Chemical ablation formulations and methods of treatments for various diseases

Abstract

To provide formulations for treatment of hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive disease, urological disease, cancers, tumors, pains, asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease.SOLUTION: The invention provides a chemical formulation for use in a method of treating a disease, the method comprising: inserting a delivery catheter into a vascular lumen adjacent to nerves, where the vascular lumen includes a pulmonary artery; infusing the chemical formulation into the vascular lumen through the delivery catheter, where the amount of the chemical formulation is an amount effective to injure or damage the nerves and provide benefits in alleviating the symptoms of the disease; and withdrawing the delivery catheter from the blood vessel. The chemical formulation is at least one of 10-100 wt.% of ethanol, and 1-100 wt.% of acetic acid. The disease includes pulmonary arterial hypertension.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 61 / 796,118, filed November 2, 2012, Application No. 61 / 797,647, filed December 12, 2012, Application No. 61 / 848,483, filed January 4, 2013, and Application No. 61 / 849,928, filed February 5, 2013, the entireties of which are hereby incorporated by reference.

[0002] Aspects of the present invention relate to chemical ablation formulations, combined thermal and chemical ablation and methods for treating diseases such as hypertension, diabetes, obesity, heart failure, end stage renal disease, gastrointestinal diseases, urological diseases, cancer, tumors, pain, asthma, pulmonary arterial hypertension and chronic obstructive pulmonary disease (COPD). The formulations include gases, vapors, liquids, solutions, emulsions and suspensions containing one or more components. The methods involve chemical ablation by delivery of the formulations and / or thermal energy to targeted diseased tissues of the human body. [Background technology]

[0003] High blood pressure, or hypertension, is a health problem of worldwide concern, affecting an estimated 30-40% of the adult population. The prevalence is expected to increase, especially in developing countries. The diagnosis and treatment of hypertension are still suboptimal, and many patients are unable to control their blood pressure at the appropriate guideline values. Therefore, there is a need to develop new methods to manage hypertension, especially for patients with so-called resistant hypertension, who are unable to control their blood pressure even with the use of multiple antihypertensive drugs at the maximum tolerated dose.

[0004] Hypertension is caused by increased renal sympathetic nerve function. Efferent and afferent renal sympathetic nerves usually run longitudinally on the outside of the artery from the aorta toward the kidney. These nerves are crucial in the initiation and maintenance of systemic hypertension. It has been shown that cutting these nerves can reduce blood pressure. Exemplary experiments have shown that ablation of renal sympathetic nerves in rats with hyperinsulinemia-induced hypertension reduces blood pressure to normotensive levels compared to controls [Huang WC,et al.Hypertension 1998;32:249-254].

[0005] Until now, renal nerve severing has been performed surgically, but recently, catheter-based treatment has been attempted in which the nerve is heated and destroyed by radiofrequency ablation within the renal artery. RF ablation catheter techniques have also been tried in humans, and it has been reported that blood pressure decreased in patients enrolled in the catheter treatment group of this clinical trial [Krum H, et al. Lancet 2009;373(9671):1228-1230].

[0006] Benign prostatic hyperplasia (BPH) is a non-cancerous enlargement of the prostate gland that affects more than 50% of men over the age of 60. In young men, the prostate is about the size and shape of a walnut and weighs about 20 grams. Prostate enlargement is considered a normal process, and as we age, the prostate gradually enlarges, becoming more than twice its normal size. As the prostate enlarges, it presses against the urethra, narrowing it and causing urinary obstruction, making it difficult to urinate.

[0007] Chronic obstructive pulmonary disease (COPD) is a term used to classify two major airway obstruction disorders: chronic bronchitis and emphysema. Approximately 16 million Americans have COPD, 80-90% of whom have been smokers for most of their lives. COPD is one of the leading causes of death in the United States. Chronic bronchitis is inflammation of the bronchi. The bronchi connect the trachea to the lungs. When inflamed, the bronchi secrete mucus, which causes chronic coughing. Emphysema is the overinflation of the alveoli, or air sacs in the lungs. This condition causes shortness of breath.

[0008] Asthma is a chronic respiratory disease characterized by inflammation of the airways, excessive mucus production and airway hyperresponsiveness, and excessive narrowing or easy reaction of the airways to stimuli. Asthma episodes or attacks cause the airways to narrow, making breathing difficult. Asthma attacks can have a significant impact on a patient's life by limiting many activities. In severe cases, asthma attacks can be life-threatening. Today, there is no known cure for asthma.

[0009] Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterized by elevated mean pulmonary artery pressure and increased pulmonary vascular resistance, leading to right ventricular dysfunction and premature death. Although recent targeted therapies have led to advances in treatment, there is no cure for PAH, and it remains a life-threatening disorder. Preliminary reports indicate that pulmonary artery radiofrequency denervation is safe and effective for patients with PAH.

[0010] Chronic sinusitis is inflammation of one or more of the sinus membranes. Chronic sinusitis takes longer than three weeks to resolve and often lasts for several months. Cases of chronic sinusitis typically also involve tissue damage. According to the Centers for Disease Control and Prevention (CDC), there are 37 million reported cases of chronic sinusitis annually in the United States.

[0011] Radiofrequency (RF) ablation has been used to treat hypertension, asthma, and chronic obstructive pulmonary disease (COPD). The use of catheter-based radiofrequency (RF) denervation is believed to be therapeutic, but the long-term effects of permanent vessel wall and nerve damage caused by RF procedures are unclear. Radiofrequency energy denervates blood vessels by producing heat within the vessel wall. An RF probe strikes the inside of the artery, and RF energy is transmitted through the tissue. This method lacks precise control. Endothelium and smooth muscle may be damaged, resulting in vascular injury and blockage. The SYMPLICITY HTN-2 clinical trial has shown that there are three groups of patients: approximately 10% are non-responders; 39% are good responders, with blood pressure below 140 mmHg; while 50% of patients respond slightly, with a reduction in blood pressure of at least 10 mmHg. However, at present, the clinical relevance of this reduction in blood pressure is unknown. Safety and efficacy need to be improved for many patients with hypertension.

[0012] A variety of ablative techniques have been developed to complement conventional surgical and oncologic procedures used to treat tumors. These techniques include hepatic arterial chemoembolization, percutaneous ablation using chemical agents such as alcohol or acetic acid, or percutaneous treatment using radiofrequency ablation or cryotherapy. Localized and focal ablative techniques used to treat tumors in the liver have been extensively characterized and have recently been used to treat a variety of other tumors. Systemic chemotherapy and external beam radiation are both limited in their use by poor tumor response and their toxicity. New ablation methods are needed to improve the safety and efficacy of treatment. Summary of the Invention

[0013] Disclosed are methods of treating diseases such as hypertension, diabetes, obesity, heart failure, end stage renal disease, digestive system disease, urological system disease, cancer, tumors, pain, asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD). In some embodiments, the methods involve delivering an effective amount of a formulation to a target diseased tissue. The formulation may include a gas, vapor, liquid, solution, emulsion, or suspension of one or more components. The methods involve delivering the formulation to tissue of the human body at various temperatures. Temperature may enhance the safety and efficacy of the therapeutic formulation. Suitable temperatures may range from -40 to 140°C, preferably from -30 to 100°C, and most preferably from -30 to 80°C. The pressure of the formulation injected may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, such as 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM. The formulation is one of two-component, three-component, four-component, or five-component or more formulations.The delivery system can be transdermal or less invasive delivery methods.In some embodiments, the formulation includes one or more components that enhance absorption and penetration into nerves in the body lumen.

[0014] In some embodiments, the method involves delivering an effective amount of energy and formulation to the target nerve. The energy can be, for example, selected from the group consisting of radio frequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound energy. As discussed above, the formulation can include gas, vapor, liquid, solution, emulsion, and suspension of one or more components. The method can include combined thermal and chemical ablation, their formulations, and methods for treating hypertension, diabetes, obesity, heart failure, end stage renal disease, gastrointestinal disease, urological disease, asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD) by thermal and chemical ablation of nerves in the human body at various temperatures. Thermal energy can increase the safety and efficacy of therapeutic chemical ablation. Chemical ablation can improve the safety and efficacy of therapeutic thermal ablation by reducing ablation temperature and ablation time. Temperature can be in the range of -40 to 140°C, preferably in the range of -30 to 100°C, and most preferably in the range of -30 to 80°C. The pressure of the formulation injected can be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the formulation injected into the target tissue can be 1-12 ATM, such as 1-8 ATM, 1-5 ATM, or 1-3 ATM. The formulation can be one of two-component, three-component, four-component, or five-component or more formulations. The delivery system can be a percutaneous less invasive delivery catheter. The catheter for the formulation delivery can be a needle-based catheter. The catheter for the formulation delivery can also be a balloon-based catheter. The balloon catheter can have a single or double balloon. The catheter for the formulation delivery can be an injection catheter. The catheter for the energy delivery can be selected from the group consisting of radiofrequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound delivery catheters. In some embodiments, the disclosed methods provide for the use of thermal energy in combination with a formulation that includes one or more components that enhance absorption and penetration into nerves in the body lumen.

[0015] In some embodiments, the disclosed methods improve the safety and efficacy of radiofrequency ablation by increasing ablation size while minimizing the risk of complications that may result from heating. Examples of such complications include thrombus formation, steam popping, vesiculation, charring of the lesion, restenosis, fibrosis of the media and adventitia, and other complications associated with catheter manipulation (i.e., drilling). Localized thermal ablation (RF ablation) is non-uniform and does not reach the nerves present in the adventitia. Insufficient localized RF ablation is less effective (does not reduce blood pressure as much). Complications can be minimized by reducing the size of the electrode (resulting in passive cooling by blood flow) or by cooling the electrode internally (closed loop) or externally (open loop) via active fluid. Cooling the electrode increases the energy delivery to the nerve tissue. In one embodiment of external cooling (open loop), a chemical formulation can replace the active cooling fluid. The formulations of the present disclosure can be used not only to cool the electrode, but also for chemical ablation. Thus, chemical ablative formulations can be delivered before, during, and after thermal ablation, which includes radiofrequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound ablation.

