WO2018218182A1 - Combination therapy for treatment of restenosis - Google Patents

Combination therapy for treatment of restenosis Download PDF

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Publication number
WO2018218182A1
WO2018218182A1 PCT/US2018/034713 US2018034713W WO2018218182A1 WO 2018218182 A1 WO2018218182 A1 WO 2018218182A1 US 2018034713 W US2018034713 W US 2018034713W WO 2018218182 A1 WO2018218182 A1 WO 2018218182A1
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WO
WIPO (PCT)
Prior art keywords
composition
temsirolimus
therapeutically effective
effective amount
dexamethasone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2018/034713
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English (en)
French (fr)
Inventor
Kirk Patrick Seward
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Mercator MedSystems Inc
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Mercator MedSystems Inc
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Filing date
Publication date
Application filed by Mercator MedSystems Inc filed Critical Mercator MedSystems Inc
Priority to KR1020197038156A priority Critical patent/KR20200008166A/ko
Priority to JP2019565179A priority patent/JP7137584B2/ja
Priority to EP18806949.6A priority patent/EP3629774A4/en
Priority to CN201880049930.2A priority patent/CN110996687A/zh
Priority to CA3064780A priority patent/CA3064780A1/en
Priority to AU2018272061A priority patent/AU2018272061A1/en
Publication of WO2018218182A1 publication Critical patent/WO2018218182A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone

Definitions

  • the present disclosure relates generally to medical methods and devices. More particularly, the present disclosure relates to medical methods and kits for distributing temsirolimus in the tissue surrounding a blood vessel. Further, the present disclosure relates to medical methods and kits for distributing temsirolimus in combination with a glucocorticoid in the tissue surrounding a blood vessel.
  • Blockages can form in blood vessels under various disease conditions.
  • atherosclerosis the narrowing of arteries in the body, particularly in the heart, legs, carotid and renal anatomy, can lead to tissue ischemia from lack of blood flow.
  • Mechanical revascularization methods such as balloon angioplasty, atherectomy, stenting, or surgical endarterectomy, are used to open the blood vessel and to improve blood flow to downstream tissues.
  • mechanical revascularization can lead to an injury cascade that causes the blood vessel to stiffen and vessel walls to thicken with a scar-like tissue, which can reduce the blood flow and necessitate another revascularization procedure.
  • the present disclosure provides methods, devices, and compositions for distributing a combination of a cell division inhibitor and a glucocorticoid into a tissue surrounding a blood vessel for treating vascular diseases.
  • compositions comprising temsirolimus and a glucocorticoid, or their pharmaceutically acceptable salts thereof. Further provided herein are pharmaceutical compositions wherein the glucocorticoid is dexamethasone or a
  • compositions wherein the ratio (by weight) of temsirolimus to the glucocorticoid, or vice versa, is between 10: 1 to 1 : 1.
  • pharmaceutical compositions wherein the composition is in an injectable dosage form.
  • pharmaceutical compositions wherein the composition further comprises at least one pharmaceutically acceptable excipient.
  • pharmaceutical compositions wherein the concentration of dexamethasone is 1.0-8.0 mg/mL.
  • pharmaceutical compositions wherein the concentration of dexamethasone is about 3.2 mg/mL.
  • pharmaceutical compositions wherein the concentration of dexamethasone is less than 4.0 mg/mL.
  • compositions wherein the concentration of temsirolimus is 0.01-2.0 mg/mL. Further provided herein are pharmaceutical compositions wherein the concentration of temsirolimus is 0.05-0.5 mg/mL. Further provided herein are pharmaceutical compositions wherein the concentration of temsirolimus is about 0.1 mg/mL. Further provided herein are pharmaceutical compositions wherein the concentration of temsirolimus is about 0.4 mg/mL. Further provided herein are pharmaceutical compositions for use in treating restenosis. Further provided herein are pharmaceutical compositions for use in treating restenosis below the knee. Further provided herein are pharmaceutical compositions for use in treating restenosis above the knee. Further provided herein are pharmaceutical compositions for use in treating restenosis in a below-knee popliteal vessel or tibial vessel.
  • compositions comprising temsirolimus or a
  • injectable compositions wherein the composition is suitable for adventitial delivery. Further provided herein are injectable compositions wherein the composition is suitable for adventitial delivery to a coronary vessel. Further provided herein are injectable compositions wherein the composition is suitable for adventitial delivery to a coronary artery. Further provided herein are injectable compositions wherein the composition is suitable for adventitial delivery below the knee.
  • injectable compositions wherein the composition is suitable for adventitial delivery above the knee. Further provided herein are injectable compositions wherein the composition is suitable for adventitial delivery to a below-knee popliteal or tibial vessel. Further provided herein are injectable compositions wherein the composition is suitable for adventitial delivery to a femoral vessel. Further provided herein are injectable compositions wherein the therapeutically effective amount of temsirolimus is about 1 ⁇ g to 50 mg. Further provided herein are injectable compositions wherein the therapeutically effective amount of temsirolimus is about 10 ⁇ g to 20 mg.
  • injectable compositions wherein the therapeutically effective amount of temsirolimus is about 100 ⁇ g to 15 mg. Further provided herein are injectable compositions wherein the therapeutically effective amount of temsirolimus is about 100 ⁇ g to 5 mg. Further provided herein are injectable compositions wherein the therapeutically effective amount is determined by a longitudinal length of a target diseased artery. Further provided herein are injectable compositions wherein the therapeutically effective amount of dexamethasone is about 0.8 mg to 8 mg per cm of longitudinal length of a disease site in the blood vessel.
  • injectable compositions wherein the therapeutically effective amount of dexamethasone is about 0.05 mg to 10 mg per cm of longitudinal length of a disease site in the blood vessel and the therapeutically effective amount of temsirolimus is about 0.005 mg to 5 mg per cm of longitudinal length of a disease site in the blood vessel. Further provided herein are injectable compositions wherein the therapeutically effective amount of dexamethasone is about 0.1 mg to 2 mg per cm of longitudinal length of a disease site in the blood vessel and the therapeutically effective amount of temsirolimus is about 0.025 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel.
  • injectable compositions wherein the injection volume of the composition is about 0.01 mL to about 50 mL. Further provided herein are injectable compositions wherein the injection volume of the composition is about 0.5 mL to about 20 mL. Further provided herein are injectable compositions wherein the injection concentration of temsirolimus is about 0.01 mg/mL to about 2.0 mg/mL. Further provided herein are injectable compositions wherein the injection concentration of temsirolimus is about 0.1 mg/mL to about 0.5 mg/mL. Further provided herein are injectable compositions wherein the injection concentration of temsirolimus is about 0.4 mg/mL.
  • injectable compositions wherein the pharmaceutically acceptable excipient is 0.9% sodium chloride injection USP, dehydrated alcohol, ⁇ i/-alpha tocopherol, anhydrous citric acid, polysorbate 80, polyethylene glycol 400, propylene glycol, or a combination thereof.
  • injectable compositions for use in treating restenosis Further provided herein are injectable compositions for use in treating restenosis below the knee. Further provided herein are injectable compositions for use in treating restenosis above the knee. Further provided herein are injectable compositions for use in treating restenosis in a below-knee popliteal vessel or tibial vessel.
  • vascular disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein, wherein the composition is administered by direct injection to a disease site.
  • methods of treating a vascular disease wherein the composition is injected though a catheter with a needle.
  • methods of treating a vascular disease wherein the composition is injected distal or proximal to the disease site.
  • methods of treating a vascular disease wherein the composition is injected at least about 2 cm away from the disease site.
  • methods of treating a vascular disease wherein the composition is injected at or adjacent to the disease site.
  • compositions are administered by injection into the blood vessel. Further provided herein are methods of treating a vascular disease wherein the composition is injected into an adventitial tissue surrounding a blood vessel. Further provided herein are methods of treating a vascular disease wherein the composition is injected into a perivascular tissue surrounding the blood vessel. Further provided herein are methods of treating a vascular disease wherein the blood vessel is an artery. Further provided herein are methods of treating a vascular disease wherein the blood vessel is a vein. Further provided herein are methods of treating a vascular disease wherein the artery is a coronary artery or a peripheral artery.
  • vascular disease wherein the artery is selected from the group consisting of renal artery, cerebral artery, pulmonary artery, and artery in the leg. Further provided herein are methods of treating a vascular disease wherein the artery is below the knee. Further provided herein are methods of treating a vascular disease wherein the blood vessel is below-knee popliteal vessel or tibial vessel. Further provided herein are methods of treating a vascular disease wherein the composition is injected into a blood vessel wall. Further provided herein are methods of treating a vascular disease wherein the composition is injected into a tissue surrounding the blood vessel wall.
  • a vascular disease wherein the therapeutically effective amount of temsirolimus is about 1 ⁇ g to 50 mg. Further provided herein are methods of treating a vascular disease wherein the therapeutically effective amount of temsirolimus is about 10 ⁇ g to 20 mg. Further provided herein are methods of treating a vascular disease wherein the therapeutically effective amount of temsirolimus is about 100 ⁇ g to 15 mg. Further provided herein are methods of treating a vascular disease wherein the therapeutically effective amount of temsirolimus is about 100 ⁇ g to 5 mg.
  • vascular disease wherein the therapeutically effective amount of dexamethasone is about 0.8 mg to 8 mg per cm of longitudinal length of the disease site in the blood vessel. Further provided herein are methods of treating a vascular disease wherein the therapeutically effective amount of dexamethasone is about 0.05 mg to 10 mg per cm of longitudinal length of the disease site in the blood vessel and the therapeutically effective amount of temsirolimus is about 0.005 mg to 5 mg per cm of longitudinal length of the disease site in the blood vessel.
  • vascular disease wherein the therapeutically effective amount of dexamethasone is about 0.1 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel and the therapeutically effective amount of temsirolimus is about 0.025 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel.
  • the injection volume of the composition is about 0.01 mL to about 50 mL.
  • the injection volume of the composition is about 0.5 mL to about 20 mL.
  • a vascular disease wherein the injection concentration of temsirolimus is about 0.01 mg/mL to about 2.0 mg/mL. Further provided herein are methods of treating a vascular disease wherein the injection concentration of temsirolimus is about 0.1 mg/mL to about 0.4 mg/mL. Further provided herein are methods of treating a vascular disease wherein the injection concentration of temsirolimus is about 0.4 mg/mL. Further provided herein are methods of treating a vascular disease wherein the injection concentration of temsirolimus is about 0.1 mg/mL. Further provided herein are methods of treating a vascular disease wherein 12 months after
  • vessel cross-sectional area at the disease site has decreased no more than 60%, when compared to vessel cross-sectional area at the disease site at the time of administration.
  • methods of treating a vascular disease wherein 12 months after administration of the pharmaceutical composition, vessel cross- sectional area at the disease site has decreased no more than 50%, when compared to vessel cross-sectional area at the disease site at the time of administration.
  • methods of treating a vascular disease wherein 12 months after administration of the
  • vessel cross-sectional area at the disease site has decreased no more than 30%, when compared to vessel cross-sectional area at the disease site at the time of administration.
  • methods of treating a vascular disease wherein the subject is human.
  • methods of treating a vascular disease wherein the vascular disease is angina, myocardial infarction, congestive heart failure, cardiac arrhythmia, peripheral artery disease, claudication, or critical limb ischemia.
  • methods of treating a vascular disease wherein the vascular disease is atherosclerosis, bypass graft failure, transplant vasculopathy, vascular restenosis, or in-stent restenosis.
  • composition results in a decrease in necrosis at the disease site relative to treating using a pharmaceutical composition comprising either temsirolimus or a glucocorticoid.
