Purified pentagalloyl glucose and delivery device

Abstract

To provide treatment protocols and compositions for stabilizing organs and tissues affected by degenerative conditions such as aneurysm, in particular, treatment protocols with phenolic compounds to provide safe and less invasive route for the stabilization of the structural architecture in order to temper the growth and / or development of such conditions.SOLUTION: Disclosed herein is a method of producing high purity pentagalloyl glucose (PGG), analogs or derivatives thereof, at least 99.9% pure, by a step of washing with dimethyl ether. PGG may be provided in a kit, including a hydrolyzer for dissolving the PGG and a saline solution. Also disclosed herein is a device for delivery of a therapeutic solution to a blood vessel. The device may be a catheter having an upstream balloon and a downstream balloon.SELECTED DRAWING: None

Description

[Background technology]

[0001] One of the most common consequences of vascular deterioration is an aneurysm. By definition, the term “aneurysm” is simply an abnormal enlargement or hypertrophy of the wall of a blood vessel. An aneurysm is a degenerative disease characterized by the destruction of an arterial structure and subsequent dilation of the vessel, which can ultimately lead to a fatal rupture. Some common locations for aneurysms include the abdominal aorta (abdominal aortic aneurysm, AAA), the thoracic aorta, and the cerebral arteries. In addition, peripheral aneurysms of the lower extremities, namely the arteries of the iliac crest, popliteal fossa, and femoral region, are common locations for this vascular lesion. The occurrence of such peripheral aneurysms is thought to be strongly related to the presence of aneurysms in other locations, as it is estimated that 30-60% of patients with peripheral aneurysms also have AAA.

[0002] Aneurysms can lead to massive bleeding, stroke, or hemorrhagic shock, and can be fatal in an estimated 80% of cases, potentially catastrophic due to the possibility of rupture or dissection. Aneurysms can be caused by any of the many classes of degenerative diseases and conditions, including atherosclerosis, defects in arterial components, genetic susceptibility, and hypertension, and can grow silently over many years. Characteristic features of aneurysms include enzymatic degradation of vascular structural proteins such as elastin and collagen, inflammatory infiltration, calcification, and eventual overall destruction of the vascular structure. The elastin content in the aorta of an aneurysm can be significantly reduced compared to that of a healthy, undamaged aorta (e.g., 70% less).

[0003] Aneurysms can grow over many years and pose a significant health risk. Aneurysms have the potential to dissociate or rupture, leading to massive bleeding, stroke, and hemorrhagic shock, which can be fatal in over 80% of cases. AAA is a serious health concern, especially for older adults, and is among the top 10 causes of death for patients over 50. The estimated incidence of abdominal aortic aneurysms is about 50 per 100,000 people per year. Approximately 50,000 surgeries for AAA alone are performed annually in the United States. In children, AAA can result from blunt abdominal injury or from Marfan syndrome, a defect in the formation of elastic fibers in the walls of major arteries such as the aorta.

[0004] Current treatment options for diagnosed aneurysms are limited to invasive surgical techniques. After the initial diagnosis of a small aneurysm, the most common medical approach is to track its development, and surgical intervention is applied once it reaches a certain size (e.g., approximately 5 cm in diameter). Current surgical interventions are limited to either endovascular stent implantation repair or, optionally, complete replacement of the affected vessel with a vascular graft. While such surgical interventions can save lives and improve the quality of life for those with aneurysms, patients still face risks that outweigh the risks of the surgery itself, due to potential postoperative complications (e.g., nerve damage, bleeding, or stroke) and device-related complications (e.g., thrombosis, leakage, or malfunction). Furthermore, depending on the location of the aneurysm, the risks of invasive surgical procedures may outweigh the potential benefits, for example, in the case of deep brain aneurysms, leaving patients with very limited treatment options. Additionally, surgical interventions do not always provide a permanent solution, as vascular grafts can loosen and detach if the aneurysm progresses after corrective surgery. In some patients, certain characteristics of the aneurysm or the patient's condition make them unsuitable for graft repair.

[0005] Aneurysms are not the only condition characterized by the enzymatic breakdown of structural proteins. Other conditions in which structural protein breakdown appears to play a significant role include Marfan syndrome and supravalvular aortic stenosis. For patients with these conditions, these conditions lead to at least a reduced quality of life and, in many cases, premature death.

[0006] Phenol compounds are a diverse group of substances recognized for their use in various applications. For example, they are naturally occurring in many plants and are often components of the human diet. Phenol compounds have been extensively studied for their efficacy as free radical scavengers and neutralizers, for example, in topical skin applications and dietary supplements. Phenol compounds are also thought to prevent cell membrane crosslinking found in certain inflammatory conditions and to influence the expression of certain genes by regulating free radicals and other oxidative species (see, for example, U.S. Patent No. 6,437,004 for Perricone). [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] U.S. Patent No. 6,437,004 [Patent Document 2] International Publication No. 87 / 05297 [Non-patent literature]

[0008] [Non-Patent Document 1] Remington's The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins (2005) [Non-Patent Document 2] Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th edition, Pergamon Press [Non-Patent Document 3] Modern Pharmaceutics, 4th edition, Chapters 9 and 10 (Banker & Rhodes, eds., 2002) [Non-Patent Document 4] Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989) [Non-Patent Document 5] Ansel, Introduction to Pharmaceutical Dosage Forms, 8th edition (2004) [Non-Patent Document 6] Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech, 1998, Vol. 52, pp. 238-311. [Non-Patent Document 7] Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech, 2011, Vol. 65, pp. 287-332. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] What is needed in this art is a treatment protocol and composition for stabilizing organs and tissues affected by degenerative conditions such as aneurysms. In particular, treatment protocols utilizing phenolic compounds can provide a safe and minimally invasive pathway for stabilizing structural construction in order to mitigate the growth and / or development of such conditions. [Means for solving the problem]

[0010] Some embodiments are compositions comprising a compound of the following formula:

[0011]

Chemical formula

[0012] or a pharmaceutically acceptable salt thereof [wherein, R 1 ~R 19 has any of the meanings described herein], and the composition is substantially free of gallic acid or methyl gallate. In some embodiments, substantially free means less than about 0.5% gallic acid. In some embodiments, substantially free means less than about 0.5% methyl gallate.

[0013] In some embodiments, R 1 , R 2 , R 3 and R 4 are each independently hydrogen or R A ; R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are each independently hydrogen or R B ; Each R A is independently -OR X , -N(R Y )2, halo, cyano, -C(=X)R Z , -C(=X)N(R Y )2, -C(=X)OR X , -OC(=X)R Z , -OC(=X)N(RY )2, -OC(=X)OR X , -NR Y C(=X)R Z , -NR Y C(=X)N(R Y )2, -NR Y C(=X)OR X , unsubstituted C 1~12 alkoxy, substituted C 1~12 alkoxy, unsubstituted C 1~8 Alkyl, substituted C 1~8 Alkyl, unsubstituted C 6又は10 Aryl substitution C 6又は10 Aryl, unsubstituted C 7~12 Aralkyl, substitution C 7~12 Aralkyl, unsubstituted 5-10 member heteroaryl, substituted 5-10 member heteroaryl, unsubstituted C 3~12 Heteroaralkyl, substitution C 3~12 Selected from the group consisting of heteroaralkyls, unsubstituted 3-10 membered heterocyclines, and substituted 3-10 membered heterocyclines; Each R B Independently, -C(=X)R Z -C(=X)N(R Y )2, -C(=X)OR X , unsubstituted C 1~8 Alkyl, substituted C 1~8 Alkyl, unsubstituted C 6又は10 Aryl substitution C 6又は10 Aryl, unsubstituted C 7~12 Aralkyl, substitution C 7~12 A selection from the group consisting of aralkyl, unsubstituted 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl, unsubstituted 3-10 membered heterocyclil and substituted 3-10 membered heterocyclil, or two adjacent R B The groups, together with the atoms to which they are bonded, form an unsubstituted 3-10 membered heterocycline, a substituted 3-10 membered heterocycline, an unsubstituted 5-10 membered heteroaryl ring, or a substituted 5-10 membered heteroaryl ring; Each X is independently either oxygen (O) or sulfur (S); Each R X and R Y These are independently hydrogen, unsubstituted C 1~8 Alkyl, substituted C1~8 Alkyl, unsubstituted C 6又は10 Aryl, substituted C 6又は10 Aryl, unsubstituted C 7~12 Aralkyl, substituted C 7~12 Aralkyl, unsubstituted 5- to 10-membered heteroaryl, substituted 5- to 10-membered heteroaryl, unsubstituted 3- to 10-membered heterocyclyl, and substituted 3- to 10-membered heterocyclyl, and is selected from the group consisting of; Each R Z is, independently, unsubstituted C 1~12 Alkoxy, substituted C 1~12 Alkoxy, unsubstituted C 1~8 Alkyl, substituted C 1~8 Alkyl, unsubstituted C 6又は10 Aryl, substituted C 6又は10 Aryl, unsubstituted C 7~12 Aralkyl, substituted C 7~12 Aralkyl, unsubstituted 5- to 10-membered heteroaryl, substituted 5- to 10-membered heteroaryl, unsubstituted 3- to 10-membered heterocyclyl, and substituted 3- to 10-membered heterocyclyl, and is selected from the group consisting of.

[0014] In some embodiments, R 1 , R 2 , R 3 and R 4 at least one of which is R A . In some embodiments, R 1 , R 2 , R 3 and R 4 at least two of which are R A . In some embodiments, each R A is, independently, -OR X , -N(R Y )2, halo, cyano, -C(=X)R Z , -C(=X)N(R Y )2, -C(=X)OR X , -OC(=X)R Z , -OC(=X)N(R Y )2, -OC(=X)OR X , -NR Y C(=X)R Z , -NR Y C(=X)N(RY )2 and -NR Y C(=X)OR X Selected from the group consisting of R A Independently, unsubstituted C 1~12 alkoxy, substituted C 1~12 alkoxy, unsubstituted C 1~8 Alkyl, substituted C 1~8 Alkyl, unsubstituted C 6又は10 Aryl substitution C 6又は10 Aryl, unsubstituted C 7~12 Aralkyl, substitution C 7~12 Aralkyl, unsubstituted 5-10 member heteroaryl, substituted 5-10 member heteroaryl, unsubstituted C 3~12 Heteroaralkyl, substitution C 3~12 Selected from the group consisting of heteroaralkyls, unsubstituted 3-10 membered heterocyclines, and substituted 3-10 membered heterocyclines. In some embodiments, each R A Independently, unsubstituted C 1~12 alkoxy, unsubstituted C 1~8 Alkyl, unsubstituted C 6又は10 Aryl, unsubstituted C 7~12 Aralkyl, unsubstituted 5-10 member heteroaryl, unsubstituted C 3~12 Selected from the group consisting of heteroaralkyls and unsubstituted 3-10 membered heterocyclines. In some embodiments, R 1 , R 2 , R 3 and R 4 Each of these is hydrogen. In some embodiments, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each of these is hydrogen. In some embodiments, R 5 , R 6 , R 7, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 At least one of them is R B In some embodiments, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 At least two of are R B In some embodiments, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 At least three of them are R B In some embodiments, each R B Independently, unsubstituted C 1~12 alkoxy, substituted C 1~12 alkoxy, unsubstituted C 1~8 Alkyl, substituted C 1~8 Alkyl, unsubstituted C 6又は10 Aryl substitution C 6又は10 Aryl, unsubstituted C 7~12 Aralkyl, substitution C 7~12 Aralkyl, unsubstituted 5-10 member heteroaryl, substituted 5-10 member heteroaryl, unsubstituted C3~12 Heteroaralkyl, substitution C 3~12 Selected from the group consisting of heteroaralkyls, unsubstituted 3-10 membered heterocyclines, and substituted 3-10 membered heterocyclines. In some embodiments, each R B Independently, unsubstituted C 1~12 alkoxy, unsubstituted C 1~8 Alkyl, unsubstituted C 6又は10 Aryl, unsubstituted C 7~12 Aralkyl, unsubstituted 5-10 member heteroaryl, unsubstituted C 3~12 Selected from the group consisting of heteroaralkyls and unsubstituted 3-10 membered heterocyclines. In some embodiments, two adjacent R B The groups, together with the atoms to which they are bonded, form an unsubstituted 3-10 membered heterocycline, a substituted 3-10 membered heterocycline, an unsubstituted 5-10 membered heteroaryl ring, or a substituted 5-10 membered heteroaryl ring.

[0015] In some embodiments, the pharmaceutical composition is formulated for administration via oral, intrafat, intra-arterial, intra-articular, intracranial, intradermal, intrafocal, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, vaginal, intravenous, intravesicular, intravitreal, liposomal, topical, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, transbuccal, transdermal, transvaginal, cream, lipid composition, via catheter, via lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via local perfusion. The pharmaceutical composition may be formulated for oral, topical, intravenous, or intravitreal administration. In some embodiments, the pharmaceutical composition is formulated as a unit dose.

[0016] In another embodiment, the Disclosure provides a method for treating and / or preventing a disease or disorder in a patient in need thereof, comprising the step of administering to the patient a composition described herein in an amount sufficient to treat and / or prevent the disease or disorder. In some embodiments, the Disclosure provides a method for treating an aneurysm.

[0017] Several embodiments provide a method for purifying a compound of formula (I), comprising the step of washing the mixture with a solvent to remove substantially all gallic acid or methyl gallate. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is selected from the group consisting of methanol, toluene, isopropyl ether, dichloromethane, methyl tert-butyl ether, 2-butanone, and ethyl acetate. In some embodiments, the washing step results in a purity of the compound of formula (I) of 99.10%, 99.20%, 99.30%, 99.40%, 99.50%, 99.60%, 99.70%, 99.80%, 99.90%, 99.91%, 99.92%, 99.93%, 99.4%, 99.95%, 99.96%, 99.97%, 99.98%, or 99.99% or higher.

[0018] Several embodiments provide a kit for treating an aneurysm, comprising a compound of formula (I) having a purity of 99% or higher and a hydrolyzing agent. In some embodiments, the hydrolyzing agent is ethanol. In some embodiments, the hydrolyzing agent is dimethyl sulfoxide (DMSO). In some embodiments, the hydrolyzing agent is a contrast agent. In some embodiments, the kit further comprises physiological saline.

[0019] Several embodiments provide a device for treating an aneurysm, comprising a shaft, a first balloon attached to a first end of the shaft, and a second balloon attached to a second end of the shaft, wherein the second balloon comprises a plurality of pores for delivering a therapeutic agent to the aneurysm. In some embodiments, the first balloon is located near the distal end of the shaft to secure the device and to stop downstream blood flow, and the second balloon is located near the proximal end of the shaft. The second balloon may be configured to stop retrograde blood flow and / or to expel blood from the aneurysm sac, which may improve the effectiveness of drug delivery to the aneurysm. In some embodiments, the second balloon is located near the distal end of the shaft to secure the device and to stop downstream blood flow, and the first balloon is located near the proximal end of the shaft to stop retrograde blood flow. In some embodiments, the device further comprises a third balloon located within the second balloon for inflating the second balloon, and the third balloon is inflatable with saline solution.

[0020] Some embodiments provide a method for treating an aneurysm, comprising the steps of: placing a first balloon upstream of the aneurysm; placing a second balloon adjacent to the aneurysm; inflating the first balloon to occlude downstream blood flow; expanding the second balloon to occlude retrograde blood flow and / or expel blood from the aneurysm sac; and delivering a therapeutic agent to the aneurysm through pores in the second balloon.

[0021] Some embodiments provide a method for purifying 1,2,3,4,6-pentagaloyl glucose (PGG) or its analogues or derivatives, comprising the step of washing the PGG with a solvent to remove substantially all gallic acid or methyl gallate. In some embodiments, the solvent may be diethyl ether, toluene, isopropyl ether, dichloromethane, methyl tert-butyl ether, 2-butanone and / or ethyl acetate, or may contain these. The step of removing substantially all gallic acid or methyl gallate may result in a gallic acid or methyl gallate content of about 0.1%, 0.2%, 0.3%, 0.4%, or less than 0.5%. The washing step may result in a purity of 99.9% or higher for 1,2,3,4,6-pentagaloyl glucose (PGG) or its analogues or derivatives.

[0022] Several embodiments provide a kit for treating aneurysms. The kit comprises PGG having a purity of 99% or higher and a hydrolyzing agent. The hydrolyzing agent may be ethanol, dimethyl sulfoxide (DMSO), and / or a contrast agent, or may contain these. The kit may also contain physiological saline.

[0023] Several embodiments provide a device for treating an aneurysm. The device comprises a shaft, a first balloon attached to a first end of the shaft, and a second balloon attached to a second end of the shaft. The second balloon contains a plurality of pores for delivering a therapeutic agent to the aneurysm. In some embodiments, the first balloon may be located near the distal end of the shaft to secure the device and to stop downstream blood flow, and the second balloon may be located near the proximal end of the shaft to stop retrograde blood flow. In some embodiments, the second balloon may be located near the distal end of the shaft to secure the device and to stop downstream blood flow, and the first balloon may be located near the proximal end of the shaft to stop retrograde blood flow. The device may include a third balloon located within the second balloon for inflating the second balloon. The third balloon may be inflatable with saline solution.

[0024] Several embodiments provide a catheter for treating an aneurysm. The catheter has an elongated body configured to be introduced into a blood vessel. The elongated body has a main shaft having a proximal end, a distal end, and a lumen extending through it. The catheter has a first inflatable balloon connected to the distal end of the elongated body, having an internal volume that is in fluid communication with a first inflation lumen. The catheter has a second inflatable balloon connected to the elongated body adjacent to the first inflatable balloon, having an internal volume that is in fluid communication with a second inflation lumen. The second inflatable balloon surrounds the elongated body circumferentially. The second inflatable balloon has a plurality of pores arranged on its surface, configured to be placed in the internal volume of the second inflatable balloon that is in fluid communication with the intravascular environment of the blood vessel.

[0025] In some embodiments, the main shaft may extend through a second inflatable balloon. The distal end of the main shaft may form the distal end of an elongated body. The first and second inflatable lumens may be formed within the main shaft. The elongated body may include a second shaft having a lumen extending through it. The second shaft may be located within the lumen of the main shaft. The first inflatable balloon may be connected to the distal end of the second shaft, and the second inflatable balloon may be connected to the distal end of the main shaft. The lumen of the main shaft may be the second inflatable lumen. The lumen of the second shaft may be the first inflatable lumen. The elongated body may extend through the internal volume of the second inflatable balloon. The second inflatable balloon may generally be donut-shaped, forming an annular internal volume surrounding the elongated body. The elongated body may have an intermediate shaft region located between the proximal end of the first inflatable balloon and the distal end of the second inflatable balloon. The intermediate shaft region may include the main shaft and / or a second shaft. The separation distance between the first inflatable balloon and the second inflatable balloon may be fixed or adjustable. The catheter may have a lumen configured to be in fluid communication with the volume of the intravascular environment between the first inflatable balloon and the second inflatable balloon.