[0016] In some embodiments, 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, derivatives thereof, and combinations thereof.

[0017] In some embodiments, the components of the formulation include one or more gases. Suitable gases include oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, and 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, derivatives thereof, and combinations thereof.

[0018] In some embodiments, the formulation components include one or more surfactants. Examples of 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, sorbitan PEG monolaurate, sorbitan PEG monolaurate, sorbitan PEG monooleate, stearin, Sorbitan PEG, oleyl ether PEG, lauroyl ether PEG, octoxynol, monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside do, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside;benzalkonium chloride, benzethonium chloride, dodecyltrimethylammonium bromide, sodium ricinoleate, dioctyl sodium sulfosuccinate, sodium lauryl sulfate, sodium dodecyl sulfate, dialkylmethylbenzylammonium salts, and dialkyl esters of sodium sulfosuccinate, 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), and 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 some embodiments, the formulation comprises at least one oil, fatty acid, or lipid, examples of which include soybean oil, vegetable oil, floral oil, animal oil, marine oil, butterfat, coconut oil, palm oil, olive oil, peanut oil, fish oil, 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, alpha-linoleic acid, gamma-linoleic acid, behenic acid, erucic acid, lignoceric acid, natural oleic acid, ... or synthetic phospholipids, mono-, di-, or tri-acylglycerol, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobee, niosomes, and derivatives thereof.

[0020] In some embodiments, the formulation comprises one or more therapeutic agents or denervation agents.Therapeutic agents include sodium channel blockers, tetrodotoxin, saxitoxin, decarbamoyl saxitoxin, vanilloids, neosaxitoxin, lidocaine, conotoxin, cardiac glycosides, digoxin, glutamate, staurosporine, amlodipine, verapamil, cymarin, digitoxin, proscillaridin, ouabain, veratridine, domoic acid, oleandrin, carbamazepine, aflatoxin, guanethidine, and guanethidine sulfate.In another embodiment, the formulation comprises one of the contrast agents for imaging denervation. Contrast agents include iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan, iodixanol, ioxaglate, and derivatives thereof.

[0021] In some embodiments, the formulation comprises an azeotrope. An azeotrope is a mixture of two or more components whose components cannot be changed by simple distillation. This phenomenon occurs when an azeotrope is boiled, and the resulting vapor has the same composition as the original mixture. Examples of azeotropes of formulations include ethanol / water, ethanol / water / contrast agent, ethanol / water / surfactant, ethanol / water / contrast agent / surfactant, propanol / water, isopropanol / water, butanol / water, acetic acid / water, acetic acid / water / ethanol, acetic acid / water / contrast agent, acetic acid / water / contrast agent / surfactant, acetic acid / water / ethanol / contrast agent, acetic acid / water / ethanol / contrast agent / surfactant, lactic acid / water, lactic acid / water / ethanol, lactic acid / water / contrast agent, lactic acid / water / contrast agent / surfactant, lactic acid / water / ethanol / contrast agent, lactic acid / water / ethanol / contrast agent / surfactant, ethyl lactate / water, ethyl lactate / ethanol, lactic acid / ethanol / water, ethyl lactate / water / ethanol, ethyl nitrate / ethanol, isopropyl acetate / ethanol, and combinations thereof.

[0022] In some embodiments, the formulation is in a gas or vapor state of one or more components. Examples of vapor or gas formulations include 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. The vapor formulation may include a surfactant. The vapor formulation may include a therapeutic agent. The vapor formulation may include a contrast agent, e.g., lipiodol, iodine. The vapor may include an azeotrope. The vapor may be one of a two-component, three-component, four-component, or five-component or more formulations. The elevated temperature of the vapor formulation may be in the range of 0-140°C, preferably 15-100°C, and most preferably 20-85°C. The pressure of the injected steam may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the steam injected into the target tissue may be 1-12 ATM, e.g., 1-8 ATM, 1-5 ATM, or 1-3 ATM.

[0023] In some embodiments, the formulation is in a liquid state of one or more components. Examples of liquid formulations include 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 others. The liquid formulation may include a therapeutic agent. The liquid formulation may include a contrast agent. The liquid formulation may include an azeotrope. The liquid formulation may be one of two-component, three-component, four-component, or five-component or more formulations. The desired temperature of the liquid formulation may be in the range of -40 to 140°C, preferably -30 to 100°C, and most preferably -20 to 80°C. The pressure of the injected liquid may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the liquid injected into the target tissue may be 1-12 ATM, e.g., 1-8 ATM, 1-5 ATM, or 1-3 ATM. The liquid formulation may include a solution. The liquid formulation may include a suspension. The liquid formulation may include an emulsion.

[0024] In some embodiments, the method of treating a disease includes percutaneously inserting a delivery catheter into a diseased tissue of the human body, injecting a formulation into the body tissue through the catheter, where the amount of formulation and / or heat or cool delivered is effective to injure or damage the tissue and produce a therapeutic effect (e.g., neuromodulation, lowering blood pressure, treating shortness of breath), and withdrawing the delivery catheter from the body. Heating or cooling can be used to enhance the effect by accelerating the reaction rate of the formulation and the tissue. Examples of diseases include hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive system disease, urinary system disease, cancer, tumors, pain, asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD). Examples of body tissues include renal arteries, vascular lumens, non-vascular lumens, airways, paranasal sinuses, esophagus, respiratory lumens, digestive lumens, cancer, tumors, pain, and urinary lumens. Examples of formulations include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. If the formulation is a vapor of one or more components, heat can be generated by condensing the vapor into a liquid within the tissue. If the formulation is a liquid or solution, cold or heat can be generated by the temperature of the formulation (i.e., by raising or lowering the temperature of the formulation above or below body temperature). The temperature of the liquid formulation may range from -40 to 140°C, preferably -30 to 100°C, and most preferably -20 to 80°C. In one embodiment, the temperature of the formulation may be room temperature. In some embodiments, the temperature of the formulation is in the range of -40 to -20°C. In some embodiments, the temperature of the formulation is in the range of 15 to 80°C. In some embodiments, the temperature of the formulation is body temperature. In some embodiments, the temperature of the formulation is in the range of 50 to 80°C. In some embodiments, the temperature of the tissue to be treated is lower than the desired temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated may range from -40 to 100°C, preferably from -30 to 80°C, and most preferably from -20 to 80°C. In some embodiments, the temperature of the tissue to be treated is in the range of -40 to -20°C. In some embodiments, the temperature of the tissue to be treated is in the range of 15 to 80°C. In some embodiments, the temperature of the tissue to be treated is body temperature.In some embodiments, the temperature of the tissue to be treated is in the range of 50-80°C. The delivery catheter is a needle or needle-based catheter, and uses image guidance. For example, the image guidance can be ultrasound, x-ray, CT scan, scope, or a combination thereof. The pressure of the formulation injected can be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the formulation injected into the target tissue can be 1-12 ATM, e.g., 1-8 ATM, 1-5 ATM, or 1-3 ATM. The delivery catheter can be a balloon catheter. For example, the balloon catheter can have a single or double balloon. The delivery catheter can be an injection catheter. In some embodiments, the catheter is a combination of a balloon catheter and an injection catheter.

