Chemical Ablation and Methods of Treatment for Various Diseases

Abstract

To provide a formulation for treating at least one of hypertension, pulmonary hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive disease, urological disease, cancers, tumors, pain, asthma or chronic obstructive pulmonary disease by delivering an effective amount of the formulation to a tissue.SOLUTION: In embodiments of the present invention, the formulation may include at least one of a gas, a vapor, a liquid, a solution, an emulsion and a suspension of one or more ingredients. In embodiments of the present invention, amounts of the formulation and / or energy are effective to injure or damage tissues, nerves and nerve endings in order to relieve disease symptoms.SELECTED DRAWING: None

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 62 / 122,818, filed October 30, 2014, U.S. Provisional Patent Application No. 62 / 124,868, filed January 5, 2015, the disclosures of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION Embodiments of the present invention relate to chemical infusion devices, formulations and methods of treatment for hypertension, pulmonary hypertension, diabetes, obesity, heart failure, end stage renal disease, gastrointestinal disease, cancer, tumors, pain, asthma and chronic obstructive pulmonary disease (COPD). The devices may include combination balloon and infusion catheters, and other delivery devices. The formulations may include gases, vapors, liquids, solutions, emulsions and suspensions of one or more components. The methods include delivery of the formulations to target tissues in the human body by chemical infusion. [Background technology]

[0003] Hypertension, or high blood pressure, is a major global health concern. An estimated 30-40% of the adult population worldwide suffers from the condition. Furthermore, prevalence is predicted to increase, especially in developing countries. Diagnosis and treatment of hypertension remain suboptimal, and many patients struggle to adequately control their blood pressure.

[0004] Benign prostatic hyperplasia is a non-cancerous enlargement of the prostate gland that affects more than 50% of men over the age of 60. When we are young, the prostate is approximately the size of a walnut weighing about 20 grams. Enlargement of the prostate over the years is considered normal. With age, the prostate gradually increases to at least twice its original size. Prostatic enlargement creates pressure that builds against the adjacent urethra, causing subsequent narrowing of the organ and ultimately causing urinary obstruction that makes it difficult to urinate.

[0005] Chronic obstructive pulmonary disease (COPD) is associated with two major airway obstruction disorders: chronic bronchitis and emphysema. Chronic bronchitis results from inflammation of the bronchial airways, which connect the trachea to the lungs. Emphysema is a disease caused by overinflation of air bubbles or air sacs in the lungs. This condition causes shortness of breath. Approximately 16 million Americans have COPD, the majority of whom (80-90%) are lifelong smokers. COPD is the leading cause of death in the United States.

[0006] Asthma is a chronic respiratory disease characterized by excessive narrowing of the airways, caused by inflammation of the airways, excessive mucus production and airway hyperresponsiveness. This narrowing of the airways can make breathing difficult, significantly affecting the patient's life and limiting participation in many activities. In severe cases, asthma attacks can be life-threatening. To date, there is no known cure for asthma.

[0007] Chronic rhinosinusitis (CS) results from inflammation of the lining of one or more paranasal sinuses and is typically associated with significant tissue damage. Approximately 37 million cases of CS are reported to the Centers for Disease Control and Prevention (CDC) each year.

[0008] Diabetes is a metabolic condition or combination of conditions in which an individual experiences high concentrations of glucose in the blood. The condition is caused by either insufficient insulin production in the body or by cells not responding properly to insulin. Glycated hemoglobin (HbA1c) serves as a marker of plasma glucose concentration and is used clinically to diagnose diabetes. In humans, normal HbA1c levels are typically <6.0%, prediabetic HbA1c levels range from 6.0-6.4%, and diabetic HbA1c levels are above 6.5%.

[0009] Diabetes is one of the leading causes of death and disability in the United States and other developed countries. It is associated with long-term complications that affect almost every part of the body. It is associated with, for example, blindness, cardiovascular disease, stroke, kidney failure, amputations and nerve damage.

[0010] In the United States, diabetes affects approximately 8% of the population and results in costs approaching $250 billion.

[0011] Diabetes is typically classified as either type 1 (also called insulin-dependent diabetes or juvenile diabetes), where the patient does not produce enough insulin; type 2 (also called non-insulin-dependent diabetes, adult-onset diabetes or obesity-related diabetes), where the patient does not respond properly to insulin; or gestational diabetes, a condition that develops late in pregnancy.

[0012] Type 2 diabetes is the most common type of diabetes, accounting for 90-95% of all patients. It is generally associated with older age, obesity, family history, history of gestational diabetes, and physical inactivity. It is also more prevalent in certain ethnicities. Type 2 diabetes is also called insulin-resistant diabetes because the pancreas typically produces sufficient amounts of insulin, but the body does not respond to it properly. Symptoms associated with type 2 diabetes include fatigue, frequent urination, increased thirst and hunger, weight loss, blurred vision, and slower healing of wounds or pain.

[0013] Obesity is another major health concern, especially in developed countries. It is a complex, multifactorial, chronic condition characterized by excess body fat, which results from an imbalance between energy expenditure and caloric intake. The causes of this imbalance are not fully understood, but genetic and / or physiological events and environmental factors are thought to contribute. The adverse health effects associated with obesity, and more specifically morbid obesity, have been established in recent years. These include, but are not limited to, cardiovascular disease, diabetes, hypertension, arthritis, and sleep apnea. In general, the higher a patient's body mass index (BMI), the higher the likelihood of suffering from the adverse effects associated with obesity. Summary of the Invention

[0014] The present invention provides novel devices and methods for the treatment of hypertension, diabetes, obesity, heart failure, end-stage renal disease, gastrointestinal disease, urological disease, cancer, tumors, pain, asthma and chronic obstructive pulmonary disease (COPD). The novel methods include chemical injection formulations and delivery systems and strategies. The methods focus on delivery of formulations to diseased tissues in the human body, which can improve the safety and efficacy of treatment.

[0015] Embodiments of the present invention relate to the treatment of hypertension, diabetes, obesity, heart failure, end stage renal disease, gastrointestinal disease, cancer, tumors, pain, asthma, and chronic obstructive pulmonary disease (COPD) by delivery of an effective amount of a formulation to diseased tissue. The formulation includes gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. The method includes controlled delivery of the formulation to luminal surfaces and tissues within the human body to effect alterations to these areas. The method may cause denervation of nerves and nerve endings in the body cavity. The method may also include beneficial severing of nerves and nerve endings to prevent nerve transmission. Temperature may improve the safety and efficacy of the treatment formulation. The temperature may range from -40 to 140°C, -30 to 100°C, or -30 to 80°C. In some embodiments, the formulation includes either two components, three components, or four components, and may include more than four components. Delivery methods include less invasive, percutaneous, and non-invasive approaches. Embodiments of the present invention provide formulations and delivery catheters that improve absorption and penetration into body tissues and intraluminal nerves and nerve endings.

[0016] In one embodiment, at least one component of the formulation is selected from water, saline, hypertonic saline, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, urea, lipiodol, surfactants, and derivatives thereof and combinations thereof.

[0017] In one embodiment, at least one component of the formulation is gas.Gas comprises oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, vapor of organic and inorganic compounds, water, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, and derivatives thereof and one of their combinations.

[0018] In one embodiment, at least one component of the formulation is a surfactant.Surfactants include PEG laurate, Tween 20, Tween 40, Tween 60, Tween 80, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, organic acids, salts of any organic acid and organic amine, polyglycidol, glycerol, multiglycerol, 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), penta(propylene glycol), poly(propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, Pluronic, Pluronic 85, and derivatives and combinations thereof.

[0019] In one embodiment, the formulation comprises at least an oil, a fatty acid and / or a lipid. In some embodiments, the at least an oil, a fatty acid and / or a lipid in the formulation is butanoic acid, hexanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, The lipids are selected from mono-, di- or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobins, niosomes, and derivatives thereof.

[0020] In another embodiment, the preparation comprises a therapeutic agent or drug for nerve denervation.The therapeutic agent comprises one of the following: sodium channel blocker, tetrodotoxin, saxitoxin, decarbamoyl saxitoxin, vanilloid, neosaxitoxin, lidocaine, conotoxin, cardiac glycoside, digoxin, glutamate, staurosporine, amlodipine, verapamil, cymarin, digitoxin, proscillaridin, ouabain, veratridine, domoic acid, ethanol, oleandrin, carbamazepine, aflatoxin, guanethidine and guanethidine sulfate.In another embodiment, the preparation comprises an imaging agent for imaging denervation. The contrast agent includes iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan, iodixanol, ioxaglate, and one of their derivatives.

[0021] In one embodiment, the formulation comprises an azeotrope. An azeotrope is a mixture of two or more components that cannot be changed by simple distillation. This occurs because the vapors generated during boiling are proportional to the components of the original mixture. Possible formulation azeotropes include ethanol / water, ethanol / water / contrast agent, ethanol / water / surfactant, ethanol / water / contrast agent / surfactant, propanol / water, isopropanol / water, butanol / water, acetic acid / water, and combinations thereof.

[0022] In one embodiment, the formulation is in a gas or vapor state and includes one or more components. The vapor or gas formulation may include one of oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, water, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, and mixtures thereof. In one embodiment, the vapor formulation may include one of two components, three components, or four components, and may include four or more components. The vapor formulation may include an azeotrope or a contrast agent, such as lipiodol or iodine, and may include a surfactant and / or a therapeutic agent. The temperature rise of the vapor formulation may range from 0°C to 140°C, 15°C to 100°C, or 20°C to 85°C.

[0023] In one embodiment, the formulation is in a liquid state and includes one or more components. The liquid formulation may include one of water, saline, hypertonic saline, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, lipiodol, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, urea, surfactants, and the like. The liquid formulation may include an azeotrope, a contrast agent, and / or a therapeutic agent. In one embodiment, the formulation may include one of two components, three components, or four components, and may also include four or more components. In some embodiments, the liquid formulation temperature may range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The liquid formulation may include a solution, a suspension, and an emulsion.

[0024] In one embodiment, the method for treating a disease includes inserting a delivery catheter into a diseased tissue in the human body percutaneously and / or orally; using the catheter to inject a therapeutic agent into the body tissue, where the amount of agent delivered is effective to injure or damage the tissue, for example, by lowering blood pressure, lowering glucose level and relieving shortness of breath; optionally removing the agent; and finally, withdrawing the delivery catheter from the body.The disease for this treatment includes one of hypertension, pulmonary hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive disease, cancer, tumor, pain, asthma and chronic obstructive pulmonary disease (COPD). The body cavities applicable for such treatment include renal arteries and veins, pulmonary arteries, vascular lumens, celiac arteries, common and proper hepatic arteries, gastroduodenal arteries, right and left hepatic arteries, splenic arteries, right and left gastric arteries, non-vascular lumens, airways, paranasal sinuses, esophagus, respiratory lumens, gastrointestinal lumens, stomach, duodenum, jejunum, cancer, tumors, pain, and urinary lumens. The gastrointestinal lumens applicable for such treatment include the esophagus, stomach, duodenum, jejunum, small and large intestines, and colon. The formulations applicable for such treatment include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. If the formulation contains vapors of one or more components, heat can be generated by condensation of the vapor into a liquid in the tissue. If the formulation contains a liquid or solution, cooling or heat can be generated from the formulation temperature being below or above body temperature. The liquid formulation temperature may range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. In one embodiment, the formulation temperature may be equal to room temperature. In one embodiment, the formulation temperature may range from -40°C to -20°C. In another embodiment, the formulation temperature may range from 15°C to 80°C. In one embodiment, the formulation temperature may be equal to body temperature. In another embodiment, the formulation temperature may range from 50°C to 80°C. In another embodiment, the temperature of the tissue to be treated may be lower than the formulation temperature and higher than body temperature. The temperature of the tissue to be treated may range from -40°C to 100°C, -30°C to 80°C, or -20°C to 80°C. In one embodiment, the temperature of the tissue to be treated may range from -40°C to -20°C.In another embodiment, the temperature of the tissue to be treated may range from 15°C to 80°C. In one embodiment, the temperature of the tissue to be treated may be equal to body temperature. In another embodiment, the temperature of the tissue to be treated may range from 50°C to 80°C. Delivery catheters applicable for such treatment include needles or needle-based catheters under imaging guidance. The imaging guidance includes one of ultrasound, x-ray, CT scan, MRI, OCT or scope. The delivery catheter may also be balloon-based. The balloon-based catheter may have a single, double or triple balloon. The delivery catheter may also be infusion-based. A combination of balloon and infusion catheters may also be used in some procedures. In one embodiment, the method includes outflow from the distal tip of the catheter, such as a wire lumen, to protect, dilute the transferred chemical, and prevent the leaked chemical from entering the distal portion of the untreated area; outflow from the infusion catheter; outflow from the endoscope; removing or withdrawing the formulation from the body tissues and lumens after treatment, and washing the target area with saline after treatment.

