BACKGROUND

One of the most common results of the degradation of vasculature is aneurysm. By definition, the term “aneurysm” is simply an abnormal widening or ballooning at the wall of a blood vessel. Aneurysms are degenerative diseases characterized by destruction of arterial architecture and subsequent dilatation of the blood vessel that may eventually lead to fatal ruptures. Some common locations for aneurysms include the abdominal aorta (abdominal aortic aneurysm, AAA), thoracic aorta, and brain arteries. In addition, peripheral aneurysms of the leg, namely the iliac, popliteal and femoral arteries are prevalent locations of this vascular pathology. The occurrence of such peripheral aneurysms appears to be strongly associated with the presence of aneurysms in other locations, as it has been estimated that 30 to 60% of peripheral aneurysm patients also have an AAA.

Aneurysms can be devastating due to the potential for rupture or dissection that can lead to massive bleeding, stroke, or hemorrhagic shock, and can be fatal in an estimated 80% of cases. Aneurysms can be caused by any of a large class of degenerative diseases and pathologies including atherosclerotic disease, defects in arterial components, genetic susceptibilities, and high blood pressure, among others, and can develop silently over a period of years. The hallmarks of aneurysms include enzymatic degradation of vascular structural proteins such as elastin, collagen, inflammatory infiltrates, calcification, and eventual overall destruction of the vascular architecture. Elastin content in an aneurysmal aorta can be greatly reduced (for example, 70% less) than that of a healthy, undamaged aorta.

Aneurysms grow over a period of years and pose great risks to health. Aneurysms have the potential to dissect or rupture, causing massive bleeding, stroke, and hemorrhagic shock, which can be fatal in more than 80% of cases. AAAs are a serious health concern, specifically for the aging population, being among the top ten causes of death for patients older than 50. The estimated incidence for abdominal aortic aneurysm is about 50 in every 100,000 persons per year. Approximately 50,000 operations are performed each year in the U.S. for AAAs alone. In children, AAAs can result from blunt abdominal injury or from Marfan's syndrome, a defect in elastic fiber formation in walls of major arteries, such as the aorta.

Current methods of treatment for diagnosed aneurysms are limited to invasive surgical techniques. After initial diagnosis of a small aneurysm, the most common medical approach is to follow up the development of the aneurysm and after reaching a predetermined size (for example, about 5 cm in diameter), surgical treatment is applied. Current surgical treatments are limited to either an endovascular stent graft repair or optionally complete replacement of the diseased vessel with a vascular graft. While such surgical treatments can save lives and improve quality of life for those suffering aneurysms, dangers beyond those of the surgery itself still exist for the patient due to possible post-surgery complications (for example, neurological injuries, bleeding, or stroke) as well as device-related complications (for example, thrombosis, leakage, or failure). Moreover, depending upon the location of the aneurysm, the danger of an invasive surgical procedure may outweigh the possible benefits of the procedure, for instance in the case of an aneurysm deep in the brain, leaving the sufferer with very little in the way of treatment options. Moreover, surgical treatments may not always provide a permanent solution, as vascular grafts can loosen and dislodge should the aneurysm progress following the corrective surgery. For some patients, the particular nature of the aneurysm or the condition of the patient makes the patient unsuitable for graft repair.

Aneurysm is not the only condition for which enzymatic degradation of structural proteins is a hallmark. Other conditions in which structural protein degradation appears to play a key role include Marfan syndrome, supravalvular aortic stenosis. For those afflicted, such conditions lead to, at the very least, a lowered quality of life and often, premature death.

Phenolic compounds are a diverse group of materials that have been recognized for use in a wide variety of applications. For instance, they naturally occur in many plants, and are often a component of the human diet. Phenolic compounds have been examined in depth for efficacy as free radical scavengers and neutralizers, for instance in topical skin applications and in food supplements. Phenolic compounds are also believed to prevent cross-linking of cell membranes found in certain inflammatory conditions and are believed to affect the expressions of specific genes due to their modulation of free radicals and other oxidative species (see, for example, U.S. Pat. No. 6,437,004 to Perricone).

What is needed in the art are treatment protocols and compositions for stabilization of the organs and tissues affected by degenerative conditions such as aneurysm. In particular, treatment protocols utilizing phenolic compounds could provide a safe, less invasive route for the stabilization of the structural architecture in order to temper growth and/or development of such conditions.

SUMMARY

Some embodiments provide a composition comprising a compound of the following Formula:

or a pharmaceutically acceptable salt thereof,wherein: R1-R19have any of the values described herein, and wherein the composition is substantially free of gallic acid or methyl gallate. In some embodiments, substantially free is less than about 0.5% gallic acid. In some embodiments, substantially free is less than about 0.5% methyl gallate.