[0025] In some embodiments, the method of treating a disease includes percutaneously inserting an irrigated thermal ablation catheter into a body lumen adjacent to a nerve, injecting a formulation into tissue in the body lumen adjacent to the nerve; ablating the tissue in the body lumen adjacent to the nerve by thermal ablation; injecting a formulation during and / or before and after thermal ablation, where the amount of formulation and / or energy delivered is an amount effective to injure or damage the nerve and provide benefits, such as lowering blood pressure and reducing shortness of breath; and withdrawing the irrigated thermal ablation catheter from the body lumen. The irrigated thermal ablation catheter may be one selected from the group consisting of radiofrequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound irrigated ablation catheter. The energy can enhance the effect by accelerating the reaction rate of the formulation with the nerve. The disease may be one selected from the group consisting of hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive system disease, urological system disease, asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD). The body lumen may include the renal artery, vascular lumen, non-vascular lumen, airway, paranasal sinuses, esophagus, respiratory lumen, digestive lumen, and / or urinary lumen. The formulation may be selected from the group consisting of a gas, vapor, liquid, solution, emulsion, and suspension of one or more components. If the formulation includes a vapor of one or more components, heat can be generated by condensing the vapor into a liquid in the tissue. If the formulation is a liquid or solution, cold or heat can be generated by raising the temperature of the formulation above or below body temperature. The temperature of the liquid formulation may range from -40 to 140°C, preferably from -30 to 100°C, and most preferably from -20 to 80°C. In some embodiments, the temperature of the formulation is room temperature. In some embodiments, the temperature of the formulation is in the range of -40 to -20°C. In some embodiments, the temperature of the formulation is in the range of 15 to 80°C. In some embodiments, the temperature of the formulation is body temperature. In some embodiments, the temperature of the formulation is in the range of 50 to 80°C. In some embodiments, the temperature of the tissue to be treated adjacent to the nerve is lower than the desired temperature of the formulation and higher than body temperature.The temperature of the treated tissue adjacent to the nerve may range from -40 to 100°C, preferably from -30 to 80°C, and most preferably from -20 to 80°C. In some embodiments, the temperature of the treated tissue adjacent to the nerve ranges from -40 to -20°C. In some embodiments, the temperature of the treated tissue adjacent to the nerve ranges from 15 to 80°C. In some embodiments, the temperature of the treated tissue adjacent to the nerve is body temperature. In some embodiments, the temperature of the treated tissue adjacent to the nerve ranges from 50 to 80°C. The pressure of the injected formulation may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, such as 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0026] In some embodiments, a non-irrigated thermal ablation catheter and a formulation delivery catheter may be used in combination or simultaneously to treat a disease. A method for treating a disease may include percutaneously inserting a non-irrigated thermal ablation catheter or / and a formulation delivery catheter into a body lumen adjacent to a nerve; injecting a formulation into tissue in the body lumen adjacent to a nerve; cauterizing tissue in the body lumen adjacent to a nerve by thermal ablation; injecting a formulation during and / or before and after thermal ablation, where the amount of formulation and / or energy delivered is an amount effective to injure or damage the nerve and provide benefits, such as reduced blood pressure and reduced shortness of breath; and withdrawing the non-irrigated thermal ablation catheter or / and a formulation delivery catheter from the body lumen. The non-irrigated thermal ablation catheter may be selected from the group consisting of radiofrequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound non-irrigated ablation catheter. The formulation delivery catheter may be a needle-based catheter. The formulation delivery catheter may be a balloon catheter. The balloon catheter may have one or two balloons. The formulation delivery catheter may be an infusion catheter. The energy may enhance the effect by accelerating the reaction rate between the formulation and the nerve. The disease may be selected from the group consisting of hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive system disease, urinary system disease, asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD). The body lumen may be selected from the group consisting of renal artery, vascular lumen, non-vascular lumen, airway, paranasal sinus, esophagus, respiratory lumen, digestive lumen, and urinary lumen. The formulation may be selected from the group consisting of gas, vapor, liquid, solution, emulsion, and suspension of one or more components. If the formulation is a vapor of one or more components, heat may be generated by condensing the vapor into a liquid in the tissue. If the formulation is a liquid or solution, cold or heat can be generated by raising the temperature of the formulation above or below body temperature.The temperature of the liquid formulation may range from -40 to 140°C, preferably from -30 to 100°C, and most preferably from -20 to 80°C. In some embodiments, the temperature of the formulation is room temperature. In some embodiments, the temperature of the formulation is in the range of -40 to -20°C. In some embodiments, the temperature of the formulation is in the range of 15 to 80°C. In some embodiments, the temperature of the formulation is body temperature. In some embodiments, the temperature of the formulation is in the range of 50 to 80°C. In some embodiments, the temperature of the tissue to be treated adjacent to the nerve is lower than the desired temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may range from -40 to 100°C, preferably from -30 to 80°C, and most preferably from -20 to 80°C. In some embodiments, the temperature of the tissue to be treated adjacent to the nerve is in the range of -40 to -20°C. In some embodiments, the temperature of the tissue to be treated adjacent to the nerve is in the range of 15 to 80°C. In some embodiments, the temperature of the tissue to be treated adjacent to the nerve is body temperature. In some embodiments, the temperature of the treated tissue adjacent to the nerve ranges from 50-80° C. The pressure of the injected formulation may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1-12 ATM, e.g., 1-8 ATM, 1-5 ATM, or 1-3 ATM.

[0027] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to be restrictive of the invention, as claimed. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 is a perspective view of an exemplary embodiment of a catheter embodiment for double balloon delivery. [Figure 2A] FIG. 2A illustrates an embodiment of formulation injection into the airways using a single balloon delivery catheter. [Figure 2B] FIG. 2B shows an embodiment of injecting a formulation into the airways using a double-balloon delivery catheter. [Figure 2C]FIG. 2C shows an embodiment of injecting a formulation into a renal artery using a double-balloon delivery catheter. [Diagram 3] FIG. 3 is an embodiment of a partial cross-sectional view of a double balloon delivery catheter in a body lumen. [Figure 4] FIG. 4 shows an embodiment of injecting a formulation into the pulmonary artery using a double-balloon delivery catheter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] Disclosed are embodiments directed to treating disease by delivering an effective amount of the formulation to a target tissue, such as a tissue affected by the disease. The term "tissue affected by the disease" includes all tissues contributing to the disease. For example, the disease may be one of hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive system disease, urinary system disease, cancer, tumor, pain, asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD). Examples of cancer include cancer of the adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, and uterus. The formulation includes one or more of a gas, vapor, liquid, solution, emulsion, and suspension of one or more components. The method may involve delivering the formulation at a desired temperature to a tissue of the human body. Examples of tissues include renal arteries, vascular lumens, non-vascular lumens, airways, paranasal sinuses, esophagus, respiratory lumens, digestive lumens, cancers, tumors, and urinary lumens. Temperature may enhance the safety and efficacy of the therapeutic formulation. Temperature may range from -40 to 140°C, preferably -30 to 100°C, most preferably -20 to 80°C. The pressure of the injected formulation may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, e.g., 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM. The temperature of the tissue to be treated may be different from the temperature of the formulation. The temperature of the tissue to be treated may range from -40 to 100°C, preferably -30 to 80°C. The amount of formulation and energy delivered to the injury or damage is preferably an amount effective to injure, damage or ablate the diseased tissue and produce a therapeutic effect, such as blood pressure reduction, tumor regression, pain relief, relief of symptoms of asthma and pulmonary arterial hypertension, and treatment of COPD. In some embodiments, the energy or heat can enhance the effect by accelerating the rate of reaction of the formulation with the tissue.

[0030] Disclosed are embodiments directed to the treatment of diseases by delivering an effective amount of energy or / and formulations to targeted neural tissue. For example, the diseases may be selected from the group consisting of hypertension, diabetes, obesity, heart failure, end stage renal disease, digestive system disease, urological system disease, asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD). The energy may be radio frequency, freeze-thaw, microwave, laser, ultrasound, and / or high intensity focused ultrasound energy. The formulation may be a gas, vapor, liquid, solution, emulsion, and / or suspension of one or more components. The method may include combined thermal and chemical ablation, their formulations, and methods for treating hypertension, diabetes, obesity, heart failure, end stage renal disease, digestive system disease, urological system disease, asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD) by thermal and chemical ablation of nerves in the human body at various temperatures. Thermal energy may enhance the safety and efficacy of therapeutic chemical ablation. Reducing the ablation temperature and / or time in chemical ablation may improve the safety and efficacy of thermal ablation. The temperature may range from -40 to 140°C, preferably from -30 to 100°C, and most preferably from -30 to 80°C. The pressure of the injected formulation may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, such as 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM. The formulation may be one of a two-component, three-component, four-component, or five or more component formulations. The delivery system may be a percutaneous, minimally invasive delivery catheter. The disclosed methods may provide for the combination of thermal energy with a formulation that includes one or more components that enhance absorption and penetration into nerves in the body lumen.

[0031] In some embodiments, the safety and efficacy of radiofrequency ablation is improved by increasing the size of the ablation while minimizing the risk of complications that may occur due to heating. Examples of such complications include thrombus formation, steam popping, vesiculation, charring of the lesion, restenosis, fibrosis of the media and adventitia, and other complications associated with catheter manipulation (i.e., drilling). Localized thermal ablation (RF ablation) is non-uniform and does not reach the nerves present in the adventitia. Insufficient localized RF ablation is less effective (does not reduce blood pressure as much). Methods include cooling the electrode internally (closed loop) or externally (open loop) via the size of the electrode (passive cooling by blood flow) or active fluid. Cooling the electrode increases energy delivery to the nerve tissue. In one embodiment of external cooling (open loop), the chemical formulation can be replaced with an active cooling fluid. The formulations of the present disclosure can be used not only to cool the electrode, but also for chemical ablation. In some embodiments, the formulation may diffuse and penetrate into nerve tissue unevenly, thereby ablating nerves present in the adventitia unevenly within the body lumen.Therefore, chemical ablation formulations can be delivered during and / or before and after thermal ablation.Examples of thermal ablation include radiofrequency, freeze-thaw, microwave, laser, ultrasound, and high-intensity focused ultrasound ablation.As a result, the method can improve the safety and efficacy of treatment.

[0032] The formulation may be one of two-component, three-component, four-component, or five-component or more formulations. The delivery system may be transdermal, a less invasive method of delivery. Also provided are formulations that include one or more components that enhance absorption and penetration into tissues of body lumens.

[0033] In some embodiments, 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, derivatives and combinations thereof.

[0034] In some embodiments, the component of the formulation is a gas, examples of which include oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, and 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.

[0035] In some embodiments, the component included in the formulation is a surfactant. Examples of 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, sorbitan PEG monolaurate, sorbitan PEG monolaurate, sorbitan PEG monooleate, stearin, Sorbitan PEG, oleyl ether PEG, lauroyl ether PEG, octoxynol, monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside do, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside;Benzalkonium chloride, benzethonium chloride, dodecyltrimethylammonium bromide, sodium ricinoleate, dioctyl sodium sulfosuccinate, sodium lauryl sulfate, sodium dodecyl sulfate, dialkylmethylbenzyl ammonium salts, and dialkyl esters of sodium sulfosuccinate, 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), tetra ... Examples of surfactants include poly(ethylene glycol), poly(ethylene glycol) oligomer, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol), and penta(propylene glycol), poly(propylene glycol) oligomer, block copolymers of polyethylene glycol and polypropylene glycol, Pluronic, Pluronic 85, and derivatives and combinations thereof. The content of the surfactant in the formulation may range from 0.1 to 80% by weight, preferably 0.5 to 50% by weight, and most preferably 1 to 15% by weight.;

[0036] In some embodiments, the formulation includes at least one oil, fatty acid, and / or lipid. For example, the formulation may include soybean oil, vegetable oil, floral oil, animal oil, marine oil, butterfat, coconut oil, palm oil, olive oil, peanut oil, fish oil, 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, alpha-linoleic acid, gamma-linoleic acid, behenic acid, erucic acid, lignoceric acid, natural or may include synthetic phospholipids, mono-, di-, or tri-acylglycerol, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobees, niosomes, and derivatives thereof.

