinations thereof.

26. 10. The balloon catheter of claim 1, wherein the water-soluble additive comprises a first water-soluble additive that is a surfactant.

27. 27. The balloon catheter of claim 26, wherein the first water-soluble additive is PEG sorbitan monolaurate, PEG sorbitan monooleate, or a combination thereof.

28. 28. The balloon catheter of claim 1, wherein the water-soluble additive comprises a second water-soluble additive that is a compound having one or more moieties that are hydroxyl, amine, carbonyl, carboxyl, or ester.

29. 29. The balloon catheter of claim 28, wherein the second water-soluble additive is sorbitol, sorbitan, xylitol, gluconolactone, or a combination thereof.

30. 2. The balloon catheter of claim 1, wherein the amount of drug remaining after use is about 70% or less of the initial drug load.

31. The initial drug load is measured when the balloon is at its nominal diameter and is measured within 1 mm of the balloon. ２ 2. The balloon catheter of claim 1, wherein the therapeutic agent is about 1 μg to about 20 μg per catheter.

32. The initial drug load is measured when the balloon is at its nominal diameter and is measured within 1 mm of the balloon. ２ 2. The balloon catheter of claim 1, wherein the therapeutic agent is about 2 to about 6 μg per catheter.

33. The balloon catheter of claim 1 , wherein the body cavity is a non-vascular body cavity or a vascular body cavity.

34. 2. The balloon catheter of claim 1, wherein the body cavity is a vascular lumen, which is one of a coronary artery and a peripheral artery, or a non-vascular body lumen, which is one of an esophagus, an airway, a paranasal sinus, a trachea, a colon, a bile duct, a stomach, a small intestine, a duodenum, a jejunum, an ileum, a rectum, a large intestine, a urinary tract, a prostate, a urethra, and a ureter.

35. 10. The balloon catheter of claim 1, 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 from about 0.05 to about 20.

36. 10. The balloon catheter of claim 1, 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 from about 0.5 to about 8.

37. 10. The balloon catheter of claim 1, 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 from about 2 to about 6.

38. 10. The balloon catheter of claim 1, wherein the balloon catheter has a stretch ratio of about 1.0 to about 20.

39. The balloon catheter of claim 1 , wherein the balloon catheter further comprises a sheath covering the elongate balloon.

40. 10. The balloon catheter of claim 1, wherein the balloon catheter is for delivering a therapeutic agent to a target site in a body cavity after the body cavity has been flushed with water, a saline solution, or an aqueous solution containing at least one water-soluble additive.

41. 1. A method for treating a body cavity stenosis, comprising: A balloon catheter is inserted into the target site of the stenosis of the body cavity. Long, thin balloons and a coating layer overlying an outer surface of the balloon, wherein the coating layer comprises one or more water-soluble additives and an initial drug loading of a therapeutic agent; the balloon is inflated until the coating layer contacts the wall of the body cavity at the target site for an inflation time and the balloon achieves an inflated balloon diameter; a) the ratio of the inflated balloon diameter to the normal body lumen diameter at the target site is from about 1.0 to about 20; or b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; 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); Deflating the balloon after the inflation period; and withdrawing the balloon catheter from the body cavity.

42. 42. The method of claim 41, wherein the balloon catheter comprises an elongated balloon having a proximal waist, a distal waist, a main body diameter, and at least one neck portion having a diameter on the balloon that is smaller than the main diameter when the balloon is inflated, the at least one neck portion dividing the balloon into at least two main portions each having a constant diameter.

43. 43. The method of claim 42, wherein the diameter of the at least two main portions is equal to the major diameter of the elongate balloon.

44. 42. The method of claim 41, further comprising flushing the body cavity with water, a saline solution, or an aqueous solution containing at least one water-soluble additive prior to inserting the balloon into the target site.

