Stents and topical compositions comprising thiosulfate

Abstract

The disclosure relates to a method for opening arteries that are occluded with calcium in a subject in need thereof, the method comprising applying a topical thiosulfate composition comprising a therapeutically effective amount of thiosulfate to an area of the subject's body comprising an artery occluded with calcium.

Description

STENTS AND TOPICAL COMPOSITONS COMPRISING THIOSULFATECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Appl. No. 63 / 606,413, filed December 5, 2024, which is incorporated by reference as if fully set forth herein.BACKGROUND

[0002] Critical limb threatening ischaemia (CLTI) is the most severe type of peripheral vascular disease. Patients with CLTI have pain at rest and skin wounds in the leg(s). In addition, the cardiovascular mortality is high. A recent systematic review and meta-analysis on the outcome of conservative treatment of CLTI patients showed that within 1 year of diagnosis 18% of the patients died and 27% underwent amputation. The one-year amputation free survival rate was 60%. In addition, a PADI-trial reported a 10-year survival of only ±20%.

[0003] With an estimated yearly incidence of 500-1000 new cases per million individuals in Western society, CLTI poses a considerable burden on patients’ health and resources.

[0004] Several histopathologic studies of amputated legs of CLTI patients have shown that calcification of the media is present in up to 72% of patients and that the classical atherosclerotic disease is less pronounced. In a group of 54 CLTI patients, it has been reported that virtually all had severely calcified peripheral vessels, coronary arteries and a severely calcified aorta. The median coronary artery calcium score was 1485 and in 19 of 45 (35%) patients, it was above 2000. The thoracic and the abdominal aorta where completely annular calcified in 37%, 31 % of cases respectively.

[0005] Although treatment of CLTI has improved, there still is a high cardiovascular mortality. Current treatment strategies target on luminal thrombosis and cholesterol-driven atherosclerosis, a process mainly located in the intima. However, a process which co-occurs with atherosclerosis, arterial calcification, may independently lead to vascular disease. Arterial calcifications, especially when located in the media, are a cause of vascular stiffening and an independent cause of vascular disease. A meta-analysis showed that calcification in any vascular bed is associated with a three to fourfold increased risk for cardiovascular events and mortality.SUMMARY

[0006] There is therefore a need for devices and methods for opening arteries that are occluded with calcium, including to treat CLTI and calcifilaxis, which is apotentially fatal disorder of abnormal calcium deposition. Patients commonly present with painful retiform to stellate purpuric lesions that often undergo ulceration and necrosis, increasing the risk of infection and life-threatening sepsis.

[0007] The disclosure relates to a stent comprising (a) a balloon expandable stent; and (b) thiosulfate, in a therapeutically effective amount. The thiosulfate can be comprised in a thiosulfate composition coated onto a surface of the stent. The stents described herein can be used to treat a number of conditions including conditions resulting from calcifications, such as valvular calcifications (e.g., calcific aortic valve disease, aortic stenosis, mitral annular calcification) and arteries that are occluded with calcium.DESCRIPTION OF THE DRAWINGS

[0008] The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed herein.

[0009] FIG. 1 is a cartoon of a crimped stent of the disclosure inserted into an artery using a guidewire, where the stent is then expanded at or near a site of calcification.

[0010] FIG. 2 is a cartoon of a crimped stent of the disclosure inserted into an artery using a guidewire, where the stent is placed at or near a site of calcification, where the calcification substantially completely blocks the artery.

[0011] Unless otherwise indicated, all figures and drawings in this document are not to scale and are chosen for the purpose of illustrating different embodiments of the invention. The dimensions of the various components are depicted in illustrative terms only, and no relationship between the dimensions of the various components should be inferred from the drawings, unless so indicated. Although terms such as “before,” “after,” “top”, “bottom”, “upper”, “lower”, “under”, “over”, “front”, “back”, “up” and “down”, and “first” and “second” can be used in this disclosure, it should be understood that those terms are used in their relative sense only unless otherwise noted.DESCRIPTION

[0012] Reference will now be made in detail to certain embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0013] The present disclosure provides stents, comprising a generally tubular structure (which includes for example, spiral shapes), the stents comprising a thiosulfate composition. In one example, stents are contemplated herein where the surface of the stent is coated with a composition comprising thiosulfate. Anexample of a stent contemplated herein is shown in FIG 1 . Panel (a) of FIG. 1 is a stent 100 of the disclosure inserted into an artery 101 having an artery wall 120. The stent in panel (a) is crimped (that is, not expanded) and is inserted at or near a site of calcification 130 using a guide wire 110. The stents of the disclosure can be expanded using a balloon (not shown) to give expanded stent 1 12 as shown in panel (b) of FIG. 1 . And even though the stent 112 is shown as being expanded at the site of calcification 130, the stent can be located at a site 131 located before the site of calcification 130; at a site 132 located after the site of calcification; at a site 133 that includes an area before the site of calcification and an area at the site of calcification; at a site 134 that includes an area at the site of calcification and an area after the site of calcification; or the stent can span a site 135 that includes the site before the site of calcification 131 , the site after the site of calcification 132, and the site of calcification 130.