  • vascular disease in an individual in need thereof, the method comprising administering to the subject a therapeutically effective amount of a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition comprises temsirolimus, and the second pharmaceutical composition comprises a glucocorticoid, wherein the first composition and the second composition are each administered by injection.
  • kits for treating a peripheral artery disease in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising temsirolimus or pharmaceutically acceptable salt thereof, and a glucocorticoid or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the composition is administered by direct injection to or near a disease site in a wall of a peripheral artery via a laterally extending injection needle of a catheter advanced through vasculature of the human subject.
  • the composition further comprises a contrast medium for visualizing the injection.
  • compositions comprising temsirolimus and a
  • composition for use in treating a vascular disease of a human subject, wherein the composition is suitable for adventitial delivery to a peripheral artery, wherein the composition is suitable for direct injection to a vascular disease site in a wall of the peripheral artery via a laterally extending needle from a catheter advanced through vasculature of the human subject. Further provided herein are methods wherein the composition further comprises a contrast medium for visualizing the injection.
  • compositions comprising a cell division inhibitor and a glucocorticoid, or their pharmaceutically acceptable salts thereof. Further provided herein are pharmaceutical compositions wherein the glucocorticoid is dexamethasone or a
  • compositions wherein the ratio (by weight) of a cell division inhibitor to the glucocorticoid, or vice versa, is between 10: 1 to 1 : 1. Further provided herein are pharmaceutical compositions wherein the composition is in an injectable dosage form. Further provided herein are
  • compositions wherein the composition further comprises at least one
  • compositions wherein the concentration of dexamethasone is 1.0-8.0 mg/mL. Further provided herein are pharmaceutical compositions wherein the concentration of dexamethasone is about 3.2 mg/mL. Further provided herein are pharmaceutical compositions wherein the concentration of dexamethasone is less than 4.0 mg/mL. Further provided herein are pharmaceutical
  • compositions wherein the concentration of a cell division inhibitor is 0.01-2.0 mg/mL. Further provided herein are pharmaceutical compositions wherein the concentration of a cell division inhibitor is 0.05-0.5 mg/mL. Further provided herein are pharmaceutical compositions wherein the concentration of a cell division inhibitor is about 0.1 mg/mL. Further provided herein are pharmaceutical compositions wherein the concentration of a cell division inhibitor is about 0.4 mg/mL. Further provided herein are pharmaceutical compositions for use in treating restenosis. Further provided herein are pharmaceutical compositions for use in treating restenosis below the knee. Further provided herein are pharmaceutical compositions for use in treating restenosis above the knee. Further provided herein are pharmaceutical compositions for use in treating restenosis in a below-knee popliteal vessel or tibial vessel. Further provided herein are pharmaceutical compositions wherein the cell division inhibitor is paclitaxel.
  • injectable compositions comprising a cell division inhibitor or a pharmaceutically acceptable salt thereof, dexamethasone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Further provided herein are injectable compositions wherein the composition is suitable for adventitial delivery. Further provided herein are injectable compositions wherein the composition is suitable for adventitial delivery to a coronary vessel. Further provided herein are injectable compositions wherein the composition is suitable for adventitial delivery to a coronary artery. Further provided herein are injectable compositions wherein the composition is suitable for adventitial delivery below the knee.
  • injectable compositions wherein the composition is suitable for adventitial delivery above the knee. Further provided herein are injectable compositions wherein the composition is suitable for adventitial delivery to a below-knee popliteal or tibial vessel. Further provided herein are injectable compositions wherein the composition is suitable for adventitial delivery to a femoral vessel. Further provided herein are injectable compositions wherein the therapeutically effective amount of a cell division inhibitor is about 1 ⁇ g to 50 mg. Further provided herein are injectable compositions wherein the therapeutically effective amount of a cell division inhibitor is about 10 ⁇ g to 20 mg. Further provided herein are injectable compositions wherein the therapeutically effective amount of a cell division inhibitor is about 100 ⁇ g to 15 mg.
  • injectable compositions wherein the therapeutically effective amount of a cell division inhibitor is about 100 ⁇ g to 5 mg. Further provided herein are injectable compositions wherein the therapeutically effective amount is determined by a longitudinal length of a target diseased artery. Further provided herein are injectable compositions wherein the therapeutically effective amount of dexamethasone is about 0.8 mg to 8 mg per cm of longitudinal length of a disease site in the blood vessel. Further provided herein are injectable compositions wherein the therapeutically effective amount of dexamethasone is about 0.05 mg to 10 mg per cm of longitudinal length of a disease site in the blood vessel and the therapeutically effective amount of a cell division inhibitor is about 0.005 mg to 5 mg per cm of longitudinal length of a disease site in the blood vessel. Further provided herein are injectable compositions wherein the therapeutically effective amount of
  • dexamethasone is about 0.1 mg to 2 mg per cm of longitudinal length of a disease site in the blood vessel and the therapeutically effective amount of a cell division inhibitor is about 0.025 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel.
  • injectable compositions wherein the injection volume of the composition is about 0.01 mL to about 50 mL. Further provided herein are injectable compositions wherein the injection volume of the composition is about 0.5 mL to about 20 mL. Further provided herein are injectable compositions wherein the injection concentration of a cell division inhibitor is about 0.01 mg/mL to about 2.0 mg/mL.
  • injectable compositions wherein the injection concentration of a cell division inhibitor is about 0.1 mg/mL to about 0.5 mg/mL. Further provided herein are injectable compositions wherein the injection concentration of a cell division inhibitor is about 0.4 mg/mL. Further provided herein are injectable compositions wherein the pharmaceutically acceptable excipient is 0.9% sodium chloride injection USP, dehydrated alcohol, ⁇ i/-alpha tocopherol, anhydrous citric acid, polysorbate 80, polyethylene glycol 400, propylene glycol, or a combination thereof. Further provided herein are injectable compositions for use in treating restenosis. Further provided herein are injectable compositions for use in treating restenosis below the knee.
  • injectable compositions for use in treating restenosis above the knee Further provided herein are injectable compositions for use in treating restenosis in a below-knee popliteal vessel or tibial vessel. Further provided herein are injectable compositions wherein the cell division inhibitor is paclitaxel.
  • vascular disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein, wherein the composition is administered by direct injection to a disease site.
  • methods of treating a vascular disease wherein the composition is injected though a catheter with a needle.
  • methods of treating a vascular disease wherein the composition is injected distal or proximal to the disease site.
  • methods of treating a vascular disease wherein the composition is injected at least about 2 cm away from the disease site.
  • methods of treating a vascular disease wherein the composition is injected at or adjacent to the disease site.
  • compositions are administered by injection into a blood vessel. Further provided herein are methods of treating a vascular disease wherein the composition is injected into an adventitial tissue surrounding a blood vessel. Further provided herein are methods of treating a vascular disease wherein the composition is injected into a perivascular tissue surrounding the blood vessel. Further provided herein are methods of treating a vascular disease wherein the blood vessel is an artery. Further provided herein are methods of treating a vascular disease wherein the blood vessel is a vein. Further provided herein are methods of treating a vascular disease wherein the artery is a coronary artery or a peripheral artery.
  • vascular disease wherein the artery is selected from the group consisting of renal artery, cerebral artery, pulmonary artery, and artery in the leg. Further provided herein are methods of treating a vascular disease wherein the artery is below the knee. Further provided herein are methods of treating a vascular disease wherein the blood vessel is below-knee popliteal vessel or tibial vessel. Further provided herein are methods of treating a vascular disease wherein the composition is injected into a blood vessel wall. Further provided herein are methods of treating a vascular disease wherein the composition is injected into a tissue surrounding the blood vessel wall.
  • vascular disease wherein the therapeutically effective amount of a cell division inhibitor is about 1 ⁇ g to 50 mg. Further provided herein are methods of treating a vascular disease wherein the therapeutically effective amount of a cell division inhibitor is about 10 ⁇ g to 20 mg. Further provided herein are methods of treating a vascular disease wherein the therapeutically effective amount of a cell division inhibitor is about 100 ⁇ g to 15 mg. Further provided herein are methods of treating a vascular disease wherein the therapeutically effective amount of a cell division inhibitor is about 100 ⁇ g to 5 mg.
  • vascular disease wherein the therapeutically effective amount of dexamethasone is about 0.8 mg to 8 mg per cm of longitudinal length of the disease site in the blood vessel. Further provided herein are methods of treating a vascular disease wherein the therapeutically effective amount of dexamethasone is about 0.05 mg to 10 mg per cm of longitudinal length of the disease site in the blood vessel and the therapeutically effective amount of a cell division inhibitor is about 0.005 mg to 5 mg per cm of longitudinal length of the disease site in the blood vessel.
  • vascular disease wherein the therapeutically effective amount of dexamethasone is about 0.1 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel and the therapeutically effective amount of a cell division inhibitor is about 0.025 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel. Further provided herein are methods of treating a vascular disease wherein the injection volume of the
  • composition is about 0.01 mL to about 50 mL. Further provided herein are methods of treating a vascular disease wherein the injection volume of the composition is about 0.5 mL to about 20 mL. Further provided herein are methods of treating a vascular disease wherein the injection concentration of a cell division inhibitor is about 0.01 mg/mL to about 2.0 mg/mL. Further provided herein are methods of treating a vascular disease wherein the injection concentration of a cell division inhibitor is about 0.1 mg/mL to about 0.4 mg/mL. Further provided herein are methods of treating a vascular disease wherein the injection concentration of a cell division inhibitor is about 0.4 mg/mL.
  • vascular disease wherein the injection concentration of a cell division inhibitor is about 0.1 mg/mL. Further provided herein are methods of treating a vascular disease wherein 12 months after administration of the pharmaceutical composition, vessel cross-sectional area at the disease site has decreased no more than 60%, when compared to vessel cross-sectional area at the disease site at the time of administration. Further provided herein are methods of treating a vascular disease wherein 12 months after administration of the pharmaceutical composition, vessel cross- sectional area at the disease site has decreased no more than 50%, when compared to vessel cross-sectional area at the disease site at the time of administration. Further provided herein are methods of treating a vascular disease wherein 12 months after administration of the
  • vessel cross-sectional area at the disease site has decreased no more than 30%, when compared to vessel cross-sectional area at the disease site at the time of administration.
  • methods of treating a vascular disease wherein the subject is human.
  • methods of treating a vascular disease wherein the vascular disease is angina, myocardial infarction, congestive heart failure, cardiac arrhythmia, peripheral artery disease, claudication, or critical limb ischemia.
  • methods of treating a vascular disease wherein the vascular disease is atherosclerosis, bypass graft failure, transplant vasculopathy, vascular restenosis, or in-stent restenosis.
  • methods of treating a vascular disease wherein treating using the pharmaceutical composition results in a decrease in apoptosis at the disease site relative to treating using a pharmaceutical composition comprising either a cell division inhibitor or a glucocorticoid.
  • methods of treating a vascular disease wherein treating using the pharmaceutical composition results in a decrease in necrosis at the disease site relative to treating using a pharmaceutical composition comprising either a cell division inhibitor or a glucocorticoid.
  • methods wherein the cell division inhibitor is paclitaxel.
  • vascular disease in an individual in need thereof, the method comprising administering to the subject a therapeutically effective amount of a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition comprises a cell division inhibitor, and the second
  • composition comprises a glucocorticoid, wherein the first composition and the second composition are each administered by injection. Further provided herein are methods wherein the cell division inhibitor is paclitaxel.
  • kits for treating a peripheral artery disease in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising a cell division inhibitor or pharmaceutically acceptable salt thereof, and a glucocorticoid or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the composition is administered by direct injection to or near a disease site in a wall of a peripheral artery via a laterally extending injection needle of a catheter advanced through vasculature of the human subject.
