Chemical ablation and method of treatment for various diseases

Abstract

To provide a device and a method for treating at least one of hypertension, pulmonary arteries, diabetes, obesity, heart failure, end-stage renal disease, digestive disease, urological disease, cancers, tumors, pain, asthma or chronic obstructive pulmonary disease by delivering an effective amount of a formulation to a tissue.SOLUTION: In embodiments of the present invention, the formulation may include at least one of a gas, a vapor, a liquid, a solution, an emulsion or a suspension of one or more ingredients. In embodiments of the present invention, amounts of the formulation and / or energy are effective in injuring or damaging tissue, nerves and nerve endings in order to relieve disease symptoms.SELECTED DRAWING: Figure 3B

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority based on U.S. Provisional Patent Application No. 62 / 122,818, filed on October 30, 2014, U.S. Provisional Patent Application No. 62 / 124,868, filed on January 5, 2015, and U.S. Provisional Patent Application No., and the disclosures thereof are incorporated herein by reference in their entirety.

[0002] (Field of the Invention) Embodiments of the present invention relate to chemical injection devices, formulations, and methods for the treatment of hypertension, pulmonary hypertension, diabetes, obesity, heart failure, end - stage renal disease, gastrointestinal diseases, cancer, tumors, pain, asthma, and chronic obstructive pulmonary disease (COPD). The devices may include combinations of balloons and infusion catheters, and other delivery devices. The formulations may include gases, vapors, liquids, solutions, emulsions, and suspensions of one or more components. The methods include the delivery of a formulation to a target tissue in a human body by chemical injection.

Background Art

[0003] Hypertension, or high blood pressure, is a major global health concern. An estimated 30 - 40% of the adult population worldwide suffers from this condition. Furthermore, the prevalence is predicted to increase, particularly in developing countries. The diagnosis and treatment of hypertension remain sub - optimal, and many patients struggle to manage their blood pressure appropriately.

[0004] Benign prostatic hyperplasia is a non - cancerous enlargement of the prostate gland, which affects more than 50% of men over 60 years of age. When young, the prostate is approximately the size of a walnut, weighing about 20 grams. The enlargement of the prostate over time is considered normal. With age, the prostate gradually increases to at least twice its original size. Prostatic hyperplasia generates pressure on the adjacent urethra, causing stenosis of the subsequent organ and ultimately urinary tract obstruction, making urination difficult.

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

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

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

[0008] Diabetes is a metabolic disorder or combination of disorders in which an individual experiences high blood glucose levels. This condition is caused by either insufficient insulin production in the body or the cells' failure to respond appropriately to insulin. Glycated hemoglobin (HbA1c) serves as a marker of plasma glucose concentration and is clinically used for the diagnosis of diabetes. In humans, normal HbA1c levels are typically <6.0%, prediabetes HbA1c levels are in the range of 6.0 - 6.4%, and diabetes HbA1c levels are above 6.5%.

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

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

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

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

[0013] Obesity is another significant health concern, particularly in developed countries. It is a complex and multifactorial chronic condition characterized by excessive body fat, which results from an imbalance between energy consumption and calorie intake. The causes of this imbalance are not fully understood, but genetic and / or physiological events and environmental factors are thought to contribute. The adverse health effects associated with obesity and more specifically morbid obesity have been established in recent years. These adverse effects include, but are not limited to, cardiovascular disease, diabetes, hypertension, arthritis, and sleep apnea. Generally, as a patient's body mass index (BMI) increases, so does the likelihood of experiencing adverse effects associated with obesity.

Summary of the Invention

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

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

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

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

[0018] In one embodiment, at least one component of the formulation is a surfactant. Surfactants include PEG laurate, Tween20, Tween40, Tween60, Tween80, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl laurate-6, polyglyceryl oleate-6, polyglyceryl myristate-6, polyglyceryl palmitate-6, polyglyceryl laurate-10, polyglyceryl oleate-10, polyglyceryl myristate-10, polyglyceryl palmitate-10, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, organic acids, salts of any organic acid and organic amine, polyglycidol, glycerol, polyglycerol, galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol) oligomers, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol), penta(propylene glycol), poly(propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, Pluronic, Pluronic 85, and derivatives thereof and combinations thereof.

[0019] In one embodiment, the formulation comprises at least an oil, a fatty acid and / or a lipid. In some embodiments, at least the oil, fatty acid and / or lipid in the formulation is selected from butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di- or triacylglycerol, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alpha tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoyl phosphatidylcholine, dioleoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobi, niosome, and derivatives thereof.

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

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

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

[0023] In one embodiment, the formulation is in a liquid state and contains one or more components. The liquid formulation can include one of water, physiological 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, a surfactant, etc. The liquid formulation can contain an azeotropic mixture, a contrast agent, and / or a therapeutic agent. In one embodiment, the formulation can contain one of two, three, or four components and can also contain four or more components. In some embodiments, the liquid formulation temperature can be in the range of -40°C to 140°C, -30°C to 100°C, or -20°C to 80°C. The liquid formulation can include solutions, suspensions, and emulsions.

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

[0025] Both the foregoing general description and the following detailed description are exemplary and explanatory only and are not to be construed as limiting the invention described in the claims.