[0037] In some embodiments, the formulation comprises one or more therapeutic agents or denervation agents.The therapeutic agent may be one of the following: 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, oleandrin, carbamazepine, aflatoxin, guanethidine, and guanethidine sulfate.In another embodiment, the formulation comprises one of the following imaging agents for imaging denervation. The contrast agent may include 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 may be in the range of 2-25% by weight, preferably 5-15% by weight.

[0038] In some embodiments, the formulation comprises an azeotrope. An azeotrope is a mixture of two or more components whose components cannot be changed by simple distillation. This phenomenon occurs when an azeotrope is boiled, and the resulting vapor has the same composition as the original mixture. Azeotropes or formulations may include ethanol / water, ethanol / water / contrast, ethanol / water / surfactant, ethanol / water / contrast / surfactant, propanol / water, isopropanol / water, butanol / water, acetic acid / water, acetic acid / water / ethanol, acetic acid / water / contrast, acetic acid / water / contrast / surfactant, acetic acid / water / ethanol / contrast, acetic acid / water / ethanol / contrast / surfactant, lactic acid / water, lactic acid / water / ethanol, lactic acid / water / contrast, lactic acid / water / contrast / surfactant, lactic acid / water / ethanol / contrast, lactic acid / water / ethanol / contrast / surfactant, ethyl lactate / water, ethyl lactate / ethanol, lactic acid / ethanol / water, ethyl lactate / water / ethanol, ethyl nitrate / ethanol, isopropyl acetate / ethanol.

[0039] In some embodiments, the formulation is in the form of gas or vapor of one or more components.Gas or vapor formulation may include oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, and vapor of organic and inorganic compounds.Vapor of organic and inorganic compounds may include 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.

[0040] The vapor formulation may include a surfactant. The vapor formulation may include a therapeutic agent. The vapor formulation may include a contrast agent, such as lipiodol and iodine. The vapor may include an azeotrope. The vapor may be one of a binary, ternary, quaternary, or quinary or more formulations. The desired temperature of the vapor formulation may range from 0 to 140°C, preferably 15 to 100°C, and most preferably 30 to 80°C. The pressure of the injected vapor may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the vapor injected into the target tissue may be 1 to 12 ATM, such as 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0041] In some embodiments, the formulation is in a liquid state of one or more components. The liquid formulation may include 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 others. The liquid formulation may include a therapeutic agent. The liquid formulation may include a contrast agent. The liquid formulation may include an azeotrope. The liquid formulation may be one of a binary, ternary, quaternary, or five or more component formulations. The liquid formulation may be a solution. The liquid formulation may be an emulsion. The liquid formulation may be a suspension. The temperature of the liquid formulation may be in the range of -40 to 140°C, preferably in the range of -30 to 100°C, and most preferably in the range of -30 to 80°C. In some embodiments, the temperature of the formulation is at room temperature. In some embodiments, the temperature of the formulation is in the range of -40 to -20°C. In some embodiments, the temperature of the formulation is in the range of 15 to 80°C. In some embodiments, the temperature of the formulation is body temperature. In some embodiments, the temperature of the formulation is in the range of 50 to 80°C. The pressure of the formulation liquid may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the liquid injected into the target tissue may be 1 to 12 ATM, e.g., 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0042] In some embodiments, the method of treating a disease includes percutaneously inserting a delivery catheter into the body; injecting a formulation into the diseased tissue of the body through the catheter, where the amount of formulation and / or heat or cold delivered is effective to damage or injure the tissue and produce a therapeutic effect, e.g., lowering blood pressure and reducing shortness of breath; and withdrawing the delivery catheter from the body. The heat or cold can be effective by accelerating the rate of reaction of the formulation with the tissue. Examples of diseases that can be treated include high blood pressure, diabetes, obesity, heart failure, end-stage renal disease, digestive disease, urinary disease, cancer, tumors, pain (chronic and / or acute), asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD). Cancer includes cancer of the adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, and uterus. Body tissues include renal arteries, vascular lumens, non-vascular lumens, airways, paranasal sinuses, esophagus, respiratory lumens, digestive lumens, cancers, tumors, and urinary lumens. The formulation may be a gas, vapor, liquid, solution, emulsion, or suspension containing one or more components. If the formulation is a vapor of one or more components, heat can be generated by condensing the vapor into a liquid in the tissue. If the formulation is a liquid or solution, cold or heat can be generated by the temperature of the formulation, i.e., by raising the temperature of the formulation above or below body temperature. The temperature of the liquid formulation may range from -40 to 140°C, preferably from -30 to 100°C, and most preferably from -30 to 80°C. In some embodiments, the temperature of the tissue to be treated may be different from the temperature of the formulation and lower or higher than body temperature. The temperature of the tissue to be treated may range from 15 to 100°C, preferably from 20 to 90°C, and most preferably from 36 to 80°C. In some embodiments, the temperature of the tissue to be treated may range from -40 to 20°C. The pressure of the injected formulation may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, e.g., 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.The delivery catheter may be a needle or a needle-based catheter, and may use image guidance. The image guidance may be one of ultrasound, x-ray, CT-scan, and scope. The delivery catheter may also be a balloon catheter. The balloon catheter may have at least one or two balloons. The delivery catheter may be an injection catheter. The catheter may be a combination balloon catheter and injection catheter.

[0043] In some embodiments, the method of treating a disease includes percutaneously inserting a delivery catheter into a body cavity adjacent to a nerve; delivering energy or / and the above-mentioned formulation at a desired temperature to the tissue of the body cavity adjacent to the nerve, where the amount of formulation and / or energy delivered is effective to injure or damage the nerve and bring about a benefit, such as a reduction in blood pressure; and withdrawing the delivery catheter from the body cavity. Examples of diseases that can be treated include hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive system disease, urinary system disease, cancer, tumors, pain (chronic and / or acute), asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD). Cancer includes cancer of the adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, and uterus. The body tissues include renal arteries, vascular lumens, non-vascular lumens, pulmonary arteries, airways, paranasal sinuses, esophagus, respiratory lumens, digestive lumens, cancers, tumors, and urinary lumens. In some embodiments, the energy can accelerate the rate of reaction between the formulation and the nerves to enhance the effect. The energy can be one of radio frequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound energy. Thus, the catheter for energy delivery can be one of radio frequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound catheters. Exemplary formulations include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. If the formulation is a vapor of one or more components, heat can be generated by condensing the vapor into a liquid in the tissue. If the formulation is a liquid or solution, heat can also be transferred from the formulation at a temperature higher than body temperature. The desired temperature of the formulation may be in the range of -40 to 140°C, preferably in the range of -30 to 100°C, and most preferably in the range of -20 to 80°C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the desired temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may be in the range of -40 to 100°C, preferably in the range of -30 to 90°C, and most preferably in the range of -20 to 80°C.The pressure of the injected formulation may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the injected formulation into the target tissue may be 1-12 ATM, e.g., 1-8 ATM, 1-5 ATM, or 1-3 ATM.

[0044] In some embodiments, the formulation is a mixture of ethanol and water. The ethanol content in the ethanol may be 10-100% by weight. The formulation may be delivered to tissues in a body lumen as a vapor or liquid at a desired temperature. The desired temperature of the vapor or liquid formulation may range from -40 to 150°C, preferably from -30 to 100°C, and most preferably from -20 to 80°C. The tissue temperature may range from -40 to 90°C, preferably from -30 to 80°C. The ethanol / water formulation may be an azeotrope. This azeotrope may be 95.63% ethanol and 4.37% water (by weight). While ethanol boils at 78.4°C and water boils at 100°C, this azeotrope boils at 78.2°C, which is lower than the boiling points of both components. 78.2°C is the lowest temperature at which any ethanol / water solution can boil at air pressure. The pressure of the ethanol and water mixture injected may be higher than the pressure in the body cavity (1 ATM). For example, the pressure range of the mixture injected into the target tissue may be 1-12 ATM, e.g., 1-8 ATM, 1-5 ATM, or 1-3 ATM.

[0045] In some embodiments, the delivery catheter is a combination of a radiofrequency catheter and an infusion catheter. The radiofrequency catheter can be modified by reducing the size of the electrode (passive cooling occurs via blood flow) and / or cooling the electrode internally (closed loop) or externally via active fluid. Cooling the electrode increases the energy delivery to the nerve tissue. In external cooling (open loop) embodiments, a chemical formulation can be replaced with an active cooling fluid. In some embodiments, the formulations of the present disclosure can be used not only to cool the electrode, but also for chemical ablation. The formulations may diffuse and penetrate the nerve tissue non-uniformly, thereby ablating the nerves present in the adventitia non-uniformly within the body lumen. Thus, chemical ablation formulations can be delivered during and before and after thermal ablation. Thermal ablation includes radiofrequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound ablation. As a result, the method can improve the safety and efficacy of the treatment.

[0046] In some embodiments, the delivery catheter comprises an infusion lumen, an energy delivery lumen, a guide wire lumen, an inflation lumen, an energy delivery port, a formulation infusion port, and a balloon inflation port at the proximal end, an energy release site, a formulation outlet, and one or two balloons at the distal end. The energy delivery element may be one of radiofrequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound. An energy generator may be connected to the energy delivery port. The energy generator may be one of radiofrequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound energy generator. The balloon inflation port may be connected to an inflation device. A supply of formulation may also be connected to the formulation infusion port at the proximal end of the delivery catheter.