  • the composition further comprises a contrast medium for visualizing the injection.
  • the cell division inhibitor is paclitaxel.
  • injectable compositions comprising a cell division inhibitor and a glucocorticoid, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient for use in treating a vascular disease of a human subject, wherein the composition is suitable for adventitial delivery to a peripheral artery, wherein the composition is suitable for direct injection to a vascular disease site in a wall of the peripheral artery via a laterally extending needle from a catheter advanced through vasculature of the human subject. Further provided herein are methods wherein the composition further comprises a contrast medium for visualizing the injection. Further provided herein are injectable compositions wherein the cell division inhibitor is paclitaxel.
  • FIG. 1A is a schematic, perspective view of an intraluminal injection catheter suitable for use in the methods and systems of the present disclosure.
  • FIG. IB is a cross-sectional view along line IB- IB of FIG. 1A.
  • FIG. 1C is a cross-sectional view along line 1C-1C of FIG. 1A.
  • FIG. 2A is a schematic, perspective view of the catheter of FIGS. 1A-1C shown with the injection needle deployed.
  • FIG. 2B is a cross-sectional view along line 2B-2B of FIG. 2A.
  • FIG. 3 is a schematic, perspective view of the intraluminal catheter of FIGS. 1A-1C injecting therapeutic agents into an adventitial space surrounding a body lumen in accordance with the methods of the present disclosure.
  • FIG. 4 is a schematic, perspective view of another embodiment of an intraluminal injection catheter useful in the methods of the present disclosure.
  • FIG. 5 is a schematic, perspective view of still another embodiment of an intraluminal injection catheter useful in the methods of the present disclosure, as inserted into one of a patient's body lumens.
  • FIG. 6 is a perspective view of a needle injection catheter useful in the methods and systems of the present disclosure.
  • FIG. 7 is a cross-sectional view of the catheter FIG. 6 shown with the injection needle in a retracted configuration.
  • FIG. 8 is a cross-sectional view similar to FIG. 7, shown with the injection needle laterally advanced into luminal tissue for the delivery of therapeutic or diagnostic agents according to the present disclosure.
  • FIG. 9A is a cross-sectional view of a step in an exemplary fabrication process employed to create a free-standing low-modulus patch within a higher modulus anchor, framework or substrate.
  • FIG. 9B is a cross-sectional view of a step in an exemplary fabrication process employed to create a free-standing low-modulus patch within a higher modulus anchor, framework or substrate.
  • FIG. 9C is a cross-sectional view of a step in an exemplary fabrication process employed to create a free-standing low-modulus patch within a higher modulus anchor, framework or substrate.
  • FIG. 9D is a cross-sectional view of a step in an exemplary fabrication process employed to create a free-standing low-modulus patch within a higher modulus anchor, framework or substrate.
  • FIG. 9E is a cross-sectional view of a step in an exemplary fabrication process employed to create a free-standing low-modulus patch within a higher modulus anchor, framework or substrate.
  • FIG. 10A is a cross-sectional view of a step in the inflation process of an intraluminal injection catheter useful in the methods of the present disclosure.
  • FIG. 10B is a cross-sectional view of a step in the inflation process of an intraluminal injection catheter useful in the methods of the present disclosure.
  • FIG. IOC is a cross-sectional view of a step in the inflation process of an intraluminal injection catheter useful in the methods of the present disclosure.
  • FIG. 10D is a cross-sectional view of a step in the inflation process of an intraluminal injection catheter useful in the methods of the present disclosure.
  • FIG. 11A is a cross-sectional view of the inflated intraluminal injection catheter useful in the methods of the present disclosure, illustrating the ability to treat multiple lumen diameters.
  • FIG. 1 IB is a cross-sectional view of the inflated intraluminal injection catheter useful in the methods of the present disclosure, illustrating the ability to treat multiple lumen diameters.
  • FIG. llC is a cross-sectional view of the inflated intraluminal injection catheter useful in the methods of the present disclosure, illustrating the ability to treat multiple lumen diameters.
  • FIG. 12A shows a schematic view of a step in treating a blood vessel affected by atherosclerosis with delivery of a pharmaceutical composition by injection by a needle through a catheter.
  • FIG. 12B shows schematic views of a step in treating a blood vessel affected by atherosclerosis with delivery of a pharmaceutical composition by injection by a needle through a catheter.
  • FIG. 12C shows schematic views of a step in treating a blood vessel affected by atherosclerosis with delivery of a pharmaceutical composition by injection by a needle through a catheter.
  • FIG. 12D shows schematic views of a step in treating a blood vessel affected by atherosclerosis with delivery of a pharmaceutical composition by injection by a needle through a catheter.
  • FIG. 12E shows schematic views of a step in treating a blood vessel affected by atherosclerosis with delivery of a pharmaceutical composition by injection by a needle through a catheter.
  • FIG. 12F shows schematic views of treating a blood vessel affected by atherosclerosis with delivery of a pharmaceutical composition by a step in injection by a needle through a catheter.
  • FIG. 13 shows a flow chart of a method of treating vascular disease in a subject.
  • FIG. 14A illustrates the percent inhibition of metabolic activity and proliferation in the presence of sirolimus (SIR), dexamethasone (DEX) or sirolimus + dexamethasone
  • FIG. 14B illustrates the percent inhibition of metabolic activity and proliferation in the presence of temsirolimus (TEM), dexamethasone (DEX) or temsirolimus + dexamethasone (TEM+CONST. DEX) in an experiment measuring metabolic activity of human aortic VSMCs in the presence of platelet-derived growth factor (PDGF).
  • TEM temsirolimus
  • DEX dexamethasone
  • TEM+CONST. DEX dexamethasone
  • FIG. 14C depicts the percent inhibition of metabolic activity and proliferation in the presence of paclitaxel (PACLI), dexamethasone (DEX) or paclitaxel + dexamethasone (PACLI+CONST. DEX) in an experiment measuring metabolic activity of human aortic VSMCs in the presence of platelet-derived growth factor (PDGF).
  • PACLI paclitaxel
  • DEX dexamethasone
  • DEX paclitaxel + dexamethasone
  • FIG. 15A depicts tissue necrosis factor a (TNFa) production in the presence of increasing concentrations of sirolimus, dexamethasone or sirolimus + 50 nM dexamethasone in an experiment measuring TNFa production of human aortic VSMCs.
  • TNFa tissue necrosis factor a
  • FIG. 15B depicts TNFa production in the presence of increasing concentrations of temsirolimus, dexamethasone or temsirolimus + 50 nM dexamethasone in an experiment measuring TNFa production of human aortic VSMCs.
  • FIG. 15C depicts TNFa production in the presence of increasing concentrations of paclitaxel, dexamethasone or paclitaxel + 50 nM dexamethasone in an experiment measuring TNFa production of human aortic VSMCs.
  • FIG. 16A depicts interleukin 6 (TL6) production in the presence of increasing concentrations of sirolimus, dexamethasone or sirolimus + 50 nM dexamethasone in an experiment measuring IL6 cytokine production of human aortic VSMCs.
  • TL6 interleukin 6
  • FIG. 16B depicts IL6 production in the presence of increasing concentrations of temsirolimus, dexamethasone or temsirolimus + 50 nM dexamethasone in an experiment measuring IL6 cytokine production of human aortic VSMCs.
  • FIG. 16C depicts IL6 production in the presence of increasing concentrations of paclitaxel or paclitaxel, dexamethasone + 50 nM dexamethasone in an experiment measuring IL6 cytokine production of human aortic VSMCs.
  • FIG. 17A depicts apoptosis by the measurement of Caspase 3 activation in the presence of increasing concentrations of sirolimus, dexamethasone or sirolimus + 50 nM dexamethasone in an experiment measuring apoptosis in human aortic VSMCs.
  • FIG. 17B depicts apoptosis by the measurement of Caspase 3 activation in the presence of increasing concentrations of temsirolimus, dexamethasone or temsirolimus + 50 nM dexamethasone in an experiment measuring apoptosis in human aortic VSMCs.
  • FIG. 17C depicts apoptosis by the measurement of Caspase 3 activation in the presence of increasing concentrations of paclitaxel, dexamethasone or paclitaxel + 50 nM dexamethasone in an experiment measuring apoptosis in human aortic VSMCs.
  • FIG. 18A depicts necrosis by the measurement of LDH release in the presence of increasing concentrations of sirolimus, dexamethasone or sirolimus + 50 nM dexamethasone in an experiment measuring necrosis in human aortic VSMCs.
  • FIG. 18B depicts necrosis by the measurement of LDH release in the presence of increasing concentrations of temsirolimus, dexamethasone or temsirolimus + 50 nM
  • FIG. 18C depicts necrosis by the measurement of LDH release in the presence of increasing concentrations of paclitaxel, dexamethasone or paclitaxel + 50 nM dexamethasone in an experiment measuring necrosis in human aortic VSMCs.
  • FIG. 19A depicts inhibition of PDGF-induced VSMC proliferation in the presence of increasing concentrations of temsirolimus (TEM), paclitaxel (PAC), or dexamethasone (DEX), and then with 500 nanomolar (nM) concentrations of either TEM or PAC as combined with increasing concentrations of DEX.
  • TEM temsirolimus
  • PAC paclitaxel
  • DEX dexamethasone
  • FIG. 19B depicts normalized VSMC apoptosis in the presence of PDGF and increasing concentrations of temsirolimus (TEM), paclitaxel (PAC), or dexamethasone (DEX), and then with 500 nanomolar (nM) concentrations of either TEM or PAC as combined with increasing concentrations of DEX.
  • TEM temsirolimus
  • PAC paclitaxel
  • DEX dexamethasone
  • FIG. 19C depicts normalized VSMC necrosis in the presence of PDGF and increasing concentrations of temsirolimus (TEM), paclitaxel (PAC), or dexamethasone (DEX), and then with 500 nanomolar (nM) concentrations of either TEM or PAC as combined with increasing concentrations of DEX.
  • TEM temsirolimus
  • PAC paclitaxel
  • DEX dexamethasone
  • FIG. 19D depicts PDGF-induced interleukin-6 (IL6) expression in the presence of increasing concentrations of temsirolimus (TEM), paclitaxel (PAC), or dexamethasone (DEX), and then with 500 nanomolar (nM) concentrations of either TEM or PAC as combined with increasing concentrations of DEX.
  • TEM temsirolimus
  • PAC paclitaxel
  • DEX dexamethasone
  • FIG. 19E depicts PDGF-induced tissue necrosis factor a (T Fa) in the presence of increasing concentrations of temsirolimus (TEM), paclitaxel (PAC), or dexamethasone (DEX), and then with 500 nanomolar (nM) concentrations of either TEM or PAC as combined with increasing concentrations of DEX.
  • TEM temsirolimus
  • PAC paclitaxel
  • DEX dexamethasone
  • FIG. 20 depicts PDGF-induced cell proliferation in the presence of decreasing concentrations (100 uM to 1 nM) of temsirolimus (TEM), sirolimus (SIR), paclitaxel (PAC), or dexamethasone (DEX), vehicle control, or cytotoxic control actinomycin D (ACT-D).
  • TEM temsirolimus
  • SIR sirolimus
  • PAC paclitaxel
  • DEX dexamethasone
  • vehicle control or cytotoxic control actinomycin D (ACT-D).
  • compositions comprise combinations of an mTOR inhibitor (such as temsirolimus) or a cell division inhibitor (such as paclitaxel) and a glucocorticoid (such as dexamethasone), or their pharmaceutically acceptable salts.
  • an mTOR inhibitor such as temsirolimus
  • a cell division inhibitor such as paclitaxel
  • a glucocorticoid such as dexamethasone
  • Blockages form in blood vessels under various disease conditions.