Brief Description of the Drawings

[0026]

Figure 1

[0027]

Figure 2

[0028]

Figure 3A

[0029]

Figure 3B

[0030]

Figure 4A

[0031]

Figure 4B

[0032]

Figure 5A

[0033]

Figure 5B

[0034]

Figure 5C

[0035]

Figure 6

[0036]

Figure 7

[0037]

Figure 8A

[0038]

Figure 8B

[0039]

Figure 9A

[0040]

Figure 9B

[0041]

Figure 9C

[0042]

Figure 10A

[0043]

Figure 10B

[0044]

Figure 11

[0045]

Figure 12

[0046]

Figure 13

[0047]

Figure 14

[0048]

Figure 15

[0049]

Figure 16

Mode for Carrying Out the Invention

[0050] Embodiments of the present invention relate to the treatment of diseases by delivering an effective amount of a formulation to a target tissue in a body cavity. The disease can be one of hypertension, pulmonary hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive diseases, cancer, tumors, pain, asthma or chronic obstructive pulmonary disease (COPD). Cancers include those of the adrenal gland, bladder, neck, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach and uterus. The formulation includes gases, vapors, liquids, solutions, emulsions and suspensions of one or more components. The method includes delivering the formulation to the luminal surface, tissue and nerves in the human body to modify the surface, tissue and nerves. Body cavities include renal arteries and veins, pulmonary arteries, vascular lumens, celiac arteries, common hepatic arteries, proper hepatic arteries, duodenal arteries, right hepatic arteries, left hepatic arteries, splenic arteries, right gastric arteries, left gastric arteries, blood vessels, non-vascular lumens, airways, nasal sinuses, esophagus, respiratory lumens, digestive lumens, stomach, duodenum, jejunum, cancerous tissue, tumors and urinary lumens. Digestive lumens include the esophagus, stomach, duodenum, jejunum, small intestine and large intestine, and the colon. Temperature can improve the safety and effectiveness of the treatment formulation. The temperature can be in the range of -40°C to 140°C, -30°C to 100°C or -20°C to 80°C. The temperature of the tissue being treated can be different from the formulation temperature. The temperature of the tissue being treated can be in the range of -40°C to 100°C or -30°C to 80°C. The amount of formulation and energy delivered is effective to damage, injure or remove diseased tissue, for example, by reducing blood pressure, shrinking tumors, relieving pain, or relieving symptoms of asthma and COPD. Energy or heat can improve the injury / damage / removal effect by accelerating the reaction rate between the formulation and the tissue. The delivery method includes delivering the formulation to excise nerves surrounding the human body cavity. The method includes removing or withdrawing the formulation from the tissue or lumen after treatment.

[0051] In one embodiment, the formulation is one chemical or one of two, three, or four components and may also include four or more components. In one embodiment, the delivery system may include a less invasive transdermal approach or a non-invasive approach. Embodiments of the present invention include formulations that modify the surface of a body cavity and include one or more components that improve both absorption and penetration into the tissue, nerves, and nerve endings of the body cavity.

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

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

[0054] In one embodiment, the components in the formulation include a surfactant. In some embodiments, the surfactant is selected from 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 laurate-6, polyglyceryl oleate-6, polyglyceryl myristate-6, polyglyceryl palmitate-6, polyglyceryl laurate-10, polyglyceryl oleate-10, polyglyceryl myristate-10, polyglyceryl palmitate-10, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, organic acids, salts of any organic acid and organic amine, polyglycidol, glycerol, polyglycerol, galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol) oligomers, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol), penta(propylene glycol), poly(propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, Pluronic, Pluronic 85, and their derivatives and combinations thereof. In some embodiments, the content of the surfactant in the formulation can range from 0.1 wt% to 80 wt%, from 0.5 wt% to 50 wt% or from 1 wt% to 15 wt%.

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

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

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

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

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

[0060] In one embodiment, the formulation is in a liquid state and contains one or more components. The liquid formulation contains one of water, physiological 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, surfactant, etc. In one embodiment, the liquid formulation contains a contrast agent and / or an azeotropic mixture and may also contain a therapeutic agent. In one embodiment, the liquid formulation is one of a two-component, three-component or four-component and may also contain four or more components. In one embodiment, the liquid formulation contains a solution, an emulsion or a suspension. The liquid formulation temperature can be in the range of -40°C to 140°C, -30°C to 100°C or -30°C to 80°C. In one embodiment, the formulation temperature can be at room temperature. In one embodiment, the formulation temperature can be in the range of -40°C to -20°C. In another embodiment, the formulation temperature can be in the range of 15°C to 80°C. In one embodiment, the formulation temperature may be equal to body temperature. In another embodiment, the formulation temperature can be in the range of 50°C to 80°C.