[0026] The pores may be located in the central part of the second inflatable balloon. The pores may be located in the distal part of the second inflatable balloon. The pores do not have to be located in the proximal part of the second inflatable balloon. In the inflated configuration, the pores do not have to be located in any part of the second inflatable balloon proximal to the maximum expanded diameter of the balloon. The maximum expanded diameter of the second inflatable balloon may be greater than the maximum expanded diameter of the first inflatable balloon. The length of the expanded second inflatable balloon may be longer than the length of the expanded first inflatable balloon.

[0027] The catheter may include a third inflatable balloon positioned within the internal volume of a second inflatable balloon. The third inflatable balloon may have an internal volume that is in fluid communication with the third inflation lumen. The inflation of the third inflatable balloon may be configured to inflate the second inflatable balloon at least partially. The inflation of the third inflatable balloon may be configured to facilitate the discharge of at least a partial volume of the inflation fluid positioned within the internal volume of the second inflatable balloon into the intravascular environment through pores.

[0028] Several embodiments provide a method for treating an aneurysm in a patient's blood vessel. The method includes the steps of: placing a first balloon upstream of the aneurysm; placing a second balloon adjacent to the aneurysm; inflating the first balloon to occlude downstream blood flow; expanding the second balloon to occlude retrograde blood flow; and delivering a therapeutic agent to the aneurysm through pores in the second balloon. In some embodiments, the step of expanding the second balloon includes introducing an inflation fluid into the internal volume of the second balloon. The step of delivering the therapeutic agent may include introducing a solution containing the therapeutic agent into the internal volume of the second balloon to expand the second balloon and / or maintaining the expanded state of the second balloon. The steps of inflating the first balloon and expanding the second balloon may create a sealed volume within the blood vessel between the first and second balloons. The step of delivering the therapeutic agent may include introducing the therapeutic agent into the sealed volume. The therapeutic agent does not need to be delivered to blood vessels outside the sealed volume while the sealed volume is being established.

[0029] The step of inflating the first balloon may fix the first and second balloons within the blood vessel. The step of placing the second balloon adjacent to the aneurysm may include placing the second balloon across the aneurysm, and the step of expanding the second balloon may create a sealed space between the second balloon and the aneurysm. The step of placing the second balloon adjacent to the aneurysm may include placing the second balloon along the downstream end of the aneurysm, and the step of expanding the second balloon may create a sealed volume between the first and second balloons surrounding the aneurysm. The step of placing the second balloon adjacent to the aneurysm may include placing the second balloon such that its entire length surrounds the length of the aneurysm along the blood vessel. The step of inflating the first balloon may occur before the step of expanding the second balloon. The steps of inflating the second balloon and / or maintaining the second balloon in an inflated state may include maintaining a pressure within the internal volume of the second balloon that is higher than the patient's diastolic blood pressure and lower than the patient's systolic blood pressure. The steps of inflating the second balloon and delivering the therapeutic agent through the pores may include introducing a solution into the internal volume of the second balloon. The solution may be introduced at a first volumetric flow rate for inflating the second balloon and a second volumetric flow rate for delivering the therapeutic agent through the pores. The first volumetric flow rate may be greater than or equal to the second volumetric flow rate.

[0030] The blood flow may be occluded within the blood vessel within approximately 3 minutes. At least 1 mL of a solution containing the therapeutic agent may be delivered while the downstream and retrograde blood flow in the blood vessel is occluded. The step of inflating the second balloon may include the step of inflating a third balloon positioned within the internal volume of the second balloon. The step of delivering the therapeutic agent may include the step of inflating the third balloon positioned within the internal volume of the second balloon to forcibly pass the volume of the solution containing the therapeutic agent within the internal volume of the second balloon through the pores. The therapeutic agent may contain pentagalloyl glucose (PGG). The PGG may be at least 99.9% pure. The therapeutic agent may be substantially free of gallic acid or methyl gallate.

[0031] The features and advantages of the systems, devices, and methods described herein will become apparent from the following description in conjunction with the accompanying drawings. These drawings represent only some embodiments of the present disclosure and should not be considered as limiting its scope. In the drawings, similar reference numerals or symbols typically identify similar components unless the context indicates otherwise. The drawings may not be drawn to scale. [Brief explanation of the drawing]

[0032] [Figure 1] Figure 1A shows the chemical structure of 1,2,3,4,6-pentagaloyl glucose (PGG) in a preferred embodiment. Figure 1B shows the chemical structure of gallic acid, a common toxic impurity in the production of PGG. Figure 1C shows the chemical structure of methyl gallate, a common toxic impurity in the production of PGG. [Figure 2A] Figure 2A schematically illustrates various examples of delivery catheters for the delivery of PGG or other therapeutic agents into blood vessels. Figure 2A shows a delivery catheter in which the downstream balloon is connected to the distal end of the main shaft at its proximal end and to the distal end of the secondary shaft, with the upstream balloon connected to the distal end of the secondary shaft. [Figure 2B] Figure 2B schematically illustrates various examples of delivery catheters for the delivery of PGG or other therapeutic agents into blood vessels. Figure 2B shows a delivery catheter in which the downstream balloon is generally a donut-shaped balloon surrounding the secondary shaft, with the downstream balloon connected to the distal end of the main shaft, and the upstream balloon connected to the secondary shaft at both the proximal and distal ends. Figure 2B also illustrates the auxiliary internal lumen, which is in fluid communication with the sealed volume created between the upstream and downstream balloons, as well as the lead region located at the distal end of the delivery catheter. [Figure 2C]Figure 2C schematically illustrates various examples of delivery catheters for the delivery of PGG or other therapeutic agents into blood vessels. Figure 2C shows a delivery catheter in which the downstream balloon is connected to the main shaft at both its proximal and distal ends, and the upstream balloon is connected to the secondary shaft at both its proximal and distal ends. Figure 2C also illustrates a secondary shaft that is open at the distal end of the delivery catheter and has a central lumen that is in fluid communication with the intravascular environment. [Figure 3A] Figure 3A schematically illustrates various examples of downstream balloons of a delivery catheter that are expanded within a blood vessel containing an aneurysm. Figure 3A shows a downstream balloon that is longer than the aneurysm, which expands to create a sealed space between the downstream balloon and the blood vessel wall of the aneurysm. Figure 3A also shows a pore located in the center of the downstream balloon. [Figure 3B] Figure 3B schematically illustrates various examples of downstream balloons of a delivery catheter that are expanded within a blood vessel containing an aneurysm. Figure 3B schematically illustrates a downstream balloon that is expanded to fluidly seal the downstream end of an aneurysm, creating a sealed volume between the downstream and upstream balloons. Figure 3B also illustrates the pores located distal to the downstream balloon. [Figure 3C] Figure 3C schematically illustrates various examples of downstream balloons of a delivery catheter that are expanded within a blood vessel containing an aneurysm. Figure 3C shows a downstream balloon that is shorter than the aneurysm, which is expanded to bring the downstream balloon into contact with the blood vessel wall of the aneurysm. [Figure 4A] Figure 4A schematically illustrates various examples of delivery catheters, including an internal balloon positioned within a downstream balloon. Figure 4A shows an internal balloon connected at its proximal end to the distal end of the main shaft and at its distal end to the secondary shaft. [Figure 4B] Figure 4B schematically illustrates various examples of delivery catheters, including an internal balloon positioned within a downstream balloon. Figure 4B shows the internal balloon connected to the secondary shaft at its proximal and distal ends. [Figure 4C]Figure 4C schematically illustrates various examples of delivery catheters, including an internal balloon positioned within a downstream balloon. Figure 4C shows the internal balloon connected to the main shaft at its proximal and distal ends. [Modes for carrying out the invention]

[0033] This specification discloses methods for purifying and delivering pentagalloyl glucose (PGG). In a preferred embodiment, PGG may be 1,2,3,4,6-pentagaloylglucose, as shown in Figure 1A. However, PGG may refer to any chemical structure encompassed in formula (I) as disclosed elsewhere in this specification. Furthermore, this specification discloses devices for the delivery of PGG or other therapeutic agents into blood vessels or other body cavities, but the PGG treatments disclosed herein are not necessarily limited to delivery by these devices. In addition, the devices disclosed herein may be used to deliver any suitable therapeutic agent to any suitable site of a subject. PGG may be delivered to a subject to treat any one or more of a variety of signs.

[0034] In a preferred embodiment, PGG may be delivered to the vascular wall for the treatment of aneurysms, such as abdominal aortic aneurysms. While not limited by theory, delivery of PGG to a vascular wall in which an aneurysm has formed may stabilize the aneurysm by at least transiently cross-linking elastin proteins in the extracellular matrix of the connective tissue of the vascular wall. Treatment of blood vessels with elastin-stabilizing compounds such as PGG may increase the mechanical integrity of the vessel in which the aneurysm resides. Treatment with PGG may prevent, inhibit, and / or delay the growth of the aneurysm and further thinning of the vascular wall, and may prevent, inhibit, reduce, and / or delay the risk of aneurysm rupture. In some cases, treatment with PGG may facilitate the spontaneous healing of aneurysms by mechanically stabilizing them. In some practices, treatment with PGG may be used before, after, and / or concurrently with other interventional procedures for aneurysms, such as surgical intervention. In some practices, treatment with PGG may be particularly suitable for treating abdominal aortic aneurysms with a diameter between approximately 4 and 5 cm. In some cases, treatment of abdominal aortic aneurysms can delay the need for more traditional, invasive treatments by at least 10 years.

[0035] In other applications, PGG may be used to treat aneurysms other than abdominal aortic aneurysms, including peripheral and neuronal aneurysms. PGG may be delivered to abdominal aortic aneurysms or similar aneurysms by the same devices described herein, or by other devices or routes of administration. For example, in some embodiments, PGG, in particular the high-purity PGG disclosed herein, may be suitable for direct injection into the bloodstream or another tissue for the treatment of other signs. In some embodiments, PGG may be used to stabilize and / or facilitate the closure of vascular access holes created by puncturing a vessel to access blood flow for therapeutic procedures via the vascular system, such as for blood collection and / or catheter delivery. PGG may facilitate the closure of vascular access sites by means for treating aneurysms. PGG may stabilize the vascular wall around the access hole by crosslinking elastin within the vessel, which may promote or accelerate spontaneous healing. PGG may be applied to access holes by intravascular application and / or by applying PGG directly to the skin above the vascular access hole. PGG may have beneficial effects on wound closure in connective tissue containing elastin outside the vessel wall, such as the superficial layer of skin above vascular access holes, including subcutaneous tissue. Similarly, PGG may be used to treat musculoskeletal conditions, including the treatment of damaged ligaments and / or tendons, by cross-linking elastin within connective tissue. PGG may be used to coat vascular stents and / or grafts. PGG delivered to the vessel wall after angioplasty may, for example, structurally stabilize the vessel wall and help prevent or inhibit restenosis of the vessel. In addition, PGG may be used to treat and / or prevent aortic dissection. Treatment of aortic dissection with PGG can help close tears in the media of the vessel, prevent the propagation of tears along the vessel wall, and / or stabilize the tears to promote spontaneous healing. In some cases, PGG may be delivered to the aortic dissection site using the delivery devices described herein or similar thereto.

[0036] PGG can also be advantageously used in situations where a fistula is created to provide access to a blood vessel. Such fistulas include arteriovenous fistulas. For example, in hemodialysis, surgeons typically place an arteriovenous fistula in the forearm or upper arm. The arteriovenous fistula creates excessive pressure and allows more blood to flow into the vein, making it larger and stronger. A larger vein provides easier and more reliable access to the blood vessel. Without this type of access, regular hemodialysis sessions would be impossible. Untreated veins cannot withstand repeated needle insertions as they collapse. Healthcare providers have recommended arteriovenous fistulas over other types of access because they provide better blood flow for dialysis, last longer than other types of access, and are less likely to cause infection or blood clots. Another device for hemodialysis is an arteriovenous graft, which is a loop-shaped plastic tube connecting an artery to a vein. An intravenous catheter is a tube that is typically inserted into a vein in the neck, chest, or a lower limb near the groin for short-term hemodialysis only. The tube is split into two after it exits the body. The two tubes have caps designed to connect to a line that carries blood to the dialysis machine and a line that carries blood back to the body from the dialysis machine. PGG can advantageously be used to coat components that access the vascular system, such as grafts or fistulas, or applied to the vascular system itself, access holes, or nearby areas to provide stabilization of the affected tissue, resulting in improved treatment outcomes. PGG can also be added to the blood subjected to hemodialysis to deliver PGG to the vascular system.

[0037] Insulin pumps deliver insulin to the body in the treatment of diabetes, such as type 1 or type 2 diabetes. Generally, there are two types of pump devices. Conventional insulin pumps have an insulin reservoir (or container) and a pumping mechanism and are attached to the body with tubing and an infusion set. The pump body includes buttons that allow programming for insulin delivery for meals, a specific type of basal rate, or pausing insulin infusion as needed. The tubing connects to the skin, typically to the layer of fat under the abdomen, or to a cannula placed in the abdominal cavity in implanted pumps. Insulin patch pumps are attached directly to the body and have a reservoir, a pumping mechanism, and an infusion set in a small case. Patch pumps are wirelessly controlled by a separate device that allows programming for insulin delivery for meals from the patch. The infusion set is made of Teflon® or steel and is attached to the skin by an adhesive patch. At the bottom of the infusion set is a short, thin tube (cannula) that is inserted into the skin with a small needle housed in a cannula for delivering insulin to the layer of adipose tissue. A needle is necessary to puncture the skin and insert the set. After insertion, the needle is removed, and a thin cannula remains under the skin. The set is usually implanted around the abdomen, but can be placed in the thigh, buttocks, upper arm, or buttocks. PGG can be advantageously used to coat the cannula or applied to the tissue through which the cannula passes, the access hole, or a nearby area to provide stabilization of the affected tissue, resulting in improved treatment outcomes. In certain embodiments, PGG can be added to the infusion fluid, such as insulin, for delivering PGG to the tissue in the area of ​​the cannula.

[0038] Purified PGG The concentration of PGG that can be safely delivered to patients is generally proportional to the purity of the PGG. For example, gallic acid, shown in Figure 1B, and methyl gallate, shown in Figure 1C, are cytotoxic impurities that can usually be removed from the raw material batch of PGG during the purification process. Steps to eliminate the presence of toxic impurities from the delivered PGG or to reduce their concentration may allow for higher concentrations of delivered PGG, due to the mitigation of the toxic side effects of impurities commonly found in isolated PGG. For example, studies have shown that substantially 100% pure PGG can be safely delivered at a maximum concentration of approximately 0.330% (w / v), 95% pure PGG can be safely delivered at a maximum concentration of approximately 0.125% (w / v), and 85% pure PGG can be safely delivered at a maximum concentration of approximately 0.06% (w / v). Delivering PGG at higher concentrations may enhance the amount of PGG uptake by target tissues, which can increase the effectiveness of PGG treatment. Delivering PGG at higher concentrations may increase the rate of PGG uptake by tissues, enabling the same amount of uptake in a shorter delivery time. Reducing or minimizing delivery time may be advantageous in reducing overall procedure time, particularly the time during which blood vessels such as the aorta are potentially occluded, as described elsewhere in this specification. Minimizing procedure time, especially the time of vascular occlusion, may improve the safety and convenience of the procedure and improve patient outcomes.

[0039] Unpurified or partially purified PGG can be obtained from any suitable source and may be purified according to the methods described herein for use as a therapeutic agent. PGG may be extracted from naturally occurring plants such as pomegranate or cinnamon. The extraction and / or isolation methods may require solvolysis (e.g., metanolysis) of tannins or polyphenol derivatives, as is known in the art. PGG hydrate is commercially available from Sigma Aldrich (St. Louis, Missouri) with a purity of 96% or higher, as confirmed by HPLC. PGG obtained from these sources may undergo further purification according to the methods described herein to obtain substantially pure PGG at the purity levels described elsewhere herein.

[0040] In some embodiments, PGG is purified by washing an initial batch of PGG (e.g., less than 99% pure) with a solvent. In preferred embodiments, the solvent may include diethyl ether. In other embodiments, the solvent may include methanol, toluene, isopropyl ether, dichloromethane, methyl tert-butyl ether, 2-butanone, and / or ethyl acetate. In some embodiments, the washing solution may contain a mixture of the solvents described herein and / or be mixed with additional solvents. In some embodiments, the initial batch of PGG may be dissolved in a solution. In some embodiments, PGG may be dissolved in dimethyl sulfoxide (DMSO). In some embodiments, PGG may be dissolved in any solvent in which PGG dissolves but is not miscible with the washing solution. The PGG solution may be mixed with the washing solution in a flask, and the PGG solution and the washing solution may be separated over time. The washing solution can then be separated from the PGG solution, for example, by draining the denser solution from the flask or by decanting the less dense solution. In some embodiments, the mixture of the washing solution and the PGG solution may contain the washing solution and the PGG solution in a volume-to-volume ratio of at least about 1:1, 1.5:1, 2:1, 3:1, 4:1, 5:1, or 10:1. In some embodiments, the washing step may be repeated at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. In some embodiments, the washed PGG solution may be evaporated during purification to precipitate the PGG in a dry (solid) form. In some embodiments, the PGG may remain dissolved, but the volume of the solution may be increased or decreased (e.g., by evaporation). In some embodiments, the initial batch of PGG may be in a dry (solid) form. The PGG may be crystallized. In some embodiments, the PGG may be freeze-dried. In some embodiments, the PGG may precipitate from the solution. In some embodiments, the initial batch of PGG may be placed on filter paper, and the washing solution may be poured from the filter paper into a drain flask.Filtration can be facilitated by applying a vacuum to the waste flask (vacuum filtration). The residual washing solution may be evaporated from the purified batch of PGG. In some embodiments, the washing step may be repeated at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. The purity of the PGG may increase with each washing. The washing procedure may be repeated until a desired level of purity is achieved.

[0041] In some embodiments, the washing step of PGG can result in a purity of at least approximately 99.000%, 99.500%, 99.900%, 99.950%, 99.990%, 99.995%, or 99.999%. Purity may be measured as the mass percentage (w / w) of PGG in the sample. The purity of PGG can be measured by any standard means known in the art, including chromatography and nuclear magnetic resonance (NMR) spectroscopy. In some embodiments, the purified PGG may contain approximately 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or less than 1% gallic acid. In some embodiments, the purified PGG may contain approximately 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% or less of methyl gallate.