[0014] The example provided in FIG. 1 is one showing calcifications 130 and 130’ that, together, only partially occlude an artery 101 . But the stents of the disclosure can also be used to treat calcifications 130 and 130’ that cause a substantially complete blockage of an artery 101 as shown in FIG. 2. In such an instance, the stent 100 and guidewire 1 10 can be advanced to a location 136 proximal to the calcifications 130 and 130’. The stent 100 can then be deployed (not shown).

[0015] The stents of the disclosure can also comprise a sheath substantially covering the entire stent. One function of the sheath is to protect the stent as it is moved to the site of deployment (e.g., near or at a calcification) from its environment, for example, to avoid releasing thiosulfate at any place other than near or at a calcification.

[0016] Generally, stents are inserted in a similar fashion regardless of the site or the disease being treated. Briefly, a pre-insertion examination, usually a diagnostic imaging procedure, endoscopy, or direct visualization at the time of surgery, is generally first performed in order to determine the appropriate positioning for stent insertion. A guidewire is then advanced through the lesion or proposed site of insertion, and over this is passed a delivery catheter which allows a stent in its collapsed form to be inserted. Typically, stents are capable of being compressed, so that they can be inserted through minuscule cavities via small catheters, and then expanded to a larger diameter once they are at the desired location. Once expanded, the stent physically forces the walls of the passageway apart and holds them open. As such, they are capable of insertion via a small opening, and yet are still able to hold open a large diameter cavity or passageway. The stent may be self-expanding (e.g., the Wallstent and Gianturco stents), balloon expandable(e.g., the Palmaz stent and Strecker stent), or implanted by a change in temperature (e.g., the Nitinol stent).

[0017] Stents are typically maneuvered into place under radiologic or direct visual control, taking particular care to place the stent precisely across the narrowing in the organ or area being treated. The delivery catheter is then removed, leaving the stent standing on its own as a scaffold. A post insertion examination, usually an x- ray, is often utilized to confirm appropriate positioning.

[0018] The instant disclosure provides, among other things, methods for eliminating vascular obstructions, comprising inserting a vascular stent into a blood vessel, the stent having a generally tubular structure, the stent comprising a thiosulfate composition (for example, a thiosulfate composition coated on the surface of the stent), such that the vascular obstruction is reduced or eliminated. Within one embodiment, angiography is first performed in order to localize the site for placement of the stent. This is typically accomplished by injecting radiopaque contrast through a catheter inserted into an artery or vein as an x-ray is taken. A catheter may then be inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering it through the vascular system under fluoroscopic guidance. A stent may then be positioned across the vascular stenosis. A post insertion angiogram may also be utilized in order to confirm appropriate positioning.

[0019] In addition, the stents described herein can generally be used to open arteries that are occluded with calcium such that they can be used to treat atherosclerosis, atheroma, arterial plaques, atherosclerotic plaques, atheroma plaques, peripheral artery disease (e.g., including disease processes like mesenteric ischemia, renal artery stenosis, carotid artery stenosis, cerebral artery stenosis), aortic calcifications, coronary artery disease, and valvular calcifications (e.g., calcific aortic valve disease, aortic stenosis, mitral annular calcification), and the like.

[0020] The stents described herein can be used as a scaffolding that can be inserted into a body passageway (for example, the vascular system including the coronary arteries; and valves, such as the aortic and the mitral valve) or a portion of a body passageway, which has been narrowed, obstructed, or occluded by calcification in order to reduce or eliminate the obstruction / occlusion of the passageway by the calcification. In the context of the present disclosure, the stent would not only function by physically holding open the walls of the body passage into which they are inserted but the thiosulfate would reduce or eliminate thecalcification at a site of obstruction (e.g., when there are multiple obstruction sites along a vessel), along the length of the stent, and / or downstream from where the stent is located. While not wishing to be bound by any specific theory, thiosulfate acts as a calcium chelator and may help prevent vascular calcification that can lead to restenosis after stenting.

[0021] A variety of stents may be utilized within the context of the present disclosure, including for example, vascular stents. Stents may be readily obtained from commercial sources, or constructed in accordance with well-known techniques. Representative examples of stents include those described in U.S. Pat. No. 4,776,337, entitled “Expandable Intraluminal Graft, and Method and Apparatus for Implanting and Expandable Intraluminal Graft;” U.S. Pat. No. 5,041 ,126 entitled “Endovascular Stent and Delivery System;” U.S. Pat. No. 5,052,998 entitled “Indwelling Stent and Method of Use;” U.S. Pat. No. 5,064,435 entitled “Self-Expanding Prosthesis Having Stable Axial Length;” U.S. Pat. No. 5,089,606, entitled “Water-insoluble Polysaccharide Hydrogel Foam for Medical Applications;” U.S. Pat. No. 5,147,370, entitled “Nitinol Stent for Hollow Body Conduits;” U.S. Pat. No. 5,176,626, entitled “Indwelling Stent;” U.S. Pat. No. 5,213,580, entitled “Biodegradable polymeric Endoluminal Sealing Process;” and U.S. Pat. No. 5,328,471 , entitled “Method and Apparatus for Treatment of Focal Disease in Hollow Tubular Organs and Other Tissue Lumens,” each of which is incorporated by reference as if fully set forth herein.