[0061] In one embodiment, a method for treating a disease comprises percutaneously or orally inserting a delivery catheter into the body; using the catheter to inject a formulation into diseased tissue or a body lumen in the body; optionally removing or withdrawing the formulation from the diseased tissue or body cavity; and finally withdrawing the delivery catheter from the body. Diseases for treatment include hypertension, pulmonary hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive diseases, urinary diseases, cancer, tumors, pain, asthma, and chronic obstructive pulmonary disease (COPD). Cancers include those of the adrenal gland, bladder, neck, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, and uterus. Body lumens include the renal artery, vascular lumen, celiac artery, common hepatic artery and proper hepatic artery, gastroduodenal artery, right and left hepatic arteries, splenic artery, right and left gastric arteries, non-vascular lumen, airway, nasal cavity, esophagus, respiratory lumen, digestive lumen, stomach, duodenum, jejunum, and urinary lumen. Digestive lumens include the esophagus, stomach, duodenum, jejunum, small intestine and large intestine, and colon. The formulation includes a gas, vapor, liquid, solution, emulsion, and suspension of one or more components. In embodiments where the formulation includes a vapor of one or more components, heat can be generated in the tissue by condensation of the vapor to a liquid. In embodiments where the formulation includes a liquid or solution, cooling or heat can be generated from a formulation temperature below or above body temperature. The liquid formulation temperature can range from -40°C to 140°C, -30°C to 100°C, or -30°C to 80°C. In one embodiment, the temperature of the tissue being treated, unlike the formulation temperature, can be lower or higher than body temperature. The temperature of the tissue being treated can range from 15°C to 100°C, 20°C to 90°C, or 36°C to 80°C. In another embodiment, the temperature of the tissue being treated can range from -40°C to -20°C. In some embodiments, the delivery catheter is a needle or needle-based catheter under an imaged guide. The imaged guide is one of ultrasound, X-ray, CT scan, MRI, OCT, or a scope. The delivery catheter can also be balloon- or injection-based. The balloon-based catheter can have single, double, or triple balloons. The injection catheter can have a dumbbell balloon.Typically, there are three parts of the dumbbell injection balloon: proximal, distal, and central. The central part has a small diameter with or without injection holes, and the proximal and distal parts of the balloon have a larger diameter without injection holes. When the central part of the dumbbell balloon has holes (Figs. 3A and 3B), the injection is from an inflatable catheter component and is defined as an inflatable injection method. The initial injection pressure can range from 0.1 atm, to 14 atm, 1 atm to 10 atm, or 3 atm to 8 atm depending on the application. The injection time can range from 0.1 minute to 2 hours, 0.5 minute to 30 minutes, or 1 minute to 10 minutes. During the injection time following the initial injection pressure, the balloon pressure can range from 0.1 atm to 3 atm, 0.1 atm to 2 atm, and 0.3 atm to 1 atm. The formulation injection temperature can range from -40°C to 150°C, -30°C to 100°C, or -20°C to 80°C.

[0062] In one embodiment, the injection feature is made from a hypo tube / tube, both of which are composed of plastic or metal and are attached to a non-porous dumbbell-shaped balloon catheter. The treatment formulation is delivered through the holes on the hypo tube / tube, and when the hypo tube / tube is moving towards the blood vessel wall together with the balloon, the injection is from a non-inflatable catheter component; this injection is defined as a hybrid method that includes a combination of non-inflatable and inflatable injection methods. Typically, the hole part of the hypo tube / tube is aligned along the central part of the dumbbell balloon to adjust the outflow position of the formulation.

[0063] In another embodiment, the injection lumen can be disposed inside the catheter shaft, for example, in a multi-lumen shaft for a non-inflatable injection method. In this case, the holes are disposed in the non-inflatable part between the balloons on the shaft (Figs. 7, 8A - 8B, 9A - 9C). More detailed examples of the device, such as double balloon and triple balloon injection catheters, are shown in the following section.

[0064] In one embodiment, the metal hypodermic tube may have the characteristics of a Bard triangle, which improves the diffusion of the formulation by creating extremely small holes inside the blood vessel wall or in the tissue. The height of the Bard triangle can range from 0.25 to 2 mm. This injection method is a hybrid method.

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

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

[0067] In another embodiment, the formulation is a vapor mixture containing water, ethanol, and oxygen. In another embodiment, the formulation is a vapor mixture containing water, ethanol, and air. In another embodiment, the formulation is a vapor mixture containing water, ethanol, oxygen, and nitrogen. Formulations with oxygen and air are particularly useful in the treatment of asthma and COPD.

[0068] In another embodiment, the formulation is a mixture of water, ethanol, and iodine vapor, where an effective amount of iodine vapor is included such that the mixture of vapor can be imaged on the body cavity wall. In another embodiment, the formulation is a mixture of water, ethanol, and a surfactant in liquid form. In another embodiment, the formulation is a mixture of water, ethanol, and a contrast agent in liquid form, where an effective amount of the contrast agent is included such that the mixture can be tracked on the body cavity wall by X-rays. The contrast agent is one of iodine, ethyl iodide, sodium iodide, lipiodol, nonoxinol iodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan, iodixanol, ioxaglate, and derivatives thereof. The content of the contrast agent in the formulation can range from 2 to 20 wt% or 5 to 15 wt%.

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

[0070] In another embodiment, the formulation is a liquid mixture comprising ethanol and LIPIODOL ULTRA-FLUIDE, wherein an effective amount of LIPIODOL is included such that it can image the vapor mixture at the body cavity wall and damage the target nerve tissue. The LIPIODOL content of the formulation can range from 10 wt% to 80 wt%, 15 wt% to 75 wt% or 20 wt% to 50 wt%. In another embodiment, the formulation is a liquid mixture comprising water and LIPIODOL. The LIPIODOL content of the formulation can range from 10 wt% to 80 wt%, 15 wt% to 75 wt% or 20 wt% to 50 wt%. In another embodiment, the formulation is a liquid mixture comprising acetic acid and LIPIODOL. The LIPIODOL content in the formulation can range from 10 wt% to 80 wt%, 15 wt% to 75 wt% or 20 wt% to 50 wt%.

[0071] In one embodiment, the delivery catheter is used in an invention for injecting the formulation into human tissue. The delivery catheter is a needle or needle-based catheter under an X-ray or ultrasound-imaged guide. The delivery catheter can be a balloon based on single, double or triple balloons. The delivery catheter can also be injection-based. A combination of a balloon and an injection catheter can be used in the procedure. The balloon in the injection system should be able to confine the formulation within the balloon wall and appropriately control the amount of the formulation.