[0025] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief description of the drawings]

[0026] [Figure 1] FIG. 1 is an exemplary embodiment of an overall view of a double balloon delivery catheter according to the present invention.

[0027] [Diagram 2] FIG. 2 is an embodiment of a side view of a distal portion of an inflated dumbbell balloon.

[0028] [Figure 3A] FIG. 3A is an embodiment of a side view of an infusion balloon having holes in the balloon wall for chemical delivery.

[0029] [Figure 3B] FIG. 3B is a side view embodiment of a chemical delivery system placed in a body cavity with an inflated balloon, with the majority of the chemical confined between two large diameter segments.

[0030] [Figure 4A] FIG. 4A is an embodiment of a side view of an infusion device having a chemical delivery tube attached to a balloon.

[0031] [Figure 4B] FIG. 4B is a side view embodiment of a dumbbell balloon injection device having a tapered transition from a larger diameter to a smaller diameter and having a chemical delivery tube attached.

[0032] [Figure 5A] FIG. 5A is an embodiment showing injection of a formulation into the airways using a single balloon delivery catheter.

[0033] [Figure 5B] FIG. 5B is an embodiment showing injection of the formulation into the airways using a double balloon delivery catheter.

[0034] [Figure 5C] FIG. 5C is an embodiment showing injection of the formulation into the renal artery using a double balloon delivery catheter.

[0035] [Figure 6] FIG. 6 is an embodiment of a partial cross-sectional view of a double balloon delivery catheter in a body lumen.

[0036] [Figure 7] FIG. 7 is an embodiment of a partial cross-sectional view of a tri-balloon on a multi-lumen shaft having an infusion lumen and a drug delivery lumen.

[0037] [Figure 8A]FIG. 8A is an embodiment of a partial cross-sectional view of a tri-balloon combined infusion device in which the unoccupied space between the two larger diameter balloons is reduced in the inflated state.

[0038] [Figure 8B] FIG. 8B is a partial cross-sectional view embodiment of a tri-balloon infusion device with different balloon waist orientations due to balloon attachment on the shaft.

[0039] [Figure 9A] FIG. 9A is a partial cross-sectional view of an embodiment of an inflated double balloon infusion device having an injection port between the balloons.

[0040] [Figure 9B] FIG. 9B is an embodiment of a partial cross-sectional view of an inflated double-balloon infusion device having a tapered diameter change and smaller diameter in the middle of the double balloons.

[0041] [Figure 9C] FIG. 9C is an embodiment of a partial cross-sectional view of an inflatable double balloon infusion device having a two-stage balloon and a small diameter coupled to the middle of the double balloon assembly.

[0042] [Figure 10A] FIG. 10A illustrates an embodiment of a formulation injection into the left gastric artery with a single balloon delivery catheter.

[0043] [Figure 10B] FIG. 10B is an embodiment of formulation injection into the hepatic artery with a single balloon delivery catheter.

[0044] [Figure 11] FIG. 11 is an embodiment of formulation injection into the duodenum with a triple balloon delivery catheter.

[0045] [Figure 12]FIG. 12 is a bar graph showing the reduction in norepinephrine (NE) following renal denervation in ethanol vs. control treated groups.

[0046] [Figure 13] FIG. 13 is a curve showing the change in body weight after duodenal treatment with acetic acid.

[0047] [Figure 14] FIG. 14 is a curve showing the change in body weight after duodenal treatment with ethanol.

[0048] [Figure 15] FIG. 15 is an embodiment of a metal injection tube having a Bard triangle feature (indicated by the white arrow).

[0049] [Figure 16] FIG. 16 is a histopathological image showing a severed renal nerve (indicated by black arrow) following ethanol treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] An embodiment of the present invention relates to the treatment of disease by delivery of an effective amount of a formulation to a target tissue in a body cavity. The disease can be one of hypertension, pulmonary hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive disease, cancer, tumor, pain, asthma, or chronic obstructive pulmonary disease (COPD). Cancer includes adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, and uterus. The formulation includes gas, vapor, liquid, solution, emulsion, and suspension of one or more components. The method includes delivering the formulation to a luminal surface, tissue, and nerve in a human body to modify the surface, tissue, and nerve. The body cavities include renal arteries and veins, pulmonary arteries, vascular lumens, celiac artery, common hepatic artery, proper hepatic artery, duodenal artery, right hepatic artery, left hepatic artery, splenic artery, right gastric artery, left gastric artery, blood vessels, non-vascular lumens, airways, paranasal sinuses, esophagus, respiratory lumens, digestive lumens, stomach, duodenum, jejunum, cancer tissue, tumors, and urinary lumens. The digestive lumens include the esophagus, stomach, duodenum, jejunum, small and large intestines, and colon. The temperature can improve the safety and efficacy of the treatment formulation. The temperature can range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The temperature of the tissue to be treated can be different from the formulation temperature. The temperature of the tissue to be treated can range from -40°C to 100°C, or -30°C to 80°C. The amount of formulation and energy delivered is effective to injure, damage or remove diseased tissue, for example, by lowering blood pressure, shrinking tumors, relieving pain, or relieving symptoms of asthma and COPD. Energy or heat can enhance the injury / damage / removal effect by accelerating the reaction rate between the formulation and tissue. The delivery method includes delivery of the formulation to ablate nerves surrounding a human body cavity. The method includes removing or withdrawing the formulation from the tissue or cavity after treatment.

[0051] In one embodiment, the formulation is one chemical or one of two, three or four components, and may include more than four components. In one embodiment, the delivery system may include a less invasive percutaneous approach or a non-invasive approach. An embodiment of the present invention includes a formulation that includes one or more components that improve both the modification of the surface of the body cavity and the absorption and penetration into the tissues and nerves and nerve endings of the body cavity.

[0052] In one embodiment, the components of the formulation are selected from water, saline, hypertonic saline, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, urea, lipiodol, surfactants, and derivatives thereof and combinations thereof.

[0053] In one embodiment, the components of the formulation include a gas, which may be selected from oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, vapors of organic and inorganic compounds, water, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, and mixtures thereof.

[0054] In one embodiment, the components in the formulation include a surfactant. In some embodiments, the surfactant is PEG laurate, Tween 20, Tween 40, Tween 60, Tween 80, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate ... The surfactant is selected from sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, organic acids, salts of any organic acid and organic amine, polyglycidol, glycerol, multiglycerol, 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), penta(propylene glycol), poly(propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, Pluronic, Pluronic 85, and derivatives thereof and combinations thereof. In some embodiments, the content of the surfactant in the formulation may be in the range of 0.1% to 80% by weight, 0.5% to 50% by weight, or 1% to 15% by weight.

[0055] In one embodiment, the formulation comprises at least one of an oil, a fatty acid and / or a lipid. At least one of the oils, fatty acids and lipids in the formulation is selected from the group consisting of butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di- or The lipid is selected from triacylglycerol, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobiosomes, niosomes, and derivatives thereof.

[0056] In another embodiment, the preparation comprises therapeutic agent or drug for denervation and surface modification.The therapeutic agent is one of sodium channel blockers, tetrodotoxin, saxitoxin, decarbamoyl saxitoxin, vanilloid, neosaxitoxin, lidocaine, conotoxin, cardiac glycoside, digoxin, glutamate, staurosporine, amlodipine, verapamil, cymarin, digitoxin, proscillaridin, ouabain, veratridine, domoic acid, ethanol, oleandrin, carbamazepine, aflatoxin, guanethidine or guanethidine sulfate.In another embodiment, the preparation comprises contrast agent for imaging denervation. The contrast agent includes iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan, iodixanol, ioxaglate, and derivatives thereof. The content of the contrast agent in the formulation can be in the range of 2-25% by weight or 5-15% by weight.

[0057] In one embodiment, the formulation comprises an azeotrope. An azeotrope is a mixture of two or more components that cannot be changed by simple distillation. This occurs because the vapors produced upon boiling are proportional to the components of the original mixture. The azeotrope is selected from ethanol / water, ethanol / water / contrast agent, ethanol / water / surfactant, ethanol / water / contrast agent / surfactant, propanol / water, isopropanol / water, butanol / water and acetic acid / water.

[0058] In one embodiment, the formulation is in gas or vapor state, containing one or more components.In one embodiment, the gas or vapor formulation comprises one of oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, and organic and inorganic vapor.The organic and inorganic vapor comprises one of water, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, and mixtures thereof.

[0059] In one embodiment, the vapor formulation includes at least one contrast agent, such as lipiodol or iodine, or an azeotrope, and may also include a surfactant and / or a therapeutic agent. In one embodiment, the vapor is one of two components, three components, or four components, and may also include more than four components. The vapor formulation temperature may range from 0°C to 140°C, 15°C to 100°C, or 30°C to 80°C.

[0060] In one embodiment, the formulation is in a liquid state comprising one or more components. The liquid formulation comprises one of water, saline, hypertonic saline, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, lipiodol, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, urea, surfactants, and the like. In one embodiment, the liquid formulation comprises a contrast agent and / or an azeotrope, and may also comprise a therapeutic agent. In one embodiment, the liquid formulation is one of two-component, three-component, or four-component, and may also comprise four or more components. In one embodiment, the liquid formulation comprises a solution, emulsion, or suspension. The liquid formulation temperature may range from -40°C to 140°C, -30°C to 100°C, or -30°C to 80°C. In one embodiment, the formulation temperature may be room temperature. In one embodiment, the formulation temperature may range from -40°C to -20°C. In another embodiment, the formulation temperature may range from 15°C to 80°C. In one embodiment, the formulation temperature may be equal to body temperature. In another embodiment, the formulation temperature may range from 50°C to 80°C.