[0022] Stents may comprise thiosulfate compositions in a variety of forms, including for example: (a) by directly affixing to the stent a thiosulfate composition (e.g., by either spraying the stent with a polymer / thiosulfate film, or by dipping the stent into a polymer / thiosulfate solution), (b) by coating the stent with a substance such as a hydrogel comprising a thiosulfate composition dissolved and / or suspended therein, (c) by interweaving a thread into the stent structure, where the thread is coated with a thiosulfate composition, (d) by inserting the stent into a sleeve or mesh which is comprised of or coated with a thiosulfate composition, or (e) constructing the stent itself with a thiosulfate composition.

[0023] In one example, the thiosulfate compositions described herein can be in the form of a coating that is adhered to the surface(s) of the stent. For example, the thiosulfate compositions described herein can adhere to the stent during storage and at the time of insertion and should not be dislodged from the stent when the diameter is expanded from its collapsed size to its full expansion size. The thiosulfate composition should not degrade during storage, prior to insertion, or when warmed to body temperature after expansion inside the body. In addition,the thiosulfate compositions described herein may coat the stent smoothly and evenly, with a uniform distribution of thiosulfate, while not changing the stent contour. The thiosulfate compositions described herein can provide a uniform, predictable, prolonged release of thiosulfate into the tissue surrounding the stent once it has been deployed. For vascular stents, in addition to the above properties, the composition should not render the stent thrombogenic (causing blood clots to form), or cause significant turbulence in blood flow (more than the stent itself would be expected to cause if it was uncoated).

[0024] Thiosulfate compositions contemplated herein include compositions comprising any suitable form of thiosulfate. The form of thiosulfate can be one or more of the following:• Sodium thiosulfate salts. Sodium thiosulfate (Na2S2O3) is a common form used in medicine and commercially available. Sodium thiosulfate is a stable, water-soluble salt. Ammonium thiosulfate ((NH4)2S2O3) is a water- soluble salt also used commercially.• Organic thiosulfates - thiosulfate can form salts with organic cations like tetraalkylammonium to improve hydrophobicity.• Thiosulfate esters - reacting thiosulfate with alcohols / phenols forms ester derivatives.• Thiosulfate polymers - thiosulfate groups can be incorporated into polymers like hydrogels for controlled drug release.• Thiosulfate complexes - thiosulfate can chelate metals and form coordination complexes.• Thiosulfate prodrugs - inactive thiosulfate derivatives converted to active thiosulfate in vivo. Improves delivery.

[0025] Organic thiosulfates can be formed by reacting thiosulfate with organic cations like tetraalkylammonium ions. Examples of organic thiosulfates include, but are not limited to, tetramethylammonium thiosulfate ((CH3)4N)2S2O3), tetraethylammonium thiosulfate ((C2H5)4N)2S2O3), and benzyltrimethylammonium thiosulfate (C6H5CH2(CH3)3N)2S2O3). The organic cations can make the thiosulfate salts more hydrophobic and lipophilic compared to sodium thiosulfate. This can help them cross cell membranes and potentially enhance delivery to target tissues. However, organic thiosulfates have reduced water solubility which could decrease bioavailability. They also tend to be less stable than sodium thiosulfate. Still, organic thiosulfates can be used in the thiosulfate compositions described herein.

[0026] Thiosulfate esters can be formed by reacting thiosulfate with alcohols or phenols. Examples of thiosulfate esters include, but are not limited to, ethyl thiosulfate (EtOS(O)2S ) - formed by reacting ethanol with thiosulfate), isopropyl thiosulfate (iPrOS(O)2S ) - formed from isopropanol, benzyl thiosulfate (BnOS(O)2S ) - formed from benzyl alcohol), and phenyl thiosulfate (PhOS(O)2S ) - formed from phenol). Thiosulfate esters can be more lipophilic than sodium thiosulfate due to the organic group. The ester bond can be hydrolyzed in vivo to gradually regenerate active thiosulfate.

[0027] Thiosulfate groups can be incorporated into polymers. Examples of thiosulfate-containing polymers include, but are not limited to thiosulfatesubstituted polyethylenimine (PEI), where the thiosulfate groups are attached to the PEI backbone to enable calcium chelation; thiosulfate-substituted chitosan, where the chitosan is modified with thiosulfate groups to chelate calcium; poly(acrylamide-co-thiosulfate), where thiosulfate is included in acrylamide copolymers; thiosulfate-functionalized hydrogels, where crosslinked networks containing thiosulfate groups can be created; and thiosulfate dendrimers, where dendrimeric polymers are created that comprise thiosulfate surface groups.

[0028] Hydrogels are crosslinked polymer networks that are hydrophilic and can absorb significant amounts of water. Common materials used for hydrogels in biomedical applications include polyethylene glycol), poly(vinyl alcohol), and poly(acrylic acid). These polymers can be chemically modified with thiosulfate groups to enable calcium chelation.