[0072] In one embodiment, an inflatable balloon catheter is used in an invention for the delivery of an active agent to a target location within a patient's body cavity, where the inflatable balloon catheter includes a proximal end, a distal end, a wire, a lumen, a balloon inflation lumen, a formulation injection lumen and / or a vacuum lumen, an inflatable balloon portion and a non-inflatable shaft portion, the inflatable balloon portion includes at least one part, the non-inflatable shaft portion includes at least one part, a first part of the inflatable portion and / or the non-inflatable portion has a plurality of voids, the voids are microholes, and at least one second part of the inflatable portion and / or the non-inflatable shaft portion has no voids. The inflatable or non-inflatable portion of the inflatable balloon catheter has at least one void that allows the permeation of a formulation to a body cavity wall at a pressure higher than that of the body cavity. The inflatable or non-inflatable portion has no voids that allow the balloon to inflate a body cavity at a pressure higher than that of the body cavity.

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

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

[0075] The materials of balloons 20 and 21 are composed of one of polyester, polyamide, nylon 12, nylon 11, polyamide 12, a block copolymer of polyether and polyamide, Pebax, polyurethane, or a block copolymer of polyether and polyester. The diameter of balloon 21 is less than or equal to that of balloon 20.

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

[0077] The volume / surface area ratio can be in the range of 0.1 mm to 10 mm, 0.2 mm to 5 mm, or 0.3 mm to 2 mm. The dosage of the chemical can thereby be constant and independent of the balloon or blood vessel size. The value of the ratio is determined by the clinical treatment necessity (dosage requirement). The dumbbell balloon or multi-groove balloon can be fabricated from a secondary heat-shrinking process including a regular cylindrical balloon or by direct molding into the shape. The diameters of the different balloon bodies between the large-diameter end and the central small-diameter part are determined by the pre-measured volume / surface area ratio value calculated using Equation 1. For example, for a combination of 6 mm and 8 mm balloons, the calculated volume / surface area ratio is 0.88 mm.

[0078] The overall diameter and length of the balloon body can each be in the range of 2 to 40 mm and 10 to 100 mm, respectively. Conventional balloon cone angles or shapes are acceptable for applications, but circular or radius cone shapes are preferred.

[0079] Any balloon material compatible with the formulation can be used for balloon fabrication, including, for example, polyethylene, polyolefin elastomers, natural rubber, polyesters such as PET and PBT, and their block copolymers including thermoplastic elastomers such as Hytrel, and polyamides such as nylon 12 and nylon 11, and their block copolymers including thermoplastic elastomers such as Pebax.

[0080] In one embodiment, a schematic view of a dumbbell balloon infusion catheter is shown in FIG. 3A, with four holes arranged at 90-degree intervals in the central small-diameter balloon portion, which is modified from FIG. 2 with a tapered transition between different diameters. The liquid formulation can be delivered from the balloon inflation lumen through the holes on the balloon; this is an inflatable infusion method. In this example, the formulation functions in two roles: inflating the balloon and acting as a treatment agent. FIG. 3B is a schematic view of an infusion balloon catheter positioned in the inflated position inside a blood vessel. Most of the treatment formulation to be delivered is confined in the space created by the smaller balloon body and the two larger balloon shoulders within the vessel wall.

[0081] To improve the diffusion distance of the chemical treatment agent, the ratio of balloon outer diameter (OD) to blood vessel inner diameter (ID) is greater than 1 at a specific control level that can be used. The ratio can be in the range of 1.01 - 10, 1.10 - 5, or 1.20 - 1.35.

[0082] The fine holes on the balloon for delivering the chemical can be made by directly micropunching or drilling the wall of the balloon body. Suitable hole sizes can range from 5 microns to 500 microns or from 20 microns to 250 microns on the balloon wall. These values appropriately consider the balance among balloon inflation, infusion rate, and formulation flow control. If the hole size is too large, the amount of formulation may not be controllable due to over-flow. Geometrically, the holes are typically arranged in the central part of the small-diameter area; however, for the purpose of delivering the formulation, they can be arranged in different ways or patterns on the balloon. The holes on the balloon can be arranged along the circumference of the wall of the balloon body at the center of the small-diameter part. The number of holes can range from 2 to 10 or more, and the size of the holes can range from 25 microns to 100 microns.

[0083] The dumbbell balloon of FIG. 3A can be considered as one grooved balloon having four evenly distributed holes in the circumference, and the above balloon embodiments include a plurality of grooves on the balloon, and each groove has its own set of holes for injection. For example, a 3-groove balloon can be made from an 80 mm long balloon, and the injectate can be confined within each groove. When the individual volume / surface area ratios are equal, the clinical results of the multi-groove balloon are the same as those of the regular dumbbell balloon shown in FIG. 3A. FIG. 3A is a device for an inflatable injection method.

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

[0085] In order to incorporate the injection tube in the embodiment shown in FIGS. 4A-4B, balloon inflation and formulation injection occur by separate independent procedures. For example, first the balloon is inflated to a predetermined pressure; then an effective amount of the chemical is delivered through the tube to the treatment site while the remainder of the formulation is confined to the central portion of the balloon small diameter area. The injection tube used on the catheter can be made from a thermoplastic material, such as polyethylene, nylon or Pebax, or a metal or alloy, such as stainless steel or nitinol, or a nitinol hypo tube, because of its excellent male characteristics.

[0086] The advantages of using a metal or alloy tube over a plastic tube are the presence of additional features for drug delivery. For example, the Bard triangle feature can be added to the metal tube (Figure 15). When the balloon expands against the vessel wall, the sharp tip of the Bard triangle helps to pinch into the tissue wall. Compared to the round hole type, this delivery system allows for deeper diffusion of chemicals into the vascular tissue due to tissue perforation. When deeper diffusion over a wider vascular wall area is required, the balloon can be inflated and deflated several times and rotated after each injection / deflation cycle. This allows for further holes to be made in the vessel wall and enables the drug to diffuse deeper and faster. The height of the Bard triangle can range from 0.25 mm to 2 mm or from 0.5 mm to 1 mm.