[0061] In one embodiment, the method for treating disease includes percutaneously or orally inserting a delivery catheter into the body; using the catheter to inject the formulation into diseased tissue or cavity in the body; optionally removing or withdrawing the formulation from diseased tissue or cavity; and finally withdrawing the delivery catheter from the body.Diseases for treatment include hypertension, pulmonary hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive disease, urinary disease, cancer, tumor, pain, asthma and chronic obstructive pulmonary disease (COPD).Cancer includes adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach and uterus. Body cavities include renal arteries, vascular lumens, celiac arteries, common and proper hepatic arteries, gastroduodenal arteries, right and left hepatic arteries, splenic arteries, right and left gastric arteries, non-vascular lumens, airways, paranasal sinuses, esophagus, respiratory lumens, digestive lumens, stomach, duodenum, jejunum, and urinary lumens. Digestive lumens include the esophagus, stomach, duodenum, jejunum, small and large intestines, and colon. The formulations include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. In embodiments where the formulation includes vapors of one or more components, heat can be generated by condensation of the vapor to a liquid in the tissue. In embodiments where the formulation includes a liquid or solution, cooling or heat can be generated from the formulation temperature being below or above body temperature. Liquid formulation temperatures can range from -40°C to 140°C, -30°C to 100°C, or -30°C to 80°C. In one embodiment, the temperature of the tissue to be treated is different from the formulation temperature and may be lower or higher than body temperature. The temperature of the tissue to be treated may range from 15°C to 100°C, 20°C to 90°C, or 36°C to 80°C. In another embodiment, the temperature of the tissue to be treated may range from -40°C to -20°C. In some embodiments, the delivery catheter is a needle or needle-based-catheter under an imaged guide. The imaged guide is one of ultrasound, x-ray, CT scan, MRI, OCT, or scope. The delivery catheter may also be balloon- or infusion-based. The balloon-based catheter may have a single, double, or triple balloon. The infusion catheter may have a dumbbell balloon.Typically, there are three parts of a dumbbell infusion balloon: proximal, distal and middle. The middle part has a small diameter with or without an infusion hole, and the proximal and distal parts of the balloon have a larger diameter without an infusion hole. If the middle part of the dumbbell balloon has a hole (Figures 3A and 3B), the infusion is from an inflatable catheter component and is defined as an inflatable infusion method. The initial infusion pressure can range from 0.1 atm to 14 atm, 1 atm to 10 atm or 3 atm to 8 atm depending on the application. The infusion time can range from 0.1 min to 2 hours, 0.5 min to 30 min or 1 min to 10 min. During the infusion time following the initial infusion pressure, the balloon pressure can range from 0.1 atm to 3 atm, 0.1 atm to 2 atm and 0.3 atm to 1 atm. The formulation infusion temperature can range from -40°C to 150°C, -30°C to 100°C or -20°C to 80°C.

[0062] In one embodiment, the injection feature is made of a hypotube / tube, either made of plastic or metal, which is attached to a non-perforated dumbbell balloon catheter. The treatment formulation is delivered through holes on the hypotube / tube, and the injection is from a non-expandable catheter component, while the hypotube / tube moves with the balloon to the vessel wall; this injection is defined as a hybrid method, which includes a combination of non-expandable and expandable injection methods. Typically, the holes of the hypotube / tube are aligned along the center of the dumbbell balloon to control the outflow location of the formulation.

[0063] In another embodiment, the infusion lumen can be located inside the catheter shaft, for example a multi-lumen shaft for non-inflatable infusion methods. In this case, the holes are located in the non-inflatable sections between the balloons on the shaft (FIGS. 7, 8A-8B, 9A-9C). More detailed examples of devices, such as double-balloon and triple-balloon infusion catheters, are shown in the following sections.

[0064] In one embodiment, the metal hypotube may feature a Bard triangle, which enhances diffusion of the formulation by creating extremely small holes within the vessel wall or tissue. The height of the Bard triangle may range from 0.25 to 2 mm. This injection method is a hybrid method.

[0065] In one embodiment, the formulation comprises ethanol. The formulation may be delivered to the tissue of the body cavity as a vapor or liquid. The vapor or liquid formulation temperature may range from -40°C to 150°C, -30°C to 100°C, or -20°C to 80°C. The tissue temperature may range from -40°C to 90°C, or -30°C to 80°C. In one embodiment, the formulation consists essentially of ethanol. In one embodiment, the formulation consists of ethanol.

[0066] In one embodiment, the formulation is a mixture of ethanol and water. The ethanol content ranges from 10 to 100% by weight. The formulation can be delivered to the tissue of the body cavity as a vapor or liquid. The vapor or liquid formulation temperature can range from -40°C to 150°C, -30°C to 100°C, or -20°C to 80°C. The tissue temperature can range from -40°C to 90°C, -30°C to 80°C. The ethanol / water formulation can be a possible azeotrope. The azeotrope can be 95.63% by weight ethanol and 4.37% by weight water. Ethanol boils at 78.4°C, water boils at 100°C, and the azeotrope boils at 78.2°C, which is lower than either of its constituent components. 78.2°C is the lowest temperature at which any ethanol / water solution can boil at atmospheric pressure.

[0067] In another embodiment, the formulation is a mixture of steam comprising water, ethanol and oxygen.In another embodiment, the formulation is a mixture of steam comprising water, ethanol and air.In another embodiment, the formulation is a mixture of steam comprising water, ethanol, oxygen and nitrogen.The formulation with oxygen and air is particularly useful for treating asthma and COPD.

[0068] In another embodiment, the formulation is a mixture of water, ethanol and vapor containing iodine, wherein an effective amount of iodine vapor is included to enable imaging of the mixture of vapor at the wall of the body cavity. In another embodiment, the formulation is a mixture of liquids containing water, ethanol and a surfactant. In another embodiment, the formulation is a mixture of liquids containing water, ethanol and a contrast agent, wherein an effective amount of the contrast agent is included to enable tracking of the mixture at the wall of the body cavity by X-ray. The contrast agent is iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan, iodixanol, ioxaglate, and one of their derivatives. The content of the contrast agent in the formulation can be in the range of 2-20% by weight or 5-15% by weight.

[0069] In one embodiment, the formulation is a mixture of acetic acid and water. The acetic acid content of the formulation may range from 1 to 100% by weight, 10 to 75% by weight, or 20 to 50% by weight. The formulation may be delivered to the tissue of the body cavity as a vapor or liquid. The vapor or liquid formulation temperature may range from -40°C to 100°C, -30°C to 100°C, or -30°C to 80°C. The tissue temperature may range from -30°C to 80°C, 60°C to 80°C, or -30°C to -20°C. The tissue temperature may range from -40°C to 0°C, or -30°C to -20°C. The acetic acid content in the formulation may range from 2% by weight to 75% by weight, or 10% by weight to 80% by weight.

[0070] In another embodiment, the formulation is a mixture of liquids including ethanol and lipiodol (LIPIODOL ULTRA-FLUIDE), where an effective amount of lipiodol is included to image the vapor mixture in the body cavity wall and injure the target nerve tissue. The lipiodol content of the formulation can be in the range of 10% to 80% by weight, 15% to 75% by weight, or 20% to 50% by weight. In another embodiment, the formulation is a mixture of liquids including water and lipiodol. The lipiodol content of the formulation can be in the range of 10% to 80% by weight, 15% to 75% by weight, or 20% to 50% by weight. In another embodiment, the formulation is a mixture of liquids including acetic acid and lipiodol. The lipiodol content in the formulation can be in the range of 10% to 80% by weight, 15% to 75% by weight, or 20% to 50% by weight.

[0071] In one embodiment, a delivery catheter is used in the invention to inject the formulation into tissues of the human body. The delivery catheter is an X-ray or ultrasound-imaged guided needle or needle-based catheter. The delivery catheter can be balloon based single, double or triple balloon. The delivery catheter can also be infusion-based. A combination of balloon and infusion catheter can be used in the procedure. The balloon in the infusion system should be able to confine the formulation within the balloon wall and appropriately control the amount of the formulation.

[0072] In one embodiment, an expanding balloon catheter is used in the invention for delivery of an active substance to a target location in a patient's body cavity, wherein the expanding balloon catheter comprises a proximal end, a distal end, a wire, a lumen, a balloon inflation lumen, a formulation infusion lumen and / or a vacuum lumen, an expandable balloon section and a non-expandable shaft section, the expandable balloon section comprises at least one section, the non-expandable shaft section comprises at least one section, the first section of the expandable section and / or the non-expandable section has a plurality of voids, the voids are microholes, and at least one second section of the expandable section and / or the non-expandable shaft section has no voids. The expandable section or the non-expandable section of the expanding balloon catheter has at least one void that allows the formulation to penetrate the wall of the body cavity at a pressure higher than that of the body cavity. The expandable section or the non-expandable section does not have any voids that allow the balloon to expand into a body cavity at a pressure higher than that of the body cavity.

[0073] As shown in FIG. 1, the delivery catheter 10 has an elongate shaft 11 with at least one internal lumen, a distal end 13, and a proximal end 14. At the distal end 13 are proximal 20 and distal 21 lumen conforming balloons. In any arrangement, the tube of the catheter shaft 11 may be molded from a plastic material, such as thermoplastic, polyimide, polyetherimide, polyethylene, polyurethane, polyester, polyamide, Pebax, nylon, fluorinated polyurethane, polyetheretherketone, polysulfone, and the like. The catheter shaft 11 may be molded or formed with a variety of lumen cross sections, including circular or elliptical lumens. Also, as shown in FIG. 1, the catheter 10 may include a distal balloon inflation port 40 for inflation of the distal balloon 21 and a proximal balloon inflation port 41 for inflation of the proximal balloon 20, allowing the proximal 20 and distal 21 balloons to be inflated, respectively. A lumen conforming balloon is a balloon that may be inflated at a lower pressure than is required to deform the lumen wall. The balloon material is selected to be flexible and usable at high temperatures so that the balloon is compliant when inflated. In one embodiment, the balloon material is one of polyamide, nylon, Pebax, polyester, polyethylene terephthalate, or copolymers thereof. The diameter of the balloon can range from about 2 millimeters to about 40 millimeters depending on the diameter of the treatment area. In one embodiment, the diameter of each balloon is about 2 millimeters ("mm"). Alternatively, the diameter of each balloon is about 3 millimeters, about 4 millimeters, about 5 millimeters, about 6 millimeters, about 7 millimeters, about 8 millimeters, about 9 millimeters, about 10 millimeters, about 12 millimeters, about 15 millimeters, about 20 millimeters, about 25 millimeters, about 30 millimeters, about 35 millimeters, or about 40 millimeters.

[0074] In one embodiment, at least one marker band 22b is located proximal to the proximal balloon 20 and at least one marker band 23a is located distal to the distal balloon 21. The balloon catheter can be a rapid exchange or over-the-wire type catheter made of any suitable biocompatible material. Marker bands can also be located at the other end of the balloon (22a and 23b). 25 is a segment between the balloons 21 and 21 that has at least one injection hole. 30 is a non-inflatable portion; 31 and 32 are small voids or holes; 24 is a shaft proximal to the balloon portion. 40 and 41 are ports for balloon inflation, which are the distal and proximal balloons, respectively. 42 is an injection port for chemical agents.

[0075] The material of balloons 20 and 21 is comprised of one of polyester, polyamide, nylon 12, nylon 11, polyamide 12, block copolymers of polyether and polyamide, Pebax, polyurethane, or block copolymers of polyether and polyester. Balloon 21 has a diameter equal to or less than balloon 20.

[0076] In one embodiment, a schematic dumbbell balloon is shown in FIG. 2. In the inflated state, its central diameter D2 is smaller than both of its end diameters D1 and D3. The lengths of D1 and D3 may be the same or different. Each diameter has its own length L1, L2 and L3, respectively. For simple illustration, a dumbbell-shaped balloon is used for the following description. However, other similar types of balloons, such as multi-groove balloons, in which the grooves are located in the center of the balloon, can achieve the same features / functions. The design of the dumbbell-shaped balloon shape allows the balloon to have better injection volume control and position control of the formulation inside the target vessel, since the two larger ends block the formulation flow path. In one embodiment, the formulation to be delivered is mostly confined to the small diameter center, as shown in FIG. 2. A controlled treatment dose is required for the safety of the procedure, which means that the diameter ratio of the large diameter to the small diameter on the dumbbell balloon is determined by the need for clinical administration. To define the diameter combinations on a dumbbell balloon, the volume per surface area is used and calculated from the volume gap (unoccupied space on the smaller diameter) between the two larger diameter ends relative to the smaller diameter center. The formula for calculating the ratio is: Volume / Surface Area = (D1 2 - D2 2 ) + (4*D1) .....Formula 1 where D1 is the diameter of the large diameter balloon portion and D2 is the diameter of the small diameter balloon portion.