[0029] A hydrogel coating can swell when hydrated, allowing diffusion of thiosulfate out of the gel over time. The hydrogel controls the thiosulfate elution kinetics to provide sustained release over weeks to months. This enables thiosulfate to act locally at the stent site to prevent calcification and reduce restenosis.

[0030] Those of skill in the art would know how to optimize the hydrogel synthesis and crosslinking density to balance stent coating integrity, mechanical properties, and drug release kinetics.

[0031] Examples of thiosulfate-functionalized hydrogels include, but are not limited to thiosulfate-PEG hydrogels (for example, those comprising a PEG backbone crosslinked with peptides or other linkers and functionalized with thiosulfate groups), thiosulfate-alginate hydrogels (for example, alginate hydrogels modified with thiosulfate), thiosulfate-chitosan hydrogels (for example, a chitosan network derivatized with thiosulfate groups), thiosulfate-hyaluronic acid hydrogels (for example, hyaluronic acid hydrogel with thiosulfate modification), andthiosulfate-agarose hydrogels (for example, agarose polysaccharide hydrogel containing thiosulfate). The thiosulfate groups can provide localized calcium chelation while the hydrogel network offers tunable swelling, porosity, degradation, and release kinetics.

[0032] Hydrogels provide a matrix for localized and sustained release of the thiosulfate composition at the stent implantation site.

[0033] Examples of thiosulfate prodrugs include, but are not limited to, thiosulfate ester prodrugs (described herein), thiosulfate phospholipid prodrugs (for example, where the thiosulfate is linked to phospholipids via biocleavable linkers), thiosulfate-peptide prodrugs (for example, where thiosulfate is conjugated to cellpenetrating peptides containing enzymatic cleavage sites to facilitate cellular uptake and controlled thiosulfate release), polymer-thiosulfate prodrugs (for example, thiosulfate attached to biodegradable polymers like polylactic acid (PLA), polylactic-co-glycolic acid) PLGA that release thiosulfate as the polymer breaks down in the body), and thiosulfate nanoparticles (for example, thiosulfate loaded into nanoparticles formulated with lipids, polymers, or other materials to enable targeted delivery and sustained thiosulfate release).

[0034] In one embodiment, the thiosulfate compositions contemplated herein comprise sodium thiosulfate.

[0035] The thiosulfate compositions of the disclosure can be formulated in a modified release form. As used herein, the term “modified release” refers to a composition in which the rate or place of release of the active ingredient(s) (in this case thiosulfate) is different from that of an immediate release form when administered by the same route. Modified release compositions include delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, and programmed-release forms. The thiosulfate compositions in modified release forms can be prepared using a variety of methods known to those skilled in the art, including, but not limited to, matrices comprising thiosulfate, multiparticulate controlled release compositions, microspheres, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes of the active ingredient(s).

[0036] For example, the thiosulfate compositions of the disclosure can be immediate release, extended release or can have immediate release and extended-release properties. Thus, for example, the stents of the disclosure comprising the thiosulfate compositions of the disclosure can provide immediate release of thiosulfate after stent implantation; sustained release of the thiosulfate after stent implantation to deliver thiosulfate over a prolonged time period (weeksto months); or have immediate release and sustained release properties. Sustained release of thiosulfate can be accomplished in any suitable fashion. For example, the thiosulfate can be incorporated into a polymer coating on the stent surface that gradually elutes the thiosulfate. As described previously herein, the polymers include polyethylene-co-vinyl acetate (PEVA), polyurethanes, polyethylene glycol (PEG), polylactic acid (PLA), and polycaprolactone (PCL). The thiosulfate release kinetics can be tuned by factors like coating thickness, polymer properties, thiosulfate loading, and by the addition of topcoat layers. Nanoreservoirs or microparticles embedded in the coating of the stents of the disclosure can be used to provide sustained delivery of thiosulfate. Bioerodible stents can also be used for sustained release of thiosulfate. The thiosulfate is released slowly as the bioerodible stent dissolves over hours, days, weeks or even months.

[0037] Bioerodible stents contemplated herein are made from materials that gradually degrade and disappear over a period of days, weeks, months or even years after implantation. Such bioerodible stents allow for the sustained release as the stent material slowly dissolves. Such bioerodible stents can be attractive in situations where having permanent metallic stent frame left in the body may not be desirable. But also contemplated herein are hybrid design stents that comprise a bioerodible polymer coating on metallic stent. Bioerodible stents can be made of any suitable material, including, but not limited to biodegradable polymers like polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), or their copolymers (PLGA). Bioerodible stents can comprise radio-opaque agents like barium sulfate or gold nanoparticles to enable their imaging for, for example, their placement.