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

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

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

[0090] The delivery system 198 of FIGS. 5A and 5B includes an intraluminal elongate assembly 200 connected to a controller 202. The elongate assembly 200 can be delivered to the trachea 20 or navigated within or through the bronchial tree 27, with or without using a delivery assembly. The elongate assembly 200 includes a distal tip 203 that can selectively affect tissue.

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

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

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

[0094] In one embodiment, a method for the treatment of hypertension comprises inserting a delivery catheter percutaneously into a renal artery and / or an extra-renal artery adjacent to a nerve and nerve endings; using the delivery catheter to inject the formulation into the tissue of the body cavity adjacent to the nerve, wherein the amount of the formulation delivered is effective to damage the nerve or nerve endings, for example by reducing blood pressure; and finally withdrawing the delivery catheter from the body cavity.

Example

[0095] In one embodiment, a balloon injection catheter, such as shown in FIGS. 3A - 3B, 4A - 4B, 7, 8A - 8B, and 9A - 9C, can be used for the treatment of hypertension. Examples of preclinical trials in this embodiment are described below.

[0096] In one example, a 47 kg pig animal was anesthetized with isoflurane, and one side of the renal artery was ablated with ethanol using a balloon catheter, while the opposite renal artery was used as a control. Using standard renal access procedures, a balloon injection catheter was placed in sequence by wire into the target renal arteries of the main kidney and the extra-renal branches. When the target ablation site was reached, the balloon inflated and chemical ablation of the renal artery with absolute ethanol was performed by an inflatable injection method. The balloon diameter was determined according to renal angiography, and a total of four catheters were used. During the ablation procedure, the balloon first rapidly inflated with ethanol to 6 - 8 atm, then was lowered to 0.5 - 1 atm and maintained at the lower pressure for about 60 seconds. By the end of the treatment time, the balloon was deflated and withdrawn, or placed at another arterial site if required for the next treatment.

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

[0098] Postoperative renal angiography was obtained to determine whether vasospasm, stenosis, or other abnormalities occurred. There was no significant renal artery spasm during and after the balloon injection procedure.

[0099] The animals were euthanized 2 weeks after the procedure, and kidney tissue samples were obtained from the cranial, central, and caudal portions of the kidney cortex, and the renal tissue norepinephrine (NE) content was measured using a known HPLC method. Norepinephrine is a neurotransmitter whose level is used as a standard measurement for renal denervation. The renal artery and surrounding tissue were similarly harvested for histopathological evaluation. Ethanol ablation of the renal artery resulted in a 72% decrease in renal norepinephrine (NE content: control: 570 ng / g; denervated kidney, i.e., RDN: 160 ng / g), as shown in Figure 12.

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

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

[0102] Six pig animals weighing 44 - 56 kg were divided into three treatment subgroups, with 2 animals treated in the main renal artery, 2 animals treated in the external renal branches, and 2 animals treated in both the main renal artery and the external renal branches. For each animal, one side of the renal artery was treated, while the contralateral renal artery was used as a control. Standard renal access procedures were performed.

[0103] During the procedure, the balloon size was determined according to a balloon OD / artery ID ratio in the range of 1.20 - 1.35. This value provided good treatment efficacy and minimal vascular injury by controlling overexpansion. The inflation pressure used in this study during the rapid inflation cycle was 10 - 12 atm; the pressure was then lowered to 0.5 - 1 atm and the treatment was maintained at a lower pressure for 2 minutes at the main renal artery site and for 1 minute at the extra-renal arterial branches. Renal angiography showed no significant renal artery spasm during and after balloon injection treatment in all six pig animals of this study.

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

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

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

[0107] In one embodiment, a cross-sectional view of the distal portion of a triple-balloon injection catheter is depicted as shown in FIG. 7. This injection device can provide a uniform filling at the treatment site. The balloons in FIG. 7 are shown in an inflated state and have D1 and D3 of two large-diameter balloons at the distal and proximal ends and one small-diameter balloon (D2) in the center. The combination of balloon diameters is determined by Equation 1 using a predetermined ratio value according to the clinical dosage requirements. The combination of balloon lengths depends on the target vessel length and tortuosity.

[0108] One design is for a four-lumen shaft that acts as an injection catheter. The four lumens can be assigned, for example, as shown in FIG. 1, to a wire (1), balloon inflation (1), and chemical treatment (2). Alternatively, the catheter can be designed to have more lumens to accommodate more injection lumens if each balloon can be inflated independently.

[0109] The chemical treatment port is disposed between the balloons on the shaft. The formulation injection holes are disposed in the non-expandable shaft portion between the expandable balloon portions. During treatment, the formulation can be discharged between the balloons through the injection holes to fill the space created by the small-diameter balloon. This is a non-expandable injection method.

[0110] In one embodiment, optionally, residues of the chemical / drug formulation can be recovered by aspiration techniques at one of the injection holes after treatment. In this case, at least two treatment lumens can be used: one for injection and the other for aspiration. The formulation injection and aspiration holes are disposed in the non-expandable shaft portion between the expandable balloon portions.

[0111] In addition to withdrawing excess treatment agent, excess drug can also be diluted with saline or water to ineffective concentrations. The flushing with saline or water can be carried out using one of the catheter wire lumens or injection lumens, or by other means. The method of use depends on the site of protection or treatment. If the distal portion of the blood vessel requires protection from chemical treatment, the flushing can be done by the wire lumen.