  • Atherosclerosis which causes the narrowing, or stenosis, of arteries in the body, particularly in the heart, legs, carotid, and renal anatomy, leads to tissue ischemia from lack of blood flow.
  • atherosclerosis in the coronary arteries causes myocardial infarction, commonly referred to as a heart attack, which can be immediately fatal, or even if survived, causes damage to the heart which can incapacitate the patient.
  • Other coronary diseases include congestive heart failure, vulnerable or unstable plaque, and cardiac arrhythmias, which cause death and incapacitation.
  • peripheral artery disease where the arteries in peripheral tissues narrow, most commonly affects the leg, renal, and carotid arteries.
  • PAD peripheral artery disease
  • blood clots and thrombus in the peripheral vasculature occlude peripheral blood flow, leading to tissue and organ necrosis.
  • Some patients with PAD experience critical limb ischemia that results in ulcers and some instances requires amputation in the worst cases.
  • PAD in a renal artery causes renovascular hypertension, and clots in the carotid artery embolize and travel to the brain, potentially causing ischemic stroke.
  • artery bypass surgery is an effective treatment for stenosed, or narrowed, arteries resulting from atherosclerosis and other causes, but it is a highly invasive procedure, expensive, requires substantial hospital and recovery time.
  • mechanical revascularization methods with balloon angioplasty, atherectomy, stenting, or surgical endarterectomy are used to open, or dilate, the artery.
  • percutaneous transluminal angioplasty commonly referred to as balloon angioplasty, is less invasive, less traumatic, and significantly less expensive than bypass surgery.
  • the effectiveness of balloon angioplasty has improved with the introduction of stenting which involves the placement of a scaffold structure within the artery which has been treated by balloon angioplasty.
  • the stent inhibits abrupt re-closure of the artery and has some benefit in reducing subsequent restenosis resulting from hyperplasia.
  • neointimal hyperplasia a scar-like tissue
  • the inner wall of the artery i.e., the intima
  • the media i.e., the middle tissue layer of the wall
  • the adventitia i.e., the outer layer of the wall
  • the thickening (or hyperplasia) and the stiffening (or sclerosis) reduces the blood flow to tissues distal to the affected site.
  • Inflammatory restenosis and reocclusion in some cases occurs due to hyperplasia and sclerosis.
  • the resolution of an inflammatory impetus in some instances leads to a stiff, narrow vessel or a functioning artery with vasomotor actions (including the ability to dilate or constrict based on signals received from the body's endocrine system.
  • vasomotor actions including the ability to dilate or constrict based on signals received from the body's endocrine system.
  • the vessel In order to maintain long-term vascular patency, the vessel must be allowed to heal without sclerosis or hyperplasia.
  • compositions and methods for reducing the buildup of sclerosis and hyperplasia following mechanical revascularization describe compositions and methods for reducing the buildup of sclerosis and hyperplasia following mechanical revascularization.
  • implanting stents coated with anti-proliferative drugs reduces the occurrence of hyperplasia.
  • mechanical endovascular revascularization alone leads to patency (the binary measure of vessel openness, typically greater than 50% in diameter compared to adjacent non-diseased vessel) rates of 33-55% at one year and 20-50% at two years, while drug-coated balloons and adventitial drug delivery have shown an ability to improve patency to better than 80% at one year and 65-70% at 2 years.
  • compositions comprising a cell division inhibitor, a glucocorticoid (such as dexamethasone or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a microtubule stabilizer (such as a taxane or a pharmaceutically acceptable salt thereof), a glucocorticoid (such as dexamethasone or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising an mTOR inhibitor (such as temsirolimus or a pharmaceutically acceptable salt thereof), a glucocorticoid (such as dexamethasone or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient.
  • an mTOR inhibitor such as temsirolimus or a pharmaceutically acceptable salt thereof
  • a glucocorticoid such as dexamethasone or a pharmaceutically acceptable salt thereof
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a taxane (such as paclitaxel or a pharmaceutically acceptable salt thereof), a glucocorticoid (such as
  • the pharmaceutical compositions are useful for treating the diseases and condition described herein (e.g., reducing the buildup of sclerosis and hyperplasia following mechanical revascularization).
  • the pharmaceutical compositions described herein comprise an mTOR inhibitor, such as a -limus drug.
  • the mTOR inhibitor is sirolimus, everolimus, zotarolimus, deforolimus, biolimus, temsirolimus, or combinations thereof.
  • the pharmaceutical compositions disclosed herein in some instances comprise temsirolimus or its pharmaceutically acceptable salts thereof.
  • the mTOR inhibitor is sirolimus, everolimus, zotarolimus, deforolimus, biolimus, temsirolimus, or combinations thereof.
  • the pharmaceutical compositions disclosed herein in some instances comprise temsirolimus or its pharmaceutically acceptable salts thereof.
  • the mTOR inhibitor is
  • compositions disclosed herein in some instances comprise temsirolimus or its pharmaceutically acceptable salts thereof.
  • the pharmaceutical compositions disclosed herein in some instances comprise temsirolimus or its pharmaceutically acceptable salts thereof.
  • the temsirolimus or its pharmaceutically acceptable salts thereof.
  • compositions comprise pharmaceutically acceptable excipients.
  • the pharmaceutical compositions further comprise excipients including 0.9% sodium chloride injection USP, dehydrated alcohol, ⁇ i/-alpha tocopherol, anhydrous citric acid, polysorbate 80, polyethylene glycol 400, propylene glycol, or a combination thereof.
  • the pharmaceutical compositions comprise nanoparticle formulations.
  • the pharmaceutical compositions further comprise excipients including albumin.
  • the pharmaceutical compositions comprise other excipients commonly used in injectable compositions.
  • the pharmaceutical compositions comprise a contrast agent to aid in visualization of the delivery of the pharmaceutical composition.
  • the pharmaceutical compositions comprising temsirolimus are injectable.
  • the pharmaceutical composition is a liquid, a suspension, a solution, or a gel.
  • the pharmaceutical compositions described herein comprise a cell division inhibitor, such as a taxane drug.
  • the cell division inhibitor is paclitaxel, docetaxel, cabazitaxel, or combinations thereof.
  • the pharmaceutical compositions disclosed herein in some instances comprise paclitaxel or its pharmaceutically acceptable salts thereof.
  • the cell division inhibitor is Abraxane®.
  • compositions disclosed herein comprise paclitaxel or its pharmaceutically acceptable salts thereof.
  • the pharmaceutical compositions comprise pharmaceutically acceptable excipients.
  • the pharmaceutical compositions further comprise excipients including cremophor EL, ethanol, or a combination thereof.
  • the pharmaceutical compositions comprise nanoparticle formulations.
  • the pharmaceutical compositions further comprise excipients including albumin.
  • the pharmaceutical compositions comprise other excipients commonly used in injectable compositions.
  • the pharmaceutical compositions comprise a contrast agent to aid in visualization of the delivery of the pharmaceutical composition.
  • the pharmaceutical compositions comprising paclitaxel are injectable.
  • the pharmaceutical composition is a liquid, a suspension, a solution, or a gel.
  • pharmaceutical compositions comprise an antihistamine.
  • pharmaceutical compositions comprise solubilizing agents, such as polyols, glycols, or glycerols.
  • pharmaceutical compositions comprise macrogolglycerol ricinoleate.
  • the pharmaceutical compositions disclosed herein comprise one or more glucocorticoids, such as dexamethasone, prenisolone, prednisone, triamcinoclone, hydrocortisone, methylpredinisolone, budesonide, betamethasone, deflazacort, beclomethasone, cortisone, or any other compound that targets the glucocorticoid receptor (GR).
  • glucocorticoids such as dexamethasone, prenisolone, prednisone, triamcinoclone, hydrocortisone, methylpredinisolone, budesonide, betamethasone, deflazacort, beclomethasone, cortisone, or any other compound that targets the glucocorticoid receptor (GR).
  • the glucocorticoid is dexamethasone.
  • compositions disclosed herein in some instances comprise dexamethasone or its pharmaceutically acceptable salts thereof.
  • pharmaceutical compositions disclosed herein in some instances comprise dexamethasone or its pharmaceutically acceptable salts thereof.
  • dexamethasone is dexamethasone sodium phosphate injection. In some instances, the
  • compositions further comprise anhydrous citric acid, sodium sulfite, benzyl alcohol, sodium citrate, water for injection, or a combination thereof.
  • the pharmaceutical compositions comprise pharmaceutically acceptable excipients.
  • the pharmaceutical compositions comprise other excipients commonly used in injectable compositions.
  • the pharmaceutical compositions comprise a contrast agent to aid in visualization of the delivery of the pharmaceutical composition.
  • the pharmaceutical composition is injectable.
  • the pharmaceutical composition is a liquid, a suspension, a solution, or a gel.
  • a cell division inhibitor such as an mTOR inhibitor and/or a glucocorticoid (such as dexamethasone) as described herein is administered as a pure chemical.
  • a pharmaceutically suitable or acceptable carrier also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier
  • an mTOR inhibitor such as temsirolimus
  • a glucocorticoid such as dexamethasone
  • glucocorticoid e.g., dexamethasone
  • individual compositions of an mTOR inhibitor or a glucocorticoid are combined with a suitable or acceptable excipient.
  • mTOR inhibitor such as temsirolimus
  • a glucocorticoid e.g., dexamethasone
  • compositions comprising an mTOR inhibitor, and a glucocorticoid together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s)
  • the carrier is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition.
  • an mTOR inhibitor and/or a glucocorticoid as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis byproducts that are created, for example, in one or more of the steps of a synthesis method.
  • the pharmaceutical compositions comprise an mTOR inhibitor and a glucocorticoid, and one or more pharmaceutically acceptable excipients.
  • pharmaceutical compositions comprising an mTOR inhibitor, glucocorticoid, or combination thereof comprise (by way of non-limiting example) excipients such as 0.9% sodium chloride injection USP, dehydrated alcohol, ⁇ i/-alpha tocopherol, anhydrous citric acid, polysorbate 80, polyethylene glycol 400, propylene glycol, benzyl alcohol, sodium citrate, sodium sulfite, albumin, or any combination thereof.
  • the pharmaceutical compositions comprise nanoparticles.
  • the pharmaceutical compositions comprise other excipients commonly used in injectable compositions.
  • the pharmaceutical compositions comprise a contrast agent to aid in visualization of the delivery of the
  • the pharmaceutical composition a liquid, a suspension, a solution, or a gel.
  • the pharmaceutical compositions comprising an mTOR inhibitor, a glucocorticoid, or combination thereof are injectable.
  • pharmaceutical compositions comprise excipients that solubilize an mTOR inhibitor, a glucocorticoid, or a combination thereof.
  • the pharmaceutical compositions comprise excipients that solubilize an mTOR inhibitor, a glucocorticoid, or a combination thereof.
  • compositions comprising an mTOR inhibitor and a glucocorticoid are provided in a dosage form for parenteral administration, which comprises one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions comprising an mTOR inhibitor, a glucocorticoid, or combination thereof are injectable.
  • the active ingredient is in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has a suitable pH, isotonicity, and stability.
  • isotonic vehicles such as Sodium Chloride injection, Ringer's injection, or Lactated Ringer's injection.
  • preservatives, stabilizers, excipients, buffers, antioxidants, and/or other additives are included.
  • a pharmaceutical composition comprising an mTOR inhibitor (such as temsirolimus) and a glucocorticoid (such as dexamethasone) is administered as a formulation comprising both drugs.
  • the percent by weight of temsirolimus to the glucocorticoid or vice versa is between 10: 1 to 1 : 1.
  • the percent by weight of temsirolimus to the glucocorticoid or vice versa is between 7: 1 to 2: 1.