[0038] The stents of the disclosure can deliver any suitable amount of thiosulfate after implantation. For example, the stents of the disclosure can deliver from about 0.001 microgram to greater than about 500 mg, greater than about 1 g, greater than about 5 g, greater than about 10 g, greater than about 15 g, greater than about 30 g, greater than about 50 g, or greater than about 70 g or more thiosulfate. For example, the stents of the disclosure can deliver 0.001 micrograms, 0.01 micrograms, 0.05 micrograms, 0.1 micrograms, 0.5 micrograms, 1 .0 micrograms, 10.0 micrograms, 50.0 micrograms, 100.0 micrograms, 500 micrograms, 1 .0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, 45.0 mg, 50.0 mg, 60.0 mg, 70.0 mg, 80.0 mg, 90.0 mg, 100.0 mg, 150.0 mg, 200.0 mg, 250.0 mg, 300.0 mg, 350.0 mg, 400.0 mg, 450.0 mg, to greater than about 500.0 mg, such as from 1 g to 10 g, 10 g to 30 g, 5 g to 30 g, 20 g to 75 g or anyincremental value thereof. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed. Any of the foregoing amounts can be delivered at least two, three, four or more times per week. Thus, for example, the stents of the disclosure can deliver from about 1 g to about 30 g, about 5 g to about 15 g, about 10 g to about 30 g, about 15 g to about 45 g, about 15 g to about 25 g, or about 20 g to about 30 g thiosulfate two or three times per week.

[0039] The stents of the disclosure can deliver thiosulfate in the range from about 0.001 / day to greater than about 100 mg / day. For example, the dosage can be 0.2 mg / day to 100 mg / day, 0.2 mg / day to 50 mg / day, 0.2 mg / day to 25 mg / day, 0.2 mg / day to 10 mg / day, 0.2 mg / day to 7.5 mg / day, 0.2 mg / day to 5 mg / day, 0.25 mg / day to 100 mg / day, 0.25 mg / day to 50 mg / day, 0.25 mg / day to 25 mg / day, 0.25 mg / day to 10 mg / day, 0.25 mg / day to 7.5 mg / day, 0.25 mg / day to 5 mg / day, 0.5 mg / day to 50 mg / day, 0.5 mg / day to 25 mg / day, 0.5 mg / day to 20 mg / day, 0.5 mg / day to 15 mg / day, 0.5 mg / day to 10 mg / day, 0.5 mg / day to 7.5 mg / day, 0.5 mg / day to 5 mg / day, 0.75 mg / day to 50 mg / day, 0.75 mg / day to 25 mg / day, 0.75 mg / day to 20 mg / day, 0.75 mg / day to 15 mg / day, 0.75 mg / day to 10 mg / day, 0.75 mg / day to 7.5 mg / day, 0.75 mg / day to 5 mg / day, 1 .0 mg / day to 50 mg / day, 1 .0 mg / day to 25 mg / day, 1.0 mg / day to 20 mg / day, 1 .0 mg / day to 15 mg / day, 1 .0 mg / day to 10 mg / day, 1 .0 mg / day to 7.5 mg / day, 1 .0 mg / day to 5 mg / day, 2 mg / day to 50 mg / day, 2 mg / day to 25 mg / day, 2 mg / day to 20 mg / day, 2 mg / day to 15 mg / day, 2 mg / day to 10 mg / day, 2 mg / day to 7.5 mg / day, or 2 mg / day to 5 mg / day.

[0040] The stents of the disclosure can deliver thiosulfate in concentrations that range from 0.01 micromolar to greater than or equal to 500 micromolar. For example, the dose can be 0.01 micromolar, 0.02 micromolar, 0.05 micromolar, 0.1 micromolar, 0.15 micromolar, 0.2 micromolar, 0.5 micromolar, 0.7 micromolar, 1 .0 micromolar, 3.0 micromolar, 5.0 micromolar, 7.0 micromolar, 10.0 micromolar, 15.0 micromolar, 20.0 micromolar, 25.0 micromolar, 30.0 micromolar, 35.0 micromolar, 40.0 micromolar, 45.0 micromolar, 50.0 micromolar, 60.0 micromolar, 70.0 micromolar, 80.0 micromolar, 90.0 micromolar, 100.0 micromolar, 150.0 micromolar, 200.0 micromolar, 250.0 micromolar, 300.0 micromolar, 350.0 micromolar, 400.0 micromolar, 450.0 micromolar, to greater than about 500.0 micromolar or any incremental value thereof. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed.

[0041] The stents of the disclosure can deliver thiosulfate in concentrations that range from 0.10 microgram / mL to 500.0 microgram / mL. For example, the concentration can be 0.10 microgram / mL, 0.50 microgram / mL, 1 microgram / mL,2.0 microgram / mL, 5.0 microgram / mL, 10.0 microgram / mL, 20 microgram / mL, 25 microgram / mL. 30 microgram / mL, 35 microgram / mL, 40 microgram / mL, 45 microgram / mL, 50 microgram / mL, 60.0 microgram / mL, 70.0 microgram / mL, 80.0 microgram / mL, 90.0 microgram / mL, 100.0 microgram / mL, 150.0 microgram / mL, 200.0 microgram / mL, 250.0 g / mL, 250.0 microgram / mL, 300.0 microgram / mL, 350.0 microgram / mL, 400.0 microgram / mL, 450.0 microgram / mL, to greater than about 500.0 microgram / mL or any incremental value thereof. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed.