[0112] In one embodiment, as shown in FIG. 8A, a new and non-conventional balloon attachment method can be applied. The new method includes placing the balloon waist inside the balloon cone or body; this helps to overcome the extra unwanted space surrounding the small-diameter balloon and is created by the length of the balloon waist and the length of the cone as shown in FIG. 7. The extra space does not benefit the chemical treatment and can result in overdosage as the therapeutic dose cannot be controlled. The formulation injection and aspiration holes are located in the non-expandable shaft portion between the expandable balloon portions.

[0113] To demonstrate the effectiveness of the new assembly when extra space is minimized, a similar balloon diameter combination was used (Figure 8A vs. Figure 7). L(ii) represented in Figure 8A is either L(i) or L(ii). In the inflated state, the cones of adjacent balloons are in closer contact with each other here, thereby minimizing extra space. Also, the formulation is delivered between the balloons, filling the space above the small-diameter balloon portion / area.

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

[0115] In a plurality of balloon assemblies on a catheter, balloons having the same L(i) can also have the same L(ii) or different ones.

[0116] In another embodiment, a regular cone-shaped balloon can be used for this catheter. However, since the cone length is short and the contact surface area between adjacent cones may be larger, circular or semi-circular cone balloons can also be used.

[0117] In one embodiment, as shown in Figure 8B, the balloon can be attached onto the shaft by placing the balloon waist upside down inside the balloon waist or partially inside the balloon body. The upside-down balloon waist makes the balloon cone rounder more naturally and allows for a larger contact surface area between the cones; also, the waist can be more easily placed inside the balloon body.

[0118] In one embodiment, when a narrow treatment band or a shorter overall balloon length is required, a double balloon combination is used. FIG. 9A shows two balloons with adjacent cones in contact in the inflated state. Chemicals can be delivered through delivery ports on the shaft located between the two balloons. Formulation injection and / or aspiration holes are located in the non-inflatable shaft portion between the inflatable balloon portions. The chemicals can remain in the narrow portion in the middle of the two balloons during the procedure. Optionally, additional ports may be available for flushing or aspiration purposes. The two balloons on the catheter may also have their own injection lumens and can thus inflate independently.

[0119] In another embodiment, as shown in FIGS. 9B-9C, a dual-diameter balloon can be used on an injection catheter to achieve a wider treatment length despite a shorter overall balloon length. This balloon has two diameters, one smaller than the other. Using the same assembly technique as the three-balloon arrangement, the dual-diameter balloon is attached to the shaft with the smaller diameter sides assembled head-to-head to form the smaller diameter central portion. The two ends of the larger diameter portion mainly confine the chemicals to the central smaller diameter portion to achieve a controlled amount of delivery. Formulation injection and / or aspiration holes are located in the non-inflatable shaft portion between the inflatable balloon portions. Also, the formulation is delivered through an injection hole in the shape of a non-inflatable shaft portion between the two inflatable balloon portions.

[0120] One of the dual-diameter balloons is the tapered balloon shown in FIG. 9B. This two-balloon configuration has a smaller diameter end located at the center of the two balloons facing head-to-head with each other. The overall diameter of the resulting central portion is smaller than the diameter of the ends.

[0121] As shown in FIG. 9C, another dual-diameter balloon is assembled from a two-stage balloon. One balloon has two different diameters, i.e., one side of the balloon is larger than the other; there is a sharp diameter change between the two diameters. The two-stage balloon can be assembled with the small-diameter sides facing each other to form the center of the whole balloon. The stepped balloon can provide a wider treatment length as shown in FIG. 9B, despite having the same overall balloon length.

[0122] Figures 10A and 10B illustrate the balloon injection catheter 365 being positioned in the gastric artery 360 or the hepatic artery 320. Figures 10A and 10B show the various arteries surrounding the liver and stomach, as well as the various nervous systems innervating the liver and stomach and the surrounding organs and tissues. The arteries surrounding the liver and stomach include the abdominal aorta 305, the celiac artery 310, the common hepatic artery 315 and the proper hepatic artery 320, the duodenal artery 322, the right hepatic artery 325 and the left hepatic artery 330, the splenic artery 335, and the esophageal branch 361. The various nervous systems innervating the liver and stomach and the surrounding organs and tissues include the celiac plexus 340 and the hepatic plexus 345. The blood supply to the liver is sent from the heart to the aorta and then descends through the abdominal aorta 305 to the celiac artery 310. From the celiac artery 310, the blood moves through the common hepatic artery 315 to the proper hepatic artery 320 and then through the right hepatic artery 325 and the left hepatic artery 330 to the liver. The common hepatic artery 315 branches from the celiac artery and gives rise to the gastroduodenal artery. The nerves innervating the liver include the celiac plexus 340 and the hepatic plexus 345. The celiac plexus 340 wraps around the celiac artery 310 and continues as the hepatic plexus 345, which wraps around the proper hepatic artery 320 and the common hepatic artery 315 and / or continues along the right hepatic artery 325 and the left hepatic artery 330. In some anatomical structures, the celiac plexus 340 and the hepatic plexus 345 adhere tightly to the arterial wall and supply blood to the liver, thereby particularly facilitating intra-to-extra-vascular neuromodulation. In some embodiments, the medial thickness of the blood vessel (e.g., the hepatic artery) ranges from about 0.1 cm to about 0.25 cm. In some embodiments, the formulation can be delivered to the inner wall of the target blood vessel or target nerve. Since the nerve adheres tightly to the outer wall of the artery and thereby supplies blood to the liver, intravascular delivery can be used (e.g., in the case of a hepatic artery branch).