  • the percent by weight of temsirolimus to the glucocorticoid or vice versa is between 5 : 1 to 1 : 1.
  • the percent by weight of temsirolimus to the glucocorticoid or vice versa is between 3 : 1 to 1 : 1
  • glucocorticoid or vice versa is about 10: 1, or about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3 : 1, about 2: 1, or about 1 : 1.
  • the percent by weight of temsirolimus to the glucocorticoid or vice versa is 10: 1 to 1 : 1, 7: 1 to 2: 1, 5: 1 to 1 : 1, or 3 : 1 to 1 : 1.
  • the combination of a cell division inhibitor (such as paclitaxel) and/or a glucocorticoid (such as dexamethasone) as described herein is administered as a pure chemical.
  • the combination of cell division inhibitor and a glucocorticoid described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub.
  • a cell division inhibitor such as paclitaxel
  • a glucocorticoid e.g., dexamethasone
  • individual compositions of a cell division inhibitor or a glucocorticoid are combined with a suitable or acceptable excipient.
  • a cell division inhibitor such as paclitaxel
  • a glucocorticoid e.g., dexamethasone
  • compositions comprising a cell division inhibitor, and a glucocorticoid together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s)
  • the carrier is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient ⁇ i.e., the subject or patient) of the composition.
  • a cell division inhibitor and/or a glucocorticoid as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • the pharmaceutical compositions comprise a cell division inhibitor and a glucocorticoid, and one or more pharmaceutically acceptable excipients.
  • pharmaceutical compositions comprising a cell division inhibitor, glucocorticoid, or combination thereof comprise (by way of non-limiting example) excipients such as 0.9% sodium chloride injection USP, dehydrated alcohol, ⁇ i/-alpha tocopherol, anhydrous citric acid, polysorbate 80, polyethylene glycol 400, propylene glycol, benzyl alcohol, sodium citrate, sodium sulfite, cremophor EL, albumin, or any combination thereof.
  • the pharmaceutical compositions comprise nanoparticles.
  • the pharmaceutical compositions comprise other excipients commonly used in injectable compositions.
  • the pharmaceutical compositions comprise a contrast agent to aid in visualization of the delivery of the pharmaceutical composition.
  • the pharmaceutical compositions comprise a liquid, a suspension, a solution, or a gel.
  • the pharmaceutical compositions comprising a cell division inhibitor, a glucocorticoid, or combination thereof are injectable.
  • pharmaceutical compositions comprise excipients that solubilize a cell division inhibitor, a glucocorticoid, or a combination thereof.
  • the pharmaceutical compositions comprising a cell division inhibitor and a glucocorticoid are provided in a dosage form for parenteral administration, which comprises one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions comprising a cell division inhibitor and a glucocorticoid are provided in a dosage form for parenteral administration, which comprises one or more pharmaceutically acceptable excipients or carriers.
  • compositions comprising a cell division inhibitor, a glucocorticoid, or combination thereof are injectable.
  • the active ingredient is in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has a suitable pH, isotonicity, and stability.
  • isotonic vehicles such as Sodium Chloride injection, Ringer's injection, or Lactated Ringer's injection.
  • preservatives, stabilizers, excipients, buffers, antioxidants, and/or other additives are included.
  • a pharmaceutical composition comprising a cell division inhibitor (such as paclitaxel) and a glucocorticoid (such as dexamethasone) is administered as a formulation comprising both drugs.
  • a cell division inhibitor such as paclitaxel
  • a glucocorticoid such as dexamethasone
  • the percent by weight of paclitaxel to the glucocorticoid or vice versa is between 10: 1 to 1 : 1.
  • the percent by weight of paclitaxel to the glucocorticoid or vice versa is between 7: 1 to 2: 1.
  • the percent by weight of paclitaxel to the glucocorticoid or vice versa is between 5: 1 to 1 : 1.
  • the percent by weight of paclitaxel to the glucocorticoid or vice versa is between 3 : 1 to 1 : 1 In some instances, the percent by weight of paclitaxel to the glucocorticoid or vice versa is about 10: 1, or about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3 : 1, about 2: 1, or about 1 : 1. In some instances, the percent by weight of paclitaxel to the glucocorticoid or vice versa is 10: 1 to 1 : 1, 7: 1 to 2: 1, 5: 1 to 1 : 1, or 3 : 1 to 1 : 1.
  • vascular smooth muscle cells located in the vessel wall are linked to inflammation, apoptosis, and matrix alterations observed in these vascular smooth muscle cells
  • paclitaxel has cytotoxic effects and may not provide the most durable solution for vascular pathologies.
  • Some embodiments herein describe the use of mTOR inhibitors combined with glucocorticoids to provide a safer and more superior approach to the regulation of activated VSMCs compared to anti-proliferatives such as paclitaxel.
  • Other embodiments herein describe the use of cell division inhibitors such as paclitaxel combined with glucocorticoids to provide safer and more superior approaches to the regulation of activated VSMCs compared to anti-proliferatives such as paclitaxel used alone.
  • rapamycin (mTOR) inhibitors have been identified drugs for treating vascular disease.
  • mTOR rapamycin
  • angiogenesis In response to physical insult of revascularization procedure, smooth muscle and endothelial cells in blood vessels activate stress response pathways, which lead to cell proliferation, secretion of pro-inflammatory mediators and extracellular matrix components, and ultimately to restenosis. In some instances, drugs successful in blocking one or more of the stress response pathways decrease the degree of restenosis. In certain instances, mTOR inhibitors reduce cellular proliferation and inflammation and have been used successfully in graft-versus-host disease, in organ transplant and in some cancers by blocking mTOR activation in response to insulin, growth factors and amino acids.
  • mTOR inhibitors include the original mTOR inhibitor, sirolimus, also known as rapamycin, and the analogs of sirolimus. These analogs include everolimus, zotarolimus, deforolimus, biolimus and temsirolimus.
  • Temsirolimus is approved for the treatment of renal cell carcinoma (RCC), but it is not approved for the treatment of vascular restenosis.
  • RRC renal cell carcinoma
  • Temsirolimus has been described as a prodrug for sirolimus (i.e., temsirolimus is metabolized to the active agent sirolimus).
  • temsirolimus is metabolized to the active agent sirolimus.
  • temsirolimus is metabolized to the active agent sirolimus.
  • temsirolimus is useful for the treatment of vascular disease. In further or additional embodiments, temsirolimus is useful for the treatment of vascular disease via direct injection into vascular or other luminal walls. In further or additional embodiments,
  • temsirolimus in combination with a glucocorticoid is useful for the treatment of vascular disease via direct injection into vascular or other luminal walls.
  • corticosteroids such as dexamethasone
  • the combination of dexamethasone and paclitaxel, exemplary agents chosen from the category of corticosteroids such as glucocorticoids
  • glucocorticoids and cell division inhibitors, respectively, influences the healing process.
  • the deployment or delivery of the drug takes place from the luminal side via drug-coated balloons or pressurized catheters, or from within the vessel wall (the media, the adventitia, or the perivascular tissues) with the use of needle injection catheters that deploy a needle from the inside to the outside of the artery.
  • drug delivery is accomplished using ultrasound guidance and penetration of a needle through the skin and surrounding tissues to the perivascular area in order to bathe the target tissues in the combination drug.
  • vascular disease is atherosclerosis in the heart, legs, carotid, or renal blood vessels.
  • the vascular disease is peripheral artery disease (PAD).
  • PAD peripheral artery disease
  • the vascular disease is angina, myocardial infarction, congestive heart failure, cardiac arrhythmia, peripheral artery disease, claudication, or critical limb ischemia.
  • the vascular disease is atherosclerosis, bypass graft failure, transplant vasculopathy, in-stent restenosis, or restenosis.
  • the vascular disease is blood clots, thrombus, or other blockages in a blood vessel that may occlude peripheral blood flow, leading to tissue and organ necrosis.
  • the vascular disease is PAD in renal artery or carotid artery.
  • the subject with restenosis had a procedure to improve the patency of the blood vessel or a revascularization procedure previously.
  • the vascular disease is restenosis.
  • the disease site of the vascular disease includes blood vessels and the tissues surrounding the blood vessel.
  • the vasculature of a subject refers to the circulatory system and in some instances comprises the arterial system, venous systems, or both arterial and venous systems and the blood vessels within those systems.
  • the blood vessel is an artery, arteriole, or other blood vessels of the arterial system.
  • the blood vessel is a vein, venule, or other blood vessels of the venous system.
  • the artery is a coronary artery or a peripheral artery.
  • the artery is below the knee.
  • the artery is in the leg above the knee.
  • the blood vessel is below- knee popliteal vessel or tibial vessel.
  • the blood vessel is a femoral vessel.
  • the artery is renal artery, carotid artery, cerebral artery, pulmonary artery, or artery in the leg. In some examples, the artery is a femoral artery.
  • Restenosis is in various tissues and blood vessels in the body.
  • the restenosis is in a coronary vessel.
  • the restenosis is in a coronary artery.
  • the restenosis is in a peripheral artery.
  • the restenosis is in the leg.
  • the restenosis is below the knee or in the leg above the knee.
  • the restenosis is in a below-knee popliteal vessel or tibial vessel.
  • the restenosis is in a femoral vessel.
  • the restenosis is in a femoral artery.
  • the tissue surrounding a blood vessel refers to any tissues outside the endothelial cell wall of the blood vessel that is radially away from the lumen of the blood vessel in a cross section and includes plaque and calcification. In some instances, the tissue
  • adventitial tissue is also known as adventitia or tunica adventitia or tunica externa.
  • adventitial tissue is outside of the external elastic membrane.
  • the tissue surrounding a blood vessel is tissues outside the tunica intima of the blood vessel.
  • the tissue surrounding a blood vessel is tissues outside the tunica media of the blood vessel.
  • the tissue surrounding a blood vessel is tissues outside the internal elastic membrane.
  • the tissue is a connective tissue.
  • the tissue is diseased tissue such as plaque, fibrosis, calcification, or combinations of diseased and healthy tissues.
  • patency refers to blood vessel openness.
  • patency at the disease site refers to patency of the blood vessel, or blood vessel openness, at the disease site.
  • vessel cross-sectional area at the disease site refers to patency of the blood vessel at the disease site.
  • vessel cross-sectional area is determined by angiography.
  • the angiography is quantitative vascular angiography (QVA).
  • vessel cross-sectional area is determined by intravascular ultrasound (IVUS).
  • patency is described as percent of diameter of the lumen of the blood vessel that is open and unobstructed.
  • patency is described as percent of cross sectional area of the lumen of the blood vessel, or vessel cross-sectional area, that is open and
  • patency is the percent of luminal volume that is open and unobstructed. In some instances, patency requires determination of the boundaries of the endothelial wall of the blood vessel. In some instances, a blood vessel that is completely open and unobstructed has 100% patency; i.e., the blood vessel has a cross-sectional area that is healthy and typical of a normal, healthy blood vessel in the same part of the body. In some instances, a blood vessel that is completely blocked and obstructed has 0% patency. In some instances, patency is the binary measure of openness greater than 50% in diameter compared to adjacent non-diseased vessel.
  • patency is the binary measure of openness greater than 50% in cross-sectional area compared to adjacent non-diseased vessel. In some instances, patency is the binary measure of openness greater than 50% in luminal volume compared to adjacent non-diseased vessel.
  • a "therapeutically effective amount” refers to an amount of drug (e.g., temsirolimus or dexamethasone) that increases vessel cross-sectional area at the disease site.
  • therapeutically effective refers to increasing the vessel cross-sectional area at the disease site after administration of a pharmaceutical composition.