[0047] In some embodiments, the formulation is a mixture of vapors containing water, ethanol and oxygen. In other embodiments, the formulation is a mixture of vapors containing water, ethanol and air. In some embodiments, the formulation is a mixture of vapors containing water, ethanol, oxygen and nitrogen. These formulations containing oxygen or air are particularly useful for the treatment of asthma and COPD.

[0048] In some embodiments, the formulation is a mixture of water, ethanol, and a vapor containing iodine, where the iodine-containing vapor is in an amount effective to image the vapor mixture at the wall of a body lumen. In some embodiments, the formulation is a liquid mixture containing water, ethanol, and a surfactant. In some embodiments, the formulation is a liquid mixture containing water, ethanol, and a contrast agent, where the contrast agent is in an amount effective to trace the mixture at the wall of a body lumen using x-rays. The contrast agent may be one or more of 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 may range from 2 to 20% by weight, and is preferably 5 to 15% by weight.

[0049] In some embodiments, the formulation is a mixture of acetic acid and water. The content of acetic acid in the formulation may range from 1 to 100% by weight, preferably 10 to 75% by weight, and most preferably 20 to 50% by weight. The formulation can be delivered to the body lumen tissue as a vapor or liquid at a desired temperature. The desired temperature of the vapor or liquid formulation may range from -40 to 100°C, preferably from -30 to 100°C, and most preferably from -30 to 80°C. The temperature of the tissue may range from -30 to 80°C, preferably from 60 to 80°C or from -40 to -20°C. The temperature of the tissue may range from -40 to 0°C, preferably from -30 to -20°C. The pressure of the mixture of acetic acid and water injected may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the mixture injected into the target tissue may be 1 to 12 ATM, such as 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM. The content of acetic acid in the formulation may be 2% to 75% by weight, preferably 10% to 60% by weight.

[0050] In some embodiments, the formulation is a liquid mixture containing water, acetic acid, and a contrast agent (e.g., sodium iodide and lipiodol), where the contrast agent is in an amount effective to image the vapor mixture in the body lumen wall. The acetic acid content in the formulation may range from 1 to 100% by weight, preferably 10 to 75% by weight, and most preferably 30 to 60% by weight. In another embodiment, the formulation is a liquid mixture containing water, acetic acid, and a surfactant. The acetic acid content in the formulation may range from 1 to 100% by weight, preferably 10 to 75% by weight, and most preferably 30 to 60% by weight. In another embodiment, the formulation is a liquid mixture containing water, acetic acid, and a contrast agent, where the contrast agent is in an amount effective to trace the mixture in the body lumen wall by X-ray. The contrast agent may be one of 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 may range from 2 to 20% by weight, preferably 5 to 15% by weight.

[0051] In some embodiments, the formulation is a mixture of liquids containing ethanol and lipiodol (LIPIODOL ULTRA-FLUIDE), where the lipiodol is in an amount effective to image the vapor mixture in the body lumen wall and to injure the target neural tissue. The lipiodol content in the formulation may range from 10 to 80% by weight, preferably 15 to 75% by weight, and most preferably 20 to 50% by weight. In another embodiment, the formulation is a mixture of liquids containing water and lipiodol. The lipiodol content in the formulation may range from 10 to 80% by weight, preferably 15 to 75% by weight, and most preferably 20 to 50% by weight. In another embodiment, the formulation is a mixture of liquids containing acetic acid and lipiodol. The lipiodol content in the formulation may range from 10 to 80% by weight, preferably 15 to 75% by weight, and most preferably 20 to 50% by weight.

[0052] In some embodiments, the formulation is a solution of phenol, water, and a certain amount of contrast agent (e.g., iodine, sodium iodide, lipiodol, and iopromide). The phenol content may range from 2 to 20% by weight, preferably 5 to 16% by weight. The formulation can be delivered to the body lumen tissue as a solution at a desired temperature. The desired temperature of the liquid formulation may range from 0 to 100°C, preferably 20 to 95°C, and most preferably 50 to 90°C. The temperature of the tissue may range from 36 to 80°C, preferably 60 to 80°C. Phenol may be an effective agent for ablation. The pressure of the injected solution may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the solution injected into the target tissue may be 1 to 12 ATM, such as 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0053] In some embodiments, the formulation is a solution of ethylene glycol, water, and a small amount of contrast agent (e.g., iodine and iopromide). The ethylene glycol content may range from 2 to 90% by weight, preferably 15 to 75% by weight. The desired temperature of the liquid formulation may range from 20 to 150°C, preferably 40 to 120°C, and most preferably 60 to 90°C. The pressure of the injected solution may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the solution injected into the target tissue may be 1 to 12 ATM, e.g., 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0054] In some embodiments, the formulation is a solution of glycerol, water, and a small amount of contrast agent (e.g., iodine and iopromide). The glycerol content may range from 2 to 90% by weight, preferably 15 to 75% by weight. The desired temperature of the liquid formulation may range from 20 to 150°C, preferably 40 to 120°C, and most preferably 60 to 90°C. The pressure of the injected solution may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the solution injected into the target tissue may be 1 to 12 ATM, such as 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0055] In some embodiments, the formulation is a mixture of propanol and water. The propanol content may range from 10-99% by weight. The formulation may be delivered to the nerve in the body lumen as a vapor or liquid at the desired temperature. The desired temperature of the vapor or liquid formulation may range from 20-100°C, preferably 40-95°C, most preferably 60-90°C. The temperature of the nerve tissue may range from 36-80°C, preferably 60-80°C. The propanol / water formulation may be an azeotrope. The azeotrope may be 71.7% propanol and 28.3% water by weight. Although propanol boils at 97.2°C and water boils at 100°C, this azeotrope boils at 87.7°C, which is lower than the boiling point of either component. The pressure of the injected mixture may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the mixture injected into the target tissue may be 1-12 ATM, such as 1-8 ATM, 1-5 ATM, or 1-3 ATM.

[0056] In some embodiments, the formulation is a mixture of isopropanol and water. The isopropanol content may range from 10-99% by weight. The formulation may be delivered to the nerve in the body lumen as a vapor or liquid at the desired temperature. The desired temperature of the vapor or liquid formulation may range from 20-100°C, preferably 40-95°C, most preferably 60-90°C. The temperature of the nerve tissue may range from 20-80°C, preferably 60-80°C. The isopropanol / water formulation may be an azeotrope. The azeotrope may be 87.9% propanol and 12.1% water by weight. Isopropanol boils at 82.5°C and water boils at 100°C, but the azeotrope boils at 80.4°C, which is lower than the boiling points of either component. The pressure of the injected mixture may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the mixture injected into the target tissue may be 1-12 ATM, such as 1-8 ATM, 1-5 ATM, or 1-3 ATM.

[0057] In some embodiments, the formulation is a mixture of ethanol and ethyl acetate. The ethyl acetate content may range from 10-99% by weight. The formulation may be delivered to the tissue of the human body as a vapor or liquid at a desired temperature. The desired temperature of the vapor or liquid formulation may range from 20-100°C, preferably 40-95°C, most preferably 60-90°C. The tissue temperature may range from 36-80°C, preferably 60-80°C. The ethyl acetate / ethanol formulation may be an azeotrope. The azeotrope may be 69.7% ethyl acetate and 30.3% ethanol by weight. Ethyl acetate boils at 77.1°C and ethanol boils at 78.4°C, but the azeotrope boils at 71.8°C, which is lower than the boiling points of either component. The pressure of the injected mixture may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the mixture injected into the target tissue may be 1-12 ATM, such as 1-8 ATM, 1-5 ATM, or 1-3 ATM.

[0058] In some embodiments, the formulation is a mixture of ethanol and ethyl iodide. The ethyl iodide content may range from 10-99% by weight. The formulation may be delivered to the nerve in the body lumen as a vapor or liquid at the desired temperature. The desired temperature of the vapor or liquid formulation may range from 20-100°C, preferably 40-95°C, most preferably 60-90°C. The tissue temperature may range from 36-80°C, preferably 60-80°C. The ethyl iodide / ethanol formulation may be an azeotrope. The azeotrope may be 87% ethyl iodide and 13% ethanol by weight. Ethyl iodide boils at 72.3°C and ethanol boils at 78.4°C, but the azeotrope boils at 63°C, which is lower than the boiling points of either component. The pressure of the injected mixture may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the mixture injected into the target tissue may be 1-12 ATM, such as 1-8 ATM, 1-5 ATM, or 1-3 ATM.

[0059] In some embodiments, the formulation is a mixture of water, ethanol, and ethyl acetate. The ethanol content may range from 2 to 99% by weight. The ethyl acetate content may range from 2 to 85% by weight. The formulation may be delivered to the tissue of the human body as a vapor or liquid at a desired temperature. The desired temperature of the vapor or liquid formulation may range from 20 to 100°C, preferably 40 to 95°C, and most preferably 60 to 90°C. The tissue temperature may range from 36 to 80°C, preferably 60 to 80°C. The ethyl acetate / ethanol formulation may be an azeotrope. This azeotrope may be a mixture of 7.8% water, 83.2% ethyl acetate, and 9.0% ethanol by weight. Ethyl acetate boils at 77.1°C, ethanol boils at 78.4°C, and water boils at 100°C, but the azeotrope boils at 70.3°C, which is lower than the boiling points of either component. The pressure of the mixture injected may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the mixture injected into the target tissue may be 1-12 ATM, e.g., 1-8 ATM, 1-5 ATM, or 1-3 ATM.