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

[0124] Continuing with FIGS. 10A and 10B, the hepatic plexus 345 is the largest offset from the celiac plexus 340. The hepatic plexus 345 is thought to carry mainly afferent and efferent parasympathetic nerve fibers, and its stimulation can increase blood glucose levels by many mechanisms. For example, stimulation of the parasympathetic nerve fibers in the hepatic plexus 345 can increase blood glucose levels by improving hepatic glucose production or decreasing hepatic glucose uptake. Therefore, disruption of parasympathetic signaling in the hepatic plexus 345 can change blood glucose levels.

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

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

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

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

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

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

[0131] The delivery / flow rate, or the rate at which the delivery system delivers the formulation, generally determines the duration of the formulation. For example, at a delivery rate of 30 cal / second, a treatment duration of 10 seconds requires delivering 300 calories. The delivery rate generally ranges from about 2 to about 200 cal / second. Also, these limitations are not definitive and can vary depending on the treatment and / or delivery parameters.

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

[0133] The delivery rate can be set by controlling the delivery system. When the user establishes the delivery rate, the formulation source determines the amount of pressure necessary to deliver the vapor or liquid at the desired rate. When the delivery rate setting is changed, the formulation generating device adjusts the amount of pressure delivered. The pressure of the vapor generating device can be in the range of about 5 psi to about 200 psi or about 10 psi to about 50 psi.

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

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

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

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

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

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

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

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

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

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

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

[0145] The chemicals used in the above study were acetic anhydride and absolute ethanol. Since white spots were localized in the chemically transected area, the treatment efficacy was clearly shown in the TTC-stained duodenal tissue for both treated animals.

[0146] Following the success of the above acute study, a chronic study was conducted to show the clinical benefit of the treatment. The study included 7 pigs of the same body weight as in the above acute study. Three of the 7 pigs were treated with absolute ethanol, three with acetic acid, and one sham pig with saline. The same procedure as described in the previous acute study was used for the treatment with absolute ethanol. As before, after the infusion balloon catheter reached the duodenum, the balloon was rapidly pre-inflated with absolute ethanol to a pressure of 1.5 atm; then about 1.5 ml - 2.0 ml of ethanol was injected into the duodenum through the balloon wall, and then the pressure was maintained at 0.5 atm or less for 2 minutes. At the end of the treatment period, the treated duodenal portion was flushed with about 10 ml of water using an endoscope.

[0147] The treatment with acetic acid was carried out in the same way as that with absolute ethanol. As before, the duodenum of the pig was treated with a dose of 0.5 ml for 1 minute this time. After each treatment, the balloon was partially deflated and retracted to a specified distance to avoid overlap with the next treatment position. Then the treatment was repeated. The bile duct was not treated. The animals were allowed to recover for chronic observation and evaluation.

[0148] The pigs treated with acetic acid in the duodenum were euthanized about 5 weeks after the treatment. The animals were judged to be healthy after clinical and pathological evaluations. As shown in Figure 13, the treatment of the duodenum with acetic acid had no significant difference in body weight compared to sham animals. The glucose levels fluctuated and no conclusion could be drawn.

[0149] Pigs that had undergone duodenal treatment with absolute ethanol were euthanized approximately 8 weeks after the treatment. The animals were determined to be healthy after clinical and pathological evaluations. As shown in Figure 14, treatment of the duodenum with absolute ethanol decreased the increase in body weight of the animals compared to sham animals. The glucose levels were inconclusive.

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

[0151] Using the above procedure, a chronic study was conducted in 7 young Yorkshire cross pigs. Three of the 7 pigs were treated with absolute ethanol, three with acetic acid, and one sham with physiological saline. Endoscopy was performed before and after the treatment. The animals were allowed to recover for chronic observation and evaluation. The animals were endoscoped again 2 weeks after the treatment, re-examined 4 weeks after the treatment, and then euthanized. The treatment effect was evaluated by endoscopy. In the acetic acid-treated esophageal part, severe stenosis was monitored. Histopathological analysis of the treated part showed epithelial hyperplasia and complete epithelialization, except in the acetic acid-treated group where the epithelial layer was sometimes absent.

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

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

[0154] In one embodiment, a method for the treatment of cancer or tumors involves inserting a needle or needle-based catheter percutaneously or orally into the cancer or tumor under an imaged guide; using the catheter to inject the formulation and / or heat into the cancerous tissue of the human body, where the amount of formulation and / or heat delivered is effective to damage, injure or remove the cancerous tissue, for example by shrinking or removing the tumor; and finally withdrawing the delivery catheter from the body. Possible imaging guides include ultrasound, X-ray, CT scan, NMR imaging and scope. Associated cancers include adrenal, bladder, cervical, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach and uterus. The purpose of heat is to improve the injury / damage / removal effect by accelerating the reaction rate between the formulation and the cancerous tissue. The formulation includes one of a gas, vapor, liquid, solution, emulsion and suspension of one or more components. When the formulation includes a vapor of one or more components, heat can be generated by the condensation of the vapor to a liquid in the tissue. When the formulation includes a liquid or solution, heat can be transferred from the formulation at a high temperature exceeding body temperature. The formulation temperature can range from -40°C to 140°C, -30°C to 100°C or -20°C to 80°C. The temperature of the tissue being treated may be lower than the formulation temperature and higher than body temperature. The temperature of the tissue being treated can range from -40°C to 100°C, -30°C to 90°C or -20°C to 80°C.

Claims

1. a) Insert a delivery catheter into a body cavity; b) Inject a formulation into diseased tissue in the body cavity, where the amount of the formulation delivered to the body cavity is effective to damage or injure the diseased tissue to relieve disease symptoms; c) Optionally, remove the formulation from the diseased tissue; and d) Withdraw the delivery catheter from the body cavity A method for treating a disease, comprising:

2. The method according to claim 1, wherein the disease is selected from hypertension, pulmonary hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive diseases, benign prostatic hyperplasia, cancer, tumors, pain, asthma, and chronic obstructive pulmonary disease (COPD).