[0042] Kit for visiting PGG PGG may be prepared in a solution for delivery to the patient as a therapeutic agent. PGG may have the purity described elsewhere in this specification. PGG may be purified by methods disclosed elsewhere in this specification or by other means. In some embodiments, PGG may be dissolved in a hydrolyzing agent for subsequent delivery to the patient. The hydrolyzing agent may contain any solvent or mixture of solvents that readily dissolves PGG and is immiscible with water. In some embodiments, the hydrolyzing agent may be ethanol. In some embodiments, the hydrolyzing agent may be dimethyl sulfoxide (DMSO). In some embodiments, the hydrolyzing agent may be a contrast agent. In some embodiments, the hydrolyzing agent may be a mixture of ethanol, DMSO and / or a contrast agent in any proportion. The hydrolyzing agent may facilitate the dissolution of PGG in more aqueous solutions, where PGG would not normally dissolve at the same concentration without first dissolving in the hydrolyzing agent. PGG may finally be dissolved in a non-toxic aqueous solution suitable for delivery, such as intravascular delivery to the patient. The aqueous solution may be a saline solution known in the art, or another aqueous solution containing a salt configured to maintain physiological equilibrium with the intravascular environment. The volume ratio of the hydrolysant to the saline solution is minimized while maintaining a sufficient volume of hydrolysant to completely dissolve the desired amount of PGG, thereby minimizing any adverse or toxic effects of the hydrolysant to the patient, especially when delivered intravascularly. In some embodiments, the volume-to-volume ratio of saline to hydrolysant may be about 10:1, 25:1, 50:1, 75:1, 100:1, 200:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, or 1000:1 or greater. The total volume of the mixture of hydrolysant and saline (including any other additional components) may be configured to prepare PGG to a desired therapeutic concentration, such as the concentrations described elsewhere in this specification. In some embodiments, PGG may be dissolved in saline or other aqueous solutions without the hydrolysant.In some embodiments, the saline solution may be warmed (e.g., above room temperature or above physiological temperature) to dissolve or assist in dissolving the PGG (or other therapeutic agent). For example, the saline solution may be warmed to at least about 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, or 60°C before dissolving the PGG. In some executions, the therapeutic solution may be raised and / or maintained at a high temperature (e.g., physiological temperature) during delivery.

[0043] In some embodiments, PGG for therapeutic treatment (e.g., purified PGG), including but not limited to those described elsewhere in this specification, may be provided in a kit containing the components necessary to prepare the PGG for delivery in a therapeutic solution. In some embodiments, the kit may contain PGG in solid (dry) form, a hydrolyzing agent, and / or a saline solution. The kit may be configured to optimize storage conditions for the PGG for short-term or long-term storage. In some embodiments, the kit may be configured to store the PGG for up to at least one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, six months, one year, two years, or three years. The kit may contain one or more aliquots of each component in pre-measured amounts or volumes. Each component may be provided in a sealed vial, tube, or other container known in the art. The containers may include plastic and / or glass, respectively. The containers may be configured to protect the components from light and / or other radiation (e.g., colored or shielded). In some embodiments, the kit may be configured for transport. For example, the components may be contained in a box or other container containing a desiccant and / or configured for temperature control. In some embodiments, PGG and / or other components may be supplied in a container purged with air (especially oxygen). The components may be stored under vacuum or purged with an inert gas such as nitrogen or argon. In some embodiments, PGG may be mixed with an antioxidant or other stabilizer in addition to or instead of purging with air. In some embodiments, the antioxidant may include vitamin C, vitamin E, and / or any other antioxidant or stabilizer known in the art and safe for treatment. In some embodiments, PGG may be provided already dissolved in a hydrolyzing agent to a predetermined concentration. In some embodiments, the volume of saline solution provided may be configured to prepare PGG at a desired therapeutic concentration.In some embodiments, the volume of saline may be configured to prepare PGG at the highest therapeutic concentration, allowing the user to dilute PGG with an additional solvent to a desired therapeutic concentration. In some embodiments, the total volume of saline may be configured to prepare PGG at a concentration below the desired concentration, and the user may use only a portion of the volume of saline to prepare PGG at the desired concentration. The saline container may have volume indicators to facilitate measurement of the saline. In some embodiments, the saline may be provided in multiple aliquots of the same and / or different volumes, allowing the user to select an aliquot of a desired volume to prepare PGG at a desired concentration, and / or combine various volumes to prepare PGG at a desired concentration. In some embodiments, the kit may include one or more additional components. For example, the kit may include a contrast agent for mixing with the therapeutic PGG solution to allow for indirect visualization of the therapeutic solution as described elsewhere in this specification.

[0044] Delivery device In some implementations, PGG and / or other therapeutic agents or pharmaceuticals, including but not limited to those described elsewhere herein, may be delivered to the site of an aneurysm, such as an abdominal aortic aneurysm, or to an isolated area of ​​the blood vessel via a catheter device as described herein. Abdominal aortic aneurysms are generally found in the abdominal aorta downstream of the renal artery, above where the aorta branches into the iliac artery. The delivery catheter may be specifically configured (e.g., dimensions) for the delivery of the therapeutic agent to the abdominal aortic aneurysm.

[0045] Figure 2A schematically represents an example of a delivery catheter 100. The delivery catheter 100 may include a proximal end (not shown) configured to remain outside the body during use, and a distal end 102 configured to be located within the vessel near (generally distally) the target aneurysm or target site or area of ​​the vessel to be treated. The delivery catheter 100 may include a main shaft 110, an upstream expandable member 104, and a downstream expandable member 106. The delivery catheter 100 may have a long axis extending from the downstream expandable member 106 to the upstream expandable member 104. The upstream expandable member 104 may be located at or near the distal end 102 of the delivery catheter 100, and the downstream expandable member 106 may be located in close proximity to the upstream expandable member 104. Such a configuration is useful for introducing the delivery catheter 100 from an access point in the vessel downstream of the target aneurysm or vessel site. For example, such a configuration is useful for introducing a delivery catheter 100 through the femoral artery to treat an abdominal aortic aneurysm. In an alternative embodiment, the delivery catheter 100 may be configured for introduction from an upstream location of the target aneurysm or target site of the blood vessel, and the upstream expandable member 104 may be located close to the downstream expandable member 102 relative to the delivery catheter.

[0046] Each expandable member 104, 106 may include an expanding configuration having an expanding radial diameter and an unexpanded configuration having an unexpanded radial diameter, the expanding radial diameter being larger than the unexpanded radial diameter. The length of one or both of the expandable members 104, 106 may increase, decrease, or remain the same during expansion. The unexpanded diameter of each expandable member 104, 106 may be configured to facilitate insertion of the delivery catheter 100 into a blood vessel. The unexpanded diameters may be smaller than, approximately the same as, or larger than the inner and / or outer diameter of the main shaft 110. The expanded diameter of each expandable member 104, 106 may be configured to occlude a target vessel, and may be the same as or larger than the diameter of the target vessel (e.g., the abdominal aorta). In some embodiments, one or both of the expandable members 104, 106 may be operable at an intermediate diameter between the unexpanded diameter and the fully expanded diameter. The unexpanded diameter of the upstream expandable member 104 may be the same as or different from the unexpanded diameter of the downstream expandable member 106. Similarly, the expanded diameter of the upstream expandable member 104 may be the same as or different from the expanded diameter of the downstream expandable member 106.

[0047] In various embodiments, the upstream expandable member 104 may be an inflatable balloon 105, as shown in Figure 2A. In various embodiments, the downstream expandable member 106 may be an inflatable balloon 107, as also shown in Figure 2A. The inflatable balloons 105, 107 may contain an elastic material that forms an expandable member known in the art and may be configured to expand upon pressurization from an expansion fluid (e.g., a gas or a liquid such as saline solution). The balloon material may be biocompatible. In some embodiments, the upstream expandable member 104 and / or the downstream expandable member 106 may be expandable by means other than or in addition to expansion. For example, one or both of the expandable members 104, 106 may include a radially expandable frame. The expandable frame may contain a shape memory material (e.g., nickel-titanium alloy (nitinol)) and / or may be configured to self-expand. One or both of the expandable members 104, 106 may be configured to self-expand upon release of a restraining mechanism, such as an outer sheath surrounding the expandable member, which can be withdrawn proximal to allow the expandable member to self-expand. In some embodiments, one or both of the expandable frames may be configured to expand mechanically, for example, by a push wire or pull wire extending through the internal lumen of the delivery catheter 100. The expandable frames may be fixed to or connected to a surrounding fluid-impermeable shielding or coating so that the expandable members 104, 106 may be configured to block the flow of fluid as described elsewhere in this specification.

[0048] The main shaft 110 of the delivery catheter 100 may extend from the proximal end of the delivery catheter 100 to the downstream balloon 107 (or other downstream expandable member 106). The main shaft 110 may have a length and diameter configured to facilitate navigation of the distal end 102 of the delivery catheter 100 to the target site, which may depend on the specific application and / or the site of access to the blood vessel. In some embodiments, the diameter may vary with the length of the main shaft 110 and / or any internal components, including internal shafts described elsewhere in this specification. For example, the diameter may be decreased from proximal to distal to make the distal portion of the delivery catheter 100 more flexible than the proximal portion. As shown in Figure 2A, the downstream balloon 107 may be attached to the distal end of the main shaft 110. The main shaft 110 may have a first central lumen 112. The main shaft 110 may generally be a tube having side walls that form the central lumen 112 of the first expansion lumen. The first central lumen 112 may function as a first inflation lumen 113 for inflating and / or deflating the downstream balloon 107. The first inflation lumen 113 may be in fluid communication with the internal volume of the downstream balloon 107. An inflation fluid (e.g., saline solution) may be introduced from the proximal end of the delivery catheter 100 through the first inflation lumen 113 into the internal volume of the downstream balloon 107 for inflating or expanding the balloon 107, and may be removed through the first inflation lumen 113 to deflate the balloon 107 (e.g., by aspirating from the balloon 107). The proximal ends of the first inflation lumen 113 and / or any other inflation lumens described herein may each be in fluid communication with a source of pressurized inflation fluid, such as a syringe, IV bag, or fluid pump. One or more of the inflatable lumens and / or balloons described herein may be in fluid communication with one or more pressure sensors for monitoring the pressure level in the internal lumens and / or balloons with which they are in fluid communication. In some embodiments in which the downstream expandable member 106 includes an expandable frame, a pull wire or push wire may extend through a first inflatable lumen 113 for acting as an expansion or compression of the downstream expandable member 106.

[0049] The secondary shaft 114 may extend from the proximal end of the delivery catheter 100 to the upstream balloon 105 (or other upstream expandable member 104). As shown in Figure 2A, the upstream balloon 105 may be attached to the distal end of the secondary shaft 114. In some embodiments, the secondary shaft 114 may extend through a first central lumen 112. The secondary shaft 114 may include a secondary central lumen 116. The secondary shaft 116 can generally be a tube having side walls that form the secondary central lumen 116. The second central lumen 116 may function as a second expansion lumen 117 for inflating and / or deflating the upstream balloon 105. The secondary expansion lumen 116 may be in fluid communication with the interior of the upstream balloon 105. An expansion fluid (e.g., saline solution) may be introduced from the proximal end of the delivery catheter 100 through the secondary expansion lumen 117 into the internal volume of the upstream balloon 105 to inflate or expand the balloon 105, and may be removed through the secondary expansion lumen 117 to deflate the upstream balloon 105 (e.g., by suction from the upstream balloon 105). In some embodiments in which the upstream expandable member 104 includes an expandable frame, a pull wire or push wire may be extended through the secondary expansion lumen 117 to actuate the expansion or compression of the upstream expandable member 104.

[0050] In some embodiments, as shown in Figure 2A, the secondary shaft 114 may extend through the first central lumen 112. In some embodiments, the secondary shaft 114 may be freely positioned within the first central lumen 112 in a substantially concentric manner. In some embodiments, the secondary shaft 114 may be substantially coaxial with respect to the first central lumen 112. A substantially annular lumen may be formed between the inner diameter of the side wall of the main shaft 110 and the outer diameter of the side wall of the secondary shaft 114. Alternatively, the secondary shaft 114 may be connected to the inner diameter of the side wall of the main shaft 110, or formed integrally with it. The distal end of the secondary shaft 114 may extend beyond the distal end of the main shaft 110, or may be configured to extend distally beyond it. The secondary shaft 114 may extend through the central portion of the downstream balloon 107 (or other downstream expandable member 105).

[0051] In some embodiments, as shown in Figure 2A, the secondary shaft 114 may extend through the interior of the downstream balloon 107. The downstream balloon 107 may include an expandable membrane having a proximal end and a distal end. The proximal end of the expandable membrane may be connected to (for example, there or near) the distal end of the main shaft 110. The distal end of the expandable membrane may be connected to the secondary shaft 114 at a point proximal to the upstream balloon 105. The proximal and distal ends of the expandable membrane may be connected to the main shaft 110 and the secondary shaft 114 to form a fluid seal around the outer diameter of the shafts 110 and 114, allowing the expanding fluid to pressurize the internal volume of the downstream balloon 107 and allowing the expandable membrane to expand radially outward between its proximal and distal ends upon introduction of the expanding fluid.

[0052] In some embodiments, the downstream balloon 107 may generally have a donut-shaped configuration, as schematically illustrated in Figure 2B, where the expandable membrane of the downstream balloon 107 has an outer surface and an inner surface, the inner surface forming a closed outer circumference defining a central hole through which the secondary shaft 114 can extend. The downstream balloon 107 may define an annular internal volume configured to be pressurized by the introduction of an expansion fluid from the first expansion lumen 113. In some embodiments, the downstream balloon 107 may be connected to the distal end of the main shaft 110 so as to be in fluid communication with an annular, molded lumen 112 as described with respect to Figure 2A. In some embodiments, the downstream balloon 107 may be connected to the outer circumference of the main shaft 110 so as to be in fluid communication with an expansion port formed in the side wall of the main shaft 110 as described elsewhere in this specification. In some embodiments, the generally donut-shaped downstream balloon 107 may include a distal connection, such as a connecting ring 111, configured to connect the distal end of the downstream balloon 107 to the main shaft 110, the secondary shaft 114, or another component of the delivery catheter 100. The distal connection may orient the downstream balloon 107 in a configuration suitable with respect to the delivery catheter 100. The distal connection may firmly fix the downstream balloon 107 to the component to be connected (e.g., the secondary shaft 114), or it may allow the component to be connected to move axially along the long axis relative to the distal end of the downstream balloon 107, as described elsewhere in this specification. In some embodiments, the inner surface of the expandable membrane of the downstream balloon 107 may be connected (e.g., bonded via adhesive) to the outer diameter of the main shaft 110, the secondary shaft 114, and / or another component of the delivery catheter 100.

[0053] In other embodiments, as shown in Figure 2C, the main shaft 110 may extend distally to or beyond the distal end of the expandable membrane of the downstream balloon 107. In such embodiments, both the proximal and distal ends of the expandable membrane may be connected to the main shaft 110. A first expansion lumen 113 may be formed within the side wall of the main shaft 110 and may be sealed at its distal end to prevent leakage of the expansion fluid. The first expansion lumen 113 may be formed separately from a first central lumen 112. The first expansion lumen 113 may be located radially outside the first central lumen 112. The first central lumen 112 may be configured to receive a secondary shaft 114, as described with respect to Figure 2A. The main shaft 110 may have one or more expansion ports 118 and the first expansion lumen 113 that are in fluid communication with the internal volume of the downstream balloon 107. The expansion ports 118 may pass through the sidewall of the main shaft 110. In some embodiments, multiple expansion ports 118 may be spaced longitudinally along the main shaft 110 between the proximal and distal ends of the expandable membrane. In some embodiments, multiple expansion ports 118 may be spaced radially around the outer diameter of the main shaft 110. The distal end of the main shaft 110 may be located at or immediately beyond the distal end of the downstream balloon 107, as shown in Figure 2C. In some embodiments, the main shaft 110 may extend to the upstream balloon 105. In some embodiments, the first central lumen 112 may be in fluid communication with a sealed volume 142, as described elsewhere in this specification, formed between the upstream balloon 105 and the downstream balloon 107. In some executions, the first central lumen 112 may be used to deliver a therapeutic agent to the sealed volume 142 and / or to draw fluid from the sealed volume 142, as described elsewhere in this specification.

[0054] The delivery catheter 100 includes an intermediate shaft region 120 that extends between the downstream balloon 107 and the upstream balloon 105 (or between other expandable members 104, 106) and is configured to space the upstream balloon 105 distally from the downstream balloon 107. The intermediate shaft region 120 may be connected to the upstream balloon 105 and the downstream balloon 107. In some embodiments, as described with respect to Figure 2A, the secondary shaft 114 may form the intermediate shaft region 120 (or at least an outer component of the intermediate shaft region 120). In some embodiments, the main shaft 110 may form the intermediate shaft region 120 (or at least an outer component of the intermediate shaft region 120) or at least a portion of the length of the intermediate shaft region 120. In some embodiments, a separate tubular connector (not shown) extending from the distal end of the downstream balloon 107 to the proximal end of the upstream balloon 105 may form the outermost component of the intermediate shaft area 120, and the main shaft 110 and / or secondary shaft 114 may pass through the tubular connector.

[0055] The upstream balloon 105 may include an expandable membrane. The expandable membrane of the upstream balloon 105 may contain the same and / or different material as the expandable membrane of the downstream balloon 107. In some embodiments, as shown in Figure 2A, the proximal end of the expandable membrane may be connected (e.g., there or near) to the distal end of the secondary shaft 114, which forms a fluid seal with the secondary shaft 114. The expandable membrane may not be further connected to any portion of the delivery catheter 100 distal to the proximal seal, as shown in Figure 2A, and the upstream balloon 105 may form the most distal portion of the delivery catheter 100. The introduction of the expanding fluid into the internal volume of the upstream balloon 105 may cause the upstream balloon 105 to expand radially and distally. In some embodiments, the proximal end of the upstream balloon 105 may be connected to a shaft located concentrically around the secondary shaft 114, such as the main shaft 110 or a separate tubular connector as described elsewhere herein, rather than the secondary shaft 114 itself. The main shaft 110 or other component to which the upstream balloon 105 is connected can be fluidically sealed (for example, between the inner diameter of the main shaft 110 and the outer diameter of the secondary shaft) so that the expansion fluid introduced into the internal volume of the upstream balloon 105 through the secondary expansion lumen 117 can pressurize the upstream balloon 105.