[0077] The volume / surface area ratio can be in the range of 0.1 mm to 10 mm, 0.2 mm to 5 mm, or 0.3 mm to 2 mm. The dose of chemical agent can thereby be constant and independent of balloon or vessel size. The value of the ratio is determined by the clinical treatment needs (dosing requirements). Dumbbell balloons or multi-grooved balloons can be made from a secondary heat shrinking process with regular cylindrical balloons or by direct molding into shapes. The diameter of the balloon body, which differs between the large diameter end and the central small diameter section, is determined by the previously measured value of the volume / surface area ratio, which is calculated using Equation 1. For example, for a combination of 6 mm and 8 mm balloons, the calculated volume / surface area ratio is 0.88 mm.

[0078] The overall balloon body diameter and length may range from 2 to 40 mm and 10 to 100 mm, respectively. Any conventional balloon cone angle or shape is acceptable for the application, although a circular or radius cone shape is preferred.

[0079] Any balloon material compatible with the formulation may be used to fabricate the balloon, such as polyethylene, polyolefin elastomers, natural rubber, polyesters such as PET and PBT, and their block copolymers, including thermoplastic elastomers such as Hytrel, and polyamides, such as Nylon 12 and Nylon 11, and their block copolymers, including thermoplastic elastomers such as Pebax.

[0080] In one embodiment, a schematic diagram of a dumbbell balloon infusion catheter is shown in FIG. 3A, with four holes spaced 90 degrees apart in the central small diameter balloon section, which is modified from FIG. 2 with a tapered transition between different diameters. Liquid formulations can be delivered from the balloon inflation lumen through holes on the balloon; this is an inflatable infusion method. In this example, the formulation functions in two roles: inflating the balloon and acting as a treatment agent. FIG. 3B is a schematic diagram of an inflated and positioned infusion balloon catheter inside a blood vessel. Most of the delivered treatment formulation is trapped in the space created by the smaller balloon body and the two larger balloon shoulders in the vessel wall.

[0081] To improve the diffusion distance of the chemical treatment agent, the ratio of balloon outer diameter (OD) to vessel inner diameter (ID) greater than 1 at certain control levels may be used. The ratio may range from 1.01 to 10, 1.10 to 5, or 1.20 to 1.35.

[0082] The fine holes on the balloon for delivering chemicals can be made by a process of micro-punching or drilling directly into the wall of the balloon body. The appropriate hole size can be in the range of 5 microns to 500 microns or 20 microns to 250 microns on the balloon wall. These values ​​properly consider the balance between balloon inflation, injection rate and formulation flow rate control. If the hole size is too large, the amount of formulation may not be controllable due to overflow. Geometrically, the holes are typically placed in the center on the small diameter area; however, they can be placed in different ways or patterns on the balloon for the purpose of delivering the formulation. The holes on the balloon can be placed along the circumference of the wall of the balloon body in the center of the small diameter section. The number of holes can range from 2 to 10 or more, and the size of the holes can range from 25 microns to 100 microns.

[0083] The dumbbell balloon in FIG. 3A can be considered as a one groove balloon with four evenly distributed holes around the circumference, whereas the balloon embodiment above includes multiple grooves on the balloon, each groove with its own group of holes for infusion. For example, a three-groove balloon can be made from an 80 mm long balloon, with infusate trapped within each groove. When the individual volume / surface area ratios are equal, the clinical results of the multi-groove balloon are the same as those of the regular dumbbell balloon shown in FIG. 3A. FIG. 3A is a device for inflatable infusion method.

[0084] In another embodiment, as shown in Figures 4A-4B, the chemical agent is delivered through a thin tube attached to the catheter at the distal and proximal balloons. In this example, a dumbbell balloon catheter with no holes on the balloon is used for the infusion system. Figures 4A-4B are devices for a hybrid infusion method. The formulation delivery tube has multiple holes located within the small diameter balloon section. The tubular hole size can range from 25 microns to 1 mm. The number of holes varies depending on the length of the small diameter balloon section. The distance between the holes can range from 2 mm to 5 mm.

[0085] To incorporate the infusion tube in the embodiment shown in Figures 4A-4B, the balloon inflation and formulation infusion occur by separate and independent procedures. For example, the balloon is first inflated to a predetermined pressure; then an effective amount of the chemical agent is delivered through the tube to the treatment site, while the remainder of the formulation is trapped in the center of the balloon's small diameter area. The infusion tube used on the catheter can be made of thermoplastics, such as polyethylene, nylon or Pebax, or metals or alloys, such as stainless steel or nitinol, or nitinol hypotubes, due to their excellent male properties.

[0086] The advantage of using metal or alloy tubes over plastic tubes is the presence of additional features for formulation delivery. For example, a Bard triangle feature can be added to the metal tube (Figure 15). When the balloon inflates against the vessel wall, the sharp tip of the Bard triangle helps to pinch into the tissue wall. Compared to the round hole type, this delivery system allows deeper diffusion of the chemical into the vessel tissue due to tissue perforation. If deeper diffusion over a larger vessel wall area is required, the balloon can be inflated and deflated several times and rotated after each injection / deflation cycle. This creates more holes on the vessel wall, allowing the formulation to diffuse deeper and faster. The height of the Bard triangle can range from 0.25 mm to 2 mm or 0.5 mm to 1 mm.

[0087] In one embodiment, a schematic diagram of a balloon delivery catheter placed in the left main bronchus for the treatment of asthma and COPD is shown in Figures 5A and 5B. The delivery catheter 198 of Figures 5A and 5B can treat airways that are distal to the main bronchi 21 and 22. For example, the delivery catheter 198 can be placed in various airways in the lung section to affect the far distal portion of the bronchial tree 27. The delivery system 198 can be navigated through tortuous airways to perform a wide range of procedures, such as denervation of a portion of a lobe, an entire lobe, multiple lobes, or one or both lungs. In some embodiments, a lobar bronchus is treated to denervate the lobe. For example, one or more treatment sites along a lobar bronchus can be targeted to denervate the entire lobe that connects to that lobar bronchus. The left lobar bronchus can be treated to affect the left upper lobe and / or the left lower lobe. The right lobar bronchus can be treated to affect the right upper lobe, the right middle lobe, and / or the right lower lobe. The lobes can be treated simultaneously or sequentially. In some embodiments, the physician may treat a lobe. Based on the effectiveness of the treatment, the physician may treat additional lobes simultaneously or sequentially. In this way, different, separate regions of the bronchial tree may be treated.

[0088] The delivery catheter 198 may also be used in the segmental or subsegmental bronchi. Each segmental bronchus may be treated by delivering the formulation to one treatment site along the segmental bronchus. For example, the formulation may be delivered to each segmental bronchus of the right lung. In some procedures, one or two applications of the formulation may treat most or all of the right lung. Depending on the anatomy of the bronchial tree, the segmental bronchi may often be denervated using one or two applications.

[0089] The delivery catheter 198 may affect the nerve tissue while preserving the function of other tissues or anatomical features, such as mucosal glands, villi, smooth muscle, body cavities (e.g., blood vessels), etc. The nerve tissue includes nerve cells, nerve fibers, dendrites, and supporting tissue, such as glia. Nerve cells transmit electrical impulses, and nerve fibers are extensions of axons that conduct the impulses. The electrical impulses are converted into chemical signals to communicate with effector cells or other cells. As an example, the delivery catheter 198 may denervate an airway portion of the bronchial tree 27 to attenuate one or more nervous system signals transmitted by the nerve tissue. Denervation may include cutting nerve tissue in a nerve trunk to prevent signals from traveling through that particular area to a more distal location along the bronchial tree. When multiple nerve trunks extend along the airway, each nerve trunk may be cut. In such cases, the nerve supply along the bronchial tree may be cut. When the signal is cut, the distal airway smooth muscle relaxes, causing airway dilation. This airway dilation reduces airflow resistance and increases gas exchange in the lungs, thereby alleviating or eliminating one or more clinical symptoms, such as shortness of breath, wheezing, chest tightness, etc. Tissues surrounding or adjacent to the targeted nerve tissue may be affected, but not permanently severed. In some embodiments, for example, bronchial blood vessels along the treated airway may deliver a similar amount of blood to the bronchial wall tissue, and pulmonary blood vessels along the treated airway may deliver a similar amount of blood to the alveolar sacs in the distal region of the bronchial tree 27 before and after treatment. These blood vessels may continue to transport blood to maintain adequate gas exchange. In some embodiments, airway smooth muscle is not injured to a significant extent. For example, a relatively small portion of the smooth muscle of the airway wall that does not obviously affect respiratory function may be reversibly altered. When a formulation is used at a controlled temperature to injure nerve tissue outside the airway, the formulation does not reach a significant portion of the non-targeted smooth muscle tissue.

[0090] 5A and 5B includes an intraluminal elongate assembly 200 that connects to a controller 202. The elongate assembly 200 may be delivered to the trachea 20 or navigated into or through the bronchial tree 27 with or without the aid of a delivery assembly. The elongate assembly 200 includes a distal tip 203 that may selectively affect tissue.

[0091] The controller 202 of FIG. 5A may include one or more processors, microprocessors, digital signal processors (DSPs), field programmable gate arrays (FPGAs), application specific integrated circuits (ASICs), storage devices, buses, power supplies, pumps, formulation sources, vapor sources, liquid sources, contrast media sources, vapor generators, desired temperature formulation generators, and the like.

[0092] The distal tip 203 of Figures 5A-5B can target various sites in the lungs, including, but not limited to, neural tissue, fibrous tissue, diseased or abnormal tissue, muscle tissue, blood, blood vessels, and various anatomical features (e.g., membranes, glands, villi, etc.).

[0093] In one embodiment, a schematic diagram of a double balloon delivery catheter placed in the renal artery is shown in FIG. 5C. The balloon catheter 107 in FIG. 5C can target hypertension. The formulation is injected into the renal artery wall adjacent to the renal nerve for denervation. Some of the components of the renal vasculature are omitted in FIG. 5C. In FIG. 5C, 102 is the kidney, 105 is the guide catheter, 106 is the main renal artery, 107 is the balloon catheter, 301 is the abdominal aorta, and 502 is the extrarenal artery.

[0094] In one embodiment, a method for treating hypertension includes percutaneously inserting a delivery catheter into a renal artery and / or a non-renal artery adjacent to a nerve and nerve ending; using the delivery catheter to inject the formulation into tissue of a body cavity adjacent to the nerve, wherein the amount of formulation delivered is effective to injure the nerve or nerve ending, e.g., by reducing blood pressure; and finally, withdrawing the delivery catheter from the body cavity. EXAMPLES

[0095] In one embodiment, a balloon infusion catheter, such as those shown in Figures 3A-3B, 4A-4B, 7, 8A-8B, and 9A-9C, can be used to treat hypertension. An example of a preclinical study of this embodiment is described below.

[0096] In one example, a 47 kg porcine animal was anesthetized with isoflurane and one side of the renal artery was ablated with ethanol using a balloon catheter, while the other side served as a control. Using standard renal access procedures, balloon infusion catheters were placed over the wire into the target renal arteries of the main renal and extrarenal branches in sequence. Upon reaching the target ablation site, the balloon was inflated and absolute ethanol-mediated chemical ablation of the renal artery was performed by the inflatable infusion method. The balloon diameter was determined according to renal angiography, and a total of four catheters were used. During the ablation procedure, the balloon was first rapidly inflated to 6-8 atm with ethanol, then reduced to 0.5-1 atm and maintained at the lower pressure for approximately 60 seconds. By the end of the procedure time, the balloon was deflated and withdrawn or placed at another arterial site if necessary for the next procedure.