45. 43. The method of claim 42, wherein the body cavity is the prostate, and wherein inserting the balloon catheter comprises positioning one of the balloon catheter stems in the prostate and positioning a second of the balloon catheter stem in the bladder.

46. 46. ​​The method of claim 45, wherein the inserting comprises positioning at least one neck of the balloon at the bladder neck.

47. 42. The method of claim 41, wherein inflating comprises increasing the pressure in the balloon at a rate of about 0.1 to about 10 atmospheres per minute.

48. 42. The method of claim 41, wherein the inflation comprises monitoring the pressure within the balloon.

49. 42. The method of claim 41, wherein inflating comprises inflating the balloon to a first pressure, stabilizing the pressure within the balloon while maintaining the first pressure within the balloon for a stabilization time, and then resuming increasing the pressure in the balloon until the desired inflated diameter is achieved.

50. 42. The method of claim 41, wherein the swelling time is from about 0.1 minutes to about 7 days.

51. 42. The method of claim 41, wherein the method is a method for treating a vascular lumen, a non-vascular lumen, a coronary artery, a peripheral artery, a benign prostatic hyperplasia (BPH) stricture, a urethra, a ureter, a prostate, an esophagus, an in-stent stricture, a bile duct, a stomach, a small intestine, a duodenum, a jejunum, an ileum, a colon, a rectum, a large intestine, a sinus, asthma, or a chronic obstructive pulmonary disease (COPD).

52. 42. The method of claim 41, wherein the method is a method of splitting an enlarged prostate or creating a commissurotomy for the treatment of benign prostatic hyperplasia.

53. 42. The method of claim 41, wherein the stricture in the body cavity is one of urethral stricture, benign prostatic hyperplasia (BPH) stricture, ureteral stricture, esophageal stricture, stricture in a stent, sinus stricture, bile duct stricture, gastric stricture, small intestinal stricture, duodenal stricture, jejunal stricture, ileal stricture, colonic stricture, rectal stricture, large intestinal stricture, prostate cancer stricture, and airway stricture.

54. 54. The method of claim 53, wherein the method is a method for treating benign prostatic hyperplasia, prostate cancer, or a combination thereof, wherein the body cavity is the prostate gland.

55. 42. The method of claim 41, wherein the one or more water-soluble additives facilitate rapid release of the therapeutic agent from the balloon at the target site during the inflation period.

56. 42. The method of claim 41, wherein the balloon has a residual amount of drug after withdrawal.

57. 57. The method of claim 56, wherein the balloon has a residual drug amount after withdrawal that is less than about 70% of the initial drug load.

58. 42. The method of claim 41, wherein the balloon catheter further comprises a sheath covering the balloon, wherein the sheath is removed from the balloon prior to balloon inflation.

59. 42. The method of claim 41, wherein a scope is used to properly position the balloon catheter.

60. 60. The method of claim 59, wherein the scope is an endoscope, enteroscope, colonoscope, sigmoidoscope, rectoscope, anoscope, nasoscope, bronchoscope, or cystoscope.

61. 60. The method of claim 59, wherein the balloon catheter is placed within the lumen of the scope.

62. 60. The method of claim 59, wherein the balloon catheter is positioned alongside the scope when in the body cavity.

63. 43. The method of claim 42, wherein the body cavity is the prostatic urethra and a scope is used to position the proximal waist of the balloon catheter at the external sphincter of the prostatic urethra when inserting the balloon catheter into the target site.

64. 42. The method of claim 41, further comprising inserting a pre-dilation balloon into a body cavity at the target site, inflating the pre-dilation balloon, and removing the pre-dilation balloon before inserting the drug-coated balloon catheter.

65. 42. The method of claim 41, wherein the balloon catheter has a ratio of inflated balloon diameter to normal body lumen diameter at the target site of 1.0, 1.1, 1.2, or 1.31 to 10, or the balloon catheter has a stretch ratio of balloon nominal diameter to normal body lumen diameter at the target site of 1.0, 1.1, 1.2, or 1.31 to 10, or a combination thereof.