[0060] In some embodiments, a delivery catheter is used to inject the formulation into tissues of the human body. The delivery catheter may be a needle or a needle-based catheter, for example, using ultrasound imaging guidance. The delivery catheter may be a balloon catheter. The balloon catheter may have at least one or two balloons, for example, including a single or double balloon. The delivery catheter may be an injection catheter. A combination of a balloon catheter and an injection catheter may be used in the procedure as well.

[0061] Referring now to the drawings, FIG. 1 shows a delivery catheter 10 including an elongated shaft 11 having at least one internal lumen, a distal end 13, and a proximal end 14. The distal end 13 has balloons at proximal 20 and distal 21 that fit into the lumens. In either configuration, the tube of the catheter shaft 11 can be extruded 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 can be extruded or molded to provide a variety of lumen cross-sections, such as circular or elliptical. Additionally, as shown in FIG. 1, the catheter 10 can include a distal balloon inflation port 40 for inflating the distal balloon 21 and a proximal balloon inflation port 41 for inflating the proximal balloon 20, such that the proximal and distal balloons 20 and 21 can be inflated separately. A balloon that is lumen-compatible is one that can be inflated at a pressure below the pressure at which the lumen wall deforms. The material of the balloon is selected to be flexible and usable at high temperatures so that the balloon conforms to the specifications when inflated. In some embodiments, the material of the balloon is one of polyamide, nylon, pebax, polyester, polyethylene terephthalate, and copolymers thereof. The diameter of the balloon can range from about 2 millimeters to about 30 millimeters, depending on the diameter of the area to be treated. In some embodiments, the diameter of each balloon is about 2 millimeters ("mm"). Alternatively, the diameter of each balloon can be about 3 millimeters, or about 4 millimeters, or about 5 millimeters, or about 6 millimeters, or about 7 millimeters, or about 8 millimeters, or about 9 millimeters, or about 10 millimeters, or about 12 millimeters, or about 15 millimeters, or about 20 millimeters, or about 25 millimeters, or about 30 millimeters.

[0062] In some embodiments, the catheter does not include electrodes. In particular, the catheter may not include ablative energy, such as radiofrequency, ultrasound, or microwave energy.

[0063] In some embodiments, 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 may be a rapid exchange catheter or an over-the-wire catheter and may be made of any suitable biocompatible material. The material of the balloons 20 and 21 may be one of polyester, polyamide, nylon 12, nylon 11, polyamide 12, polyether and polyamide block copolymers, pebax, polyurethane, and polyether and polyester block copolymers. The diameter of the balloon 21 may be the same as or smaller than the diameter of the balloon 20.

[0064] 2A and 2B are schematic diagrams of a balloon delivery catheter 198 in the left main bronchus to treat asthma and COPD. The delivery catheter 198 of FIGS. 2A and 2B can treat airways distal to the main bronchi 21, 22. For example, the delivery catheter 198 can be placed in an airway (e.g., airways 2 and onward) to affect distal to the bronchial tree 27. The delivery system 198 can be guided along the tortuous airways to perform various procedures, such as partial lobe, whole lobe, multiple lobes, or unilateral or bilateral lung denervation. In some embodiments, the lobar bronchus is treated to denervate the lobe. For example, one or more sites along the lobar bronchus can be targeted to perform denervation of the entire lobe connected to that lobar bronchus. The left lobar bronchus can also be treated to affect the left upper and / or lower lobe. The right lobe bronchus may also be treated to affect the right upper lobe, right middle lobe, and / or right lower lobe. The lobes may be treated simultaneously or sequentially. In some embodiments, the physician may treat one lobe. Depending on the effect of the treatment, the physician may treat other lobes simultaneously or sequentially. In this manner, separate regions of the bronchial tree may be treated.

[0065] The delivery catheter 198 may also be used to treat segmental or subsegmental bronchi. Each segmental bronchus may be treated by delivering the formulation to a single treatment site along each segmental bronchus. For example, the formulation may be delivered to each segmental bronchus of the right lung. In some procedures, most or substantially all of the right lung may be treated with one or two applications of the formulation. In some procedures, most or substantially all of both lungs may be treated with no more than two to six separate applications. Due to bronchial anatomy, segmental bronchi are often ablated with one or two applications.

[0066] The delivery catheter 198 can affect nerve tissue while preserving the function of other tissues or anatomical features, such as mucus glands, cilia, smooth muscle, and body lumens (e.g., blood vessels). Nerve tissue includes nerve cells, nerve fibers, dendrites, and supporting tissue, such as glial cells. Nerve cells transmit electrical impulses, and nerve fibers extend along axons along which the impulses travel. The electrical impulses are converted into chemical signals that communicate with effector cells or with other nerve cells. As an example, the delivery catheter 198 can be used to ablate a portion of the airway of the bronchial tree 27 to attenuate one or more nervous system signals transmitted by the nerve tissue. Denervation can include damaging the entire nerve tissue contained in a portion of a nerve trunk along the airway to stop substantially all signals from traveling through the damaged portion of the nerve trunk to the more distal bronchial tree. If multiple nerve trunks extend along the airway, each nerve trunk can be damaged. That is, the innervation along a portion of the bronchial tree can be blocked. When the signal is blocked, the smooth muscle of the distal airway can relax, causing the airway to dilate. The dilation of the airway reduces airway resistance and increases gas exchange in the lungs, thereby reducing, limiting, or substantially eliminating one or more symptoms, such as shortness of breath, wheezing, and chest tightness. Tissues surrounding or adjacent to the targeted nerve tissue can be affected, but are not permanently damaged. In some embodiments, for example, before and after treatment, bronchial blood vessels along the treated airway can deliver a similar amount of blood to bronchial wall tissue, and pulmonary blood vessels along the treated airway can deliver a similar amount of blood to alveolar sacs in the distal region of the bronchial tree 27. These blood vessels continue to transport blood and are sufficient to maintain gas exchange. In some embodiments, the smooth muscle of the airway is not significantly damaged. For example, a relatively small portion of smooth muscle in the airway wall may be reversibly altered, which does not significantly affect respiratory function. When a formulation at a desired temperature is used to destroy nerve tissue outside the airway, a therapeutically effective amount of the formulation will not reach the bulk of the non-targeted smooth muscle tissue.

[0067] 2A and 2B, the delivery system 198 may include a therapy control unit 202 and an intraluminal extension assembly 200 connected to the control unit 202. The extension assembly 200 may be inserted into the trachea 20 and advanced into and through the bronchial tree 27 with or without a delivery assembly. The extension assembly 200 may include a distal end 203 that can selectively act on tissue.

[0068] The control unit 202 of FIG. 2A may include one or more processors, microprocessors, digital signal processors (DSPs), field programmable gate arrays (FPGAs), and / or application specific integrated circuits (ASICs), memory devices, buses, power sources, pumps, formulation supplies, vapor supplies, liquid supplies, contrast supplies, vapor generators, desired temperature material generators, and the like.

[0069] The distal end 203 of Figures 2A and 2B can be targeted to various sites within the lung 10, such as, but not limited to, neural tissue, fibrous tissue, diseased or abnormal tissue, muscle tissue, blood, blood vessels, anatomical features (e.g., membranes, glands, cilia, etc.), or other sites of interest.

[0070] FIG. 2C is a schematic diagram of a double balloon delivery catheter positioned in a renal artery. The delivery catheter 106 of FIG. 2C can be used to treat hypertension. The formulation can be injected into the wall of the renal artery adjacent to the renal nerve to be severed. Some elements of the renal vasculature are omitted in FIG. 2C.

[0071] In some embodiments, the catheter 10 disclosed herein allows for a substantially uniform distribution of the formulation throughout the therapeutic window 30, as shown in FIG. 3. The location, diameter, number and frequency of the side holes 31 allow for a substantially uniform filling of the therapeutic window 30. In FIG. 3, the catheter is shown positioned in a body lumen 5. The catheter has two side holes 31 at the therapeutic window 30 for delivery of a therapeutic agent 3. The side holes 31 shown in FIG. 3 are in fluid communication with the inner lumen 25. The side holes 31 at the therapeutic window 30 can be in communication with the exterior 24 or interior 25 of the lumen to allow for uniform delivery of the formulation to the therapeutic window 30.

[0072] FIG. 4 is a schematic diagram of a double balloon delivery catheter positioned in the pulmonary artery. The delivery catheter of FIG. 4 can be used to treat pulmonary hypertension. A formulation can be injected into the wall of the pulmonary artery adjacent to the nerve to be ablated. The front balloon of the delivery catheter is shown positioned at the bifurcation. A baseline pulmonary artery angiogram can be performed to identify the level of the pulmonary artery bifurcation and calculate the arterial diameter. An 8F sheath is shown inserted through the femoral vein and advanced into the main pulmonary artery. A double balloon catheter is advanced along the long sheath. The front balloon is positioned at the bifurcation. A nerve near the bifurcation is damaged by ablation from the formulation injected by the delivery catheter.

[0073] Some embodiments of the invention also include a step of delivering a formulation, e.g., a vapor or liquid, to a region of a body lumen at a constant rate and for a predetermined period of time. Prior to delivery, the formulation may be heated to at least 80°C, or at least 100°C, or at least 150°C. A delivery catheter having a balloon and shaft functions when the temperature of the formulation is at least 80°C, 100°C, or 150°C. Materials contained within the balloon and shaft of the catheter maintain such elevated temperatures. In some embodiments, the delivery of the vapor induces the vapor to turn into a liquid, and the energy released during this phase transition is transferred to the region or subregion of tissue.