[0056] In some embodiments, as shown in Figure 2C, the expandable membrane of the upstream balloon 105, like the downstream balloon 107 shown in Figure 2C, can form proximal and distal seals with one or more shafts of the delivery catheter 100. The proximal end of the expandable membrane may be connected to a proximal point on the secondary shaft 114, and the distal end of the expandable membrane may be connected (e.g., there or near) to the distal end of the secondary shaft 114 at a point distal to the proximal point. The proximal and distal ends of the expandable membrane can be connected to the secondary shaft 114 to form a fluid seal around the outer diameter of the shaft 114, allowing the expansion fluid to pressurize the internal volume of the upstream balloon 105, and allowing the expandable membrane to expand radially outward between its proximal and distal ends upon introduction of the expansion fluid. A second expansion lumen 117 may be formed separately from the second central lumen 116, as shown in Figure 2C. The second expansion lumen 117 may be located radially outside the second central lumen 116. The second central lumen 116 may be configured to receive additional components, such as guidewires, as described elsewhere in this specification. In other embodiments, as shown in Figure 2B, the secondary shaft 114 may be sealed at or near its distal end, and the second central lumen 116 may function as the secondary expansion lumen 117. The secondary shaft 114 may have one or more secondary expansion ports 122 and the secondary expansion lumen 117, which are in fluid communication with the internal volume of the upstream balloon 105. The secondary expansion ports 122 may pass through the sidewalls of the secondary shaft 114. In some embodiments, the multiple secondary expansion ports 122 may be spaced longitudinally along the secondary shaft 114 between the proximal and distal ends of the expandable membrane. In some embodiments, the multiple secondary expansion ports 122 may be spaced radially around the outer diameter of the secondary shaft 114. The distal end of the secondary shaft 114 may be located at or immediately beyond the distal end of the upstream balloon 105, as shown in Figure 2C.In some embodiments, as described elsewhere in this specification, additional shafts and / or lumens may extend through the second central lumen 116 of the secondary shaft 114 and distally beyond the secondary shaft 114.

[0057] In some embodiments, the lead area 124, such as a rod, may be located at the distal end of the delivery catheter 100, as schematically shown in Figure 2B. The lead area 124 may be connected to or formed from the distal end of the secondary shaft 114 and / or the distal end of the upstream balloon 105. The lead area 124 may include an intact (e.g., circular) distal end. The lead area 124 can facilitate the introduction and navigation of the delivery catheter 100 within the vascular system. In some embodiments, the lead area 124 may include a radiopaque material.

[0058] In various embodiments, the delivery catheter may be combined with or replaced with various features illustrated and / or described with respect to Figures 2A-2C. For example, the configuration of the upstream balloon 105 and / or downstream balloon 107 in each example may be replaced.

[0059] In some embodiments, the upstream balloon 105 may be configured to fix the delivery catheter 100 within the vascular system, in an expanded configuration which may include full or partial expansion. Fixation of the delivery catheter 100 within the vascular system may allow the downstream balloon 107 and / or other portions of the delivery catheter 100 to be stably positioned in an appropriate location within the vascular system adjacent to the aneurysm or other target site. In the expanded configuration, the upstream balloon 105 may be configured to occlude blood flow (e.g., downstream or anterograde blood flow) within at least a sealed volume between the upstream balloon 105 and the downstream balloon 107. The expandable membrane of the upstream balloon 105 may be sufficiently compliant or adaptable to take the shape of the target vascular system and occlude it. In some embodiments, the upstream balloon 105 may be configured to occlude the abdominal aorta.

[0060] In some embodiments, the downstream balloon 107 may be configured to occlude blood flow (e.g., upstream or retrograde blood flow) in an expanded configuration. In some embodiments, the downstream balloon 107 may be configured to expel blood from the aneurysm sac of the aneurysm. For example, in some executions, the downstream balloon 107 may be aligned with the aneurysm (e.g., the length of the aneurysm may encompass the length of the downstream balloon 107), and inflation or expansion of the downstream balloon 107 may expel blood from the volume of the aneurysm sac. By expelling blood from the aneurysm sac, the effectiveness of delivering the therapeutic agent to the aneurysm (e.g., through the downstream balloon 107) may be improved. For example, the therapeutic agent may not be diluted by the blood in the aneurysm sac, or may be slightly diluted. The expandable membrane of the downstream balloon 107 may be sufficiently compliant or adaptable to take the shape of the target vascular system and occlude it. In some embodiments, the downstream balloon 107 may not be compliant (e.g., a bag member having a membrane enclosing an expandable internal volume), or may not be as compliant as the upstream balloon 105. In some embodiments, the downstream balloon 107 may be equally compliant with the upstream balloon 105. In some embodiments, the downstream balloon 107 may be configured to occlude the abdominal aorta. In some executions, the downstream balloon 107 may require a lower threshold pressure to occlude or fluidly seal retrograde blood flow if antegrade blood flow has already been stopped. For example, the upstream balloon 105 may require an inflation pressure above the systolic blood pressure to maintain its expanded configuration, and the downstream balloon 107 may require a pressure above the diastolic blood pressure to maintain its expanded configuration. In some executions, the roles of the downstream balloon 107 and the upstream balloon 105 may be reversed, for example, when the delivery catheter 100 is introduced from an upstream location.

[0061] In some embodiments, the downstream balloon 107 may be configured to deliver a therapeutic agent, such as a PGG solution, to an aneurysm or other target vascular site. The downstream balloon 107 may be a leachate balloon known in the art. The downstream balloon 107 may include a plurality of pores 126 arranged in the expandable membrane of the balloon, configured to fluidize the internal volume of the downstream balloon 107 with the intravascular environment. The therapeutic agent solution may be used as the inflation fluid. The pores 126 may be configured to provide fluid communication between the internal volume of the downstream balloon 107 and the intravascular environment, while enabling pressurization and inflation of the downstream balloon 107. In some embodiments, the size of the pores 126 may increase as the expandable membrane of the downstream balloon expands. The elastic properties of the expandable membrane of the downstream balloon 107 may allow for continuous expansion of the pore size of the pores 126 as the internal volume of the downstream balloon 107 increases and the expandable membrane stretches. The volumetric flow rate of the inflation fluid leaking from the internal volume of the downstream balloon 107 into the intravascular environment may increase as the balloon 107 expands. In some embodiments, the pore 126 may allow a constant or substantially constant volumetric flow rate of fluid traversing the pore 126 over a range of pressures in the internal volume. The volumetric flow rate out of the downstream balloon 107 may be maximized at some level of pressurization or volumetric flow rate of the inflation fluid into the downstream balloon 107. The inflation fluid may be introduced into the internal volume of the downstream balloon 107 at a volumetric flow rate higher than the volumetric flow rate of the inflation fluid flowing through the pore 126, so that the downstream balloon 107 can expand even while the fluid is leaking or leaking through the pore 126. In some executions, the downstream balloon 107 may be expanded using an inflation fluid without a therapeutic agent (e.g., saline solution). The inflation fluid may be switched with a therapeutic solution, or a therapeutic agent may be added to the inflation fluid after the downstream balloon has expanded and / or after the vessel has been sealed from retrograde blood flow. By staggering the delivery of the therapeutic agent, the agent can be conserved, and / or the amount of the agent released into the bloodstream before a downstream fluid seal is fully formed with the blood vessel can be prevented, reduced, or minimized.

[0062] The pores 126 of the downstream balloon 107 may be uniformly distributed across the entire surface of the downstream balloon 107 or on a portion of the surface. In some embodiments, the pores 126 may be located in the central part of the downstream balloon 107 with respect to its long axis. For example, in some embodiments, the length of the downstream balloon 107 may be configured such that the downstream balloon 107 extends over the entire length of the aneurysm 202 or target region of the blood vessel 200, and when the downstream balloon 107 is expanded to its minimum diameter, as shown in Figure 3A, it may create a sealed space 140 within the aneurysm or region of the blood vessel 200. The downstream balloon 107 may form a fluid seal with the inner diameter of the blood vessel at points proximal and / or distal to the aneurysm. The expandable membrane of the downstream balloon 107 may be configured to partially expand into the sealed space 140, or to expand entirely into the sealed space 140, rather than expanding radially outward into the sealed space 140 between the proximal and distal sealing points, so that the outer surface of the downstream balloon 107 conforms to the shape of the aneurysm 202, depending on the properties (e.g., elasticity) of the expandable membrane of the downstream balloon 107. In some embodiments, the downstream balloon 107 may be sufficiently compliant to conform to the shape of the aneurysm 202 and the vessel wall 200, as shown in Figure 3A. In some embodiments, the expanded downstream balloon 107 may slightly expand the diameter of the vessel wall adjacent to the location where the downstream balloon 107 forms a fluid seal with the aneurysm 202. The pore 126 may be positioned along a central portion configured to be located between the proximal and distal fluid seals, so that at least a portion of the pore 126 is in fluid communication with the sealed space 140 and allows for the delivery of therapeutic inflation fluid to the sealed space 140 or the tissue within the sealed space. In some embodiments, any remaining pores 126 of the downstream balloon 107 that are not in fluid communication with the sealed space 140 may be positioned on the downstream balloon 107 in such a configuration that the pores 126 are configured to exert pressure against the wall of the blood vessel 200 in the expanded configuration.When the downstream balloon 107 is inflated, the back pressure of the vessel wall relative to the outer diameter of the downstream balloon 107 can effectively seal the pores 126 in contact with the vessel wall from the intravascular environment so that the fluid cannot flow through those pores 126 at any significant flow rate. This configuration can prevent or minimize the delivery of the therapeutic agent to non-target volumes of the vessel and / or to downstream portions of the vessel where the therapeutic agent could diffuse into the blood flow in the downstream vascular system. In some embodiments, contact between the therapeutic agent in the inflating fluid and the tissue sealed to the pores 126 can be used to treat the vessel wall. In some embodiments, the multiple pores 126 may be densely spaced across an entire region configured to contact and pressurize the vessel wall, such as a portion of an aneurysm. In some embodiments, the pores 126 may be close to the target vascular tissue (e.g., 0.3 mm or less, 0.2 mm or less, 0.1 mm or less, 0.075 mm or less, 0.05 mm or less, 0.025 mm or less, 0.001 mm or less, etc.), but should not be in substantial contact, thereby reducing the volume of the sealed space 140 between the expandable membrane of the downstream balloon 107 and the vascular wall.

[0063] In some embodiments, the pores 126 may be located along the distal portion of the downstream balloon 107, as shown in Figure 3B. The downstream balloon 107 may be located near the proximal end of a vascular aneurysm or target area and expanded, causing the balloon to form a fluid seal at or near the proximal end of the aneurysm or target portion. The distal portion of the downstream balloon 107 where the pores 126 are located may be located distal to the proximal fluid seal formed by the downstream balloon 107, such that at least a portion of the pores 126 is in fluid communication with the sealed volume 142 between the proximal seal formed by the downstream balloon 107 and the distal seal formed by the upstream balloon 105. The portion of the downstream balloon 107 proximal to the distal portion may not contain pores 126, or may contain fewer pores 126 than the distal portion. In some embodiments, the distal portion may be defined as part of the balloon generally distal to the maximum expanded diameter of the downstream balloon 107. Some pores 126 may be configured to pressurize the vessel wall so that the back pressure of the vessel wall effectively seals the pores 126 from the intravascular environment, as described elsewhere in this specification, forming a proximal fluid seal. This configuration may prevent or minimize the delivery of the therapeutic agent to the downstream portion of the vessel, where the therapeutic agent could diffuse into the blood flow in the downstream vascular system. In some embodiments, the downstream balloon 107 may be configured to be located entirely downstream of the aneurysm, creating a sealed volume 142 between the upstream balloon 105 and the downstream balloon 107 in which the aneurysm is confined.

[0064] In some embodiments, as schematically illustrated in Figure 3C, the downstream balloon 107 may include a length shorter than the length of the aneurysm and may be entirely located within the aneurysm. The expanded configuration of the downstream balloon 107 may be in contact with or in close proximity to the vessel wall of the aneurysm, thereby locating the expandable membrane of the downstream balloon. The delivery catheter 100 may be configured to position the downstream balloon 107 within the aneurysm such that a midpoint along the length of the balloon 107 is substantially aligned longitudinally with a midpoint in the aneurysm, or that a midpoint of the balloon 107 may be located within the proximal or distal portion of the aneurysm. The downstream balloon 107 may be entirely located within the length of the aneurysm, or the balloon 107 may be partially located within the aneurysm and partially outside the aneurysm. In other embodiments, the upstream balloon 105 may be a leachate balloon in addition to or replacing the downstream balloon 107, and may include some or all of the same or similar features described with respect to the downstream balloon 107.

[0065] In some embodiments, including those shown in Figure 2A and optionally in Figures 2B and 2C, the upstream balloon 105 is connected to the downstream balloon 107 in a fixed spatial relationship separated by an intermediate shaft region 120. The length of the intermediate shaft region 120 may be configured such that the downstream balloon 107 is located a specific distance downstream from the upstream balloon 105. For example, the upstream balloon 105 may be fixed within the abdominal aorta between the renal arteries. The upstream balloon 105 may occlude antegrade blood flow from the descending aorta and retrograde blood flow from the renal arteries from flowing toward the downstream balloon 107. The length of the intermediate shaft region 120 may be configured such that the downstream balloon 107 is located near or adjacent to a typical location of an abdominal aortic aneurysm, as in one of the configurations described with respect to Figures 3A-3C. As described elsewhere in this specification, the delivery catheter 100 may be configured such that the downstream balloon 107 is positioned across the aneurysm if the length of the balloon 107 is substantially the same as or longer than the length of the aneurysm, or if it is near the downstream end of the aneurysm. In some executions, the length of the downstream balloon 107 may be shorter than the length of the aneurysm. In some executions, the size (e.g., length) and / or positioning (e.g., length of the intermediate shaft section 120) of the downstream balloon 107 may depend on the size of the aneurysm and / or the stage of progression of the aneurysm. Abdominal aortic aneurysms may increase in size (and the length of the corresponding vessel) over time. Users may choose from various configurations of the delivery catheter 100 configured for aneurysms of different sizes, locations, and / or stages of progression.

[0066] In some embodiments, the separation distance between the upstream balloon 105 and the downstream balloon 107 may be adjustable. For example, in the embodiments illustrated in Figures 2B and 2C, the secondary shaft 114 may optionally be freely movable within the main shaft 110 along the long axis of the delivery catheter 100 so that the distance between the upstream balloon 105 and the downstream balloon 107 is variable and adjustable (e.g., continuously or gradually). The distal end of the main shaft 110 may include a sealing feature located between the inner diameter of the main shaft 110 and the outer diameter of the secondary shaft 114, which allows the secondary shaft 114 to move axially (e.g., slide) relative to the main shaft 110 while preventing or reducing the flow of fluid from the intravascular environment to the first expansion lumen 112. The relative positioning of the main shaft 110 and the secondary shaft 114 may be temporarily locked in place by a locking mechanism located at the proximal end of the delivery catheter 100. In some embodiments, the secondary shaft 114 may be prevented from advancing distally beyond a distal threshold relative to the main shaft 110 and / or retracting proximally beyond a proximal threshold relative to the main shaft 110. For example, in some embodiments, the upstream balloon 105 may not be configured to be withdrawn proximally past the distal end of the main shaft 110. The upstream balloon 105 may not be configured to be received within the first central lumen 112 (e.g., dimensions). In some embodiments, features at the proximal end of the delivery catheter 100 and / or features within the first central lumen 112 between the inner diameter of the main shaft 110 and the outer diameter of the secondary shaft 114 may prevent axial movement in the proximal and / or distal directions beyond a certain point.

[0067] In some embodiments, the secondary shaft 114 may be removable from the first central lumen 112 of the main shaft 110. The secondary shaft 114 may be reversibly insertable into and removable from the main shaft 110. The secondary shaft 114 may be configured to be removed only when the upstream balloon 105 is in an uninflated or compressed state. In some executions, the secondary shaft 114 may be inserted into the main shaft 110 and, after the main shaft 110 has been navigated to a target site in the vascular system or a general target area, may advance distally beyond the distal end of the main shaft 110. In some executions, the main shaft 110 may advance over the secondary shaft 114 after the secondary shaft 114 has been navigated to a target site in the vascular system or a general target area. The delivery catheter 100 may be removed from the vascular system as a single unit after the treatment procedure, or the main shaft 110 or the secondary shaft may be removed thereafter in any order. The expandable members 104 and 106 may be compressed or deflated before the delivery device 100 or its components are removed from the vascular system (for example, balloons 105 and 107 may be deflated).

[0068] In some embodiments, one or more components of the delivery catheter 100 may include radiopaque material, or radiopaque elements (e.g., radiopaque rings) may be added to the delivery catheter 100. For example, radiopaque rings may be added to one or more of the following: the distal end of the main shaft 110, the distal end of the secondary shaft 114, the distal and / or proximal end of the intermediate shaft section 120, and the upstream or downstream balloons 105, 107 (e.g., at the proximal and distal ends of the balloons). The use of radiopaque elements or other detectable elements may enable visual tracking of the delivery catheter within the vascular system by fluoroscopy or other suitable imaging means, and / or enable evaluation of the positioning of the upstream balloon 105 and / or downstream balloon 107 within the vascular system. In some implementations, the inflation fluid of one or both of the upstream balloon 105 and the downstream balloon 107 may contain a contrast agent. The use of contrast agents may allow the user to assess the state or amount of balloon inflation, to determine whether the balloon has occluded the blood vessel, and / or, in the case of the downstream balloon 107, to monitor the delivery of therapeutic agents to the blood vessel and / or aneurysm.

[0069] In some embodiments, the delivery catheter 100 may be used with one or more guidewires to facilitate the introduction and / or navigation of the device into and within the vascular system. In some embodiments, the guidewire may be received in the first central lumen 112, for example, if the secondary shaft 114 is removable from the first central lumen 112, and / or the guidewire may be received in the secondary central lumen 116. In some embodiments, lumens such as the secondary central lumen 116 may be configured to prevent the guidewire from extending distally beyond a certain point along the length of the lumen. For example, the secondary lumen may have a catch or tapered or step-down dimension with a diameter that prevents the guidewire from extending any further distally. The secondary central lumen 116 may be open or closed at the distal end of the secondary shaft 114. The guidewire may be configured to extend distally beyond the distal end of the secondary shaft 114 in embodiments where the central lumen is open distally to the intravascular environment. In some executions, the delivery catheter 100 may be introduced on a guidewire after the guidewire has navigated to or near the target site. In some executions, the delivery catheter 100 may be able to navigate to the target site without using a guidewire. For example, for intra-abdominal aortic application, the delivery catheter 100 may be easily advanced to position via access through the femoral artery without the need for maneuverability. In some embodiments, the delivery catheter 100 may include maneuverable components such as a main shaft 110, which may be configured to bend near the distal end 102 of the device. The delivery catheter 100 may include one or more pull wires extending from or near the distal end 102 of the device to the proximal end of the device. Control operations at the proximal end of the delivery catheter 100 may be configured to bend the distal portion of the delivery catheter 100 in one or more directions. Maneuverability of the delivery catheter 100 may facilitate its introduction and / or navigation.