[0097] For better clinical results, the balloon outer diameter (OD, large diameter part) and the artery inner diameter (ID) may be in a certain ratio. A slightly oversized balloon OD relative to the vessel ID may be used, for example, balloon OD / vessel ID = 1.10-1.40; or = 1.20-1.35.

[0098] Post-resection renal angiograms were obtained to determine whether vasospasm, stenosis, or other abnormalities had occurred. There was no significant renal artery spasm during or after the balloon injection procedure.

[0099] Animals were euthanized 2 weeks after treatment and kidney tissue samples were obtained from the cranial, middle and caudal renal cortex to measure kidney tissue norepinephrine (NE) content using known HPLC methods. Norepinephrine is a neurotransmitter whose levels are used as a standard measurement for renal denervation. Renal arteries and surrounding tissues were similarly harvested for histopathological evaluation. Ethanol ablation of the renal artery resulted in a 72% reduction in renal norepinephrine (NE content: control: 570 ng / g; denervated kidney, i.e., RDN: 160 ng / g), as shown in FIG. 12.

[0100] After ethanol ablation, not only was there a decrease in NE content, but histopathological evaluation also demonstrated renal nerve injury as shown in FIG. 16, where the nerve is depicted within the outer border of the adventitia surrounded by mild fibrosis (black arrows).

[0101] To confirm the results of the above study, a second study was conducted. The same infusion device and the same study duration (a 2-week chronic study) were used in this confirmatory study.

[0102] Six porcine animals weighing 44-56 kg were divided into three treatment subgroups: two treated in the main renal artery, two treated in the extrarenal branches, and two treated in both the main renal artery and the extrarenal branches. For each animal, one side of the renal artery was treated, while the contralateral renal artery served as a control. Standard renal access procedures were performed.

[0103] During the procedure, the balloon size was determined according to the balloon OD / artery ID ratio, which ranged from 1.20 to 1.35. This value provided good treatment efficacy and minimal vascular injury by controlling overinflation. The inflation pressure used in this study during the rapid inflation cycle was 10-12 atm; the pressure was then lowered to 0.5-1 atm, and the procedure was maintained at the lower pressure for 2 min at the main renal artery site and 1 min at the extrarenal branch artery. Renal angiography showed no significant renal artery spasm during and after the balloon implantation procedure in all six porcine animals in this study.

[0104] Renal artery ethanol ablation of only the main renal artery produced a mean norepinephrine (NE) reduction of approximately 40%. Ethanol ablation of the extrarenal arterial branches produced a norepinephrine reduction of approximately 80%. Chemical ablation of the main renal artery and the extrarenal arterial branches produced an overall reduction in NE content of more than 90%; cranial cortex norepinephrine reduction: 93.81%, 94.07%, 94.43%, central cortex tissue norepinephrine reduction: 91.98%, 92.19%, 93.20%, caudal cortex tissue norepinephrine reduction: 73.27%, 31.80%, 47.06%. This study showed that both the quality of the balloon and the degree of renal artery tissue contact during the procedure contributed to high efficacy.

[0105] In addition to the reduction in NE, histopathological evaluation showed renal nerve injury (shown in FIG. 16), which indicates large caliber vascular nerves surrounded by fibrosis and inflammation and multifocal degenerated and / or necrotic tissue. A circumferential effect was also observed. Overall, a mean renal nerve injury value of 50% was estimated in treated renal arteries.

[0106] In one embodiment, the catheter 10 (FIG. 1) described herein helps regulate the formulation flow rate and treatment dose through the treatment window 30, as shown in FIG. 6. The balloon can be inflated by the infusion lumen. The location, diameter, number and frequency of the outer ports 31 result in homogeneous filling of the treatment window 30. FIG. 6 shows a catheter placed in a body cavity 5 with two outer ports 31 located within the treatment window 30 for delivery of a therapeutic agent 3. The catheter tip 13, marker bands 23a and 23b, and inflatable balloons 20 and 21 are shown in FIG. 6. As shown in FIG. 6, the outer ports 31 are in fluid communication with the inner lumen 25. The outer ports 31 located within the treatment window 30 can be in communication with either the outer 24 or inner 25 lumen so that the formulation is delivered homogeneously to the treatment window 30.

[0107] In one embodiment, the cross-sectional view of the distal portion of the tri-balloon infusion catheter is depicted as shown in Figure 7. This infusion device can provide homogeneous filling at the treatment site. The balloon in Figure 7 is shown in an inflated state, with two large diameter balloons D1 and D3 at the distal and proximal ends, and one small diameter balloon (D2) in the middle. The combination of balloon diameters is determined by Formula 1 with a predetermined ratio value according to clinical dose requirements. The combination of balloon length depends on the target vessel length and tortuosity.

[0108] One design is for a 4-lumen shaft to act as an infusion catheter. The four lumens can be allocated for wire (1), balloon inflation (1) and chemical treatment (2), for example as shown in Figure 1. Alternatively, the catheter can be designed with more lumens to accommodate more infusion lumens where each balloon can be independently inflated.

[0109] The chemical treatment port is located between the balloons on the shaft. The formulation injection hole is located in the non-expandable shaft section between the expandable balloon sections. During treatment, the formulation can be pumped through the injection hole between the balloons to fill the space created by the small diameter balloon. This is a non-expandable injection method.

[0110] In one embodiment, optionally, residual chemicals / formulations can be collected after treatment by aspiration techniques at one of the infusion holes. In this case, at least two treatment lumens can be used: one for infusion and the other for aspiration. The formulation infusion and aspiration holes are located in the non-inflatable shaft section between the inflatable balloon sections.

[0111] In addition to withdrawing excess treatment agent, excess agent may also be diluted with saline or water to an ineffective concentration. Saline or water flushing may be performed using one of the catheter wire lumens or the infusion lumen, or by other means. The method of use depends on the site of protection or treatment. If a distal portion of the vessel requires protection from chemical treatment, flushing may be performed through the wire lumen.

[0112] In one embodiment, a new non-conventional balloon attachment method can be applied, as shown in Figure 8A. The new method involves placing the balloon waist inside the balloon cone or body; this helps to overcome the extra unwanted space surrounding the small diameter balloon, which is created by the length of the balloon waist and the length of the cone as shown in Figure 7. The extra space does not benefit the chemical treatment and may result in overdosing due to the inability to control the amount of treatment. The formulation infusion and aspiration holes are located in the non-inflatable shaft section between the inflatable balloon sections.

[0113] Similar balloon diameter combinations were used to demonstrate the effectiveness of the new assembly when excess space is minimized (Figure 8A vs. Figure 7). L(ii) as depicted in Figure 8A is L(i) or L(ii). In the inflated state, the cones of adjacent balloons are now in closer contact with each other, thereby minimizing excess space. Also, the formulation is delivered between the balloons to fill the space above the smaller diameter balloon section / area.

[0114] This new balloon assembly method can be explained by the difference in the length of the balloon before and after the upper assembly. Here, the balloon length L(i) is defined as the length from the distal waist / cone transition point to the proximal cone / waist transition point before the shaft assembly; the balloon length L(ii) is defined as the length from the distal waist / cone transition point to the proximal cone / waist transition point after the shaft assembly. In this new assembly method, the balloon waist was placed inside the cone, or in some cases, even inside the balloon body when the cone length was short. The relationship between L(i) and L(ii) is as follows: (1) L(i) = L(ii); when the balloon is assembled using conventional methods. (2) L(i) > L(ii); if the balloon is assembled using the new method. Depending on the length of the balloon cone, the new infusion catheters have the cone / waist transition point at least 25% inside the cone, or 50 or 100% inside the cone, or partially or completely inside the balloon body. For illustrative purposes, consider an example for an 8 x 20 mm balloon with a cone length of 5 mm both distally and proximally. In this case, L(i) = body length + distal cone length + proximal cone length = 20 + 5 + 5 = 30 mm. Situation 1: If the cone / waist transition point is located 50% inside the cone, then L(ii) = 20 + 2.5 + 2.5 = 25 mm; L(i) > L(ii). Situation 2: If the cone / waist transition point is located 100% inside the cone or at the cone / body transition line, then L(ii) = 20 + 0 + 0 = 20 mm; L(i) > L(ii). If the waist is located further inside, it will be located inside the balloon body.

[0115] In a multiple balloon assembly on a catheter, balloons with the same L(i) may also have the same L(ii) or different.

[0116] In another embodiment, a regular cone shaped balloon may be used for this catheter, however, a circular or semicircular cone balloon may also be used due to the shorter cone length and the potential for a larger contact surface area between adjacent cones.

[0117] In one embodiment, the balloon can be mounted onto the shaft by inverting the balloon waist and placing it inside the balloon waist or partially inside the balloon body, as shown in Figure 8B. The inverted balloon waist allows the balloon cones to be more naturally rounded, allowing for a larger contact surface area between the cones; and the waist can be more easily placed inside the balloon body.

[0118] In one embodiment, a double balloon combination is used when a narrower treatment band or a shorter total balloon length is required. Figure 9A shows two balloons with adjacent cones touching in the inflated state. Chemical agents can be delivered through a delivery port on the shaft located between the two balloons. A formulation infusion and / or aspiration hole is located in the non-inflatable shaft section between the inflatable balloon sections. Chemical agents can remain in the central narrow section of the two balloons during treatment. Optionally, additional ports can be available for flushing or aspiration purposes. The two balloons on the catheter can also have their own infusion lumen, allowing them to inflate independently.

[0119] In another embodiment, as shown in Figures 9B-9C, a dual-diameter balloon can be used in the infusion catheter to achieve a wider treatment length despite a shorter total balloon length. The balloon has two diameters, one smaller than the other. Using the same assembly technique as the three-balloon arrangement, the dual-diameter balloon is mounted on the shaft and assembled head-to-head on the smaller diameter side to form a smaller diameter central section. The two ends of the larger diameter section confine the chemical agent primarily to the central smaller diameter section to achieve a controlled amount of delivery. The formulation infusion and / or aspiration holes are located in the non-inflatable shaft section between the inflatable balloon sections. The formulation is also delivered through an infusion hole in the non-inflatable shaft section between the two inflatable balloon sections.

[0120] One dual diameter balloon is the tapered balloon shown in Figure 9B. This two-balloon configuration has the smaller diameter ends located in the middle of the two balloons facing head-to-head with respect to one another. The resulting overall diameter of the middle is smaller than the diameter of the ends.

[0121] Another dual diameter balloon is assembled from a two-stage balloon, as shown in FIG. 9C. There are two different diameters in one balloon, i.e., one side of the balloon is larger than the other; there is an abrupt diameter change between the two diameters. The two-stage balloon can be assembled with the smaller diameter sides facing each other to form the center of the entire balloon. The stage balloon can provide a wider treatment length, as in FIG. 9B, despite having the same overall balloon length.