  • therapeutically effective refers to minimally decreasing the vessel cross-sectional area at the disease site after administration when compared to the vessel cross-sectional area at the disease site at the time of administration.
  • therapeutically effective refers to increasing the vessel cross-sectional area at the disease site.
  • therapeutically effective refers to increasing minimally the vessel cross-sectional area at the disease site after
  • therapeutically effective refers to decreasing the vessel cross- sectional area at the disease site no more than 30%, 20%, 10%, or 0% when compared to the vessel cross-sectional area at the disease site at the time of administration; in other words the patency decreases no more than 30%, 20%, 10%, or 0% when compared to the patency at the disease site at the time of administration.
  • the vessel cross-sectional area at the disease site decreases no more than 60%, 50%, 40%, 30%, 20%, or 10% when compared to vessel cross-sectional area at the disease site at the time of administration.
  • the vessel cross-sectional area at the disease site increases at least 60%, 50%, 40%, 30%, 20%, or 10%) when compared to vessel cross-sectional area at the disease site at the time of
  • the pharmaceutical composition is injected at various locations at or near the disease site.
  • the disease site refers to a blood vessel affected by a vascular disease.
  • the disease site refers to a blood vessel with a partial or complete blockage of the lumen.
  • the disease site refers to a blood vessel with a vessel cross-sectional area of less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%), or 0% of vessel cross-sectional area of an unobstructed vessel as determined from the vessel wall.
  • the pharmaceutical composition is injected distal or proximal to the disease site. In some instances, the pharmaceutical composition is injected at least about 2 cm away from the disease site.
  • the pharmaceutical composition is injected at or adjacent to the disease site. In some instances, the pharmaceutical composition is injected into a blood vessel. In some instances, the pharmaceutical composition is injected into an adventitial tissue surrounding a blood vessel. In some instances, the pharmaceutical composition is injected into a perivascular tissue surrounding a blood vessel.
  • Temsirolimus administered as part of a combination therapy with a glucocorticoid has a range of doses that are therapeutically effective for treating the vascular disease.
  • the therapeutically effective amount of temsirolimus is about 1 ⁇ g to 50 mg, about 10 ⁇ g to 20 mg, about 25 ⁇ g to 10 mg, about 1 ⁇ g to 2 mg, about 10 ⁇ g to 500 ⁇ g, about 100 ⁇ g to about 2 mg or about 100 ⁇ g to 500 ⁇ g.
  • the therapeutically effective amount of temsirolimus is about 100 ⁇ g to 5 mg.
  • the therapeutically effective amount of temsirolimus is about 100 ⁇ g to 15 mg.
  • the therapeutically effective amount of temsirolimus is about 100 ⁇ g to 50 mg.
  • therapeutically effective amount of temsirolimus is about 10 ⁇ g, about 25 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 500 ⁇ g, about 1.0 mg, about 5.0 mg, about 10.0 mg, or about 15.0 mg.
  • the therapeutically effective volume of temsirolimus is about 0.01 ml to about 50 ml, about 0.5 ml to about 20 ml, about 0.5 ml to about 25 ml, about 0.5 ml to about 5 ml, or about 1 ml to about 5 ml.
  • the therapeutically effective concentration of temsirolimus is about 0.1 mg/mL to about 0.4 mg/mL, about 0.1 mg/mL to about 0.5 mg/mL, or about 0.01 mg/mL to about 2.0 mg/mL. In some instances, the therapeutically effective concentration of temsirolimus is about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 1.0 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, or 3.0 mg/ml.
  • the therapeutically effective amount of temsirolimus is about 0.005 mg to 5 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.025 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.05 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel, or about 0.1 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel. In some instances, the
  • therapeutically effective amount of temsirolimus is about 0.025 mg to 1 mg per cm of longitudinal length of the blood vessel.
  • the longitudinal length of the disease site in the blood vessel also known as the longitudinal length of the lesion, is about 1 cm, 5 cm, 10 cm, 20 cm, 30 cm, 40 cm, or 50 cm.
  • Paclitaxel administered as part of a combination therapy with a glucocorticoid in some instances has a range of doses that are therapeutically effective for treating the vascular disease.
  • the therapeutically effective amount of paclitaxel is about 1 ⁇ g to 50 mg, about 10 ⁇ g to 20 mg, about 25 ⁇ g to 10 mg, about 1 ⁇ g to 2 mg, about 10 ⁇ g to 500 ⁇ g, about 100 ⁇ g to about 2 mg or about 100 ⁇ g to 500 ⁇ g.
  • the therapeutically effective amount of paclitaxel is about 10 ⁇ g, about 25 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 500 ⁇ g, about 1.0 mg, about 5.0 mg, about 10.0 mg, or about 15.0 mg. In some instances, the
  • therapeutically effective volume of paclitaxel is about 0.01 ml to about 50 ml, about 0.5 ml to about 20 ml, about 0.5 ml to about 25 ml, about 0.5 ml to about 5 ml, or about 1 ml to about 5 ml.
  • the therapeutically effective concentration of paclitaxel is about 0.1 mg/mL to about 0.4 mg/mL, about 0.1 mg/mL to about 0.5 mg/mL, or about 0.01 mg/mL to about 2.0 mg/mL.
  • the therapeutically effective concentration of paclitaxel is about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 1.0 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, or 3.0 mg/ml.
  • the therapeutically effective amount of paclitaxel is about 0.005 mg to 5 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.025 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.05 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel, or about 0.1 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel. In some instances, the therapeutically effective amount of paclitaxel is about 0.025 mg to 1 mg per cm of longitudinal length of the blood vessel.
  • the longitudinal length of the disease site in the blood vessel also known as the longitudinal length of the lesion, is about 1 cm, 5 cm, 10 cm, 20 cm, 30 cm, 40 cm, or 50 cm.
  • a glucocorticoid administered in combination with temsirolimus comprises a range of dosages that are therapeutically effective for treating the vascular disease.
  • the glucocorticoid is dexamethasone.
  • the therapeutically effective amount of dexamethasone is about 1 ⁇ g to 50 mg, about 10 ⁇ g to 20 mg, about 25 ⁇ g to 10 mg, about 1 ⁇ g to 2 mg, about 10 ⁇ g to 500 ⁇ g, about 100 ⁇ g to 50 mg, about 100 ⁇ g to 20 mg, about 100 ⁇ g to 10 mg, about 100 ⁇ g to 1 mg, or about 100 ⁇ g to 500 ⁇ g.
  • the therapeutically effective amount of dexamethasone is about 10 ⁇ g, about 25 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 500 ⁇ g, about 1.0 mg, about 5.0 mg, about 10.0 mg, about 20.0 mg, about 30.0 mg, about 40.0 mg, or about 50.0 mg.
  • the therapeutically effective volume of dexamethasone is about 0.01 mL to about 50 mL, about 0.5 mL to about 20 mL, about 0.5 mL to about 25 mL, about 0.5 mL to about 5 mL, 1 mL to 10 mL, or about 1 mL to about 5 mL.
  • the therapeutically effective concentration of dexamethasone is about 0.1 mg/mL to about 0.4 mg/mL, about 0.1 mg/mL to about 0.5 mg/mL, about 0.01 mg/mL to about 2.0 mg/mL, or about 1.0 mg/mL to about 10.0 mg/mL.
  • the therapeutically effective concentration of dexamethasone is about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 1.0 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, about 3.0 mg/ml, about 4.0 mg/mL, about 6.0 mg/mL, about 8.0 mg/mL or about 10.0 mg/mL.
  • the therapeutically effective amount of dexamethasone is about 0.05 mg to 10 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.05 mg to 7 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.1 mg to 4 mg per cm of longitudinal length of the disease site in the blood vessel, or about 0.1 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel. In some instances, the therapeutically effective amount of dexamethasone is about 0.8 mg to 8 mg per cm of longitudinal length of the disease site in the blood vessel. In some instances, the therapeutically effective amount of dexamethasone is about 0.1 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel.
  • the longitudinal length of the disease site in the blood vessel also known as the longitudinal length of the lesion, is about 1 cm, 5 cm, 10 cm, 20 cm, 30 cm, 40 cm, or 50 cm.
  • a glucocorticoid administered in combination with paclitaxel comprises a range of dosages that are therapeutically effective for treating the vascular disease.
  • the glucocorticoid is dexamethasone.
  • the therapeutically effective amount of dexamethasone is about 1 ⁇ g to 50 mg, about 10 ⁇ g to 20 mg, about 25 ⁇ g to 10 mg, about 1 ⁇ g to 2 mg, about 10 ⁇ g to 500 ⁇ g, about 100 ⁇ g to 50 mg, about 100 ⁇ g to 20 mg, about 100 ⁇ g to 10 mg, about 100 ⁇ g to 1 mg, or about 100 ⁇ g to 500 ⁇ g.
  • the therapeutically effective amount of dexamethasone is about 10 ⁇ g, about 25 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 500 ⁇ g, about 1.0 mg, about 5.0 mg, about 10.0 mg, about 20.0 mg, about 30.0 mg, about 40.0 mg, or about 50.0 mg.
  • the therapeutically effective volume of dexamethasone is about 0.01 mL to about 50 mL, about 0.5 mL to about 20 mL, about 0.5 mL to about 25 mL, about 0.5 mL to about 5 mL, 1 mL to 10 mL, or about 1 mL to about 5 mL.
  • the therapeutically effective concentration of dexamethasone is about 0.1 mg/mL to about 0.4 mg/mL, about 0.1 mg/mL to about 0.5 mg/mL, about 0.01 mg/mL to about 2.0 mg/mL, or about 1.0 mg/mL to about 10.0 mg/mL.
  • the therapeutically effective concentration of dexamethasone is about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 1.0 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, about 3.0 mg/ml, about 4.0 mg/mL, about 6.0 mg/mL, about 8.0 mg/mL or about 10.0 mg/mL.
  • the therapeutically effective amount of dexamethasone is about 0.05 mg to 10 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.05 mg to 7 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.1 mg to 4 mg per cm of longitudinal length of the disease site in the blood vessel, or about 0.1 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel. In some instances, the therapeutically effective amount of dexamethasone is about 0.8 mg to 8 mg per cm of longitudinal length of the disease site in the blood vessel. In some instances, the therapeutically effective amount of dexamethasone is about 0.1 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel.
  • the longitudinal length of the disease site in the blood vessel also known as the longitudinal length of the lesion, is about 1 cm, 5 cm, 10 cm, 20 cm, 30 cm, 40 cm, or 50 cm.
  • a pharmaceutical composition of temsirolimus administered in combination with a glucocorticoid comprises a range of dosages that are therapeutically effective for treating the vascular disease.
  • the therapeutically effective amount of temsirolimus is about 1 ⁇ g to 50 mg, about 10 ⁇ g to 20 mg, about 25 ⁇ g to 10 mg, about 1 ⁇ g to 2 mg, about 10 ⁇ g to 500 ⁇ g, about 100 ⁇ g to about 2 mg or about 100 ⁇ g to 500 ⁇ g.
  • the therapeutically effective amount of temsirolimus is about 10 ⁇ g, about 25 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 500 ⁇ g, about 1.0 mg, about 5.0 mg, about 10.0 mg, or about 15.0 mg.
  • the therapeutically effective volume of temsirolimus is about 0.01 ml to about 50 ml, about 0.5 ml to about 20 ml, about 0.5 ml to about 25 ml, about 0.5 ml to about 5 ml, or about 1 ml to about 5 ml.
  • the therapeutically effective concentration of temsirolimus is about 0.1 mg/mL to about 0.4 mg/mL, about 0.1 mg/mL to about 0.5 mg/mL, or about 0.01 mg/mL to about 2.0 mg/mL. In some instances, the therapeutically effective concentration of temsirolimus is about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 1.0 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, or 3.0 mg/ml.