[0070] In some embodiments, the distal end of the secondary central lumen 116 may be open to the intravascular environment, as shown in Figure 2C. In some embodiments, the distal end of the main internal lumen 112 may be at least partially open to the intravascular environment. In these embodiments, some blood may flow proximally through these lumens across the delivery catheter device. The delivery catheter 100 may be configured such that the blood flow through these lumens does not enter the sealed volume 142 between the expanded upstream balloon 105 and the expanded downstream balloon 107, as described elsewhere in this specification. In some embodiments, the blood flow through the internal lumen of the delivery catheter 100 may be in fluid communication with the proximal end of the delivery catheter 100. In some embodiments, the delivery catheter 100 may include one or more ports (not shown) located close to the downstream balloon 107 that are in fluid communication with the intravascular environment, allowing the blood flow or at least a portion thereof to return to the downstream blood vessel in the sealed volume 142. The first central lumen 112 and / or secondary central lumen 116 may be sealed at the proximal end during use to facilitate blood flow into the space in the downstream vessel rather than through the proximal end of the delivery catheter 100. In some executions, blood flow through these lumens may be negligible. For example, the diameter of the lumen may be small enough that a significant volume of blood is not propelled through the lumen during use of the delivery catheter 100. In some executions, blood flow through these lumens may be significant. In some embodiments, the lumens may be used to maintain blood flow through the aorta during the procedure, which may facilitate blood occlusion and prolong the time of the therapeutic procedure.

[0071] In some embodiments, the lumens described elsewhere in this specification do not have to be formed from the concentric positioning of two or more shafts, but rather may be configured as internal lumens formed as channels within the body of one or more single shafts. For example, the main shaft 110 may extend from the proximal end of the device through the center of the downstream balloon 107 to the upstream balloon 105. The main shaft 110 may include a plurality of internal lumens (e.g., non-concentric lumens) formed within the body material of the main shaft 110. The internal lumens may move substantially parallel to each other. The internal lumens may extend to different lengths along the long axis of the delivery catheter 100. The internal lumens may be in fluid communication with different components of the delivery catheter 100. For example, one internal lumen may be in fluid communication with the upstream balloon 105, and another internal lumen may be in fluid communication with the downstream balloon 107. The main shaft 110 or other shaft components may include additional lumens beyond those described elsewhere in this specification. For example, the delivery catheter 100 may have a lumen configured to receive a guidewire and / or a lumen configured to provide aspiration.

[0072] For example, in some embodiments, the delivery catheter 100 may include a suction lumen that is in fluid communication with a suction port located along the intermediate shaft region 120. Figure 2B schematically shows a replenishment internal lumen 138 that is in fluid communication with a replenishment fluid port 139 located in the intermediate shaft region 120. The replenishment internal lumen 138 may be used as a suction lumen or a drug delivery lumen, as described elsewhere in this specification. In some executions, the suction lumen may be used to aspirate the intravascular environment within a sealed volume between the upstream balloon 105 and the downstream balloon 107. Aspiration of fluid (e.g., blood) from the sealed volume before and / or during the delivery of the therapeutic agent may increase the volume and / or concentration of the therapeutic agent that can be delivered to the sealed volume using the delivery device 100. In some executions, the sealed volume 142 may be aspirated after the procedure using the therapeutic agent and before deflating the upstream balloon 105 and / or the downstream balloon 107. Removal of the therapeutic agent from the intravascular environment before restoring blood flow can eliminate, reduce, or mitigate any downstream and / or non-localization effects that release the therapeutic agent into the bloodstream. In some embodiments, a supplemental internal lumen 138, which is in fluid communication with the sealed volume 142, may be used in addition to or instead of the leachate balloon to deliver the therapeutic agent to the sealed volume 142.

[0073] Figures 4A–4C schematically illustrate an example of a delivery catheter 100 including a third expandable member 108. The third expandable member 108 may be an internal balloon 109, as shown in Figure 4A. Figures 4A and 4B may contain the same or relatively similar features as those described with respect to Figure 2A, and Figure 4B may contain the same or relatively similar features as those described with respect to Figure 2C, except for the inclusion of the internal balloon 109. The internal balloon 109 may be entirely located inside the downstream balloon 105, as shown in Figures 4A–4C. The internal balloon 109 may be in fluid communication with a tertiary expansion lumen 134. As shown in Figure 4A, the tertiary expansion lumen 134 may be formed within the main shaft 110. In some embodiments, the tertiary expansion lumen 134 may be formed radially inside the first expansion lumen 113. The tertiary expansion lumen 134 may be formed by the first central lumen 112, as shown in Figure 4A. In some embodiments, the tertiary expansion lumen 134 may be formed from another tubular component carried into the first central lumen 112 of the main shaft 110.

[0074] The internal balloon 109 may include an expandable membrane. The expandable membrane of the internal balloon 109 may contain the same and / or different material as the expandable membranes of the downstream balloon 107 and / or the upstream balloon 105. In some embodiments, as shown in Figure 4A, the expandable membrane is connected (e.g., there or near) to the secondary shaft 114, forming a fluid seal with the secondary shaft 114, so that the internal volume of the internal balloon 109 can be pressurized. The introduction of the expanding fluid into the upstream balloon 105 may cause the internal balloon 109 to expand radially outward between the tertiary expansion lumen 134 and the distal fluid seal. The distal end of the expandable membrane of the internal balloon 109 may be aligned substantially longitudinally with the distal end of the expandable membrane of the downstream balloon 107, or it may be connected to the secondary shaft 114 at a point proximal to where the expandable membrane of the downstream balloon 107 is connected to the secondary shaft 114.

[0075] In some embodiments, as shown in Figure 4B, the proximal and distal ends of the expandable membrane of the inner balloon 109 may be connected to the secondary shaft 114, forming a fluid seal around the outer diameter of the secondary shaft 114. The distal end of the expandable membrane of the inner balloon 109 may be substantially aligned along its longitudinal axis with the distal end of the expandable membrane of the downstream balloon 107, or connected to the secondary shaft 114 at a point proximal to where the expandable membrane of the downstream balloon 107 is connected to the secondary shaft 114. The proximal end of the expandable membrane of the inner balloon 109 may be substantially aligned along its longitudinal axis with the proximal end of the expandable membrane of the downstream balloon 107, or connected to the secondary shaft 114 at a point distal to the proximal end of the downstream balloon 109. An expansion fluid may be introduced to pressurize the internal volume of the inner balloon 109, allowing the expandable membrane to expand radially outward between the proximal and distal ends of the expandable membrane of the inner balloon 109 upon introduction of the expansion fluid. The expansion fluid can be introduced into the interior of the internal balloon 109 through one or more tertiary expansion ports 136 formed in the sidewall of the secondary shaft 114. The tertiary expansion lumen 134 may be located in the secondary shaft 114 rather than in the main shaft 110. The tertiary expansion ports 136 may pass through the sidewall of the secondary shaft 114. In some embodiments, the multiple tertiary expansion ports 136 may be spaced longitudinally along the secondary shaft 114 between the proximal and distal ends of the expandable membrane of the internal balloon 109. In some embodiments, the multiple tertiary expansion ports 136 may be spaced radially around the outer diameter of the secondary shaft 114.

[0076] In some embodiments, as shown in Figure 4C, the tertiary expansion port 136 may be formed in the side wall of the main shaft 110, and the internal balloon 109 may be connected to the outer diameter of the main shaft 110 at proximal and distal sealing points. In some embodiments, the internal balloon 109 may generally be a donut-shaped balloon, as described elsewhere in this specification with respect to the downstream balloon 107. The donut-shaped internal balloon 109 may be positioned within the internal volume of the downstream balloon 107. In some embodiments, the inner surface of the expandable membrane of the donut-shaped internal balloon 109 may be connected to the main shaft 110 or the secondary shaft 114 at the proximal end, distal end, or along the length or part of the length of the inner surface, depending on the configuration of the delivery catheter 100. In some embodiments, the internal donut-shaped balloon 109 may be connected to the expandable membrane of the downstream balloon 107. In some embodiments, the internal donut-shaped balloon 109 may be connected to the shaft and the expandable membrane of the downstream balloon 107. In some embodiments, the donut-shaped inner balloon 109 may float within the internal volume of the downstream balloon 107. In some embodiments, the downstream balloon 107 may generally be a donut-shaped balloon as described elsewhere in this specification, and the inner balloon 109 may be located within the annular internal volume of the downstream balloon 107. Generally, the donut-shaped inner balloon 109 may be connected to the inner and / or outer surfaces of the expandable membrane of the generally donut-shaped downstream balloon 107, or the inner balloon 109 may float within the annular internal volume of the downstream balloon 107.

[0077] The internal balloon 109 can facilitate the expansion of the downstream balloon 107 and / or the discharge of the expansion fluid (including the therapeutic agent) from the downstream balloon 107. The inclusion and expansion of the internal balloon 109 can advantageously reduce the volume of expansion fluid within the downstream balloon 107 required to expand the downstream balloon and / or allow the expansion fluid to be discharged through the pores 126 of the downstream balloon 107. Reducing the amount of expansion fluid used within the downstream balloon 109 can conserve the therapeutic agent. The use of the internal balloon 109 can reduce the pressure inside the downstream balloon 107 through which the expansion fluid is discharged via the pores 126. In some implementations, the volume of expansion fluid can be introduced into an internal volume of the downstream balloon 107 that is insufficient to fully expand the downstream balloon 107 or to expand the downstream balloon 107 to the inner diameter of the target vessel. The internal balloon 109 can be expanded so that the volume of expansion fluid inside the downstream balloon 107 pressurizes the expandable membrane of the downstream balloon 107, thereby expanding the downstream balloon 107. In some embodiments, the volume of the expanding fluid can be delivered through the pores 126 at a considerable (e.g., non-negligible) rate as soon as the total volume of the inner balloon 109 and the volume of the expanding fluid in the downstream balloon 107 become substantially equal to the internal volume of the downstream balloon 107, or as soon as the reduction in volume available for the volume of the expanding fluid is small enough that the internal pressure in the downstream balloon 107 exceeds a minimum threshold.

[0078] Any or all of the balloons described herein may include a variety of shapes. The balloon shapes of the devices may be the same or different. In various embodiments, the shape of the balloon may be defined by the surface of rotation. In some embodiments, the balloon may include a substantially spherical shape. In some embodiments, the balloon may include a spherical shape such as an elongated spherical shape or an oblate spherical shape. The long axis of the spherical body may be aligned with the long axis of the delivery catheter 100. In various embodiments, the length of the balloon may be longer than the diameter of the balloon in its extended configuration (e.g., elongated spherical). In some embodiments, the balloon may include a pointed football shape. In some embodiments, the balloon may include a cylindrical shape. The balloon may include distinctly different proximal and distal surfaces extending from the long axis of the delivery device 100 that form the outer surface and end of the balloon. The proximal and / or distal surfaces may be substantially flat, generally concave and / or generally convex. The outer surface of the balloon may be extended to a diameter that is larger than, substantially equal to, or smaller than, the diameter of the proximal and / or distal surfaces. The outer surface may generally be flat, concave, or convex. In some embodiments, the pores 126 of the exfiltration balloon may be located on the outer surface of the balloon, or only on the outer surfaces of the proximal and distal surfaces, or only on one of them (e.g., the distal surface of the downstream balloon 107). In some embodiments, the downstream balloon 107 may include one or more internal layers containing internal pores. In some embodiments, the internal pores may generally have a diameter that is larger than or equal to the diameter of the pores 126. The internal pores may function as baffles that can help facilitate the uniform distribution of the expansion fluid (and therapeutic agent) within the downstream balloon 107.

[0079] The outer diameter of the upstream balloon 105 in the expanded configuration (e.g., at the point of its widest point) may be at least approximately 1.5 cm, 1.75 cm, 2.0 cm, 2.25 cm, 2.5 cm, 3.0 cm, or 3.5 cm. The outer diameter of the upstream balloon 105 in the expanded configuration may be configured to match, or slightly exceed, the diameter of a healthy abdominal aorta (e.g., near the renal artery). In some embodiments, the downstream balloon 107 may be configured to expand to the diameter of a healthy aorta, or to a diameter slightly exceeding the diameter of a healthy aorta, so that it can form a fluid seal with the downstream and optionally upstream aorta of the abdominal aortic aneurysm, or with the relatively unexpanded portion or multiple portions of the aneurysm (e.g., near the proximal and / or distal end of the aneurysm). In such embodiments, the outer diameter of the downstream balloon 107 in the expanded configuration may be substantially equal to the outer diameter of the upstream balloon 105, or slightly larger than the outer diameter of the upstream balloon 105 in the expanded configuration. The outer diameter of the downstream balloon 107 in the expanded configuration may be at least approximately 1.5 cm, 1.75 cm, 2.0 cm, 2.25 cm, 2.5 cm, 3.0 cm, 3.5 cm, or 4.0 cm. In embodiments where the downstream balloon 107 is configured to expand the wall into the sac of the abdominal aortic aneurysm, the downstream balloon 107 may have an outer diameter in the expanded configuration that is substantially larger than the outer diameter of the upstream balloon 105. The outer diameter of the downstream balloon 107 in the expanded configuration may be at least approximately 1.5 cm, 1.75 cm, 2.0 cm, 2.25 cm, 2.5 cm, 3.0 cm, 3.5 cm, or 4.0 cm, 4.5 cm, 5.0 cm, 5.5 cm, 6.0 cm, 6.5 cm, 7.0 cm, 7.5 cm, or 8.0 cm. In some embodiments, the expanded diameter of the downstream balloon 107 may be at least about 100%, 125%, 150%, 175%, 200%, 300%, 400%, or 500% of the expanded diameter of the upstream balloon 105.In some embodiments, the total volume of the downstream balloon 107 (e.g., in an expanded configuration) or the fluid-holding capacity of the delivery catheter 100 (e.g., the internal volume of the downstream balloon 107 and the first inflated lumen 113) may be at least about 1 mL, 2 mL, 3 mL, 5 mL, 10 mL, 20 mL, 30 mL, 40 mL, 50 mL, 60 mL, 70 mL, 80 mL, 90 mL, 100 mL, 125 mL, 150 mL, 175 mL, or 200 mL.

[0080] A delivery catheter 100 in which a downstream balloon 107 is expanded into or in contact with an abdominal aortic aneurysm and pressurized may be particularly suitable for aneurysms with a low tendency to rupture. In some cases, the risk of rupture may be characterized by the size of the aneurysm (e.g., maximum diameter). Smaller aneurysms (e.g., approximately 6 cm, 5 cm, 4 cm, or 3 cm or less) may have a lower tendency to rupture. Abdominal aortic aneurysms may tend to grow in size over time, and their tendency to rupture may increase. The vessel wall of the aneurysm may weaken as the aneurysm grows. In some practices, the delivery catheter 100 described herein may be particularly useful for initial intervention of diagnosed abdominal aortic aneurysms.

[0081] The length of the downstream balloon 107 may be at least about 0.5 cm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, or 10 cm. In some embodiments, the length of the downstream balloon 107 may be configured to extend to the length of the abdominal aortic aneurysm, as described elsewhere in this specification. In some embodiments, the abdominal aortic aneurysm may be relatively small or in the early stages of development. In some embodiments, the length of the upstream balloon 105 may be the same as the length of the downstream balloon 107, or it may be shorter than the length of the downstream balloon 107. In some embodiments, the length of the upstream balloon 105 may be at least about 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, or 3 cm. In some embodiments, the upstream balloon 105 may generally have a spherical shape, and the downstream balloon 107 may generally have an elongated spherical shape.

[0082] In embodiments including an internal balloon 109, the internal balloon 109 may have the same or a different shape as the downstream balloon 107. The internal balloon 109 may have the same or a smaller expanded diameter as the downstream balloon 107. The internal balloon 109 may have the same or a smaller length as the downstream balloon 105. The internal balloon 109 may have the same or a smaller maximum internal volume as the downstream balloon 105. In some embodiments, the volume, length, and / or expanded diameter of the internal balloon 109 may be approximately 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% or more of the downstream balloon 107. In embodiments where the length of the internal balloon 109 is shorter than the length of the downstream balloon 107, the internal balloon 109 may be located in the center of the downstream balloon with respect to its long axis, or in the direction of the proximal or distal end of the downstream balloon 107. The proximal end of the inner balloon 109 may or may not be aligned with the proximal end of the downstream balloon 107. The distal end of the inner balloon 109 may or may not be aligned with the distal end of the downstream balloon 107.

[0083] In some embodiments, the unexpanded diameters of the upstream balloon 105, downstream balloon 107, and / or internal balloon 109 of the delivery catheter 100 may be approximately 0.5 mm, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, or 10 mm or less. The unexpanded diameters of one or more balloons may be configured to be received within a concentrically surrounded shaft or lumen of an access sheath.

[0084] In some embodiments, the leachate balloon (e.g., the downstream balloon 107) may contain at least about 5, 10, 20, 30, 40, 50, 100, 200, 300, 500, or 1000 pores 126. The diameters (or maximum diameters) of the individual pores 126 may be the same or different. The diameters of the pores 126 (e.g., in an expanded configuration) may be approximately 0.01 mm, 0.02 mm, 0.03 mm, 0.05 mm, 0.04 mm, 0.05 mm, 0.06 mm, 0.07 mm, 0.08 mm, 0.09 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, or 1 mm or less. In some embodiments, the diameter of the pores 126 in the expanded configuration may be at least about 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, or 10 times the diameter of the pores 126 in the unexpanded configuration. In some embodiments, particularly when the downstream balloon 107 contains a non-compliant expandable membrane, the pores 126 may be the same size regardless of the expansion state. In some embodiments, the pores 126 may be located over the entire length of the downstream balloon 107. In some embodiments, the pores 126 may be located over only approximately 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of the length of the downstream balloon 107 (e.g., in the expanded configuration). In some embodiments, the pores 126 may be located only in the distal portion of the length of the downstream balloon 107, the distal portion including about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% or less of the length of the downstream balloon 107 (e.g., in an extended configuration).