[0122] 10A and 10B illustrate that a balloon infusion catheter 365 is placed in the gastric artery 360 or the hepatic artery 320. The various arteries surrounding the liver and stomach, as well as the various nervous systems that innervate the liver and stomach and the surrounding organs and tissues, are shown in FIG. 10A and 10B. The arteries surrounding the liver and stomach include the abdominal aorta 305, the celiac artery 310, the common hepatic artery 315 and the proper hepatic artery 320, the duodenal artery 322, the right hepatic artery 325 and the left hepatic artery 330, the splenic artery 335, and the esophageal branch 361. The various nervous systems innervating the liver and stomach and the stomach and the surrounding organs and tissues include the celiac plexus 340 and the hepatic plexus 345. The blood supply to the liver is pumped from the heart to the aorta, which then descends through the abdominal aorta 305 to the celiac artery 310. From the celiac artery 310, blood travels through the common hepatic artery 315 to the proper hepatic artery 320, then through the right hepatic artery 325 and the left hepatic artery 330 to the liver. The common hepatic artery 315 branches off from the celiac artery to give rise to the gastroduodenal artery. Nerves that innervate the liver include the celiac plexus 340 and the hepatic plexus 345. The celiac plexus 340 wraps around the celiac artery 310 and continues to the hepatic plexus 345, which wraps around the proper hepatic artery 320 and the common hepatic artery 315, and / or continues to the right hepatic artery 325 and the left hepatic artery 330. In some anatomical structures, the celiac plexus 340 and the hepatic plexus 345 are tightly attached to the arterial walls and supply blood to the liver, making intra-to-extra-vascular neuromodulation particularly advantageous. In some embodiments, the thickness of the inside of a blood vessel (e.g., hepatic artery) ranges from about 0.1 cm to about 0.25 cm. In some embodiments, the formulation can be delivered to the inner wall of a target blood vessel or target nerve. Intravascular delivery can be used (e.g., in the case of hepatic artery branches) because nerves are tightly attached to the outer wall of the artery, thereby supplying blood to the liver.

[0123] The arteries surrounding the stomach include the abdominal aorta 305, the celiac artery 310, the right gastric artery 355 and the left gastric artery 360, and the esophageal branch 361. The blood supply to the stomach is pumped from the heart into the aorta, which then descends through the abdominal aorta 305 into the celiac artery 310. From the celiac artery 310, blood travels through the right gastric artery 355 and the left gastric artery 360, to the esophageal branch 361, and then to the stomach.

[0124] Continuing with Figures 10A and 10B, the hepatic plexus 345 is the largest offset from the celiac plexus 340. The hepatic plexus 345 is primarily afferent and efferent. Intersection It is believed to carry sensory nerve fibers, the stimulation of which can increase blood glucose levels by a number of mechanisms. For example, in the hepatic plexus 345 Intersection Stimulation of the hepatic nerve fibers can increase blood glucose levels by either improving hepatic glucose production or decreasing hepatic glucose uptake. Exchange Disruption of sensory nerve signaling can alter blood glucose levels.

[0125] In one embodiment, Figure 10B shows a schematic diagram of a balloon delivery catheter placed in the hepatic artery for the treatment of diabetes. In another embodiment, Figure 10A shows a schematic diagram of a balloon delivery catheter placed in the left gastric artery for the treatment of obesity and diabetes.

[0126] Certain embodiments of the present invention include delivering a vapor or liquid formulation to a body cavity at a specific delivery rate for a predetermined time. The formulation can be heated to at least 80°C, for example 100°C or 150°C, before delivery. The catheter materials, particularly the balloon and shaft, can function at the above temperatures, i.e., the materials are made to withstand high temperatures. In certain embodiments, the vapor delivered can undergo a phase change to a liquid, resulting in an energy release that is transferred to the tissue.

[0127] In certain embodiments, for example, a safe and effective dose for treating tissue ranges from about 2 cal / g to about 150 cal / g or from about 5 cal / g to about 100 cal / g, and the energy flow rate of the delivery system ranges from about 2 cal / sec to about 500 cal / sec or from about 5 cal / sec to about 150 cal / sec. In one embodiment, the formulation generator produces a vapor or liquid formulation, the pressure ranges from about 2 psi to 200 psi, and the temperature ranges from about 20°C to 150°C or from about 50°C to 120°C.

[0128] A safe and effective amount of the formulation and / or energy should be applied to adequately injure the tissue. Generally, the dosage correlates with the degree of injury to the tissue.

[0129] In some embodiments, the effective amount of energy ranges from about 1 to about 100 cal / g and / or the effective amount of the formulation ranges from 0.2 microliters to 200 milliliters. These dosage limits may vary along with other delivery parameters (e.g., delivery rate or duration, etc.) and may require different doses to achieve the best therapeutic benefit.

[0130] After dosing, the total amount of energy (cal) or formulation (ml) to be applied by the delivery system must be determined. This value is calculated by multiplying the dose (cal / g) by the amount of tissue to be treated (grams).

[0131] The delivery / flow rate, or the rate at which the delivery system delivers the formulation, generally determines the duration of the formulation. For example, a delivery rate of 30 cal / sec is required for a 10 second treatment duration to deliver 300 calories. Delivery rates generally range from about 2 to about 200 cal / sec. Again, these limits are not definite and may vary depending on treatment and / or delivery parameters.

[0132] Treatment time may vary depending on the volume of tissue to be treated and the intended degree of injury to the target tissue. Treatment time may vary from about 2 seconds to about 60 minutes. In some embodiments, a safe and effective treatment time for inducing injury to relieve symptoms ranges from about 4 seconds to about 30 minutes.

[0133] The delivery rate may be set by controlling the delivery system. Once the user establishes the delivery rate, the formulation source determines the amount of pressure required to deliver vapor or liquid at the desired rate. Upon changing the delivery rate setting, the formulation generator adjusts the amount of pressure delivered. The vapor generator pressure may range from about 5 psi to about 200 psi or from about 10 psi to about 50 psi.

[0134] In one embodiment, the method for the treatment of hypertension includes percutaneously inserting a delivery catheter into a renal artery adjacent to a nerve; using the catheter to inject the formulation and / or heat into tissue in a body cavity adjacent to the nerve, where the amount of formulation and / or heat delivered is effective to injure or damage the nerve, for example by lowering blood pressure; and finally, withdrawing the delivery catheter from the body cavity. The purpose of the heat is to enhance the effect of the injury / damage by accelerating the reaction rate between the formulation and the nerve. Possible formulations include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. If the formulation includes a vapor of one or more components, heat can be generated in the tissue by condensation of the vapor into a liquid. If the formulation includes a liquid or solution, heat can be transferred from the formulation at a high temperature above body temperature. The formulation temperature can range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The temperature of the tissue to be treated adjacent to the nerve can be lower than the formulation temperature and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may range from -40° C. to 100° C., -30° C. to 90° C., or -20° C. to 80° C. The formulation injection pressure may range from 0.1 atm to 14 atm, 3 atm to 10 atm, or 4 atm to 8 atm.

[0135] In one embodiment, the method for the treatment of asthma includes inserting a delivery catheter into an airway adjacent to a nerve; using the catheter to inject the formulation and / or heat into tissue of the airway adjacent to the nerve, where the amount of formulation and / or heat delivered is effective to injure or damage the nerve, for example by relieving shortness of breath; and finally, withdrawing the delivery catheter from the body cavity. The purpose of the heat is to enhance the effect of the injury / damage by accelerating the reaction rate between the formulation and the nerve. Possible formulations include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. If the formulation includes a vapor of one or more components, heat can be generated in the tissue by condensation of the vapor into a liquid. If the formulation includes a liquid or solution, heat can be transferred from the formulation at a high temperature above body temperature. The liquid formulation temperature can range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The temperature of the tissue to be treated adjacent to the nerve can be lower than the formulation temperature and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may range from -40° C. to 100° C., -30° C. to 90° C., or -20° C. to 80° C. The formulation injection pressure may range from 0.1 atm to 14 atm, 3 atm to 10 atm, or 4 atm to 8 atm.

[0136] In one embodiment, the method for the treatment of COPD includes inserting a delivery catheter into an airway adjacent to a nerve; using the catheter to inject the formulation and / or heat into tissue of the body cavity adjacent to the nerve, where the amount of formulation and / or heat delivered is effective to injure or damage the nerve, for example by relieving COPD symptoms; and finally, withdrawing the delivery catheter from the airway. The purpose of the heat is to enhance the effect of the injury / damage by accelerating the reaction rate between the formulation and the nerve. Possible formulations include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more formulations. If the formulation includes a vapor of one or more components, heat can be generated by condensation of the vapor into a liquid. If the formulation includes a liquid or solution, heat can be transferred from the formulation at a high temperature above body temperature. The formulation temperature can range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The temperature of the tissue to be treated adjacent to the nerve can be lower than the formulation temperature and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may range from -40° C. to 100° C., -30° C. to 90° C., or -20° C. to 80° C. The formulation injection pressure and / or balloon inflation pressure may range from 0.1 atm to 14 atm, 3 atm to 10 atm, or 4 atm to 8 atm.

[0137] In one embodiment, the method for the treatment of diabetes includes percutaneously inserting a delivery catheter into the hepatic artery adjacent to the nerve, particularly the celiac artery, the proper hepatic artery, and the left and right hepatic arteries; using the catheter to inject the formulation and / or heat into tissue in the body cavity adjacent to the nerve, where the amount of formulation and / or heat delivered is effective to injure or damage the nerve, for example by lowering glucose levels; and finally, withdrawing the delivery catheter from the body cavity. The purpose of the heat is to enhance the effect of the injury / damage by accelerating the reaction rate between the formulation and the nerve. Possible formulations include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. If the formulation includes vapors of one or more components, heat can be generated in the tissue by condensation of the vapor into a liquid. If the formulation includes a liquid or solution, heat can be transferred from the formulation at a temperature higher than body temperature. The formulation temperature can range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The temperature of the treated tissue adjacent to the nerve may be lower than the formulation temperature and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may range from -40°C to 100°C, -30°C to 90°C, or -20°C to 80°C. The formulation injection pressure and / or balloon inflation pressure may range from 0.1 atm to 14 atm, 3 atm to 10 atm, or 4 atm to 8 atm.

[0138] In one embodiment, the method for the treatment of obesity and diabetes includes inserting a delivery catheter into the left and / or right gastric artery adjacent to the nerves of the stomach and esophagus; using the catheter to inject the formulation and / or heat into tissue of the gastric artery adjacent to the nerves, where the amount of formulation and / or heat delivered is effective to injure or damage the nerves, for example by reducing body weight; and finally withdrawing the delivery catheter from the gastric artery. Possible formulations include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. If the formulation includes a vapor of one or more components, heat can be generated by condensation of the vapor into a liquid. If the formulation includes a liquid or solution, heat can be transferred from the formulation at a high temperature above body temperature. The liquid formulation temperature can range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The temperature of the tissue to be treated adjacent to the nerves can be lower than the formulation temperature and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may range from -40° C. to 100° C., -30° C. to 90° C., or -20° C. to 80° C. The formulation injection pressure and / or balloon inflation pressure may range from 0.1 atm to 14 atm, 3 atm to 10 atm, or 4 atm to 8 atm.

[0139] In one embodiment, the method for treating obesity and diabetes includes percutaneously inserting a delivery catheter into the hepatic artery adjacent to the nerve, particularly the hepatic celiac artery, the proper hepatic artery, and the left and right hepatic arteries; using the catheter to inject the formulation and / or heat into the tissue of the hepatic artery adjacent to the nerve; withdrawing the delivery catheter from the hepatic artery; inserting a delivery catheter into the left and / or right gastric artery adjacent to the nerve of the stomach and esophagus; using the catheter to inject the formulation and / or heat into the tissue of the gastric artery adjacent to the nerve, wherein the amount of formulation and / or heat delivered is effective to injure or damage the nerve, for example by reducing body weight and glucose level; and finally withdrawing the delivery catheter from the gastric artery.Possible formulations include gas, vapor, liquid, solution, emulsion, and suspension of one or more components.If the formulation includes vapor of one or more components, heat can be generated by condensation of the vapor into liquid.If the formulation includes liquid or solution, heat can be transferred from the formulation at a high temperature above body temperature. The liquid formulation temperature may range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The temperature of the treated tissue adjacent to the nerve may be lower than the formulation temperature and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may range from -40°C to 100°C, -30°C to 90°C, or -20°C to 80°C. The formulation injection pressure and / or balloon inflation pressure may range from 0.1 atm to 14 atm, 3 atm to 10 atm, or 4 atm to 8 atm.