66. 1. A method for treating a body cavity stenosis, comprising: Inserting a scope into the narrowed body cavity; inserting a balloon catheter having a drug coating into the stenosis of the body cavity; Inflate the balloon catheter to an initial pressure of 0.5 to 1.5 atmospheres and maintain the initial pressure until the pressure stops decreasing; inflating to a next higher pressure of at least 0.5 atmospheres to 1.5 atmospheres above the initial pressure, and maintaining the next higher pressure until the pressure within the balloon no longer drops; Repeating inflation to the next higher pressure and maintaining the pressure until the lumen is expanded to the desired diameter; Keep the balloon inflated for 1 minute to 7 days to release the drug into the tissue and prevent bleeding; Deflate the balloon catheter; and and withdrawing the scope and balloon catheter from the body cavity.

67. 67. The method of claim 66, wherein the scope and balloon catheter are positioned side-by-side in the body cavity.

68. 67. The method of claim 66, wherein the balloon catheter is loaded onto the scope prior to insertion into the body cavity.

69. 67. The method of claim 66, wherein the desired diameter of the body cavity is 1.0 to 20 times the normal diameter of the body cavity at the treatment location.

70. 67. The method of claim 66, wherein the balloon catheter further comprises a sheath covering the balloon, wherein the sheath is removed from the balloon prior to inflation of the balloon to the initial pressure.

71. 1. A method for treating a body cavity stenosis, comprising: Insert a flexible scope into the stenosis of the body cavity; Insert a balloon catheter alongside the scope into the stenosis; flushing the balloon catheter with water, saline, or a solution of water-soluble additives before, during, or after insertion into the stenosis; Inflate to an initial pressure of 0.5 to 1.5 atmospheres and maintain the initial pressure until the pressure stops decreasing; Inflate the balloon to a pressure 0.5 to 1.5 atmospheres higher than the initial pressure, and maintain the high pressure until the pressure inside the balloon stops decreasing; Repeated inflation to and maintenance of high pressure until tissue in the body cavity is produced; Keep the balloon inflated for 1 minute to 7 days to release the drug into the tissue and prevent bleeding; Deflate the balloon catheter; and The method includes withdrawing the scope and balloon catheter assembly from the body cavity.

72. Q ｍａｘ 1. A method for increasing inserting a balloon catheter into a target site of a urinary tract stricture, the balloon catheter comprising an elongate 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 balloon is inflated for an inflation time until the coating layer contacts the wall of the urinary stricture, a) the ratio of the inflated balloon diameter to the normal urinary tract diameter at the target site is from about 1.0 to about 20; or b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the normal urinary tract diameter at the target site is from about 1.0 to about 20; 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); Deflating the balloon after the inflation period; and withdrawing the balloon catheter from the urinary tract; Here, Q ｍａｘ to a minimum of 15 mL / sec.

73. 73. The method of claim 72, wherein the target site is a urethral stricture.

74. 74. The method of claim 73, wherein the ratio of the inflated balloon diameter to the normal diameter of the body lumen at the target site is from about 1.31 to about 20, or the stretch ratio of the nominal diameter of the balloon catheter to the normal diameter of the body lumen at the target site is from about 1.31 to about 20, or a combination thereof.

75. 73. The method of claim 72, wherein the target site is the prostate.

76. 76. The method of claim 75, wherein the elongate balloon has a main diameter and at least one neck portion dividing the balloon into at least two portions, the neck portion comprising a diameter smaller than the main diameter of the balloon when the balloon is inflated.

77. 77. The method of claim 76, wherein the main portions of the at least two balloons each have a diameter equal to the main portion of the balloon when the balloon is inflated.

78. Q ｍａｘ 73. The method of claim 72, wherein the blood flow rate is still greater than 15 mL / sec six months after the first treatment.