[0074] In some embodiments, a safe and effective dose for treating tissue is between about 2 Cal / g and about 150 Cal / g, preferably between about 5 Cal / g and about 100 Cal / g, and the energy transfer rate of the delivery system is between about 2 Cal / sec and about 500 Cal / sec, preferably about 5 Cal / g and about 150 Cal / g. In some embodiments, the generator can produce the formulation, e.g., a vapor or liquid, at a pressure of about 1-12 ATM and a temperature of about 20-150°C, preferably about 50-120°C.

[0075] Depending on the degree of damage desired to be applied to the tissue, a safe and effective amount of the formulation and / or energy, or the dosage of the formulation and / or energy (e.g., calories / gram) applied to the tissue can be determined to produce the desired result. Generally, the higher the dosage, the higher the degree of damage the tissue will receive. The degree of damage desired to be applied to the tissue can therefore be controlled by varying the dosage of the formulation, e.g., steam or liquid, used on the tissue at the desired temperature.

[0076] To be effective, the energy dose in preferred embodiments varies from about 1 calorie / g to about 100 calorie / g, and / or the dose of the formulation in some embodiments varies from 0.2 microliters to 200 milliliters. However, these limitations are not meant to be definitive limitations on the doses used, as other delivery parameters described below (e.g., delivery rate, delivery time, etc.) may use different doses to cause the same or similar damage to tissue.

[0077] After determining the dose to be delivered to the tissue, one can determine the total amount of energy or formulation required to be delivered to the tissue by a delivery system (such as a delivery system described in the present invention). This is typically done by multiplying the dose (calories / g) by the amount of tissue to be treated (grams) to determine the amount of formulation (ml) and energy (calories) to deliver.

[0078] Typically, the delivery (or flow) rate, i.e., how quickly the delivery system delivers the formulation, determines the duration over which the formulation is delivered to generate a determined amount of energy. For example, to deliver 300 calories to a lung segment at a delivery rate of 30 calories / second, the treatment period would be 10 seconds. Delivery rates are typically from about 2 calories / second to about 200 calories / second. Again, these limitations are not meant to be definitive and delivery rates may be higher or lower depending on other treatment and / or delivery indicators.

[0079] Treatment times may vary depending on the volume, mass, and degree of injury desired to be inflicted on the tissue to be treated. Treatment times may vary from about 2 seconds to about 60 minutes. In some embodiments for inflicting injury and relieving symptoms, safe and effective treatment times are between about 4 seconds and about 30 minutes.

[0080] The delivery rate can be set by a control unit of the delivery system. Once the user sets the delivery rate, the formulation supply can establish the amount of pressure needed to deliver vapor or liquid at the desired rate by adjusting the applied pressure. Changing the delivery rate setting can induce the generator to adjust the amount of pressure in the generator. The pressure in the vapor generator can range from about 5 psi to greater than about 200 psi, and is preferably from about 10 psi to greater than 50 psi.

[0081] In some embodiments, the method of treating hypertension includes percutaneously inserting a delivery catheter into a renal artery adjacent to a nerve; delivering a formulation described herein to tissue in a body lumen adjacent to the nerve at a desired temperature, where the amount of formulation and / or heat delivered is an amount effective to injure or damage the nerve and provide a benefit, e.g., blood pressure reduction; and withdrawing the delivery catheter from the body lumen. Heat can be used to enhance the effect by accelerating the rate of reaction of the formulation with the nerve. The formulation can be a gas, vapor, liquid, solution, emulsion, or suspension of one or more components. If the formulation includes a vapor of one or more components, heat can be generated by condensing the vapor into a liquid in the tissue. If the formulation is a liquid or solution, heat can be transferred by increasing the temperature of the formulation above body temperature. The desired temperature of the formulation can range from -40 to 140°C, preferably -30 to 100°C, and most preferably -20 to 80°C. The temperature of the tissue to be treated adjacent to the nerve can be lower than the desired temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may range from -40 to 100°C, preferably from -30 to 90°C, and most preferably from -20 to 80°C. The pressure of the injected formulation may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, e.g., 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0082] In some embodiments, the method of treating pulmonary arterial hypertension includes performing an angiogram of the pulmonary artery (PA) to identify the branching level of the PA; percutaneously inserting a delivery catheter through the femoral vein to the pulmonary artery adjacent to the nerve near the PA branch; placing the front balloon of a double balloon catheter at the bifurcation site; injecting a formulation described herein at a desired temperature into tissue in a body lumen adjacent to the nerve, where the amount of formulation and / or heat delivered is an amount effective to injure or damage the nerve to produce a benefit, such as a reduction in blood pressure; and withdrawing the delivery catheter from the body lumen. The effect can be enhanced by using heat to accelerate the reaction rate of the formulation with the nerve. The formulation may include a gas, vapor, liquid, solution, emulsion, or suspension of one or more components. If the formulation includes vapor of one or more components, heat can be generated by condensing the vapor into a liquid in the tissue. If the formulation is a liquid or solution, heat can be transferred by raising the temperature of the formulation above body temperature. The desired temperature of the formulation may range from -40 to 140°C, preferably from -30 to 100°C, most preferably from -20 to 80°C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the desired temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may range from -40 to 100°C, preferably from -30 to 90°C, most preferably from -20 to 80°C. The pressure of the formulation injected may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, such as 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0083] In some embodiments, the method of treating asthma includes inserting a delivery catheter into an airway adjacent to a nerve; injecting a formulation described herein into tissue of the airway adjacent to the nerve at a desired temperature (wherein the amount of formulation and / or heat delivered is an amount effective to injure or damage the nerve and provide a benefit, e.g., relief from shortness of breath); and withdrawing the delivery catheter from the body lumen. Heat may enhance the effect by accelerating the rate of reaction between the formulation and the nerve. The formulation may 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 condensing the vapor into a liquid in the tissue. If the formulation includes a liquid or solution, heat can be transferred by raising the temperature of the formulation above body temperature. The desired temperature of the liquid formulation may range from -40 to 140°C, preferably -30 to 100°C, and most preferably -20 to 80°C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the desired temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may range from -40 to 100°C, preferably from -30 to 90°C, and most preferably from -20 to 80°C. The pressure of the injected formulation may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, e.g., 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0084] In some embodiments, the method of treating COPD includes inserting a delivery catheter into an airway adjacent to a nerve, injecting a formulation described herein into tissue in a body lumen adjacent to the nerve at a desired temperature (wherein the amount of formulation and / or heat delivered is an amount effective to injure or damage the nerve and provide a benefit, e.g., relief of COPD symptoms); and withdrawing the delivery catheter from the airway. The heat may increase the rate of reaction between the formulation and the nerve, thereby enhancing efficacy. The formulation may include a gas, vapor, liquid, solution, or suspension of one or more formulations. If the formulation includes a vapor of one or more components, heat can be generated by condensing the vapor into a liquid. If the formulation includes a liquid or solution, heat can be transferred by raising the temperature of the formulation above body temperature. The desired temperature of the formulation may range from -40 to 140°C, preferably -30 to 100°C, and most preferably -20 to 80°C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the desired temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may range from -40 to 100°C, preferably from -30 to 90°C, and most preferably from -20 to 80°C. The pressure of the injected formulation may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, e.g., 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0085] In some embodiments, the method of treating obesity includes inserting a delivery catheter into the digestive lumen adjacent to the nerve, injecting a formulation described herein into tissue in the digestive lumen adjacent to the nerve at a desired temperature (wherein the amount of formulation and / or heat delivered is an amount effective to injure or damage the nerve and result in a benefit, e.g., weight loss); and withdrawing the delivery catheter from the digestive lumen. Heat may enhance the effect by accelerating the rate of reaction between the formulation and the nerve. The formulation may 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 condensing the vapor into a liquid. If the formulation includes a liquid or solution, heat can be transferred by raising the temperature of the formulation above body temperature. The desired temperature of the liquid formulation may range from -40 to 140°C, preferably -30 to 100°C, and most preferably -20 to 80°C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the desired temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may range from -40 to 100°C, preferably from -30 to 90°C, and most preferably from -20 to 80°C. The pressure of the injected formulation may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, e.g., 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0086] In some embodiments, the method of treating a urological condition includes inserting a delivery catheter into the urinary lumen adjacent to a nerve, injecting a formulation described herein into tissue in the urinary lumen adjacent to the nerve at a desired temperature (wherein the amount of formulation and / or heat delivered is an amount effective to injure or damage the nerve and provide a benefit, e.g., urination control); and withdrawing the delivery catheter from the urinary lumen. Heat may enhance the effect by accelerating the rate of reaction between the formulation and the nerve. The formulation may 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 condensing the vapor into a liquid. If the formulation includes a liquid or solution, heat can be transferred by raising the temperature of the formulation above body temperature. The desired temperature of the liquid formulation may range from -40 to 140°C, preferably -30 to 100°C, and most preferably -20 to 80°C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the desired temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may range from -40 to 100°C, preferably -30 to 90°C, and most preferably -20 to 80°C. The pressure of the injected formulation may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, such as 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0087] In some embodiments, the method of treating cancer or tumor includes inserting a needle or a needle-based delivery catheter percutaneously into the cancer or tumor under image guidance; injecting the formulation described herein into the cancer tissue of the human body at a desired temperature, where the amount of formulation and / or heat delivered is an amount effective to injure or damage or eliminate the cancer tissue and cause a therapeutic effect, such as tumor regression or elimination; and withdrawing the delivery catheter from the body. Image guidance may include ultrasound, x-ray, CT scan, NMR imaging, scope, or a combination thereof. Examples of cancer include cancer of the adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, and uterus. Using heat to accelerate the rate of reaction of the formulation with the cancer tissue may be more effective. The formulation may 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 condensing the vapor into a liquid. When the formulation contains a liquid or solution, heat can be transferred by raising the temperature of the formulation above body temperature. The desired temperature of the formulation may be in the range of -40 to 140°C, preferably -30 to 100°C, and most preferably -20 to 80°C. The temperature of the tissue to be treated may be lower than the desired temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated may be in the range of -40 to 100°C, preferably -30 to 90°C, and most preferably -20 to 80°C. The pressure of the formulation injected may be higher than the pressure of the body cavity (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, such as 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