3. The method according to claim 2, wherein the cancer is selected from the adrenal gland, bladder, neck, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, duodenum, jejunum, and uterus.

4. The method according to claim 1, wherein the body cavity is selected from the renal artery, pulmonary artery, vascular lumen, celiac artery, common hepatic artery, proper hepatic artery, duodenal artery, right hepatic artery, left hepatic artery, splenic artery, right gastric artery, left gastric artery, non-vascular lumen, airway, nasal cavity, esophagus, lumen of the respiratory system, lumen of the digestive system, stomach, duodenum, jejunum, prostate, urethra, ureter, and / or lumen of the urinary system.

5. The method according to claim 1, wherein the formulation consists essentially of ethanol.

6. The method according to claim 1, wherein the formulation consists of ethanol.

7. The method according to claim 1, wherein the formulation comprises a gas, vapor, liquid, solution, emulsion, or suspension of one or more components.

8. The method according to claim 7, wherein when the formulation comprises a vapor of one or more components, heat is generated by condensation of the vapor to a liquid.

9. The method according to claim 7, wherein when the formulation comprises a liquid or solution, heat is transferred from the formulation to the diseased tissue.

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

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

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

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

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

15. The method according to claim 1, wherein the temperature of the diseased tissue is lower than the temperature of the formulation.

16. The method according to claim 1, wherein the temperature of the diseased tissue is higher than the temperature of the formulation.

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

18. The method according to claim 1, wherein the diseased tissue is at a temperature in the range of -40°C to 100°C.

19. The method according to claim 1, wherein the diseased tissue is at a temperature in the range of -40°C to 0°C.

20. The method according to claim 1, wherein the diseased tissue is at a temperature equal to body temperature.

21. The method according to claim 1, wherein the pressure of the formulation during injection is in the range of about 2 psi to 200 psi at a temperature in the range of about -40°C to 150°C.

22. The method according to claim 1, wherein the amount of the formulation injected into the diseased tissue is in the range of 0.2 microliters to 200 milliliters.

23. The method according to claim 1, wherein the method includes inserting a delivery catheter into a body cavity for about 2 seconds to about 60 minutes.

24. The method according to claim 1, wherein the method delivers an amount of heat or energy in the range of about 2 cal / g to about 150 cal / g to the diseased tissue.

25. The method according to claim 1, wherein the delivery catheter is selected from a needle or needle-based delivery catheter, a single balloon delivery catheter, a double balloon delivery catheter, an injection catheter, a balloon injection catheter, a balloon catheter, a dumbbell balloon injection catheter, and combinations thereof.

26. The method according to claim 25, wherein the delivery catheter expands at a pressure in the range of 0.1 atm to 14 atm.

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

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

29. The method according to claim 1, wherein the formulation contains a therapeutic agent for denervation, and the therapeutic agent is selected from sodium channel blockers, tetrodotoxin, saxitoxin, decarbamoyl saxitoxin, vanilloids, neosaxitoxin, lidocaine, conotoxin, cardiac glycosides, digoxin, glutamate, staurosporine, amlodipine, verapamil, simarine, digitoxin, proscillaridin, ouabain, veratridine, domoic acid, oleandrin, carbamazepine, aflatoxin, guanethidine and guanethidine sulfate.

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

31. The method according to claim 1, wherein the formulation contains an azeotropic mixture.

32. The method according to claim 31, wherein the azeotropic mixture is selected from ethanol / water, propanol / water, isopropanol / water, butanol / water, acetic acid / water, lactic acid / water, ethyl lactate / water, ethyl lactate / ethanol, lactic acid / ethanol / water, ethyl lactate / water / ethanol, ethyl acetate / ethanol, ethyl nitrate / ethanol, and isopropyl acetate / ethanol.

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

34. An inflatable balloon catheter for delivering a formulation to a target location within a patient's body cavity, the inflatable balloon catheter including a proximal end, a distal end, a wire lumen, a balloon inflation lumen, a formulation injection lumen and / or a vacuum lumen, an inflatable balloon and a non-inflatable shaft, the inflatable balloon portion and / or the non-inflatable shaft including at least a first portion having a plurality of voids, the voids being microholes, and the inflatable balloon portion and / or the non-inflatable shaft including at least a second portion having no voids, the inflatable balloon catheter.

35. The inflatable balloon catheter according to claim 34, wherein the inflatable portion has a first distal portion, a first central portion and a first proximal portion, and the diameters of the first distal portion and the first proximal portion are larger than the diameter of the first central portion.

36. The inflatable balloon catheter according to claim 34, wherein the inflatable portion or the non-inflatable portion has at least one void that allows the formulation to permeate the body cavity wall at a pressure higher than that of the body cavity; and the inflatable portion or the non-inflatable portion has no void that allows the balloon to inflate the body cavity at a pressure higher than that of the body cavity.

37. The inflatable balloon catheter according to claim 34, wherein the body cavity is selected from the renal artery, pulmonary artery, vascular lumen, celiac artery, common hepatic artery, proper hepatic artery, duodenal artery, right hepatic artery, left hepatic artery, splenic artery, right gastric artery, left gastric artery, non-vascular lumen, airway, nasal cavity, esophagus, respiratory lumen, digestive lumen, stomach, duodenum, jejunum, prostate, urethra, ureter, and urinary lumen.

38. The inflatable balloon catheter according to claim 34, wherein the pressure during delivery of the formulation is in the range of 0.1 atm to 14 atm, and the balloon catheter to be inflated inflates at a pressure in the range of 0.1 atm to 14 atm.

Images