[0042] The stents of the disclosure can include one or more therapeutic agents, in addition to thiosulfate. For example, the thiosulfate compositions of the disclosure can include such one or more therapeutic agents, in addition to thiosulfate. The one or more therapeutic agents that can be included in the stents, whether in the thiosulfate compositions or otherwise, include steroids, anti-cancer agents, and anti-inflammatory agents.

[0043] Examples of one or more therapeutic agents include, but are not limited to, adrenocorticoids and corticosteroids, alkylating agents, antiandrogens, antiestrogens, androgens, aclamycin and aclamycin derivatives, estrogens, antimetabolites such as cytosine arabinoside, purine analogs, pyrimidine analogs, and methotrexate, busulfan, carboplatin, chlorambucil, cisplatin and other platinum compounds, taxanes, such as tamoxiphen, taxol, paclitaxel, paclitaxel derivatives, Taxotere®, and the like, maytansines and analogs and derivatives thereof, cyclophosphamide, daunomycin, doxorubicin, rhizoxin, T2 toxin, plant alkaloids, prednisone, hydroxyurea, teniposide, mitomycins, discodermolides, microtubule inhibitors, epothilones, tubulysin, cyclopropyl benz[e]indolone, seco-cyclopropyl benz[e]indolone, O-Ac-seco-cyclopropyl benz[e]indolone, bleomycin and any other antibiotic, nitrogen mustards, nitrosureas, vincristine, vinblastine, and analogs and derivative thereof such as deacetylvinblastine monohydrazide, colchicine, colchicine derivatives, allocolchicine, thiocolchicine, trityl cysteine, Halicondrin B, dolastatins such as dolastatin 10 and 15, amanitins such as a amanitin, camptothecin, irinotecan, and other camptothecin derivatives thereof, geldanamycin and geldanamycin derivatives, estramustine, nocodazole, MAP4, colcemid, inflammatory and proinflammatory agents, peptide and peptidomimetic signal transduction inhibitors, and any other art recognized drug or toxin. Other drugs that can be used in accordance with the invention include penicillins, cephalosporins, vancomycin, erythromycin, clindamycin, rifampin, chloramphenicol, aminoglycoside antibiotics, gentamicin, amphotericin B,acyclovir, trif luridine , ganciclovir, zidovudine, amantadine, ribavirin, and any other art recognized antimicrobial compound. Additional examples of one or more therapeutic agents are statins, such as simvastatin, lovastatin, and fluvastatin; and compounds having immunosuppressant and / or antiangiogenic properties, such as sirolimus, everolimus, and zotarolimus.

[0044] The thiosulfate compositions described herein, which can be coated on the stents described herein, can be used as a primary treatment, pre-emptive with an anticipated difficult intervention or upon failure to succeed in opening an artery with the anticipation to return to a more forgiving blockage. In the case for valvular calcifications, thiosulfate can be used in a similar way but also possibly a palliative intervention when surgical or endovascular valve repair / replacement is not feasible.

[0045] The stents of the disclosure can be used alone or in combination with other methods for delivering thiosulfate to a subject (e.g., a human subject) including, but not limited to, one or more of systemic or topical modes of delivery. For example, for the treatment of calciphylaxis, in addition to the stents of the disclosure, intralesional and / or intravenous thiosulfate can be used. For example, intralesional sodium thiosulfate may be an effective treatment for the deeper lesions of cutaneous calciphylaxis. The use of topical thiosulfate has also been successfully reported for superficial calcium deposits in the skin from other processes. Examples of thiosulfate compositions for topical use include those comprising sodium thiosulfate pentahydrate, EMULSIFIX base (e.g., EMULSIFIX -205), medium chain triglycerides, KRISGEL, purified water, and optionally a fragrance (e.g., a lavender fragrance oil). Such compositions can comprise additional components than those listed. Percutaneous ultrasound guided approaches for delivery of thiosulfate are also contemplated herein.

[0046] Thiosulfate compositions of the disclosure for use alone (e.g., as a topical composition) or in conjunction with the stents described herein can be formulated in water. Such thiosulfate compositions can comprise from about 1 gram to about 100 grams, about 1 gram to about 75 grams, about 1 gram to about 50 grams, about 1 gram to about 25 grams or about 1 gram to about 12.5 grams of sodium thiosulfate provided herein in about 1 mL to about 1000 mL, about 1 mL to about 750 mL, about 1 mL to about 500 mL, about 1 mL to about 250 mL about 1 mL to about 100 mL, about 1 mL to about 50 mL or about 1 mL to about 25 mL of water. For example, thiosulfate compositions of the disclosure for use in conjunction with the stents described herein can comprise about 5 grams, about 10 grams, about 12.5 grams, about 15 grams, about 20 grams, about 25 grams, about 30 grams,about 50 grams, about 75 grams or about 100 grams or more of sodium thiosulfate provided herein in about 25 mL, about 50 mL, about 100 mL, about 250 mL, about 500 mL, about 750 mL or about 1000 mL or more of water.