79. Q ｍａｘ 73. The method of claim 72, wherein the blood flow rate is still greater than 15 mL / sec 12 months after the first treatment.

80. 1. A method for reducing International Prostate Symptom Score (IPSS), comprising: inserting a balloon catheter into a target site of a urinary tract stricture, the balloon catheter comprising an elongate 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 balloon is inflated for an inflation time until the coating layer contacts the wall of the urinary stricture, a) the ratio of the inflated balloon diameter to the normal body lumen diameter at the target site is from about 1.0 to about 20; or b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; or c) the inflation includes inflation to a pressure greater than the nominal pressure of the balloon catheter, the nominal diameter of the balloon catheter being less than the inflated balloon diameter and the nominal pressure being less than the inflation pressure; or d) a combination of (a), (b) and (c); Deflating the balloon after the inflation period; and withdrawing the balloon catheter from the urinary stricture; wherein the method reduces the IPSS to 14 or less.

81. 81. The method of claim 80, wherein the target site is a urethral stricture.

82. 82. The method of claim 81, wherein the ratio of the inflated balloon diameter to the normal diameter of the body lumen at the target site is from about 1.31 to about 20, or the stretch ratio of the balloon catheter's minimum diameter to the normal body diameter at the target site is from about 1.31 to about 20, or a combination thereof.

83. 81. The method of claim 80, wherein the target site is the prostate.

84. 84. The method of claim 83, wherein the elongate balloon has a main diameter and at least one neck portion dividing the balloon into at least two portions, the neck portion comprising a diameter smaller than the main diameter of the balloon when the balloon is inflated.

85. 85. The method of claim 84, wherein the main portions of the at least two balloons each have a diameter equal to the main portion of the balloon when the balloon is inflated.

86. 81. The method of claim 80, wherein the IPSS is still less than 14 six months after the first treatment.

87. 81. The method of claim 80, wherein the IPSS is still less than 14 12 months after the first treatment.

88. 81. The method of claim 72 or 80, wherein the therapeutic agent is selected from paclitaxel, docetaxel, taxol, analogs thereof, rapamycin, sirolimus, everolimus, tacrolimus, mTOR inhibitors, analogs thereof, and combinations thereof.

89. 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, 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, monomyristin, 81. The method of claim 72 or 80, wherein the hydroxybenzoate is selected from 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.

90. 90. The method of claim 89, wherein the water-soluble additive is selected from pentaerythritol ethoxylates and pentaerythritol propoxylates and combinations thereof.

91. 81. The method of claim 72 or 80, wherein the water-soluble additive comprises a first water-soluble additive that is a surfactant.

92. 92. The method of claim 91, wherein the first water-soluble additive is PEG sorbitan monolaurate, PEG sorbitan monooleate, or a combination thereof.

93. 81. The method of claim 72 or 80, wherein the water-soluble additive comprises a second water-soluble additive that is a compound having one or more moieties that are hydroxyl, amine, carbonyl, carboxyl, or ester.

94. 81. The method of claim 72 or 80, wherein the urethra is flushed with water, saline, or a solution of a water-soluble additive prior to insertion of the balloon catheter into the urethra.

95. 81. The method of claim 72 or 80, wherein the balloon is wetted with water, saline, or a solution of a water-soluble additive prior to insertion of the balloon catheter into the urethra.

96. The balloon is measured when the balloon is at its nominal diameter, and ２ 81. The method of claim 72 or 80, wherein the dosage is about 2 to about 6 μg of therapeutic agent per tablet.

97. 81. The method of claim 72 or 80, wherein a scope is used to properly position the balloon catheter.

98. 98. The method of claim 97, wherein the scope is one of an endoscope, enteroscope, colonoscope, sigmoidoscope, rectoscope, anoscope, nasoscope, bronchoscope, or cystoscope.

99. 81. The method of claim 72 or 80, wherein the balloon catheter is placed within the lumen of the scope.