  • the therapeutically effective amount of temsirolimus is about 0.005 mg to 5 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.025 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.05 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel, or about 0.1 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel. In some instances, the therapeutically effective amount of temsirolimus is about 0.025 mg to 1 mg per cm of longitudinal length of the blood vessel.
  • the longitudinal length of the disease site in the blood vessel also known as the longitudinal length of the lesion, is about 1 cm, 5 cm, 10 cm, 20 cm, 30 cm, 40 cm, or 50 cm.
  • a pharmaceutical composition of paclitaxel administered in combination with a glucocorticoid comprises a range of dosages that are therapeutically effective for treating the vascular disease.
  • the therapeutically effective amount of paclitaxel is about 1 ⁇ g to 50 mg, about 10 ⁇ g to 20 mg, about 25 ⁇ g to 10 mg, about 1 ⁇ g to 2 mg, about 10 ⁇ g to 500 ⁇ g, about 100 ⁇ g to about 2 mg or about 100 ⁇ g to 500 ⁇ g.
  • the therapeutically effective amount of paclitaxel is about 10 ⁇ 3 ⁇ 4 about 25 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 500 ⁇ g, about 1.0 mg, about 5.0 mg, about 10.0 mg, or about 15.0 mg.
  • the therapeutically effective volume of paclitaxel is about 0.01 ml to about 50 ml, about 0.5 ml to about 20 ml, about 0.5 ml to about 25 ml, about 0.5 ml to about 5 ml, or about 1 ml to about 5 ml.
  • the therapeutically effective concentration of paclitaxel is about 0.1 mg/mL to about 0.4 mg/mL, about 0.1 mg/mL to about 0.5 mg/mL, or about 0.01 mg/mL to about 2.0 mg/mL. In some instances, the therapeutically effective concentration of paclitaxel is about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 1.0 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, or 3.0 mg/ml.
  • the therapeutically effective amount of paclitaxel is about 0.005 mg to 5 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.025 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.05 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel, or about 0.1 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel. In some instances, the therapeutically effective amount of paclitaxel is about 0.025 mg to 1 mg per cm of longitudinal length of the blood vessel.
  • the longitudinal length of the disease site in the blood vessel also known as the longitudinal length of the lesion, is about 1 cm, 5 cm, 10 cm, 20 cm, 30 cm, 40 cm, or 50 cm.
  • a pharmaceutical composition of a glucocorticoid administered in combination with temsirolimus comprises a range of dosages that are therapeutically effective for treating the vascular disease.
  • the glucocorticoid is dexamethasone.
  • the therapeutically effective amount of dexamethasone is about 1 ⁇ g to 50 mg, about 10 ⁇ g to 20 mg, about 25 ⁇ g to 10 mg, about 1 ⁇ g to 2 mg, about 10 ⁇ g to 500 ⁇ g, about 100 ⁇ g to 50 mg, about 100 ⁇ g to 20 mg, about 100 ⁇ g to 10 mg, about 100 ⁇ g to 1 mg, or about 100 ⁇ g to 500 ⁇ g.
  • the therapeutically effective amount of dexamethasone is about 10 ⁇ g, about 25 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 500 ⁇ g, about 1.0 mg, about 5.0 mg, about 10.0 mg, about 20.0 mg, about 30.0 mg, about 40.0 mg, or about 50.0 mg.
  • the therapeutically effective volume of dexamethasone is about 0.01 mL to about 50 mL, about 0.5 mL to about 20 mL, about 0.5 mL to about 25 mL, about 0.5 mL to about 5 mL, 1 mL to 10 mL, or about 1 mL to about 5 mL.
  • the therapeutically effective concentration of dexamethasone is about 0.1 mg/mL to about 0.4 mg/mL, about 0.1 mg/mL to about 0.5 mg/mL, about 0.01 mg/mL to about 2.0 mg/mL, or about 1.0 mg/mL to about 10.0 mg/mL.
  • the therapeutically effective concentration of dexamethasone is about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 1.0 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, about 3.0 mg/ml, about 4.0 mg/mL, about 6.0 mg/mL, about 8.0 mg/mL or about 10.0 mg/mL.
  • the therapeutically effective amount of dexamethasone is about 0.05 mg to 10 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.05 mg to 7 mg per cm of longitudinal length of the disease site in the blood vessel, about 0.1 mg to 4 mg per cm of longitudinal length of the disease site in the blood vessel, or about 0.1 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel. In some instances, the therapeutically effective amount of dexamethasone is about 0.1 mg to 2 mg per cm of longitudinal length of the disease site in the blood vessel.
  • the longitudinal length of the disease site in the blood vessel also known as the longitudinal length of the lesion, is about 1 cm, 5 cm, 10 cm, 20 cm, 30 cm, 40 cm, or 50 cm.
  • composition comprising temsirolimus and a glucocorticoid as described herein differ, depending upon the patient's condition, that is, stage of the disease, general health status, age, and other factors.
  • composition comprising paclitaxel and a glucocorticoid as described herein differ, depending upon the patient's condition, that is, stage of the disease, general health status, age, and other factors.
  • compositions described herein are administered in a manner appropriate to the disease to be treated (or prevented).
  • An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome), or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • the pharmaceutical compositions of temsirolimus and a glucocorticoid described herein, or pharmaceutically acceptable salts thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from administration of any one of the compounds disclosed.
  • compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
  • the pharmaceutical compositions of temsirolimus and a glucocorticoid described herein are administered for prophylactic and/or therapeutic treatments.
  • the pharmaceutical compositions of paclitaxel and a glucocorticoid described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • the pharmaceutical composition of temsirolimus and a glucocorticoid described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • the pharmaceutical composition of paclitaxel and a glucocorticoid described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • Such an amount is defined to be a "prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like.
  • prophylactic treatments include administering to a mammal, in which the mammal previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • the administration of a pharmaceutical composition of temsirolimus and a glucocorticoid are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • the administration of a pharmaceutical composition of paclitaxel and a glucocorticoid are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • a maintenance injection is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50.
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the dosage amount of the compounds described herein lies within a range of circulating
  • the dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the pharmaceutical composition of temsirolimus and a glucocorticoid described herein, including further embodiments in which the composition is administered once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the pharmaceutical composition of paclitaxel and a glucocorticoid described herein, including further embodiments in which the composition is administered once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (e.g., a "drug holiday").
  • the length of the drug holiday is between 1 month and 5 years, including by way of example only, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 1 year, 2 years, 3 years, 4 years, 5 years, or more than 5 years.
  • the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%), 85%), 90%), 95%), and 100%.
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 6 months to 2 years. In one embodiment, the length of the drug holiday is 1 year. In one embodiment, the length of the drug holiday is 2 years. In one embodiment, the length of the drug holiday is 3 years.
  • the direct delivery of drug into vascular and other luminal walls in some instances enhances the therapeutic concentrations of pharmaceutical agents in targeted tissues.
  • devices efficiently deliver the drugs into the targeted tissue and limit or avoid the loss of drugs into the luminal blood flow.
  • the persistence of such therapeutic concentrations of the pharmaceutical agent in the tissue were also increased, particularly in targeted tissues away from the blood vessel wall, including the adventitial tissue surrounding the blood vessel wall.
  • the uniformity and extent of pharmaceutical agent delivery over remote, extended, and distributed regions of the adventitia and other tissues surrounding the blood vessels is increased.
  • pharmaceutical agents are delivered through the blood vessel walls at non-diseased sites within the blood vessel, where the agent then migrate through the adventitia or other tissues to the diseased site(s).
  • intravascular delivery of pharmaceutical agents treats diseases and conditions of the tissues and organs in addition to those directly related to the vasculature.
  • drug injection or infusion catheters and devices are suitable for use with the methods described herein to inject pharmaceutical compositions into blood vessels the treat restenosis.
  • An example of a device includes the Mercator Bullfrog® Micro-Infusion Device available from Mercator MedSystems of Emeryville, CA.
  • Other examples include the devices described in U.S. patent applications nos. 14/605,865 and 15/691,138, the entire disclosures of which are incorporated herein by reference. Examples of suitable devices and their use are described as follows. In some instances, injections are performed using needles or microneedles.
  • a pharmaceutical composition to treat the vascular disease is delivered to the tissue surrounding a blood vessel using a drug injection or infusion catheter.
  • a drug injection or infusion catheter as shown in FIGS. 1A-2B, a microfabricated
  • intraluminal catheter 10 includes an actuator 12 having an actuator body 12a and central longitudinal axis 12b.
  • the actuator body more or less forms a C-shaped outline having an opening or slit 12d extending substantially along its length.
  • a microneedle 14 is located within the actuator body, as discussed in more detail below, when the actuator is in its unactuated condition (furled state) (FIG. IB).
  • the microneedle is moved outside the actuator body when the actuator is operated to be in its actuated condition (unfurled state) (FIG. 2B).
  • the actuator is capped at its proximal end 12e and distal end 12f by a lead end 16 and a tip end 18, respectively, of a therapeutic catheter 20.
  • the catheter tip end serves as a means of locating the actuator inside a body lumen by use of a radio opaque coatings or markers.
  • the catheter tip also forms a seal at the distal end 12f of the actuator.
  • the lead end of the catheter provides the necessary interconnects (fluidic, mechanical, electrical or optical) at the proximal end 12e of the actuator.
  • Retaining rings 22a and 22b are located at the distal and proximal ends, respectively, of the actuator.
  • the catheter tip is joined to the retaining ring 22a, while the catheter lead is joined to retaining ring 22b.
  • the retaining rings are made of a thin, on the order of 10 to 100 microns ( ⁇ ), substantially flexible but relatively non-distensible material, such as Parylene (types C, D or N), or a metal, for example, aluminum, stainless steel, gold, titanium or tungsten.
  • the retaining rings form a flexible but relatively non-distensible substantially "C"- shaped structure at each end of the actuator.
  • the catheter is joined to the retaining rings by, for example, a butt-weld, an ultra-sonic weld, integral polymer encapsulation or an adhesive such as an epoxy.
  • the actuator body further comprises a central, expandable section 24 located between retaining rings 22a and 22b.
  • the expandable section 24 includes an interior open area 26 for rapid expansion when an activating fluid is supplied to that area.
  • the central section 24 is made of a thin, semi-flexible but relatively non-distensible or flexible but relatively non-distensible, expandable material, such as a polymer, for instance, Parylene (types C, D or N), silicone, polyurethane or polyimide.
  • the central section 24, upon actuation, is expandable somewhat like a balloon-device.
  • the central section is capable of withstanding pressures of up to about 200 psi upon application of the activating fluid to the open area 26.
  • the material from which the central section is made of is flexible but relatively non-distensible or semi-flexible but relatively non- distensible in that the central section returns substantially to its original configuration and orientation (the unactuated condition) when the activating fluid is removed from the open area 26.
  • the central section is very much unlike a balloon which has no inherently stable structure.
  • the open area 26 of the actuator is connected to a delivery conduit, tube or fluid pathway 28 that extends from the catheter's lead end to the actuator's proximal end.
  • the activating fluid is supplied to the open area via the delivery tube.
  • the delivery tube often is constructed of Teflon or other inert plastics.
  • the activating fluid often is a saline solution or a radio-opaque dye.
  • the microneedle 14 is located approximately in the middle of the central section 24. However, as discussed below, this is not necessary, especially when multiple microneedles are used.
  • the microneedle is affixed to an exterior surface 24a of the central section.
  • the microneedle is affixed to the surface 24a by an adhesive, such as cyanoacrylate.
  • the microneedle often is joined to the surface 24a by a metallic or polymer meshlike structure 30 (See FIG. 4), which is itself affixed to the surface 24a by an adhesive.