In some embodiments, R1, R2, R3and R4are each independently hydrogen or RA;R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18and R19are each independently hydrogen or RB;each RAis independently selected from the group consisting of —ORX, —N(RY)2, halo, cyano, —C(═X)RZ, —C(═X)N(RY)2, —C(═X)ORX, —OC(═X)RZ, —OC(═X)N(RY)2, —OC(═X)ORX, —NRYC(═X)RZ, —NRYC(═X)N(RY)2, —NRYC(═X)ORX, unsubstituted C1-12alkoxy, substituted C1-12alkoxy, unsubstituted C1-8alkyl, substituted C1-8alkyl, unsubstituted C6or10aryl, substituted C6or10aryl, unsubstituted C7-12aralkyl, substituted C7-12aralkyl, unsubstituted 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl, unsubstituted C3-12heteroaralkyl, substituted C3-12heteroaralkyl, unsubstituted 3-10 membered heterocyclyl, and substituted 3-10 membered heterocyclyl;each RBis independently selected from the group consisting of —C(═X)RZ, —C(═X)N(RY)2, —C(═X)ORX, unsubstituted C1-8alkyl, substituted C1-8alkyl, unsubstituted C6or10aryl, substituted C6or10aryl, unsubstituted C7-12aralkyl, substituted C7-12aralkyl, unsubstituted 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl, unsubstituted 3-10 membered heterocyclyl and substituted 3-10 membered heterocyclyl, or two adjacent RBgroups together with the atoms to which they are attached form an unsubstituted 3-10 heterocyclyl, a substituted 3-10 heterocyclyl, unsubstituted 5-10 membered heteroaryl ring or substituted 5-10 membered heteroaryl ring;each X is independently oxygen (O) or sulfur (S);each RXand RYis independently selected from the group consisting of hydrogen, unsubstituted C1-8alkyl, substituted C1-8alkyl, unsubstituted C6or10aryl, substituted C6or10aryl, unsubstituted C7-12aralkyl, substituted C7-12aralkyl, unsubstituted 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl, unsubstituted 3-10 membered heterocyclyl and substituted 3-10 membered heterocyclyl; andeach RZis independently selected from the group consisting of unsubstituted C1-12alkoxy, substituted C1-12alkoxy, unsubstituted C1-8alkyl, substituted C1-8alkyl, unsubstituted C6or10aryl, substituted C6or10aryl, unsubstituted C7-12aralkyl, substituted C7-12aralkyl, unsubstituted 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl, unsubstituted 3-10 membered heterocyclyl and substituted 3-10 membered heterocyclyl.

In some embodiments, at least one of R1, R2, R3and R4is RAIn some embodiments, at least two of R1, R2, R3and R4are RA. In some embodiments, each RAis independently selected from the group consisting of —ORX, —N(RY)2, halo, cyano, —C(═X)RZ, —C(═X)N(RY)2, —C(═X)ORX, —OC(═X)RZ, —OC(═X)N(RY)2, —OC(═X)ORX, —NRYC(═X)RZ, —NRYC(═X)N(RY)2, and —NRYC(═X)ORX. In some embodiments, each RAis independently selected from the group consisting of unsubstituted C1-12alkoxy, substituted C1-12alkoxy, unsubstituted C1-8alkyl, substituted C1-8alkyl, unsubstituted C6or10aryl, substituted C6or10aryl, unsubstituted C7-12aralkyl, substituted C7-12aralkyl, unsubstituted 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl, unsubstituted C3-12heteroaralkyl, substituted C3-12heteroaralkyl, unsubstituted 3-10 membered heterocyclyl, and substituted 3-10 membered heterocyclyl. In some embodiments, each RAis independently selected from the group consisting of unsubstituted C1-12alkoxy, unsubstituted C1-8alkyl, unsubstituted C6or10aryl, unsubstituted C7-12aralkyl, unsubstituted 5-10 membered heteroaryl, unsubstituted C3-12heteroaralkyl, and unsubstituted 3-10 membered heterocyclyl. In some embodiments, R1, R2, R3and R4are each hydrogen. In some embodiments, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18and R19are each hydrogen. In some embodiments, at least one of R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18and R19is RB. In some embodiments, at least two of R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18and R19are RB. In some embodiments, at least three of R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18and R19are RB. In some embodiments, each RBis independently selected from the group consisting of unsubstituted C1-12alkoxy, substituted C1-12alkoxy, unsubstituted C1-8alkyl, substituted C1-8alkyl, unsubstituted C6or10aryl, substituted C6or10aryl, unsubstituted C7-12aralkyl, substituted C7-12aralkyl, unsubstituted 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl, unsubstituted C3-12heteroaralkyl, substituted C3-12heteroaralkyl, unsubstituted 3-10 membered heterocyclyl, and substituted 3-10 membered heterocyclyl. In some embodiments, each RBis independently selected from the group consisting of unsubstituted C1-12alkoxy, unsubstituted C1-8alkyl, unsubstituted C6or10aryl, unsubstituted C7-12aralkyl, unsubstituted 5-10 membered heteroaryl, unsubstituted C3-12heteroaralkyl, and unsubstituted 3-10 membered heterocyclyl. In some embodiments, two adjacent RBgroups together with the atoms to which they are attached form an unsubstituted 3-10 heterocyclyl, a substituted 3-10 heterocyclyl, unsubstituted 5-10 membered heteroaryl ring or substituted 5-10 membered heteroaryl ring.