[0085] In some embodiments, the outer diameter of the main shaft 110 may be approximately 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, or 10 mm or less. In some embodiments, the outer diameter of the main shaft 110 may be approximately 9 Fr, 10 Fr, 11 Fr, 12 Fr, 13 Fr, 14 Fr, 15 Fr, 16 Fr, 17 Fr, or 18 Fr. The main shaft 110 may have a sidewall thickness of approximately 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 1.25 mm, 1.5 mm, 1.75 mm, or 2.0 mm or less. The secondary shaft 114 may have an outer diameter substantially equal to or slightly smaller than the inner diameter of the main shaft 110. In some embodiments, the length of the delivery catheter 100 from the proximal end to the distal end 102 may be at least about 20 cm, 25 cm, 30 cm, 35 cm, 40 cm, 45 cm, or 50 cm.

[0086] Various components of the delivery catheter 100 may be manufactured from one or more materials known in the art of catheter design. Materials, particularly those configured to be placed in contact with the intravascular environment, may be manufactured from biocompatible materials. In some embodiments, one or more components of the delivery catheter, such as the main shaft 110 and / or secondary shaft 114, may include polyurethane (PU), polyethylene (PE), polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), other fluoropolymers, polyether block amides (e.g., PEBAX® or Vestamid®), nylon, etc. In various embodiments, the shafts and / or balloons may be chemically and / or mechanically treated / processed (e.g., plasma etching) or coated to provide biocompatibility or mechanical properties (e.g., lubricity and / or hydrophilic surface properties). For example, one or more components of the delivery catheter 100 may be coated with a formulation containing polyethylene glycol (PEG).

[0087] In some embodiments, the delivery catheter 100 may include a handle at its proximal end. The main shaft 110 of the delivery catheter 100 may extend from the distal end of the handle. The main shaft 110 may continue through the handle and / or be in fluid communication with a channel formed within the handle. The handle may include a grip portion for the operator to hold. The handle may be used to advance the delivery catheter 100 distally and / or retract it proximal. In embodiments in which the delivery catheter 100 is maneuverable, the handle may include one or more controls for maneuvering the delivery catheter 100 (e.g., bending its distal end) by controlling the extension and retraction of one or more pull wires. In some embodiments, the handle may include one or more fluid ports that are in fluid communication with one or more internal lumens, such as a first expansion lumen 113 and a secondary expansion lumen 117. The fluid port may include a Luer connector for connecting to a fluid line, such as for supplying expansion fluid to the delivery catheter 100. In some embodiments, the fluid port may include a two-way cock or other valve for regulating the flow of fluid from the fluid source to the handle. The fluid line may extend to a source of pressurized fluid (e.g., expansion fluid), such as a syringe or pump and / or a vacuum source for providing suction. In some embodiments, another fluid port may be configured to receive components of the delivery catheter 100. For example, in an embodiment in which the secondary shaft 114 is removable from the main shaft 110, the secondary shaft 114 may be insertable into the proximal end of the handle through a fluid port that is received by the main shaft 110. The secondary shaft 114 may advance through the fluid port until it extends distally beyond the main shaft 110. The handle may include means for temporarily fixing the relative positioning of the shafts 110, 114, as described elsewhere in this specification.Similarly, in some embodiments, a guidewire may be insertable into the proximal end of the handle through one or more fluid ports that are received in the first central lumen 112 or the secondary central lumen 116. In some embodiments where the expansion fluid is supplied by a pump or mechanized syringe and / or suction is provided, a controller may be present for controlling the flow rate through the internal lumens. The controller may be separate from the handle or may be connected to or integrated with the handle. The handle may include one or more controls for regulating (e.g., increasing, decreasing, stopping, and / or starting) the flow rate of the expansion fluid and / or the vacuum pressure supplied to one or more internal lumens. In some embodiments, the controls may be separate from the handle (e.g., as part of a remote controller).

[0088] Delivery method In some executions, the delivery catheter 100 described elsewhere herein, or a device having similar features to the delivery catheter 100, may be used to therapeutically treat an aneurysm or target site in a blood vessel by delivering a therapeutic agent to the aneurysm or target site. This specification describes an example of treating an abdominal aortic aneurysm using the delivery catheter 100 to deliver a therapeutic solution containing PGG. Variations of the procedure described herein may also be included. In some executions, a device different from the delivery catheter 100 may be used. In some executions, a therapeutic agent other than PGG, or a therapeutic agent in addition to PGG, may be delivered. In some executions, the therapeutic agent may be delivered to a blood vessel or body cavity other than the aorta. In some executions, the procedure may be applied for a different type of aneurysm, or for the treatment of a healthy blood vessel wall or region of a blood vessel that does not contain an aneurysm and is suffering from a different pathological condition, and / or the therapeutic agent may be intended to be delivered across the blood vessel wall to target the cellular or extracellular environment adjacent to the blood vessel.

[0089] Methods for treating abdominal aortic aneurysms are described herein. The methods may include, or omit, any of the steps described elsewhere in this specification with respect to the delivery catheter 100. In some embodiments, the delivery catheter 100 is introduced into the patient's femoral artery. The delivery catheter 100 may be introduced using all expandable components in an unexpanded configuration (e.g., the upstream balloon 105 and the downstream balloon 107). The delivery catheter 100 may be introduced through an optional access sheath. The distal end 102 of the delivery catheter 100 may be navigated to the abdominal aorta and the upstream balloon 105 located upstream of the target abdominal aneurysm. In some embodiments, a guidewire may be navigated to the target location, and the delivery catheter 100 may be introduced on the guidewire as described elsewhere in this specification. In some embodiments, the delivery catheter 100 may be received on a guidewire using a guidewire to maneuver the distal end 102 of the delivery catheter 100, and may be navigated to the target location simultaneously with the guidewire. In some embodiments, the delivery catheter 100 may be introduced without the use of a guidewire. The upstream balloon 105 may be located approximately between the renal arteries. Partial inflation of the upstream balloon 105 into the renal artery may help to secure the balloon. The total procedure time may be sufficiently short (e.g., 2-3 minutes or less), as described elsewhere herein, so that occlusion of blood flow to the renal artery can be safely maintained during the procedure. In some embodiments, the upstream balloon 107 may be secured downstream of the renal artery. Securement within a location downstream of the renal artery may allow for a longer operating time while the blood flow is occluded. The upstream balloon 105 may be inflated by introducing inflation fluid into the upstream balloon 105. The upstream balloon 105 may be inflated until the delivery catheter 100 is securely secured to the vessel and / or until the blood flow downstream of the upstream balloon 105 is occluded. In some embodiments, the operation may be performed under indirect visualization, such as fluoroscopy.A suitable contrast agent for visualization (e.g., a radiographic contrast medium for fluoroscopy) may be injected into the bloodstream before and / or during the procedure to visualize the blood flow. Thus, blood flow occlusion can be visually assessed by indirect visualization.

[0090] The downstream balloon 107 may be located in, downstream of, or along the downstream end of the abdominal aneurysm. In embodiments in which the length of the intermediate shaft section 120 is adjustable, the delivery catheter 100 may be adjusted so that the downstream balloon 107 is positioned after the upstream balloon 105 has been fixed in place. The downstream balloon 107 may be inflated by introducing inflation fluid into the upstream balloon 105. The downstream balloon 107 may be inflated until retrograde blood flow is occluded from downstream of the downstream balloon 107. Injection of contrast agent into the blood flow may be used to confirm the occlusion of blood flow as described elsewhere in this specification. Inflation of the upstream balloon 105 and the downstream balloon 107 may create a fluidly sealed volume 142 within the vascular region between the two balloons 105, 107. In some executions, the downstream balloon 107 may be inflated immediately after the inflation of the upstream balloon 105 so that the amount of retrograde blood flow into the sealed volume is prevented or minimized before the inflation of the downstream balloon 107 is complete. In some embodiments, the upstream balloon 105 and the downstream balloon 107 may be partially inflated sequentially or simultaneously, and then the upstream balloon 105 may be further expanded to block the anterograde flow, and then the downstream balloon 107 may be further expanded to block the retrograde flow. In some embodiments, the downstream balloon 107 may be inflated at the same time as, or before, the inflation of the upstream balloon 105.

[0091] In some embodiments, the delivery catheter 100 may include an internal balloon 109 located within the downstream balloon 107, as described elsewhere in this specification. In some embodiments, the internal balloon 109 may be partially or completely inflated before the expansion fluid is introduced into the downstream balloon 107. In some embodiments, the downstream balloon 107 may be filled with the volume of the expansion fluid before or simultaneously with the expansion of the internal balloon 109. The first expansion lumen 113 may be configured at a proximal end to prevent unintended proximal flow of the expansion fluid resulting from the expansion of the internal balloon 109. For example, the expansion fluid line may be clamped, or pressure may be maintained in the syringe to prevent fluid flow of the proximal expansion fluid from the downstream balloon 107 as the internal balloon 109 expands. By preventing or inhibiting the proximal flow of the expansion fluid, the expansion of the internal balloon 109 can effectively facilitate the discharge of the volume of the expansion fluid into the downstream balloon 107 through the pore 126. In some embodiments, the inflation fluid communicating with the downstream balloon 107 may be switched to a solution containing a therapeutic agent after or during the inflation of the downstream balloon 107, or the therapeutic agent may be added to the inflation fluid during or after the inflation of the downstream balloon 107, as described elsewhere in this specification. In some embodiments, the initial volume of the inflation fluid introduced into the downstream balloon 107 may contain a therapeutic agent.

[0092] During inflation of the downstream balloon 107 or the downstream balloon 107 and the inner balloon 109, the inflation fluid in the downstream balloon 107 or a portion thereof may be discharged into the intravascular environment through the pores 126 or a portion of the pores 126. The pores 126 may be located on the surface of the expandable membrane of the downstream balloon 127 so that at least a portion, but not all or most, of the delivered inflation fluid is delivered to a sealed volume 142 or a sub-volume thereof between the upstream balloon 105 and the downstream balloon 107. The sub-volume may be a sealed volume (e.g., a sealed space 140) formed by the downstream balloon 107 positioned in contact with a blood vessel. In embodiments without the inner balloon 109, the inflation fluid containing the therapeutic agent may continue to be supplied to the downstream balloon 107 at a pressure or volumetric flow rate configured to maintain the downstream balloon 107 in the expanded configuration after inflation. The delivery device 100 may be configured to provide an injection of the therapeutic agent at a constant pressure. The introduction of the therapeutic inflating fluid into the downstream balloon 107 may be maintained for a sufficiently long time to deliver the therapeutic inflating fluid through the pores 126 and / or to deliver a predetermined volume of the therapeutic inflating fluid through the pores 126 for a desired period of time. In embodiments including an inner balloon 109, the therapeutic inflating fluid may continue to be introduced into the downstream balloon 107 after the downstream balloon 107 and the inner balloon 109 have been inflated. In some embodiments, the volume of the inflating fluid in the downstream balloon 107 may not need to be replenished because the inner balloon 109 expands to discharge the therapeutic inflating fluid through the pores 126.

[0093] In some embodiments, the therapeutic agent may be PGG. PGG may be dissolved in a therapeutic swelling solution at a final concentration of approximately 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% (w / v) or higher. As described elsewhere in this specification, higher concentrations of PGG may provide a more effective treatment, particularly over shorter treatment times. Therefore, higher concentrations may allow for shorter treatment substitutions. Higher purity PGG may be less toxic than lower purity PGG due to the absence of toxic impurities. Therefore, higher purity PGG may be safer to the user at higher concentrations than lower purity PGG. PGG may be dissolved in a swelling fluid such as saline solution (e.g., by a hydrolyzing agent as described elsewhere in this specification). The volume of the therapeutic inflating fluid delivered may be approximately 150 mL, 125 mL, 100 mL, 75 mL, 50 mL, 40 mL, 30 mL, 20 mL, 15 mL, 10 mL, 8 mL, 5 mL, 3 mL, or 1 mL or less. In some embodiments, the inflating fluid may be delivered through the downstream balloon 107 until the sealed volume described elsewhere in this specification is filled. In some embodiments, the volume filling may be detectable by an increase in resistance (constant pressure) to the delivery of the inflating fluid. In some embodiments, the volume filling may be visually recognizable if the inflating fluid contains a detectable contrast agent. The delivery time may be approximately 30 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, 45 seconds, 30 seconds, 20 seconds, or 10 seconds or less. The delivery time may be shorter in embodiments in which the renal artery is occluded by the delivery catheter 100. In some executions, procedures involving aortic occlusion of approximately 10 minutes or less may be advantageously performed without the need for general anesthesia. The exact volume of the fluid delivered and / or the delivery time may depend on the size of the aneurysm or the volume of the treated area of ​​the treated blood vessel. In some embodiments, the therapeutic inflation solution may be delivered to the downstream balloon 107 at a volumetric flow rate of approximately 0.05 mL / min to 20 mL / min, 0.1 mL / min to 10 mL / min, 0.5 mL / min to 8 mL / min, or 1 mL / min to 5 mL / min during the delivery of the therapeutic agent to the blood vessel.In some embodiments, the downstream balloon 107 may be inflated by the delivery of the expansion fluid at the same volumetric flow rate that will be introduced during the delivery of the therapeutic agent after expansion. In some embodiments, the downstream balloon 107 may be inflated at a faster volumetric flow rate than the volumetric flow rate of delivery after expansion. A faster flow rate during the expansion of the downstream balloon 105 may facilitate the expansion of the balloon as the expansion fluid leaks out through the pores 126.

[0094] By inflating the upstream balloon 107 and occluding the downstream blood flow before the expansion of the downstream balloon 105, the back pressure required to cause the expansion of the downstream balloon 107 in the intravascular environment can be advantageously reduced. After the downstream blood flow is occluded, the downstream balloon 107 may expand to exceed the patient's diastolic blood pressure (e.g., approximately 60–80 mmHg), but if the downstream blood flow is not occluded, it may be necessary to exceed the systolic pressure (e.g., approximately 90–120 mmHg). Therefore, occluding the downstream blood flow before the expansion (or complete expansion) of the downstream blood flow can facilitate the expansion of a leachate balloon such as the downstream balloon 107, from which pressure can be continuously released.

[0095] In some embodiments, a blood vessel or a portion thereof (e.g., a sealed volume 142 between the upstream balloon 105 and the downstream balloon 107) may be rinsed before or after the delivery of the therapeutic agent. A rinsing solution (e.g., saline solution) may be introduced into the intravascular space through the downstream balloon 107 before (e.g., during the dilation described elsewhere in this specification) or after the delivery of the therapeutic agent. In some embodiments, the rinsing solution may be introduced through a separate internal lumen described elsewhere in this specification. For example, the rinsing solution may be introduced into the sealed volume through a fluid port located along the intermediate shaft area 120.

[0096] In some embodiments, fluid within a blood vessel or a portion thereof (e.g., a sealed volume 142 between the upstream balloon 105 and the downstream balloon 107) may be aspirated through the delivery catheter 100. For example, aspiration may be provided through a separate internal lumen via an aspiration port located along the intermediate shaft section 120, as described elsewhere in this specification. In some embodiments, the sealed volume 142 may be aspirated to remove any blood and / or rinse solution before delivery of the therapeutic agent. In some embodiments, the sealed volume 142 may be rinsed concurrently with the delivery of the therapeutic agent (e.g., continuously or intermittently) so that a fresh volume of therapeutic inflation fluid is introduced into the space within the blood vessel. In some embodiments, the sealed volume 142 may be aspirated to remove the therapeutic agent and / or rinse solution before deflating the upstream balloon 105 and / or the downstream balloon 107. Aspiration may advantageously prevent off-target delivery of the therapeutic agent to blood vessels or other parts of the body by releasing the therapeutic agent into the bloodstream as balloons 105, 107 deflate.

[0097] Upon completion of the therapeutic procedure, the expandable members 104 and 106 may be compressed or deflated to allow for the removal of the delivery catheter 100 from the vascular system. The upstream balloon 105 and the downstream balloon 107, and / or the internal balloon 109, may be deflated by withdrawing the inflation fluid proximal to the first inflation lumen 113 and the secondary inflation lumen 117, respectively. In some embodiments, the downstream balloon 107 may be deflated, or at least partially deflated, by forcibly passing all or part of the inflation fluid through the pores 126 of the expandable membrane without replenishing the inflation fluid within the downstream balloon 107. The upstream balloon 105 may be deflated before, after, or substantially simultaneously with the deflation of the downstream balloon 107. The internal balloon 109, if present, may be deflated before or substantially simultaneously with the downstream balloon 107. When the balloons are deflated, blood flow may be restored in the portion of the aorta downstream of each balloon. The total time during which blood flow is blocked may be approximately 30 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, 45 seconds, 30 seconds, 20 seconds, or 10 seconds or less.

[0098] The delivery catheter 100 can be removed from the body by withdrawing it proximal through a vascular access point. In some embodiments, the delivery catheter 100 includes multiple components (e.g., a main shaft 110 and a secondary shaft 114 are separable) or is used in conjunction with accessory components (e.g., an access sheath and / or guidewire), the components may be withdrawn in the reverse order in which they were introduced, the components may be withdrawn in different orders, and / or the components or their subgroups may be withdrawn simultaneously. In some embodiments, one or both of the expandable members 104, 106 may need to be positioned in an unexpanded configuration or at least partially de-expanded in order to withdraw the delivery catheter 100.

[0099] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which this disclosure pertains. All patents, applications, published applications and other publications are incorporated by reference in their entirety. Where multiple definitions of a term exist herein, the definitions in this section shall prevail unless otherwise specified.

[0100] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers, or as mixtures of such isomers, including racemates. Separation of individual isomers, or selective synthesis of individual isomers, can be achieved by applying various methods well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms, including any polymorphs, are included within the scope of the compounds disclosed herein. In addition, some of the compounds disclosed herein may form solvates (i.e., hydrates) with water or with common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein.

[0101] Those skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of compounds that can be correctly represented by other chemical structures, even if kinetically, and that such structures may represent only a very small portion of a sample of such compounds. Such compounds are considered to fall within the range of the depicted structures, but such resonance forms or tautomers are not represented herein.

[0102] Isotopes may be present in the compounds described. Each chemical element represented in the structure of a compound may contain any isotope of that element. For example, in the structure of a compound, it may be explicitly disclosed or understood that a hydrogen atom is present in the compound. At any position in a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, references to compounds herein encompass all possible isotopic forms unless the context explicitly indicates otherwise.