[0140] In one embodiment, the method for treating obesity includes inserting a delivery catheter into the digestive lumen adjacent to a nerve; using the catheter to inject the formulation and / or heat into tissue in the digestive lumen, where the amount of the formulation and / or heat delivered is effective to injure or damage the tissue, for example by reducing body weight; and finally withdrawing the delivery catheter from the digestive lumen. Possible digestive lumens for this embodiment include the esophagus, stomach, duodenum, jejunum, small and large intestines, and colon. The purpose of the heat is to enhance the effect of injury / damage by accelerating the reaction rate between the formulation and the nerve. Possible formulations include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. If the formulation includes vapors of one or more components, heat can be generated by condensation of the vapor into a liquid. If the formulation includes liquids or solutions, heat can be transferred from the formulation at a high temperature above body temperature. The liquid formulation temperature may range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the formulation temperature and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may range from -40°C to 100°C, -30°C to 90°C, or -20°C to 80°C.

[0141] In one embodiment, the method for the treatment of obesity and diabetes includes inserting a delivery catheter into the left and / or right gastric artery adjacent to the nerves of the stomach and esophagus; using the catheter to inject the formulation and / or heat into tissue of the gastric artery adjacent to the nerves, where the amount of formulation and / or heat delivered is effective to injure or damage the nerves, for example by reducing body weight; and finally withdrawing the delivery catheter from the gastric artery. Possible formulations include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. If the formulation includes a vapor of one or more components, heat can be generated by condensation of the vapor into a liquid. If the formulation includes a liquid or solution, heat can be transferred from the formulation at a high temperature above body temperature. The liquid formulation temperature can range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The temperature of the tissue to be treated adjacent to the nerves can be lower than the formulation temperature and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may range from -40°C to 100°C, -30°C to 90°C, or -20°C to 80°C.

[0142] In one embodiment, the method for the treatment of obesity and / or diabetes includes inserting an infusion catheter orally into the duodenum and / or jejunum via the mouth, esophagus and stomach; using the catheter to infuse the formulation or heat into the surface tissue of the duodenum and / or jejunum for 1-30 minutes, where the amount of formulation and / or heat delivered is effective to injure or damage the surface, tissue and nerves of the body cavity, e.g., the duodenum or jejunum, e.g., by reducing body weight and glucose levels; optionally removing or withdrawing the formulation; and finally withdrawing the delivery catheter from the gastrointestinal lumen, e.g., the duodenum or jejunum. Possible formulations include gases, vapors, liquids, solutions, emulsions and suspensions of one or more components. If the formulation includes vapors of one or more components, heat can be generated by condensation of the vapor into a liquid. If the formulation includes a liquid or solution, heat can be transferred from the formulation at a temperature above body temperature. The formulation injection pressure and / or balloon inflation pressure may range from 0.1 atm to 14 atm, 3 atm to 10 atm or 4 atm to 8 atm. The liquid formulation temperature may range from -40°C to 140°C, -30°C to 100°C or -20°C to 80°C. The temperature of the tissue to be treated, which in this case is the superficial tissue, may be lower than the temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated may range from -40°C to 100°C, -30°C to 90°C, 36°C to 80°C or 60°C to 80°C. The treatment requires modifying the surface of the duodenum or jejunum. The therapeutic benefit, e.g., reduction in body weight, glucose levels and / or HbA1c (A1C) levels, depends on the formulation dose and temperature, the length of treatment time, and the surface area and thickness of the duodenum to be treated. For safety reasons, perforation of the duodenum is not recommended. Surface treatments modify the morphology, nerves, and food absorption capacity of the duodenum.

[0143] In one embodiment, the method for treating obesity and / or diabetes includes non-invasively inserting an infusion catheter into the duodenum and / or jejunum orally via the mouth, esophagus and stomach; using the catheter to inject a chemical agent into the surface tissue of the duodenum and / or jejunum for 1-10 minutes, where the amount of chemical agent delivered is effective to injure or damage the surface, tissue and nerves of the body cavity, e.g., the duodenum or jejunum, for example, by reducing body weight and glucose levels; optionally removing or withdrawing the agent; and finally withdrawing the delivery catheter from the lumen of the digestive tract, e.g., the duodenum or jejunum. The chemical agent includes a formulation of the chemical agent and / or absolute ethanol. The following is a description of a preclinical study for treating obesity and / or diabetes.

[0144] All the infusion catheters in the above embodiments are applicable to the following studies. For example, in one study, a 2-3-groove dumbbell-shaped balloon with 4 holes per groove was used for the treatment of obesity and / or diabetes. The balloon diameter and length ranged from 12-15 mm and 55-80 mm, respectively. The study was performed according to the above procedure. Two young Yorkshire crossbred pigs (each weighing approximately 9 kg) were anesthetized with isoflurane. The infusion balloon catheter was inserted into the duodenum via the mouth, stomach and pylorus under the guidance of a pediatric endoscope and fluoroscope. The ligament of Treitz was used as the anatomical mark of the distal end of the duodenum. During the delivery of the infusion balloon catheter into the duodenum, the balloon was rapidly pre-inflated to 1.5 atm, followed by injection of 1.5-2.0 volumes of absolute ethanol. The treatment agent played two roles in this procedure: (1) balloon inflation and (2) delivery of chemicals to the target vascular tissue through the holes on the balloon wall. After treatment, the balloon was partially deflated and pulled back a specified distance to avoid overlapping with the next treatment site. The treatment was then repeated. The bile duct was not treated. Two hours after treatment, the animals were euthanized. The duodenal tissue was examined and suspended in triphenyltetrazolium chloride (TTC) solution for 30 minutes. After chemical treatment, necrotic tissue shows white spots.

[0145] The chemicals used in the study were acetic anhydride and absolute ethanol. Treatment efficacy was clearly demonstrated in TTC stained duodenal tissue for both treated animals, as white spots were localized in the chemically cut areas.

[0146] Following the success of the acute study above, a chronic study was performed to demonstrate the clinical benefit of the treatment. The study included seven pigs of similar weight to the acute study above. Three of the seven pigs were treated with absolute ethanol, three with acetic acid, and one sham pig with saline. The same procedure described in the acute study above was used for the treatment with absolute ethanol. As before, after the infusion balloon catheter reached the duodenum, the balloon was rapidly pre-inflated with absolute ethanol to a pressure of 1.5 atm; an additional 1.5 ml to 2.0 ml of ethanol was then injected through the balloon wall into the duodenum, after which the pressure was held below 0.5 atm for 2 minutes. At the end of the treatment period, the treated duodenal segment was flushed with approximately 10 ml of water using an endoscope.

[0147] Treatment with acetic acid proceeded in the same way as with absolute ethanol. As before, the pig duodenum was treated for 1 min, this time with a dose of 0.5 ml. After each treatment, the balloon was partially deflated and pulled back a specified distance to avoid overlapping treatment with the next treatment site. The treatment was then repeated. The bile duct was not treated. The animals were allowed to recover for chronic observation and evaluation.

[0148] Pigs that were duodenal treated with acetic acid were euthanized approximately 5 weeks after treatment. The animals were deemed healthy after clinical and pathological evaluation. As shown in Figure 13, duodenal treatment with acetic acid did not have a significant difference in body weight compared to sham animals. Glucose levels were variable and inconclusive.

[0149] Pigs that received duodenal treatment with absolute ethanol were euthanized approximately 8 weeks after treatment. The animals were deemed healthy after clinical and pathological evaluation. As shown in Figure 14, duodenal treatment with absolute ethanol reduced the animals' weight gain compared to sham animals. Glucose levels were inconclusive.

[0150] In one embodiment, the method for the treatment of Barrett's esophageal disease includes an infusion balloon device, procedure, and chemical agent. In this method, a balloon infusion catheter was inserted into the esophagus through the mouth under the guidance of a pediatric endoscope. A 15 mm balloon is typically used, with a length ranging from 55 to 80 mm, three grooves in the middle and four micro holes per groove for chemical formulation infusion. When the balloons are placed in the esophagus, they are rapidly pre-inflated to full size at a pressure of up to 1.5 atm. Examples of delivered doses are as follows: (1) for treatment with absolute ethanol, 1.5 ml is delivered for 4 minutes in the distal part of the esophagus and 2 minutes in the proximal part; (2) for treatment with acetic acid, 0.5 ml is delivered for 2 minutes in the distal part of the esophagus and 1 minute in the proximal part. At the end of the treatment period, the treated area was flushed with about 10 ml of water using the endoscope channel. After each treatment, the balloon is partially deflated and moved to another location for further treatment.

[0151] Using the above procedure, a chronic study was performed in seven young Yorkshire crossbred pigs. Three of the seven pigs were treated with absolute ethanol, three with acetic acid, and one sham with saline. Endoscopy was performed before and after treatment. The animals were allowed to recover for chronic observation and evaluation. Two weeks after treatment the animals were again examined endoscopi- cally and four weeks after treatment, when they were euthanized. The therapeutic effect was evaluated by endoscopy. In the esophageal segments treated with acetic acid, a severe stricture phenomenon was observed. Histopathological analysis of the treated segments showed thickening of the epithelium and complete epithelialization, except in the acetic acid treated group, where the epithelial layer was sometimes absent.

[0152] The above preclinical findings indicate that ethanol treatment is effective and safe. On the other hand, acetic acid treatment caused severe narrowing and stricture in the treated esophagus. Also, no difference in body weight change was observed in duodenal treated animals compared to untreated animals. It is well known that acid can erode and damage the esophagus; acetic acid caused lesions in the duodenal wall after topical application. These observations indicate that acetic acid may not be suitable for treatment of the duodenum and esophagus.

[0153] In one embodiment, a method for the treatment of urological diseases and / or benign prostatic hyperplasia (BPH) includes inserting a delivery catheter into the lumen of the urinary tract; using the catheter to inject the formulation and / or heat into the lumen of the urinary tract tissue, such as the prostate, urethra, and ureter, where the amount of formulation and / or heat delivered is effective to injure or damage the tissue, for example by controlling urine flow; and finally, withdrawing the delivery catheter from the lumen of the urinary tract. The purpose of the heat is to enhance the effect of the injury / damage by accelerating the reaction rate between the formulation and the nerve. The formulation comprises one of a gas, vapor, liquid, solution, emulsion, and suspension of one or more components. If the formulation comprises a vapor of one or more components, heat can be generated by condensation of the vapor into a liquid. If the formulation comprises a liquid or solution, heat can be transferred from the formulation at a high temperature above body temperature. The liquid formulation temperature can range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The temperature of the treated tissue adjacent to the nerve may be lower than the formulation temperature and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may range from -40°C to 100°C, -30°C to 90°C, or -20°C to 80°C. The formulation injection pressure and / or balloon inflation pressure may range from 0.1 atm to 14 atm, 3 atm to 10 atm, or 4 atm to 8 atm.