In some embodiments, the pharmaceutical composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in crémes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized 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.

In yet another aspect, the present disclosure provides methods of treating and/or preventing a disease or a disorder in a patient in need thereof, comprising 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 present disclosure provides methods of treating aneurysms.

Some embodiments provide a method of purifying a compound of Formula (I) comprising: washing a 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 results in a purity of the compound of Formula (I) thereof greater than or equal to 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%.

Some embodiments provide a kit for treating aneurysms, comprising: a compound of Formula (I) having a purity greater than or equal to 99%; and a hydrolyzer. In some embodiments, the hydrolyzer is ethanol. In some embodiments, the hydrolyzer is dimethyl sulfoxide (DMSO). In some embodiments, the hydrolyzer is contrast media. In some embodiments, the kit further comprises a saline solution.

Some 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, the second balloon comprising a plurality of pores for delivering a therapeutic agent to the aneurysm. In some embodiments, the first balloon is positioned near a distal end of the shaft for anchoring the device and stopping downstream blood flow, and wherein the second balloon is positioned near a proximal end of the shaft. The second balloon may be configure for stopping retrograde blood flow and/or for displacing blood for the aneurysmal sac, which may improve the efficacy of drug delivery to the aneurysm. In some embodiments, the second balloon is positioned near a distal end of the shaft for anchoring the device and stopping downstream blood flow, and wherein the first balloon is positioned near a proximal end of the shaft for stopping retrograde blood flow. In some embodiments, the device further comprises a third balloon positioned within the second balloon for expanding the second balloon, the third balloon expandable with saline.

Some embodiments provide a method for treating an aneurysm, comprising: positioning a first balloon upstream the aneurysm; positioning a second balloon adjacent the aneurysm; inflating the first balloon to occlude downstream blood flow; expanding the second balloon to occlude retrograde blood flow and/or to displace blood from the aneurysmal sac; and delivering a therapeutic agent to the aneurysm through pores in the second balloon.

Some embodiments provide a method of purifying 1,2,3,4,6-pentagalloyl glucose (PGG) or analogues or derivatives thereof comprising washing the PGG with a solvent to remove substantially all gallic acid or methyl gallate. In some embodiments, the solvent may be or may comprise diethyl ether, toluene, isopropyl ether, dichloromethane, methyl tert-butyl ether, 2-butanone, and/or ethyl acetate. Removing substantially all gallic acid or methyl gallate may result in less than about 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% gallic acid or methyl gallate. The washing may results in a purity of the 1,2,3,4,6-pentagalloyl glucose (PGG) or analogues or derivatives thereof greater than or equal to 99.9%.

Some embodiments provide a kit for treating aneurysms. The kit includes PGG having a purity greater than or equal to 99% and a hydrolyzer. The hydrolyzer may be or may comprise ethanol, dimethyl sulfoxide (DMSO), and/or contrast media. The kit may include a saline solution.

Some embodiments provide a device for treating an aneurysm. The device has 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 includes a plurality of pores for delivering a therapeutic agent to the aneurysm. In some embodiments, the first balloon may be positioned near a distal end of the shaft for anchoring the device and stopping downstream blood flow, and the second balloon may be positioned near a proximal end of the shaft for stopping retrograde blood flow. In some embodiments, the second balloon may be positioned near a distal end of the shaft for anchoring the device and stopping downstream blood flow, and the first balloon may be positioned near a proximal end of the shaft for stopping retrograde blood flow. The device may include a third balloon positioned within the second balloon for expanding the second balloon. The third balloon may be expandable with saline.

Some embodiments provide a catheter for treating an aneurysm. The catheter has an elongate body configured to be introduced into a blood vessel. The elongate body has a proximal end, a distal end, and a main shaft having a lumen extending therethrough. The catheter has a first inflatable balloon coupled to the distal end of the elongate body and having an interior volume in fluid communication with a first inflation lumen. The catheter has a second inflatable balloon coupled to the elongate body proximally to the first inflatable balloon and having an interior volume in fluid communication with a second inflation lumen. The second inflatable balloon circumferentially surrounds the elongate body. The second inflatable balloon has a plurality of pores disposed on a surface of the second inflatable balloon configured to place the interior volume of the second inflatable balloon in fluid communication with an intravascular environment of the blood vessel.