[0103] As used herein, the term “solvate” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and should not be limited to any specific or special meaning), and refers to a compound formed by the interaction of a solvent with a compound or a salt thereof described herein. A suitable solvate is a pharmaceutically acceptable solvate, including a hydrate.

[0104] As used herein, the term “pharmaceutically acceptable salt” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and should not be limited to any specific or special meaning), and refers to a salt of a compound that retains the bioefficiency and properties of the compound, but is not biologically or otherwise undesirable for use in pharmaceuticals. In many cases, the compounds disclosed herein can form salts of acids and / or bases in the presence of an amino group and / or a carboxyl group or a similar group. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Examples of inorganic acids that can derivate salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids that can derivate salts include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Examples of inorganic bases that can derivate salts include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, with salts of ammonium, potassium, sodium, calcium, and magnesium being particularly preferred. Examples of organic bases that can derivate salts include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, with examples of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine being particularly noteworthy. Many such salts are known in the art, as described in Johnston et al.'s International Publication No. 87 / 05297, published on September 11, 1987 (the entire publication is incorporated herein by reference).

[0105] As used herein, "a" and "b" are integers. a ~C b " or "C a~b" refers to the number of carbon atoms in the specified group. That is, the group can contain carbon atoms from "a" to "b". Therefore, for example, "C1~C4 alkyl" or "C 1~4 The "alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, (CH3)2CHCH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0106] As used herein, the terms “halogen” or “halo” are broad terms and should be given their common and idiomatic meanings to those skilled in the art (and should not be limited to any specific or special meaning), and, without limitation, refer to any one of the radioactively stable atoms in the seventh column of the periodic table of elements, such as fluorine, chlorine, bromine, or iodine.

[0107] As used herein, “alkyl” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), and refers to a fully saturated (i.e., without containing double or triple bonds) linear or branched hydrocarbon chain. Alkyl groups may have 1 to 20 carbon atoms (wherever it appears herein, numerical ranges such as “1 to 20” refer to each integer within a given range; for example, “1 to 20 carbon atoms” means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms, but this definition also extends to instances of the term “alkyl” where no numerical range is specified). Alkyl groups may also be intermediate-sized alkyl groups having 1 to 9 carbon atoms. Alkyl groups may also be lower alkyl groups having 1 to 4 carbon atoms. 1~4 It may be specified as "alkyl" or a similar designation. Just as an example, "C 1~4The term "alkyl" indicates that the alkyl chain contains 1 to 4 carbon atoms; that is, alkyl chains are selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups are by no means limited, but include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl.

[0108] As used herein, “haloalkyl” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), referring to an alkyl moiety substituted with at least one halo group. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, or -CH2CF2CF3.

[0109] As used herein, “alkoxy” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to, formula -OR (wherein R is alkyl as defined above), for example, “C 1~9 The term "alkoxy" refers to, but is not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy, among others.

[0110] As used herein, “alkylthio” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to, formula -SR (wherein R is alkyl as defined above), for example, “C 1~9This term refers to, but is not limited to, alkylthio compounds, and includes methyl mercapto, ethyl mercapto, n-propyl mercapto, 1-methylethyl mercapto (isopropyl mercapto), n-butyl mercapto, isobutyl mercapto, sec-butyl mercapto, tert-butyl mercapto, etc.

[0111] As used herein, “alkenyl” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and should not be limited to any specific or special meaning), referring to a linear or branched hydrocarbon chain containing one or more double bonds. An alkenyl group may have 2 to 20 carbon atoms, but this definition also extends to instances of the term “alkenyl” where no numerical range is specified. An alkenyl group may also be an intermediate-sized alkenyl having 2 to 9 carbon atoms. An alkenyl group may also be a lower alkenyl having 2 to 4 carbon atoms. An alkenyl group is a “C 2~4 It may be designated as "Alkenil" or a similar designation. Just as an example, "C 2~4 The term "alkenyl" indicates that the alkenyl chain contains 2 to 4 carbon atoms. Specifically, the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groups are by no means limited, but include ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0112] As used herein, “alkynyl” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and should not be limited to any specific or special meaning), and refers to a linear or branched hydrocarbon chain containing one or more triple bonds. An alkynyl group may have 2 to 20 carbon atoms, but this definition also extends to occurrences of the term “alkynyl” where no numerical range is specified. An alkynyl group may also be an intermediate-sized alkynyl having 2 to 9 carbon atoms. An alkynyl group may also be a lower alkynyl having 2 to 4 carbon atoms. An alkynyl group is a “C 2~4 It may be designated as "Alkinyl" or a similar designation. Just as an example, "C 1~4 The term "alkynyl" indicates that the alkynyl chain contains 2 to 4 carbon atoms. That is, the alkynyl chain is selected from the group consisting of ethynyl, propyne-1-yl, propyne-2-yl, butyne-1-yl, butyne-3-yl, butyne-4-yl, and 2-butynyl. Typical alkynyl groups are by no means limited, but include ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0113] As used herein, the term “aromatic” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), and refers to a ring or ring system having a conjugated pi-electron system, including both carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent atoms) groups, provided that the entire ring system is aromatic.

[0114] As used herein, “aryl” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and should not be limited to any specific or special meaning), and refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) containing only carbon atoms in its ring skeleton, but not limited to these. If the aryl is a ring system, all rings in the system are aromatic. An aryl group may have 6 to 18 carbon atoms, but this definition also extends to instances where the term “aryl” does not specify a numerical range. In some embodiments, an aryl group has 6 to 10 carbon atoms. An aryl group is “C 6~10 "Aryl", "C6 or C 10 It may be designated as "aryl" or a similar designation. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azlenyl, and anthracenyl.

[0115] As used herein, “aryloxy” and “arylthio” are broad terms and should be given to those skilled in the art their ordinary and conventional meanings (and not limited to specific or special meanings), but not limited to RO- and RS- (wherein R is aryl as defined above), for example, “C 6~10 "aryloxy" or "C 6~10 This refers to, and is not limited to, "arylthio" and other similar compounds, but includes phenyloxy.

[0116] As used herein, “aralkyl” or “arylalkyl” are broad terms and should be given to those skilled in the art their common and conventional meanings (and not limited to specific or special meanings), and not limited to, but including aryl groups bonded via alkylene groups as substituents, for example, “C 7~14 The term "aralkyl" refers to, but is not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl groups. In some cases, the alkylene group is a lower alkylene group (i.e., C 1~4 (Alkylene group)

[0117] As used herein, “alkylene” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and should not be limited to any specific or special meaning), and refers to a branched or linear fully saturated diradical chemical group (i.e., alkanediyl) containing only carbon and hydrogen, bonded to the remainder of the molecule via two bonds. An alkylene group may have 1 to 20 carbon atoms, but this definition also extends to occurrences of the term “alkylene” where no numerical range is specified. An alkylene group may also be an intermediate-sized alkylene having 1 to 9 carbon atoms. An alkylene group may also be a lower alkylene having 1 to 4 carbon atoms. An alkylene group is “C 1~4 It may be specified as "alkylene" or a similar designation. Just as an example, "C 1~4 "Alkylene" indicates that there are 1 to 4 carbon atoms in the alkylene chain, that is, the alkylene chain is selected from the group consisting of methylene, ethylene, ethane-1,1-diyl, propylene, propane-1,1-diyl, propane-2,2-diyl, 1-methylethylene, butylene, butane-1,1-diyl, butane-2,2-diyl, 2-methylpropane-1,1-diyl, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, and 1-ethylethylene.

[0118] As used herein, “heteroaryl” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and should not be limited to any specific or special meaning), and refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) containing one or more heteroatoms in the ring skeleton, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. If the heteroaryl is a ring system, all rings in the system are aromatic. A heteroaryl group may have 5 to 18 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), but this definition also extends to occurrences of the term “heteroaryl” without a specified numerical range. In some embodiments, a heteroaryl group has 5 to 10 ring members or 5 to 7 ring members, each containing one or more nitrogen, oxygen, and sulfur in the ring skeleton. A heteroaryl group may be designated as a “5-7 membered heteroaryl,” a “5-10 membered heteroaryl,” or similar designations. Examples of heteroaryl rings, though not limited to them, include furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0119] As used herein, “heteroaralkyl” or “heteroarylalkyl” are broad terms and should be given their common and conventional meanings to those skilled in the art (and not limited to any specific or special meaning), and refer to heteroaryl groups bonded via an alkylene group as a substituent, but not limited to these. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C1~4 (Alkylene group)

[0120] As used herein, “carbocyclyl” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), referring to a non-aromatic cyclic ring or cyclic system containing only carbon atoms in its cyclic framework. If a carbocyclyl is a cyclic system, two or more rings may be linked together by condensation, bridging, or spirobonding. A carbocyclyl may have any degree of saturation, provided that at least one ring in the cyclic system is non-aromatic. Therefore, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. A carbocyclyl group may have 3 to 20 carbon atoms, but this definition also applies to instances where the term “carbocyclyl” does not specify a numerical range. A carbocyclyl group may also be an intermediate-sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl group may also be a carbocyclyl having 3 to 6 carbon atoms. 3~6 It may be designated as "carbocykrill" or a similar designation. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydroindene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0121] As used herein, “cycloalkyl” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), referring to, but not limited to, a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0122] As used herein, “cycloalkenyl” is a broad term and should be given its ordinary and idiomatic meaning to those skilled in the art (and not limited to any specific or special meaning), and refers to a carbocyclyl ring or ring system having at least one double bond, wherein the ring in the ring system is non-aromatic. An example is cyclohexenyl.

[0123] As used herein, “heterocyclyl” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), and refers to a non-aromatic cyclic ring or cyclic system containing at least one heteroatom in its cyclic framework. Heterocyclyls may be linked together by condensation, bridging, or spirobonding. Heterocyclyls may have any degree of saturation, provided that at least one ring in the cyclic system is non-aromatic. Heteroatoms may be present in either a non-aromatic or aromatic ring in the cyclic system. A heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms constituting the cyclic framework, including carbon atoms and heteroatoms), but this definition also extends to instances where the term “heterocyclyl” does not specify a numerical range. A heterocyclyl group may also be an intermediate-sized heterocyclyl having 3 to 10 ring members. A heterocyclyl group may also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be specified as a "3- to 6-membered heterocyclyl" or a similar designation. In a preferred 6-membered monocyclic heterocyclyl, the heteroatoms are selected from one to a maximum of three O, N, or S atoms, and in a preferred 5-membered monocyclic heterocyclyl, the heteroatoms are selected from one or two heteroatoms selected from O, N, or S atoms.Examples of heterocyclyl rings, though not limited to them, include azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanil, imidazolinyl, imidazolidinyl, morpholinil, oxylanil, oxepanil, thiepanil, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxynyl, 1,3-dioxanyl, 1,4-dioxynyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trio Examples include xanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiadinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0124] As used herein, “acyl” is a broad term and should be given its ordinary and idiomatic meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to, -C(=O)R(wherein R is hydrogen, C as defined herein). 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. Non-exclusive examples include formyl, acetyl, propanoyl, benzoyl, and acrylic.

[0125] As used herein, the “O-carboxyl” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to the “-OC(=O)R” group (wherein R is hydrogen, C as defined herein). 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines).

[0126] As used herein, the “C-carboxyl” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to the “-C(=O)OR” group (wherein R is hydrogen, C as defined herein). 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines). A non-restrictive example is carboxyl (i.e., -C(=O)OH).

[0127] As used herein, the “cyano” group is a broad term and should be given its common and idiomatic meaning to those skilled in the art (and not limited to any specific or special meaning), and refers to, but is not limited to, the “-CN” group.

[0128] As used herein, the "cyanato" group is a broad term and should be given its ordinary and idiomatic meaning to those skilled in the art (and not limited to any specific or special meaning), and refers to the "-OCN" group, but is not limited to this.

[0129] As used herein, the “isocyanato” group is a broad term and should be given its common and idiomatic meaning to those skilled in the art (and not limited to any specific or special meaning), and refers to, but is not limited to, the “-NCO” group.

[0130] As used herein, the “thiocyanato” group is a broad term and should be given its common and idiomatic meaning to those skilled in the art (and not limited to any specific or special meaning), and refers to, but is not limited to, the “-SCN” group.

[0131] As used herein, the “isothiocyanate” group is a broad term and should be given its common and idiomatic meaning to those skilled in the art (and not limited to any specific or special meaning), and refers to, but is not limited to, the “-NCS” group.

[0132] As used herein, the “sulfinyl” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to the “-S(=O)R” group (wherein R is hydrogen, C as defined herein). 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines).

[0133] As used herein, the “sulfonyl” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to the “-SO2R” group (wherein R is hydrogen, C as defined herein). 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines).

[0134] As used herein, the “S-sulfonamide” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to “-SO2NR A R B ” group (wherein, R A and R B Each is independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines).

[0135] As used herein, the “N-sulfonamide” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to “-N(R A )SO2R B ” group (wherein, R A and R B Each is independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines).

[0136] As used herein, the “O-carbamyl” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to “-OC(=O)NR A R B ” group (wherein, R A and R B Each is independently, as defined herein, hydrogen, C 1~6 Alkyl, C2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines).

[0137] As used herein, the “N-carbamyl” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to “-N(R A )C(=O)OR B ” group (wherein, R A and R B Each is independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines).

[0138] As used herein, the “O-thiocarbamyl” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to “-OC(=S)NR A R B ” group (wherein, R A and R B Each is independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines).

[0139] As used herein, the “N-thiocarbamyl” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to “-N(RA )C(=S)OR B ” group (wherein, R A and R B Each is independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines).

[0140] As used herein, the “C-amide” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to “-C(=O)NR A R B ” group (wherein, R A and R B Each is independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines).

[0141] As used herein, the “N-amide” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to “-N(R A )C(=O)R B ” group (wherein, R A and R B Each is independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryls (selected from 5-10 membered heteroaryls and 5-10 membered heterocyclines).

[0142] As used herein, the “amino” group is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), but not limited to “-NR”. A R B ” group (wherein, R A and R B Each is independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to aryl molecules (selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl molecules). A non-limiting example is free amino acids (i.e., -NH2).

[0143] As used herein, the “aminoalkyl” group is a broad term and should be given its common and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), and refers to an amino group linked via an alkylene group.

[0144] As used herein, the term “alkoxyalkyl” is a broad term and should be given its common and conventional meaning to those skilled in the art (and not limited to any specific or special meaning), and not limited to, an alkoxy group bonded via an alkylene group, for example, “C 2~8 This refers to terms such as "alkoxyalkyl."

[0145] As used herein, "haloalkoxy" refers to the formula -OR (wherein R is a haloalkyl as defined above, e.g., -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, or -CH2CF2CF3).

[0146] As used herein, the term “substituted” in substituted groups is a broad term and should be given its ordinary and idiomatic meaning to those skilled in the art (and should not be limited to any specific or special meaning), and refers to a group derived from an unsubstituted parent group in which there is an exchange of one or more hydrogen atoms with another atom or group. Unless otherwise indicated, when a group is considered to be “substituted,” it means that the group is substituted with C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclyl-C1-C6 alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 halo (may be substituted with alkoxy), 5-10 member heterocyclyl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 member heterocyclyl-C1-C6-alkyl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C 6-haloalkyl and C1-C6 haloalkoxy (may be substituted), aryl(C1-C6)alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, may be substituted), 5-10 member heteroaryl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, may be substituted), 5-10 member heteroaryl(C1-C6)alkyl (halo (may be substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino,This means that the molecule is substituted with one or more substituents independently selected from amino(C1~C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O).

[0147] It should be understood that certain radical naming conventions can include either monoradicals or diradicals, depending on the context. For example, if a substituent requires two bonding sites to the rest of the molecule, it is understood to be a diradical. Examples of substituents identified as alkyls requiring two bonding sites include diradicals such as -CH2-, -CH2CH2-, and -CH2CH(CH3)CH2-. Other radical naming conventions clearly indicate that the radical is a diradical, such as an alkylene.

[0148] When two R groups are said to form a ring (e.g., a heterocyclyl or heteroaryl ring) "together with the atom to which they are bonded," it means that the set of atoms and the two R groups are enumerated as a ring. The ring is not limited by the definition of each R group as would otherwise be interpreted individually.

[0149] Similarly, when two "adjacent" R groups are said to form a ring "together with the atom they bond to," it means an enumerated ring of atomic units, intervening bonds, and the two R groups. For example, the following substructure:

[0150] [ka]

[0151] Represents R 5 and R 6 However, hydrogen or R A Defined as adjacent R AHowever, if they form a heterocyclyl or heteroaryl ring together with the atoms they bond to, R 5 and R 6 to hydrogen or R A You can choose from, or a substructure, structure:

[0152] [ka]

[0153] [In the formula, A is a heterocyclyl or heteroaryl ring containing the expressed double bond.]

[0154] Even when a substituent is represented as a diradical (i.e., having two bonding points to the rest of the molecule), it should be understood that, unless otherwise indicated, the substituent can be bonded in any orientation. Therefore, for example, -AE-, or

[0155] [ka]

[0156] The substituents represented as include not only substituents oriented so that A is bonded at the leftmost bond point of the molecule, but also substituents where A is bonded at the rightmost bond point of the molecule.

[0157] As used herein, the term “Subjects” is a broad term and should be given its ordinary and idiomatic meaning to those skilled in the art (and should not be limited to any specific or special meaning), and refers to, but is not limited to, human or non-human mammals, e.g., dogs, cats, mice, rats, cattle, sheep, pigs, goats, non-human primates, or birds, e.g., chickens, and any other vertebrates or non-vertebrates.

[0158] As used herein, the term "mammal" is a broad term and should be given its ordinary and customary meaning to those skilled in the art (and should not be limited to a specific or special meaning), and is used in its ordinary biological meaning. Thus, in particular, but not limited to, it includes primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, etc.

[0159] "Effective amount" or "therapeutically effective amount" is a broad term and should be given its ordinary and customary meaning to those skilled in the art (and should not be limited to a specific or special meaning), and without limitation, refers to the amount of a therapeutic agent that is effective to reduce or lower to some extent the likelihood of the onset of one or more symptoms of a disease or condition, including the curing of the disease or condition. "Curing" means that the symptoms of the disease or condition are removed, however, a long-term or permanent effect may still exist even after a cure has been obtained (such as extensive tissue damage, etc.).