100. 81. The method of claim 72 or 80, wherein the balloon catheter is positioned alongside the scope when in the body cavity.

101. 81. The method of claim 72 or 80, wherein the body cavity is the prostatic urethra and a scope is used to position the proximal waist of the balloon catheter at the external sphincter of the prostatic urethra when inserting the balloon catheter into the target site.

102. 81. The method of claim 72 or 80, further comprising inserting a pre-dilation balloon into a body cavity at the target site, inflating the pre-dilation balloon, and removing the pre-dilation balloon before inserting the drug-coated balloon catheter.

103. 81. The method of claim 72 or 80, wherein the balloon catheter is inflated to an inflated balloon diameter to the normal diameter of the body lumen at the target site of 1.31 to 15, or the balloon catheter has an expansion ratio of the balloon nominal diameter to the normal diameter of the body lumen at the target site of 1.31 to 15, or a combination thereof.

104. 81. The method of claim 72 or 80, further comprising performing direct visual intraurethrotomy (DVIU) before treating the body cavity with the drug-coated balloon catheter.

105. 1. A method of splitting an enlarged prostate or creating a commissural incision for the treatment of benign prostatic hyperplasia, comprising: Inserting a drug-coated balloon catheter-sheath assembly and a scope; Place the scope and balloon catheter side-by-side near the external sphincter; Remove the sheath from over the balloon and slowly inflate it until the pressure is reduced and the prostate tissue is exposed and a commissural incision is made; Further increasing the pressure to the rated burst pressure to further expand the prostate; Keep the balloon inflated for 1 minute to 7 days to release the drug into the tissue and prevent bleeding; Deflate the balloon catheter and retract the balloon into the sheath; and withdrawing the scope and balloon catheter assembly from the body cavity, a) the ratio of the inflated balloon diameter to the normal body lumen diameter at the target site is from about 1.0 to about 20; or b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; 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). method.

106. 1. A method of splitting an enlarged prostate or creating a commissural incision for the treatment of benign prostatic hyperplasia, comprising: Inserting an uncoated balloon catheter-sheath assembly and a scope; Place the scope and balloon catheter side-by-side near the external sphincter; Remove the sheath from over the balloon and slowly inflate it until the pressure is reduced and the prostate tissue is exposed and a commissural incision is made; Further increasing the pressure to the rated burst pressure to further expand the prostate; Keep the balloon inflated for 1 minute to 7 days to prevent bleeding. Deflate the uncoated balloon catheter and retract the balloon into the sheath; withdrawing the scope and uncoated balloon catheter assembly from the body cavity; Inserting a drug-coated balloon catheter-sheath assembly and a scope; The scope and drug-coated balloon catheter are placed side-by-side near the external sphincter; Remove the sheath from over the drug-coated balloon and slowly inflate it to its rated burst pressure to further expand the prostate; and maintaining the balloon inflated for 1 minute to 7 days to release the drug into the tissue and prevent bleeding, a) the ratio of the inflated balloon diameter to the normal body lumen diameter at the target site is from about 1.0 to about 20; or b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; 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). method.

107. 1. A method of treating benign prostatic hyperplasia, comprising: inserting a balloon catheter into a target site in the prostate, the balloon catheter comprising 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 load of a therapeutic agent; the balloon is inflated until the coating layer contacts the wall of the body cavity at the target site for an inflation time and the balloon achieves an inflated balloon diameter; a) the ratio of the inflated balloon diameter to the normal body lumen diameter at the target site is from about 1.0 to about 20; or b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; 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); Deflating the balloon after the inflation period; and withdrawing the balloon catheter from the body cavity; A method wherein the prostatic urethra and prostate are divided and the prostatic urethra diameter is at least 12 mm, and wherein the inflated diameter of the balloon catheter is at least 25 mm.