[0047] The thiosulfate compositions of the disclosure for use alone (e.g., as a topical composition) or in conjunction with the stents described herein can be formulated in a modified release form, such as in delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, and programmed-release forms. The thiosulfate compositions for use in conjunction with the stents described herein can be formulated in matrices comprising thiosulfate, multiparticulate controlled release compositions, microspheres, and combinations thereof.

[0048] The thiosulfate compositions of the disclosure for use alone (e.g., as a topical composition) or in conjunction with the stents described herein can comprise additional therapeutic agents, including vasoactive compounds such as vasodilators. The vasoactive compounds, including vasodilators, can be in an amount that is effective to cause increased permeation of fluid through the walls of blood vessels in the skin of the patient. General classes of vasodilators contemplated herein include centrally acting agents, adrenergic neuron blocking agents, ganglion blocking agents, calcium channel blockers, calcium antagonists, potassium channel openers, ACE inhibitors, angiotensin-ll receptor antagonists, a- adrenergic and imidazole receptor antagonists, p1 -adrenergic agonists, phosphodiesterase-type-5 (PDE-5) inhibitors, eicosanoids, prostaglandins, and NO donors, derivatives of any of the foregoing (e.g., salts thereof, such as chloride, citrate, and ascorbate salts, and the like) and combinations of the foregoing.

[0049] Examples of vasodilators include, but are not limited to, amrinone, arginine, bamethan sulphate, bencyclane fumarate, benfurodil hemisuccinate, benzyl nicotinate, buflomedil hydrochloride, buphenine hydrochloride, butalamine hydrochloride, cetiedil citrate, ciclonicate, cinepazide maleate, cyclandelate, di isopropylammonium dichloroacetate, ethyl nicotinate, hepronicate, hexyl nicotinate, ifenprodil tartrate, inositol nicotinate, isoxsuprine hydrochloride, kallidinogenase, methyl nicotinate, naftidrofuryl oxalate, nicametate citrate, niceritrol, nicoboxil, nicofuranose, nicotinyl alcohol, nicotinyl alcohol tartrate, nitric oxide, nonivamide, oxpentifylline, papaverine, papaveroline, pentifylline, peroxynitrite, pinacidil, pipratecol, propentofyltine, raubasine, suloctidil, teasuprine, thymoxamine hydrochloride, tocopherol nicotinate, tolazoline, xanthinol nicotinate, diazoxide, hydralazine, minoxidil, and sodium nitroprusside. Centrally acting agents include clonidine, quanaberz, and methyl dopa. Alphaadrenoceptor blocking agents include indoramin, phenoxybenzamine, phentolamine, and prazosin. Adrenergic neuron blocking agents include bedmidine, debrisoquine, and guanethidine. ACE inhibitors include benazepril, captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, and ramipril. Ganglion blocking agents include pentolinium and trimetaphan. Calcium channel blockers include amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil. Prostaglandins including prostacyclin, thrombuxane A2, leukotrienes, PGA, PGA1 , PGA2, PGE1 , PGE2, PGD, PGG, and PGH. Angiotensin II analogs include saralasin. Other suitable vasodilators include nitroglycerin, labetalol, thrazide, isosorbide dinitrate, pentaerythritol tetranitrate, digitalis, hydralazine, diazoxide, and sodium nitroprusside, derivatives of these (e.g., salts thereof, such as chloride, citrate, and ascorbate salts, and the like) and combinations of the foregoing. Phosphodiesterase-type-5 (PDE-5) inhibitors include sildenafil, vardenafil, tadalafil, and avanafil and derivatives of these (e.g., salts thereof, such as chloride, citrate, and ascorbate salts, and the like) and combinations of the foregoing.

[0050] The disclosure relates to a method for opening arteries in a subject that are occluded with calcium, the method comprising applying a topical thiosulfate composition comprising a therapeutically effective amount of thiosulfate to an area of the subject’s body comprising an artery occluded with calcium.

[0051] Topical thiosulfate compositions can further comprise one or more therapeutic agents, in addition to thiosulfate, a vasoactive composition, a steroid, an anti-cancer agent, and an anti-inflammatory agent, and combinations thereof. For example, the one or more therapeutic agents, in addition to thiosulfate, comprises a vasoactive composition. In one example, the vasoactive composition comprises a vasodilator.

[0052] The thiosulfate in topical thiosulfate compositions can comprise a thiosulfate salt, an organic thiosulfate, a thiosulfate ester, a thiosulfate polymer, or a thiosulfate prodrug. For example, the thiosulfate salt comprises sodium thiosulfate or ammonium thiosulfate. In one example, the thiosulfate salt comprises sodium thiosulfate.

[0053] Topical thiosulfate compositions can comprise an immediate release thiosulfate composition, an extended-release thiosulfate composition, or thiosulfate composition comprising immediate release and extended-release properties.

[0054] The disclosure also relates to a method for treating peripheral artery disease, calciphylaxis, atherosclerosis, atheroma, arterial plaques, atheroscleroticplaques, and / or atheroma plaques in a subject, the method comprising applying a topical thiosulfate composition comprising a therapeutically effective amount of thiosulfate to an area of the subject’s body. In one example, the method does not include treating calciphylaxis.