In some embodiments, the main shaft may extend through the second inflatable balloon. The distal end of the main shaft may form the distal end of the elongate body. The first inflation lumen and the second inflation lumen may be formed within the main shaft. The elongate body may include a second shaft having a lumen extending therethrough. The second shaft may be disposed within the lumen of the main shaft. The first inflatable balloon may be coupled to a distal end of the second shaft and the second inflatable balloon may be coupled to a distal end of the main shaft. The lumen of the main shaft may be the second inflation lumen. The lumen of the second shaft may be the first inflation lumen. The elongate body may extend through the interior volume of the second inflatable balloon. The second inflatable balloon may be generally toroidal forming an annular interior volume that surrounds the elongate body. The elongate body may have an intermediate shaft segment positioned between a proximal end of the first inflatable balloon and a distal end of the second inflatable balloon. The intermediate shaft segment may include the main shaft and/or the second shaft. A separation distance between the first inflatable balloon and the second inflatable balloon may be fixed or may be adjustable. The catheter may have a lumen configured to be placed in fluid communication with a volume of the intravascular environment between the first inflatable balloon and the second inflatable balloon.

The pores may be disposed on a central portion of the second inflatable balloon. The pores may be disposed on a distal portion of the second inflatable balloon. The pores may not be disposed on a proximal portion of the second inflatable balloon. The pores may not be disposed on any portion of the second inflatable balloon proximal to a maximum expanded diameter of the balloon in an inflated configuration. 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 greater than the length of the expanded first inflatable balloon.

The catheter may include a third inflatable balloon disposed within the interior volume of the second inflatable balloon. The third inflatable balloon may have an interior volume in fluid communication with a third inflation lumen. Expansion of the third inflatable balloon may be configured to at least partially expand the second inflatable balloon. Expansion of the third inflatable balloon may be configured to facilitate expulsion of at least a partial volume of inflation fluid disposed within the interior volume of the second inflatable balloon through the pores into the intravascular environment.

Some embodiments provide a method for treating an aneurysm in a blood vessel of a patient. The method comprises positioning a first balloon upstream the aneurysm, positioning a second balloon adjacent 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, expanding the second balloon comprises introducing an inflation fluid into an interior volume of the second balloon. Delivering the therapeutic agent may comprise introducing a solution comprising the therapeutic agent into an interior volume of the second balloon to expand and/or maintain an expanded state of the second balloon. Inflating the first balloon and expanding the second balloon may create a sealed volume within the blood vessel between the first balloon and the second balloon. Delivering the therapeutic agent may comprise introducing the therapeutic agent into the sealed volume. The therapeutic agent may not be delivered into the blood vessel outside of the sealed volume while the sealed volume is established.

Inflating the first balloon may anchor the first balloon and the second balloon within the blood vessel. Positioning the second balloon adjacent the aneurysm may comprise positioning the second balloon across the aneurysm and expanding the second balloon may create a sealed space between the second balloon and the aneurysm. Positioning the second balloon adjacent the aneurysm may comprise positioning the second balloon along a downstream edge of the aneurysm and expanding the second balloon may create a sealed volume between the first balloon and the second balloon which encompasses the aneurysm. Positioning the second balloon adjacent the aneurysm may comprise positioning the second balloon such that a length of the aneurysm along the blood vessel encompasses an entire length of the second balloon. Inflating the first balloon may occur prior to expanding the second balloon. Expanding the second balloon and/or maintaining the second balloon in an expanded state may comprise maintaining a pressure within an interior volume of the second balloon greater than a diastolic blood pressure of the patient and less than a systolic blood pressure of the patient. Expanding the second balloon and delivering the therapeutic agent through the pores may comprise introducing a solution into an interior volume of the second balloon. The solution may be introduced at a first volumetric flow rate to expand the second balloon and at a second volumetric flow rate to deliver the therapeutic agent through the pores. The first volumetric flow rate may be greater than or equal to the second volumetric flow rate.

Blood flow may be occluded within the blood vessel for no longer than approximately 3 minutes. At least 1 mL of solution comprising the therapeutic agent may be delivered while downstream blood flow and retrograde blood flow vessel is occluded. Expanding the second balloon may comprise inflating a third balloon disposed within an interior volume of the second balloon. Delivering the therapeutic agent may comprise inflating a third balloon disposed within an interior volume of the second balloon to force a volume of solution comprising the therapeutic agent within the interior volume of the second balloon through the pores. The therapeutic agent may comprise 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.