[0088] In some embodiments, the method of treating pain includes percutaneously inserting a needle or a needle-based delivery catheter into the painful tissue under image guidance; injecting the formulations described herein into the painful tissue of the human body, particularly the painful tissue of low back pain and cancer pain, at a desired temperature, where the amount of formulation and / or heat delivered is an amount effective to injure or damage nerve tissue or remove nerve tissue to produce a therapeutic effect, such as pain relief or remission; and withdrawing the delivery catheter from the body. Image guidance can include ultrasound, x-ray, CT scan, NMR imaging, scope, or combinations thereof. Examples of pain include pain in the head, arms, face, legs, eyes, jaw, scar, groin, adrenal glands, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, and uterus. Heat can be used to accelerate the rate of reaction between the formulation and the painful tissue, enhancing efficacy. The formulation may 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 condensing the vapor into a liquid. If the formulation includes a liquid or solution, heat can be transferred by raising the temperature of the formulation above body temperature. The desired temperature of the formulation may range from -40 to 140°C, preferably -30 to 100°C, and most preferably -20 to 80°C. The temperature of the tissue to be treated may be lower than the desired temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated may range from -40 to 100°C, preferably -30 to 90°C, and most preferably -20 to 80°C. The pressure of the formulation injected may be higher than the pressure of the body lumen (1 ATM). For example, the pressure range of the formulation injected into the target tissue may be 1 to 12 ATM, such as 1 to 8 ATM, 1 to 5 ATM, or 1 to 3 ATM.

Claims

1. a) inserting a delivery catheter into a tissue afflicted with a disease; injecting the tissue of the body at a constant temperature and pressure an amount of the formulation effective to injure or damage said tissue and to benefit the alleviation of symptoms of the disease; and b) A method of treating a disease comprising withdrawing said delivery catheter from said body, wherein said formulation interacts with said tissue.

2. 2. The method of claim 1, wherein the disease is selected from the group consisting of hypertension, diabetes, obesity, heart failure, end stage renal disease, gastrointestinal disease, urinary disease, cancer, tumors, pain, asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD).

3. 3. The method of claim 1 or 2, wherein the disease is selected from the group consisting of cancer of the head, arm, face, lower limb, eye, jaw, scar, groin, adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, and uterus.

4. 4. The method of any one of claims 1 to 3, wherein the diseased tissue is selected from the group consisting of the renal artery, a vascular lumen, a non-vascular lumen, an airway, a paranasal sinus, an esophagus, a respiratory lumen, a digestive lumen, and a urinary lumen.

5. The method of any one of claims 1 to 4, wherein the formulation comprises a gas, vapour, liquid, solution, emulsion or suspension of one or more components.

6. 6. The method of claim 5, wherein when the formulation contains vapors of one or more components, heat is generated by condensing the vapors into a liquid.

7. 6. The method of claim 5, wherein when the formulation comprises a liquid or solution, the temperature of the formulation is greater than body temperature and heat is transferred from the formulation.

8. 10. The method of claim 1, wherein the formulation comprises an emulsion or suspension, the temperature of the formulation is greater than body temperature, and heat is transferred from the formulation.

9. 9. The method according to any one of claims 1 to 8, wherein the temperature of the formulation is in the range of -40 to 140°C.

10. 10. The method of claim 9, wherein the temperature of the formulation is in the range of -30 to 100°C.

11. 10. The method of claim 9, wherein the temperature of the formulation is in the range of -20 to 80°C.

12. 9. The method according to any one of claims 1 to 8, wherein the temperature of the formulation is in the range of 0 to 140°C.

13. The method of claim 12, wherein the temperature of the formulation is in the range of 20 to 100°C.

14. The method of claim 12, wherein the temperature of the formulation is in the range of 30 to 80°C.

15. The method according to any one of claims 1 to 8, wherein the temperature of the formulation is in the range of -40 to 0°C.

16. 16. The method of claim 15, wherein the temperature of the formulation is in the range of -30 to -10°C.

17. 16. The method of claim 15, wherein the temperature of the formulation is in the range of -20 to -30°C.

18. The method according to any one of claims 1 to 8, wherein the temperature of the formulation is room temperature.

19. The method according to any one of claims 1 to 8, wherein the temperature of the formulation is body temperature.

20. The method of any one of claims 1 to 19, wherein the temperature of the tissue is different from the temperature of the formulation.

21. 21. The method of claim 20, wherein the temperature of the tissue is lower than the temperature of the formulation.

22. 21. The method of claim 20, wherein the temperature of the tissue is greater than the temperature of the formulation.

23. 20. The method of any one of claims 1 to 19, wherein the temperature of the tissue is in the range of -40 to 100°C.

24. 24. The method of claim 23, wherein the tissue temperature is in the range of -30 to 80°C.

25. 24. The method of claim 23, wherein the tissue temperature is in the range of -20 to 80°C.

26. 20. The method of any one of claims 1 to 19, wherein the temperature of the tissue is in the range of -40 to 0°C.

27. 27. The method of claim 26, wherein the tissue temperature is in the range of -10 to -35°C.

28. 24. The method of claim 23, wherein the temperature of the tissue is in the range of -20 to -30°C.

29. The method of any one of claims 1 to 19, wherein the temperature of the tissue is body temperature.

30. 30. The method of any one of claims 1 to 29, wherein the pressure of the formulation is about 1 to 12 ATM at a temperature of about -40 to 150°C.

31. 30. The method of any one of claims 1 to 29, wherein the pressure of the formulation is in the range of 1 to 12 ATM.

32. 32. The method of claim 31, wherein the pressure of the formulation is in the range of 1 to 8 ATM.

33. 32. The method of claim 31, wherein the pressure of the formulation is in the range of 1 to 5 ATM.

34. 32. The method of claim 31, wherein the pressure of the formulation is in the range of 1 to 3 ATM.

35. The method of claims 1-29, wherein the pressure of the formulation is greater than the pressure of a body cavity or tissue.

36. 36. The method of any one of claims 1 to 35, wherein the volume of the formulation ranges from 0.2 microliters to 200 milliliters.

37. 37. The method of any one of claims 1 to 36, wherein the treatment time is between about 2 seconds and about 60 minutes.

38. 38. The method of any one of claims 1 to 37, wherein the amount of heat or energy delivered from the formulation is between about 2 calories / g and about 150 calories / g.

39. 39. The method of any one of claims 1 to 38, wherein the delivery catheter is a needle-based delivery catheter, a balloon catheter, a balloon catheter, an injection catheter, or a combination thereof.

40. 40. The method of claim 39, wherein the balloon catheter comprises a single balloon delivery catheter or a double balloon delivery catheter.

41. 41. The method of any one of claims 1-40, wherein the formulation of one or more components comprises 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 and combinations thereof.

42. 42. The method of any one of claims 1 to 41, wherein the formulation comprises a gas or vapor 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.

43. The method of any one of claims 1 to 42, wherein the formulation comprises a therapeutic agent for denervation.

44. 44. The method of claim 43, wherein the therapeutic agent is selected from the group consisting of 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.

45. The method of any one of claims 1 to 44, wherein the formulation comprises an imaging agent for imaging the denervation procedure.

46. 46. ​​The method of claim 45, wherein the contrast agent is selected from the group consisting of iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan, iodixanol, ioxaglate, and derivatives thereof.

47. 47. The method of any one of claims 1 to 46, wherein the formulation comprises an azeotrope, which is a mixture of two or more components whose components cannot be altered by simple distillation.

48. 48. The method of claim 47, wherein the azeotrope is selected from the group consisting of 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.

49. 47. The method of any one of claims 1 to 46, wherein the formulation comprises 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, acetic acid / water, acetic acid / water / oxygen, acetic acid / water / air, acetic acid / water / ethanol, acetic acid / water / contrast agent, acetic acid / water / contrast agent / surfactant, acetic acid / water / ethanol / contrast agent, acetic acid / water / ethanol / contrast agent / surfactant, lactic acid / water, lactic acid / water / ethanol, lactic acid / water / contrast agent, lactic acid / water / contrast agent / surfactant, lactic acid / water / ethanol / contrast agent, lactic acid / water / ethanol / contrast agent / surfactant, ethyl lactate / water, ethyl lactate / ethanol, lactic acid / ethanol / water, ethyl lactate / water / ethanol, ethyl nitrate / ethanol, or isopropyl acetate / ethanol.

50. 1. A method for treating a disease by combined thermal and chemical ablation, comprising: a) inserting a delivery catheter into a body lumen adjacent to a nerve; b) delivering an amount of energy and / or a compound at a desired temperature to said nerve tissue in said body lumen that will damage or injure said nerves and benefit the alleviation of symptoms of said disease; and c) withdrawing the delivery catheter from the body lumen. A method for treating a disease, comprising:

51. 51. The method of claim 50, wherein the energy is selected from the group consisting of radiofrequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound.

52. 51. The method of claim 50, wherein the thermal ablation is selected from the group consisting of radiofrequency, freeze-thaw, microwave, laser, ultrasound, and high intensity focused ultrasound ablation.

53. 53. The method of any one of claims 50 to 52, wherein the formulation is injected into the neural tissue before, during or after the delivery of the energy.

54. 53. The method of any one of claims 50 to 52, wherein the formulation is injected into the neural tissue before, during, or after the thermal ablation.

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