[0160] "Treat", "treatment" or "treating" as used herein are broad terms and should be given their ordinary and customary meaning to those skilled in the art (and should not be limited to a specific or special meaning), and without limitation, refer to the administration of a compound or pharmaceutical composition to a subject for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who has not yet shown symptoms of a disease or condition but is susceptible to or at risk of a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a patient who is already suffering from a disease or condition.

[0161] Administration and Pharmaceutical Compositions <00009Administration of any of the compounds or pharmaceutically active substances disclosed herein, or any pharmaceutically acceptable salts thereof, can be via any of the acceptable modes of administration for agents that serve a similar utility, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, vaginal, rectal or intraocular.

[0162] The useful compounds described above can be formulated into pharmaceutical compositions for use in the treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2005), which is incorporated by reference in its entirety. Thus, some embodiments include pharmaceutical compositions comprising (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs and solvates thereof) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0163] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic compositions is contemplated, except in cases where any conventional media or agent is incompatible with the active ingredient. Additionally, various adjuvants commonly used in the art may be included. Considerations regarding the inclusion of the various components in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated herein by reference in its entirety.

[0164] Some examples of substances that can function as pharmaceutically acceptable carriers or components thereof include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; tragacanth powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEEN®; humectants such as sodium lauryl sulfate; colorants; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solution.

[0165] The selection of a pharmaceutically acceptable carrier to be used in conjunction with the subject compound is essentially determined by the method by which the compound is administered.

[0166] The compositions described herein are preferably provided in unit dosage forms. As used herein, “unit dosage form” is a composition containing an amount of the compound appropriate for administration to an animal, preferably a mammalian, in a single dose, according to good medical practice. However, the preparation of a single dose or unit dosage form does not mean that the dosage form is administered once per day or once per course of treatment. Such dosage forms are intended to be administered once, twice, three times or more times per day, and may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2 to 6 hours), or as a continuous infusion, and may be given two or more times during the course of treatment, but single doses are not particularly excluded. Those skilled in the art will understand that the formulation is not specifically intended for an entire course of treatment, and that such decisions are left to those skilled in the art of treatment rather than to the formulation.

[0167] The useful compositions described above may be any of a variety of suitable forms for various routes of administration, e.g., oral, nasal, rectal, topical (including percutaneous), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. Those skilled in the art will understand that oral and nasal compositions include compositions administered by inhalation and prepared using available methodologies. Depending on the specific route of administration desired, a variety of pharmaceutically acceptable carriers known in the art may be used. Examples of pharmaceutically acceptable carriers include solid or liquid fillers, diluents, hydrotropic agents, surfactants, and encapsulating materials. They may also contain optionally selected pharmaceutically active materials, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. The techniques and compositions for producing useful dosage forms in the methods described herein are described in the following references, which are incorporated herein by reference: Modern Pharmaceutics, 4th edition, Chapters 9 and 10 (Banker & Rhodes, eds., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th edition (2004).

[0168] Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and mixed powders. Tablets may be compressed, crushed, enterically coated, sugar-coated, film-coated, or multi-compressed, containing suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow inducers, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions restored from non-foaming granules, and effervescent preparations restored from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorings.

[0169] Suitable pharmaceutically acceptable carriers for the preparation of unit dosage forms for oral administration are well known in the art. Tablets typically contain inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders such as starch, gelatin, and sucrose; disintegrants such as starch, alginic acid, and croscarmellose; and conventional pharmaceutically acceptable adjuvants such as lubricants such as magnesium stearate, stearic acid, and talc. Flow enhancers such as silicon dioxide can be used to improve the flow characteristics of powder mixtures. Colorants such as FD&C dyes can be added for appearance. Sweeteners and flavorings such as aspartame, saccharin, menthol, peppermint, and fruit flavors are useful adjuvants for chewable tablets. Capsules typically contain one or more of the solid diluents disclosed above. The selection of carrier components depends on secondary considerations such as taste, cost, and storage stability, which are not critical and can be easily done by those skilled in the art.

[0170] Oral compositions may also include liquid solutions, emulsions, and suspensions. Suitable pharmaceutically acceptable carriers for the preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. Typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components from the sweeteners, flavorings, and colorings disclosed above.

[0171] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, so that the subject compound is released in the gastrointestinal tract near the desired topical application or at various times to extend the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose phthalate acetate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, eudragit coating, wax, and shellac.

[0172] The compositions described herein may optionally contain other pharmacoactive substances.

[0173] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, transbuccal, and transnasal dosage forms. Such compositions typically contain soluble filler substances such as sucrose, sorbitol, and mannitol; and one or more binders such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. Flow enhancers, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may also be included.

[0174] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be administered topically to the eye. Comfort can be maximized as much as possible, but formulation considerations (e.g., drug stability) may necessitate a less-than-optimal level of comfort. Where comfort cannot be maximized, the liquid may be formulated so that it is tolerable to the patient for topical ophthalmic use. In addition, ophthalmally acceptable liquids may be packaged for single use or may contain preservatives to prevent contamination over multiple uses.

[0175] For ophthalmic applications, solutions or pharmaceuticals are often prepared using physiological saline solution as the primary vehicle. The eye drops may preferably be maintained at a comfortable pH by a suitable buffering system. The formulations may also contain conventionally pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0176] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercury acetate, and phenylmercury nitrate. A useful surfactant is, for example, Tween® 80. Similarly, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0177] Isotonic modifiers may be added as needed or for convenience. These may include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable and ophthalmologically acceptable isotonic modifiers.

[0178] Various buffers and means may be used to adjust the pH, provided that the resulting preparation is ophthalmologically acceptable. For many compositions, the pH is between 4 and 9. Therefore, suitable buffers include acetate buffer, citrate buffer, phosphate buffer, and borate buffer. If necessary, acids or bases may be used to adjust the pH of these formulations.

[0179] Similarly, ophthalmologically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0180] Other excipients that may be included in ophthalmic preparations are chelating agents. A useful chelating agent is disodium edetate, but other chelating agents may be used instead or in combination with it.

[0181] For topical use, creams, ointments, gels, solutions, or suspensions containing the compounds disclosed herein are used. Topical formulations may generally consist of a pharmaceutical carrier, a co-solvent, an emulsifier, a penetration enhancer, a preservative system, and a emollient.

[0182] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent such as saline or dextrose solution. Suitable excipients, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid, may be included to achieve the desired pH. In various embodiments, the pH of the final composition ranges from 2 to 8, preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable additives found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech, 1998, Vol. 52, pp. 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech, 2011, Vol. 65, pp. 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents, including but not limited to phenyl mercury nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol, may be included to achieve a bacteriostatic or fungistatic solution.

[0183] The composition for intravenous administration may be provided to the caregiver in another solid form, which is restored immediately before administration with a suitable diluent such as sterile water, saline solution, or dextrose in water. In other embodiments, the composition is provided as a solution that can be administered parenterally immediately. In yet another embodiment, the composition is provided as a solution that is further diluted before administration. In embodiments comprising the step of administering a combination of the compound described herein and another active substance, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two active substances before administration, or the two active substances may be administered separately.

[0184] The actual doses of the active compounds described herein depend on the specific compound and the condition being treated, and the selection of an appropriate dose is well within the knowledge of those skilled in the art. In some embodiments, the daily dose may be about 0.25 mg / kg body weight to about 120 mg / kg body weight or more, about 0.5 mg / kg body weight or less to about 70 mg / kg body weight, about 1.0 mg / kg body weight to about 50 mg / kg body weight, or about 1.5 mg / kg body weight to about 10 mg / kg body weight. Therefore, for administration to a person weighing 70 kg, the dose range would be about 17 mg to about 8000 mg per day, about 35 mg or less to about 7000 mg or more per day, about 70 mg to about 6000 mg per day, about 100 mg to about 5000 mg per day, or about 200 mg to about 3000 mg per day.

[0185] Treatment method Some embodiments include methods for treating aneurysms with compositions comprising the compounds described herein. Some methods include the step of administering the compounds, compositions, and pharmaceutical compositions described herein to a subject in need. In some embodiments, the subject may be an animal, such as a mammal or a human. In some embodiments, the subject is a human.

[0186] Further embodiments include the step of administering a combination of compounds to a target requiring it. The combination may include the compounds, compositions, and pharmaceutical compositions described herein together with additional pharmaceuticals.

[0187] Some embodiments include the step of co-administering the compounds, compositions, and / or pharmaceutical compositions described herein together with additional pharmaceuticals. "Co-administration" means that two or more active ingredients may be found simultaneously in the patient's bloodstream, regardless of when or how they are actually administered. In one embodiment, the active ingredients are administered simultaneously. In one such embodiment, administration in combination is achieved by combining the active ingredients in single dosage forms. In another embodiment, the active ingredients are administered sequentially. In one embodiment, the active ingredients are administered through the same route, such as orally. In another embodiment, the active ingredients are administered through different routes, for example, one orally and the other intravenously.

[0188] Examples of additional pharmaceuticals include collagen crosslinking agents such as glutaraldehyde, genipin acyl azide, and / or epoxyamines.

[0189] To further illustrate the present invention, the following embodiments are provided. Naturally, these embodiments should not be construed as specifically limiting the present invention. Variations of these embodiments within the claims are within the scope of those skilled in the art and are considered to be within the scope of the present invention as described herein and as defined in the claims. Readers will recognize that those skilled in the art with this disclosure and those with skills in the art can prepare and use the present invention without exhaustive embodiments.

[0190] Although the present invention has been described with reference to embodiments and examples, it should be understood that a number of various modifications can be made without departing from the spirit of the invention. Accordingly, the present invention is limited only to the following claims.

[0191] It will be understood that this disclosure is in many respects only an example of a number of alternative device embodiments of the present invention. Modifications may be made in more detail, particularly with respect to the shape, size, material and arrangement of the components of various devices, without exceeding the scope of the various embodiments of the present invention. Those skilled in the art will understand that the exemplary embodiments and their descriptions as a whole are merely examples of the present invention. While some principles of the present invention are revealed in the exemplary embodiments described above, those skilled in the art will understand that modifications of structure, arrangement, proportion, elements, materials and methods of use may be utilized in the practice of the present invention, otherwise, without departing from the scope of the present invention, to be particularly adapted to specific environments and operating requirements. In addition, while certain features and elements are described in relation to specific embodiments, those skilled in the art will understand that these features and elements can be combined with other embodiments disclosed herein.

[0192] Where a feature or element is referred to herein as being "on" another feature or element, it may also be directly on or interposing to the other feature or element. In contrast, where a feature or element is referred to as being "directly on" another feature or element, there is no interposing feature or element. Where a feature or element is referred to as being "connected," "attached," or "linked" to another feature or element, it is also understood that it may be directly connected to, attached to, or linked to the other feature or element, or that there may be an interposing feature or element. In contrast, where a feature or element is referred to as being "directly connected," "directly attached," or "directly linked" to another feature or element, there is no interposing feature or element. Features and elements described or shown in relation to one embodiment may be applicable to other embodiments. A person skilled in the art will also understand that a reference to a structure or feature positioned on another feature "adjacent" may have a portion that overlaps with or is beneath the adjacent feature.

[0193] The technical terms used herein are for the sole purpose of describing specific embodiments and are not intended to limit the invention. For example, as used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well unless the context explicitly indicates otherwise. As used herein, the terms “include” and / or “include” specify the presence of the described features, processes, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, processes, operations, elements, components, and / or groups thereof. As used herein, the terms “and / or” include any combination of one or more of the related enumerated items and may be abbreviated as “ / ”.

[0194] Spatially relative terms, such as “under,” “below,” “lower,” “over,” and “upper,” may be used herein for ease of description to describe the relationship between one element or feature and another element or feature illustrated in the drawings. It is understood that spatially relative terms are intended to encompass different orientations of a device in use or operation, in addition to the orientation shown in the drawings. For example, if a device in a drawing is reversed, an element described as “under” or “beneath” another element or feature would be in the “over” orientation of that other element or feature. Thus, the exemplary term “under” may encompass both the over and under directions. A device may also be in other orientations (rotated 90 degrees or in other directions), and the spatially relative descriptive terms used herein may be interpreted accordingly. Similarly, terms such as “upwardly,” “downwardly,” “vertical,” and “horizontal” are used herein for illustrative purposes only, unless otherwise indicated.

[0195] The terms “First” and “Second” may be used herein to describe various features / elements (including processes), and these features / elements should not be limited by these terms unless the context indicates otherwise. These terms may be used to distinguish one feature / element from another. Thus, without departing from the teachings of the invention, the first feature / element discussed below may be referred to as the second feature / element, and similarly, the second feature / element discussed below may be referred to as the first feature / element.

[0196] Throughout this specification and the subsequent claims, unless the context requires otherwise, the word “comprise” and variations such as “comprises” and “comprising” mean that various components can be used together in a method and article (e.g., a composition, and an apparatus including a device, and a method). For example, the term “comprising” is understood to mean the inclusion of any stated element or process, but not the exclusion of any other element or process.

[0197] Where used herein and in the claims, including where used in the examples, all numbers may be read as if preceded by the words “about” or “approximately,” even when the terms “about” or “approximately” are not explicitly stated, unless otherwise expressly provided. The words “about” or “approximately” may be used when describing a magnitude and / or location to indicate that the stated value and / or location is within a reasonable expected range of the value and / or location. For example, a number may have a value that is ±0.1% of the stated value (or range of value), ±1% of the stated value (or range of value), ±2% of the stated value (or range of value), ±5% of the stated value (or range of value), ±10% of the stated value (or range of value), etc. Any number given herein should also be understood to include its value about or approximate, unless the context indicates otherwise. For example, if the value “10” is disclosed, “about 10” is also disclosed as a result. Any range of numbers enumerated herein is intended to include all subranges contained herein. Where a value is disclosed, it is understood that, as will be well understood by those skilled in the art, possible ranges between the value and the values ​​"less than or equal to", "greater than or equal to", and the values ​​themselves are also disclosed. For example, if a value "X" is disclosed, not only "less than or equal to X" but also "greater than or equal to X" (e.g., X is a number) are disclosed. Throughout this application, it is understood that data is provided in many different forms, and that this data represents a range of endpoints and starting points, as well as any combination of data points. For example, if a particular data point "10" and a particular data point "15" are disclosed, it is understood that greater than 10 and 15, 10 and 15 or greater, less than 10 and 15, 10 and 15 or less, and equal to 10 and 15 are considered to be disclosed as well as between 10 and 15. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then consequently 11, 12, 13, and 14 are also disclosed.

[0198] While various exemplary embodiments are described above, many modifications may be made to various embodiments without departing from the scope of the invention as described in the claims. For example, the order in which the steps of various described methods are performed may often be changed in alternative embodiments, and in other alternative embodiments, one or more steps of the method may be skipped entirely. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for illustrative purposes and should not be construed as limiting the scope of the invention as described in the claims.

[0199] The examples and illustrations included herein illustrate, for illustrative purposes only and not limiting, specific embodiments in which the subject matter may be carried out. As stated, other embodiments may be utilized and derived from them so that structural and logical substitutions and modifications may be made without departing from the scope of this disclosure. Such embodiments of the subject matter of the present invention are referred to herein, individually or collectively, by the term “invention” merely for convenience and without the intention of spontaneously limiting the scope of this application to any single invention or inventive concept when more than one is actually disclosed. Accordingly, specific embodiments are illustrated and described herein, but any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover all possible adaptations or variations of various embodiments. Combinations of the embodiments described herein, and other embodiments not specifically described herein, will be apparent to those skilled in the art when considering the foregoing description. [Explanation of symbols]

[0200] 100 delivery catheters 102 Distal end 104 Upstream expandable member 105 Upstream balloon 106 Downstream expandable member 107 Downstream Balloon 108 Third expandable member 109 Internal balloon 110 Main shaft 111 Connecting rings 112 central lumens 113 Expanded Lumens 114 Secondary shaft 116 central lumens 117 lumens 118 Expansion Port 120 Intermediate shaft area 122 Secondary expansion port 124 Lead Section 126 pores 134 tertiary expansion lumens 136 Tertiary Expansion Port 138 internal lumens (refillable) 139 Refill fluid port 140 enclosed space 142 sealed volume 200 blood vessels 202 Aneurysm

Claims

1. A kit for treating aneurysms, including the following: A device, and the following: shaft; A first balloon attached to the distal end of a shaft, the first balloon being configured to fix the device; and A second balloon attached to the proximal end of a shaft, wherein the maximum expanded diameter of the second balloon is greater than the maximum expanded diameter of the first balloon. Includes, The first balloon is positioned near the distal end of the shaft to fix the device and stop downstream blood flow, and the second balloon is positioned near the proximal end of the shaft to stop regurgitated blood flow. The second balloon is configured to be in line with the aneurysm. The second balloon is configured to drain blood from the aneurysm sac when inflated. The second balloon has multiple pores for delivering medication to the aneurysm. The outer surface of the second balloon can conform to the shape of the aneurysm sac. The device has multiple pores in the second balloon configured to allow the internal volume of the second balloon to fluidly communicate with the intravascular environment of the aneurysm; Purified pentagalloyl glucose (PGG); and Hydrolyzed agent A kit that includes this.

2. The kit according to claim 1, wherein the hydrolyzing agent is ethanol.

3. The kit according to claim 1, wherein the hydrolyzing agent is dimethyl sulfoxide (DMSO) or a contrast agent.

4. The kit according to claim 1, further comprising physiological saline.

5. The kit according to claim 1, wherein the purified pentagalloyl glucose (PGG) has a purity of 99% or more.

6. The kit according to claim 1, wherein the second balloon forms an annular internal volume when inflated and surrounds the shaft in a circumferential direction.

7. The kit according to claim 1, wherein the second balloon is generally donut-shaped or generally elongated spherical in shape.

8. The kit according to claim 1, wherein the separation distance between the first balloon and the second balloon is fixed.

9. The kit according to claim 1, wherein the separation distance between the first balloon and the second balloon is adjustable.

10. The kit according to claim 1, wherein the plurality of pores include between 30 and 200 pores.

11. The kit according to claim 1, wherein the diameter of each pore is between 0.05 mm and 0.2 mm.

12. The kit according to claim 1, wherein a plurality of pores are configured to deliver fluid at a volumetric flow rate between 0.05 mL / min and 20 mL / min.

13. The kit according to claim 1, the device further comprises a handle including a first port configured to introduce a first fluid for inflating a first balloon and a second port configured to introduce a second fluid for inflating a second balloon, the second port being further configured to introduce a therapeutic agent for delivery through a plurality of pores.

14. The kit according to claim 1, wherein the length of the second balloon is greater than the length of the first balloon.

15. The kit according to claim 1, wherein the first balloon is generally spherical in shape, and the second balloon is generally elongated spherical in shape.

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