108. 1. A method for treating a urethral stricture, comprising: A balloon catheter is inserted into a target site in the urethra, the balloon catheter comprising 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 load of a therapeutic agent; wherein the therapeutic agent is paclitaxel, docetaxel, taxol, analogs thereof, rapamycin, sirolimus, everolimus, tacrolimus, an MTOR inhibitor, analogs thereof, and combinations thereof, and the water-soluble additive is N-acetylglucosamine, N-octyl-D-gluconamide, N-nonanoyl-N-methylglucan. amine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerebroside, sphingomyelin, galactocerebroside, lactocerebroside, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-octnoyl-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 at least one of benzophenone, 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 balloon is inflated until the coating layer contacts the wall of the body cavity at the target site for an inflation time and the balloon achieves an inflated balloon diameter; a) the ratio of the inflated balloon diameter to the normal body lumen diameter at the target site is from about 1.0 to about 20; or b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; 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); Deflating the balloon after the inflation period; and withdrawing the balloon catheter from the body cavity; wherein the urethral diameter after dilation is at least 6.7 mm and the inflated diameter of the balloon catheter is at least 7 mm.

109. A balloon catheter for treating urethral stricture, and a coating layer covering the outer surface of the balloon, wherein the coating layer comprises one or more water-soluble additives and an initial drug load of a therapeutic agent; wherein the therapeutic agent is paclitaxel, docetaxel, taxol, analogs thereof, rapamycin, sirolimus, everolimus, tacrolimus, an MTOR inhibitor, analogs thereof, and combinations thereof, and the water-soluble additive is 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, 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 caprylate Plate, 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 at least one of methylpropane, (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; where: After treatment ｍａｘ is at least 15 mL / sec and IPSS does not exceed 14; The urethral diameter after dilation is at least 6.7 mm, and The inflated diameter of the balloon catheter is at least 7 mm; and where a) the ratio of the inflated balloon diameter to the normal body lumen diameter at the target site is from about 1.0 to about 20; or b) the inflation includes inflating the balloon to a pressure equal to or greater than the nominal pressure of the balloon catheter, and the inflation ratio of the nominal diameter of the balloon catheter to the normal body lumen diameter at the target site is about 1.0 to about 20; 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). Balloon catheter.

110. 1. A method of forming a balloon, comprising: placing the tube containing the balloon material into a balloon mold, wherein the balloon mold has a shape including a proximal cone, at least one body portion, at least one neck portion having a smaller diameter than the at least one body portion, at least one other body portion, and a distal cone; Pressurizing the interior of the balloon material tube; and The method includes expanding a tube of balloon material until it contacts the interior of a mold.

111. 111. The method of claim 110, further comprising assembling the balloon into a balloon catheter.

112. 112. The method of claim 111, wherein the balloon catheter is selected from a fixed-wire catheter, a movable-wire catheter, an over-the-wire catheter, and a rapid-exchange catheter.

113. 111. The method of claim 110, wherein a neck reinforcement is added to the neck portion.

114. 111. The method of claim 110, further comprising coating the balloon of the balloon catheter with a therapeutic agent and at least one water-soluble additive.

115. 111. The method of claim 110, wherein the therapeutic agent is selected from paclitaxel, docetaxel, taxol, analogs thereof, rapamycin, sirolimus, everolimus, tacrolimus, mTOR inhibitors, analogs thereof, and combinations thereof.

116. 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, 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, Monomyristyl 111. The method of claim 110, wherein the hydroxybenzoate is selected from the group consisting of benzoyl esters of hydroxybenzoates, 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.

117. 117. The balloon catheter of claim 116, wherein the water-soluble additive is selected from pentaerythritol ethoxylates and pentaerythritol propoxylates and combinations thereof.

118. 111. The balloon catheter of claim 110, wherein the water-soluble additive comprises a second water-soluble additive that is a compound having one or more moieties that are hydroxyl, amine, carbonyl, carboxyl, or ester.

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