[0055] Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range were explicitly recited. For example, a range of “about 0.1 % to about 5%” or “about 0.1 % to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1 %, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1 % to 0.5%, 1 .1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0056] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading can occur within or outside of that particular section. Furthermore, all publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

[0057] In the methods described herein, the steps can be carried out in any order without departing from the principles of the invention, except when a temporal or operational sequence is explicitly recited. Furthermore, specified steps can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed step of doing X and a claimed step of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0058] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1 % of a stated value or of a stated limit of a range.

[0059] The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.

[0060] The term “substantially no” as used herein refers to less than about 30%, 25%, 20%, 15%, 10%, 5%, 3%, 2%, 1 %, 0.5%, 0.1%, 0.05%, 0.001 %, or at less than about 0.0005% or less or about 0% or 0%.

[0061] Those skilled in the art will appreciate that many modifications to the embodiments described herein are possible without departing from the spirit and scope of the present disclosure. Thus, the description is not intended and should not be construed to be limited to the examples given but should be granted the full breadth of protection afforded by the appended claims and equivalents thereto. In addition, it is possible to use some of the features of the present disclosure without the corresponding use of other features. Accordingly, the foregoing description of or illustrative embodiments is provided for the purpose of illustrating the principles of the present disclosure and not in limitation thereof and can include modification thereto and permutations thereof.

Claims

What is claimed is:

1. A method for opening arteries in a subject that are occluded with calcium, the method comprising applying a topical thiosulfate composition comprising a therapeutically effective amount of thiosulfate to an area of the subject’s body comprising an artery occluded with calcium.

2. The method of claim 1 , wherein the topical thiosulfate composition further comprises one or more therapeutic agents, in addition to thiosulfate, a vasoactive composition, a steroid, an anti-cancer agent, and an anti-inflammatory agent, and combinations thereof.

3. The method of claim 2, wherein the one or more therapeutic agents, in addition to thiosulfate, comprises a vasoactive composition.

4. The method of claim 3, wherein the vasoactive composition comprises a vasodilator.

5. The method of claim 1 , wherein the topical thiosulfate composition comprises an immediate release thiosulfate composition, an extended-release thiosulfate composition, or thiosulfate composition comprising immediate release and extended-release properties.

6. The method of claim 1 , wherein the thiosulfate comprises a thiosulfate salt, an organic thiosulfate, a thiosulfate ester, a thiosulfate polymer, or a thiosulfate prodrug.

7. The method of claim 6, wherein the thiosulfate salt comprises sodium thiosulfate or ammonium thiosulfate.

8. The method of claim 7, wherein the thiosulfate salt comprises sodium thiosulfate.

9. A method for treating peripheral artery disease, calciphylaxis, atherosclerosis, atheroma, arterial plaques, atherosclerotic plaques, and / or atheroma plaques in a subject, the method comprising applying a topical thiosulfate composition comprising a therapeutically effective amount of thiosulfate to an area of the subject’s body.

10. A stent comprising:(a) a balloon expandable stent; and(b) thiosulfate, in a therapeutically effective amount.1 1 . The stent of claim 10, wherein the thiosulfate is comprised in a thiosulfate composition coated onto a surface of the stent.

12. The stent of claim 1 1 , wherein the thiosulfate composition comprises an immediate release thiosulfate composition, an extended-release thiosulfate composition, or thiosulfate composition comprising immediate release and extended-release properties.

13. The stent of claim 10, wherein the stent comprises a therapeutically effective amount of thiosulfate.

14. The stent of claim 10, wherein the thiosulfate comprises a thiosulfate salt, an organic thiosulfate, a thiosulfate ester, a thiosulfate polymer, or a thiosulfate prodrug.

15. The stent of claim 14, wherein the thiosulfate salt comprises sodium thiosulfate or ammonium thiosulfate.

16. The stent of claim 15, wherein the thiosulfate salt comprises sodium thiosulfate.

17. The stent of claim 10, wherein the stent comprises a bioerodible material.

18. The stent of claim 10, wherein the stent comprises an one or more therapeutic agents, in addition to thiosulfate.

19. The stent of claim 18, wherein the one or more therapeutic agents, in addition to thiosulfate, comprises a steroid, an anti-cancer agent, and an anti-inflammatory agent, and combinations thereof.

20. The stent of claim 10, wherein the stent is a vascular stent.21 . A method for opening arteries that are occluded with calcium in a subject in need thereof, the method comprising implanting the stent of claim 10 in an artery occluded with calcium.

22. A method for treating peripheral artery disease, valvular calcification, calciphylaxis, atherosclerosis, atheroma, arterial plaques, atherosclerotic plaques, atheroma plaques, aortic calcifications, and coronary artery disease in a subject in need thereof, the method comprising implanting the stent of claim 10 in the subject.

23. The method of claim 22, wherein the peripheral artery disease includes mesenteric ischemia, renal artery stenosis, carotid artery stenosis, and cerebral artery stenosis.

24. The method of claim 22, wherein the valvular calcification includes calcific aortic valve disease, aortic stenosis, and mitral annular calcification.

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