[0154] In one embodiment, the method for treating cancer or tumor includes inserting a needle or needle-based catheter percutaneously or orally into the cancer or tumor under imaging guidance; using the catheter to inject the formulation and / or heat into the cancer tissue of the human body, where the amount of formulation and / or heat delivered is effective to injure, damage or remove the cancer tissue, for example by shrinking or removing the tumor; and finally withdrawing the delivery catheter from the body. Possible imaging guidance includes ultrasound, x-ray, CT scan, NMR imaging and scope. Relevant cancers include adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach and uterus. The purpose of the heat is to improve the injury / damage / removal effect by accelerating the reaction rate between the formulation and the cancer tissue. The formulation includes one of gas, vapor, liquid, solution, emulsion and suspension of one or more components. If the formulation includes vapor of one or more components, heat can be generated by condensation of the vapor into liquid in the tissue. If the formulation comprises a liquid or solution, heat may be transferred from the formulation at a temperature above body temperature. The formulation temperature may range from -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The temperature of the tissue to be treated may be lower than the formulation temperature and higher than body temperature. The temperature of the tissue to be treated may range from -40°C to 100°C, -30°C to 90°C, or -20°C to 80°C. The present invention includes the following aspects and embodiments. [1] a) inserting a delivery catheter into a body cavity; b) injecting the formulation into diseased tissue in the body cavity, where the amount of the formulation delivered to the body cavity is effective to injure or damage the diseased tissue to alleviate disease symptoms; c) removing the formulation from the diseased tissue; and d) withdrawing the delivery catheter from the body cavity. A method for treating a disease comprising: [2] The method according to [1], wherein the disease is selected from hypertension, pulmonary hypertension, diabetes, obesity, heart failure, end stage renal disease, gastrointestinal disease, benign prostatic hyperplasia, cancer, tumor, pain, asthma and chronic obstructive pulmonary disease (COPD). [3] The method according to [2], wherein the cancer is selected from the group consisting of adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, duodenum, jejunum and uterus. [4] The method of claim 1, wherein the body cavity is selected from the renal artery, pulmonary artery, vascular lumen, celiac artery, common hepatic artery, proper hepatic artery, duodenal artery, right hepatic artery, left hepatic artery, splenic artery, right gastric artery, left gastric artery, non-vascular lumen, airway, paranasal sinuses, esophagus, respiratory lumen, digestive lumen, stomach, duodenum, jejunum, prostate, urethra, ureter and / or urinary lumen. [5] The method of [1], wherein the formulation consists essentially of ethanol. [6] The method according to [1], wherein the formulation consists of ethanol. [7] The method of claim 1, wherein the formulation comprises a gas, vapor, liquid, solution, emulsion or suspension of one or more components. [8] The method according to [7], wherein when the formulation contains vapors of one or more components, heat is generated by condensation of the vapors into a liquid. [9] The method according to [7], wherein the formulation comprises a liquid or solution, and heat is transferred from the formulation to the diseased tissue.

[10] The method according to [1], wherein the formulation comprises an emulsion or suspension, and heat is transferred from the formulation to the diseased tissue.

[11] The method according to [1], wherein the formulation is at a temperature in the range of 40°C to 140°C.

[12] The method according to [1], wherein the formulation is at a temperature in the range of 0°C to 140°C.

[13] The method according to [1], wherein the formulation is at a temperature in the range of -40°C to 0°C.

[14] The method according to [1], wherein the formulation is at a temperature equal to room temperature.

[15] The method according to [1], wherein the temperature of the diseased tissue is lower than the temperature of the preparation.

[16] The method according to [1], wherein the temperature of the diseased tissue is higher than the temperature of the preparation.

[17] The method according to [1], wherein the pressure of the formulation during injection is in the range of 0.1 atm to 14 atm.

[18] The method according to [1], wherein the diseased tissue has a temperature in the range of -40°C to 100°C.

[19] The method according to [1], wherein the diseased tissue has a temperature in the range of -40°C to 0°C.

[20] The method according to [1], wherein the diseased tissue is at a temperature equal to body temperature. [twenty one] The method according to [1], wherein the pressure of the formulation during injection is in the range of about 2 psi to 200 psi at a temperature in the range of about -40°C to 150°C. [twenty two] The method according to [1], wherein the amount of the formulation injected into the diseased tissue is in the range of 0.2 microliters to 200 milliliters. [twenty three] The method of [1], wherein the method comprises inserting the delivery catheter into the body cavity for about 2 seconds to about 60 minutes. [twenty four] The method of claim 1, wherein the method delivers an amount of heat or energy to the diseased tissue in the range of about 2 cal / g to about 150 cal / g. [twenty five] The method of claim 1, wherein the delivery catheter is selected from a needle or needle-based delivery catheter, a single balloon delivery catheter, a double balloon delivery catheter, an injection catheter, a balloon injection catheter, a balloon catheter, a dumbbell balloon injection catheter, and combinations thereof.

[26] The method according to

[25] , wherein the delivery catheter is inflated at a pressure ranging from 0.1 atm to 14 atm.

[27] 2. The method of claim 1, wherein the formulation comprises one or more components selected from water, saline, hypertonic saline, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, lipiodol, urea, and derivatives thereof and combinations thereof.

[28] 13. The method of claim 1, wherein the formulation comprises a gas or vapor selected from oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, water, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, and ethyl lactate, and mixtures thereof.

[29] The method of claim 1, wherein the formulation comprises a therapeutic agent for denervation, and the therapeutic agent is selected from sodium channel blockers, tetrodotoxin, saxitoxin, decarbamoylsaxitoxin, vanilloids, neosaxitoxin, lidocaine, conotoxins, cardiac glycosides, digoxin, glutamate, staurosporine, amlodipine, verapamil, cymarin, digitoxin, proscillaridin, ouabain, veratridine, domoic acid, oleandrin, carbamazepine, aflatoxin, guanethidine and guanethidine sulfate.

[30] The method according to [1], wherein the formulation comprises a contrast agent for imaging denervation, and the contrast agent is selected from iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan, iodixanol, or ioxaglate, and derivatives thereof.

[31] The method of claim 1, wherein the formulation comprises an azeotrope.

[32] 31. The method of claim 30, wherein the azeotrope is selected from ethanol / water, propanol / water, isopropanol / water, butanol / water, acetic acid / water, lactic acid / water, ethyl lactate / water, ethyl lactate / ethanol, lactic acid / ethanol / water, ethyl lactate / water / ethanol, ethyl acetate / ethanol, ethyl nitrate / ethanol, and isopropyl acetate / ethanol.

[33] The method of claim 1, wherein the formulation comprises one of ethanol, ethanol / water, ethanol / water / oxygen, ethanol / water / air, ethanol / water / contrast agent, ethanol / water / surfactant, ethanol / water / contrast agent / surfactant, propanol / water, isopropanol / water, butanol / water, and / or acetic acid / water.

[34] An inflatable balloon catheter for delivery of a pharmaceutical formulation to a target location in a body cavity of a patient, the inflatable balloon catheter comprising a proximal end, a distal end, a wire lumen, a balloon inflation lumen, a pharmaceutical formulation infusion lumen and / or a vacuum lumen, an inflatable balloon and a non-inflatable shaft, the inflatable balloon portion and / or the non-inflatable shaft comprising at least a first portion having a plurality of voids, the voids being microholes, and the inflatable balloon portion and / or the non-inflatable shaft comprising at least a second portion having no voids.

[35] The expandable balloon catheter of

[34] , wherein the expandable portion has a first distal portion, a first central portion and a first proximal portion, and the diameters of the first distal portion and the first proximal portion are larger than the diameter of the first central portion.

[36] An expandable balloon catheter as described in

[34] , wherein the expandable portion or the non-expandable portion has at least one void that allows the formulation to penetrate into a wall of a body cavity at a pressure higher than that of the body cavity; and the expandable portion or the non-expandable portion does not have a void that allows the balloon to inflate a body cavity at a pressure higher than that of the body cavity.

[37] The inflatable balloon catheter of

[34] , wherein the body cavity is selected from the renal artery, pulmonary artery, vascular lumen, celiac artery, common hepatic artery, and proper hepatic artery, duodenal artery, right hepatic artery, left hepatic artery, splenic artery, right gastric artery, left gastric artery, non-vascular lumen, airway, paranasal sinuses, esophagus, respiratory lumen, digestive lumen, stomach, duodenum, jejunum, prostate, urethra, ureter, and urinary lumen.

[38] The inflatable balloon catheter of

[34] , wherein the formulation is at a pressure in the range of 0.1 atm to 14 atm during delivery, and the inflatable balloon catheter is inflated at a pressure in the range of 0.1 atm to 14 atm.

Claims

1. 1. A chemical ablation formulation comprising ethanol for use in a method for treating diabetes, characterized in that the ethanol is delivered to a first artery at at least one location by injection with a balloon delivery catheter, Injury or damage the nerves and nerve endings of the first artery; The first artery is the common hepatic artery.

2. 10. The formulation of claim 1, wherein the formulation comprises one or more additional components selected from water, saline, hypertonic saline, phenol, methanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, lipiodol, urea, derivatives thereof, and combinations thereof.

3. 3. The formulation of claim 1 or 2, wherein the formulation further comprises a gas or vapor selected from oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, water, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, and ethyl lactate, and mixtures thereof.

4. 4. The formulation of any one of claims 1 to 3, wherein the formulation further comprises a therapeutic agent for denervation, the therapeutic agent being selected from sodium channel blockers, tetrodotoxin, saxitoxin, decarbamoylsaxitoxin, vanilloids, neosaxitoxin, lidocaine, conotoxins, cardiac glycosides, digoxin, glutamate, staurosporine, amlodipine, verapamil, cymarin, digitoxin, proscillaridin, ouabain, veratridine, domoic acid, oleandrin, carbamazepine, aflatoxin, guanethidine, guanethidine sulfate, and mixtures thereof.

5. The formulation of any one of claims 1 to 4, wherein the formulation comprises an azeotrope.

6. 6. A formulation according to any one of claims 1 to 5, wherein the formulation comprises absolute ethanol, ethanol, an azeotrope of ethanol and water or ethanol / water.

7. 2. The formulation of claim 1, wherein the formulation comprises or consists of ethanol.

8. 8. The formulation of any one of claims 1 to 7, wherein the formulation comprises a gas, vapour, liquid, solution, emulsion or suspension of one or more formulation components, or a combination thereof.

9. 9. The formulation of claim 8, wherein the formulation comprises a vapor of one or more formulation components and heat is generated by condensation of the vapor into a liquid in the wall of the body cavity adjacent to the nerve or nerve ending at the first artery, or wherein the formulation comprises a liquid, solution, emulsion or suspension and heat is transferred from the formulation to the wall of the body cavity adjacent to the nerve or nerve ending at the first artery, or a combination thereof.

10. The formulation of any one of claims 1 to 9, wherein the balloon delivery catheter is selected from a single balloon delivery catheter, a double balloon delivery catheter, a dumbbell balloon injection catheter, a needle-based delivery catheter, and combinations thereof.

11. 11. The formulation of any one of claims 1 to 10, wherein the balloon delivery catheter is an inflatable balloon catheter, the inflatable balloon catheter comprising a proximal end, a distal end, a wire lumen, a balloon inflation lumen, a formulation infusion and / or vacuum lumen, an inflatable balloon, and a non-inflatable shaft.

12. 12. The formulation of claim 11, wherein the expandable portion comprises a first distal portion, a first central portion and a first proximal portion, the diameters of the first distal portion and the first proximal portion being greater than the diameter of the first central portion.

13. 13. The formulation of claim 11 or 12, wherein the inflatable balloon portion and / or the non-expandable shaft comprises at least a first portion having a plurality of voids, the voids being microholes, and the inflatable balloon portion and / or the non-expandable shaft comprises at least a second portion having no voids, and the voids in the inflatable or non-expandable portion allow penetration of the formulation into the wall of the first artery at a higher pressure than the first artery.

14. The formulation according to any one of claims 1 to 13, characterized in that after delivery of the ethanol, the first artery is flushed with saline or water.

15. The formulation of any one of claims 1 to 14, wherein the formulation is delivered to one or more locations in the first artery.

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