  • the mesh-like structure often is-made of, for instance, steel or nylon.
  • the microneedle includes a sharp tip 14a and a shaft 14b.
  • the microneedle tip can provide an insertion edge or point.
  • the shaft 14b can be hollow and the tip can have an outlet port 14c, permitting the injection of a pharmaceutical or drug into a patient.
  • the microneedle does not need to be hollow, as it often is configured like a neural probe to accomplish other tasks.
  • the microneedle extends approximately perpendicularly from surface 24a.
  • the microneedle will move substantially perpendicularly to an axis of a lumen into which has been inserted, to allow direct puncture or breach of body lumen walls.
  • the microneedle further includes a pharmaceutical or drug supply conduit, tube or fluid pathway 14d which places the microneedle in fluid communication with the appropriate fluid interconnect at the catheter lead end.
  • This supply tube often is formed integrally with the shaft 14b, or it often is formed as a separate piece that is later joined to the shaft by, for example, an adhesive such as an epoxy.
  • the needle 14 is a 30-gauge, or smaller, steel needle.
  • the microneedle is microfabricated from polymers, other metals, metal alloys or semiconductor materials.
  • the needle for example, is made of Parylene, silicon or glass. Microneedles and methods of fabrication are described in U.S. Application Serial No. 09/877,653, filed June 8, 2001, entitled "Microfabricated Surgical Device", assigned to the assignee of the subject application, the entire disclosure of which is incorporated herein by reference.
  • the catheter 20, in use, is inserted through an opening in the body (e.g. for bronchial or sinus treatment) or through a percutaneous puncture site (e.g. for artery or venous treatment) and moved within a patient's body passageways 32, until a specific, targeted region 34 is reached (see FIG. 3).
  • the targeted region 34 is the site of tissue damage or more usually will be adjacent the sites typically being within 100 mm or less to allow migration of the therapeutic or diagnostic agent.
  • the catheter 20 follows a guide wire 36 that has previously been inserted into the patient.
  • the catheter 20 also follows the path of a previously-inserted guide catheter (not shown) that encompasses the guide wire.
  • MRI magnetic resonance imaging
  • the ends of the actuator at the retaining rings 22a and 22b remain fixed to the catheter 20. Thus, they do not deform during actuation. Since the actuator begins as a furled structure, its so-called pregnant shape exists as an unstable buckling mode. This instability, upon actuation, in some cases produces a large-scale motion of the microneedle approximately perpendicular to the central axis of the actuator body, causing a rapid puncture of the body lumen wall without a large momentum transfer. As a result, a microscale opening is produced with very minimal damage to the surrounding tissue. Also, since the momentum transfer is relatively small, only a negligible bias force is required to hold the catheter and actuator in place during actuation and puncture.
  • microneedle aperture in fact, travels with such force that it can enter body lumen tissue 32b as well as the adventitia, media, or intima surrounding body lumens. Additionally, since the actuator is "parked” or stopped prior to actuation, more precise placement and control over penetration of the body lumen wall are obtained.
  • the activating fluid is exhausted from the open area 26 of the actuator, causing the expandable section 24 to return to its original, furled state. This also causes the microneedle to be withdrawn from the body lumen wall. The microneedle, being withdrawn, is once again sheathed by the actuator.
  • microfabricated devices can be integrated into the needle, actuator and catheter for metering flows, capturing samples of biological tissue, and measuring pH.
  • the device 10 could include electrical sensors for measuring the flow through the microneedle as well as the pH of the pharmaceutical being deployed.
  • the device 10 could also include an
  • IVUS intravascular ultrasonic sensor
  • the microneedle has have an overall length of between about 200 and 3,000 microns ( ⁇ ).
  • the interior cross-sectional dimension of the shaft 14b and supply tube 14d often is on the order of 20 to 250 um, while the tube's and shaft's exterior cross-sectional dimension often is between about 100 and 500 ⁇ .
  • the overall length of the actuator body often is between about 5 and 50 millimeters (mm), while the exterior and interior cross-sectional dimensions of the actuator body can be between about 0.4 and 4 mm, and 0.5 and 5 mm, respectively.
  • the gap or slit through which the central section of the actuator unfurls has in some instances a length of about 4-40 mm, and a cross-sectional dimension of about 50-500 ⁇ .
  • the diameter of the delivery tube for the activating fluid often is about 100 ⁇ .
  • the catheter size often is between 1.5 and 15 French (Fr).
  • Variations of the present disclosure include a multiple-buckling actuator with a single supply tube for the activating fluid.
  • the multiple-buckling actuator includes multiple needles that can be inserted into or through a lumen wall for providing injection at different locations or times.
  • the actuator 120 includes microneedles 140 and 142 located at different points along a length or longitudinal dimension of the central, expandable section 240.
  • the operating pressure of the activating fluid is selected so that the microneedles move at the same time.
  • the pressure of the activating fluid is selected so that the microneedle 140 moves before the microneedle 142.
  • the microneedle 140 is located at a portion of the expandable section 240 (lower activation pressure) that, for the same activating fluid pressure, will buckle outwardly before that portion of the expandable section (higher activation pressure) where the microneedle 142 is located.
  • the operating pressure of the activating fluid within the open area of the expandable section 240 is two pounds per square inch (psi)
  • the microneedle 140 will move before the microneedle 142. It is only when the operating pressure is increased to four psi, for instance, that the microneedle 142 will move.
  • this mode of operation provides staged buckling with the microneedle 140 moving at time ti, and pressure pi, and the
  • microneedle 142 moving at time t 2 and p 2 , with ti, and pi, being less than t 2 and p 2 , respectively.
  • This sort of staged buckling can also be provided with different pneumatic or hydraulic connections at different parts of the central section 240 in which each part includes an individual microneedle.
  • an actuator 220 could be constructed such that its needles 222 and 224A move in different directions. As shown, upon actuation, the needles move at angle of approximately 90° to each other to puncture different parts of a lumen wall.
  • a needle 224B (as shown in phantom) could alternatively be arranged to move at angle of about 180° to the needle 224A.
  • a needle injection catheter 310 constructed in accordance with the principles of the present disclosure comprises a catheter body 312 having a distal end 314 and a proximal 316.
  • a guide wire lumen 313 will be provided in a distal nose 352 of the catheter, although over-the-wire and embodiments which do not require guide wire placement will also be within the scope of the present disclosure.
  • a two-port hub 320 is attached to the proximal end 316 of the catheter body 312 and includes a first port 322 for delivery of a hydraulic fluid, e.g., using a syringe 324, and a second port 326 for delivering the
  • a reciprocatable, deflectable needle 330 is mounted near the distal end of the catheter body 312 and is shown in its laterally advanced configuration in FIG. 6.
  • the proximal end 314 of the catheter body 312 has a main lumen 336 which holds the needle 330, a reciprocatable piston 338, and a hydraulic fluid delivery tube 340.
  • the piston 338 is mounted to slide over a rail 342 and is fixedly attached to the needle 330.
  • the piston 338 often is advanced axially toward the distal tip in order to cause the needle to pass through a deflection path 350 formed in a catheter nose 352.
  • the catheter 310 often is positioned in a coronary blood vessel BV, over a guide wire GW in a conventional manner. Distal advancement of the piston 338 causes the needle 330 to advance into luminal tissue T adjacent to the catheter when it is present in the blood vessel.
  • the therapeutic or diagnostic agents often are introduced through the port 326 using syringe 328 in order to introduce a plume P of agent in the cardiac tissue, as illustrated in FIG. 8.
  • the plume P will be within or adjacent to the region of tissue damage as described above.
  • the needle 330 in some cases extends the entire length of the catheter body 312 or, more usually, will extend only partially into the therapeutic or diagnostic agents delivery lumen 337 in the tube 340.
  • a proximal end of the needle can form a sliding seal with the lumen 337 to permit pressurized delivery of the agent through the needle.
  • the needle 330 will be composed of an elastic material, typically an elastic or super elastic metal, typically being nitinol or other super elastic metal.
  • the needle 330 could be formed from a non-elastically deformable or malleable metal which is shaped as it passes through a deflection path.
  • non-elastically deformable metals are less preferred since such metals will generally not retain their straightened configuration after they pass through the deflection path.
  • the bellows structure 344 is made by depositing parylene or another conformal polymer layer onto a mandrel and then dissolving the mandrel from within the polymer shell structure.
  • the bellows 344 could be made from an elastomeric material to form a balloon structure.
  • a spring structure can be utilized in, on, or over the bellows in order to drive the bellows to a closed position in the absence of pressurized hydraulic fluid therein.
  • the needle is retracted and the catheter either repositioned for further agent delivery or withdrawn.
  • the needle will be retracted simply by aspirating the hydraulic fluid from the bellows 344.
  • needle retraction is assisted by a return spring, e.g., locked between a distal face of the piston 338 and a proximal wall of the distal tip 352 (not shown) and/or by a pull wire attached to the piston and running through lumen 341.
  • FIGS. 9A-9E illustrate an exemplary process for fabricating a dual modulus balloon structure or anchored membrane structure in accordance with the principles of the present disclosure.
  • the first step of the fabrication process is seen in FIG. 9A, in which a low modulus "patch", or membrane, material 400 is layered between removable (e.g. dissolvable) substrates 401 and 402.
  • the substrate 401 covers one entire face of the patch 400, while the substrate 402 covers only a portion of the opposite face, leaving an exposed edge or border region about the periphery.
  • a layer of a "flexible but relatively non-distensible" material 403 is deposited onto one side of the sandwich structure from FIG. 9A to provide a frame to which the low- modulus patch is attached.
  • This material is, for example, parylene N, C, or D, though it can be one of many other polymers or metals.
  • the flexible but relatively non-distensible material is parylene and the patch material is a silicone or siloxane polymer, a chemomechanical bond is formed between the layers, creating a strong and leak-free joint between the two materials.
  • the joint formed between the two materials usually has a peel strength or interfacial strength of at least 0.05 N/mm 2 , typically at least 0.1 N/mm 2 , and often at least 0.2 N/mm 2 .
  • the "flexible but relatively non-distensible" frame or anchor material 403 has been trimmed or etched to expose the substrate material 402 so that it can be removed.
  • Materials 401 and 402 is dissolvable polymers that can be removed by one of many chemical solvents.
  • FIG. 9D the materials 401 and 402 have been removed by dissolution, leaving materials 400 and 403 joined edge-to-edge to form the low modulus, or elastomeric, patch 400 within a frame of generally flexible but relatively non-distensible material 403.
  • the non-distensible frame 403 deforms only slightly, while the elastomeric patch 400 deforms much more.
  • the low modulus material in some instances has a material modulus which is always lower than that of the high modulus material and is typically in the range from 0.1 to 1,000 MPa, more typically in the range from 1 to 250 MPa.
  • the high modulus material in some instances has a material modulus in the range from 1 to 50,000 MPa, more typically in the range from 10 to 10,000 MPa.
  • the material thicknesses often ranges in both cases from approximately 1 micron to several millimeters, depending on the ultimate size of the intended product. For the treatment of most body lumens, the thicknesses of both material layers 402 and 403 are in the range from 10 microns to 2 mm.
  • FIGS. 10A-10D the elastomeric patch of FIGS. 9A-9D is integrated into the intraluminal catheter of Fig 1-5.
  • Fig 10A-D the progressive pressurization of such a structure is displayed in order of increasing pressure.
  • the balloon is placed within a body lumen L.
  • the lumen wall W divides the lumen from periluminal tissue T, or adventitia A*, depending on the anatomy of the particular lumen.
  • the pressure is neutral, and the non- distensible structure forms a U-shaped involuted balloon 12 similar to that in FIG. 1 in which a needle 14 is sheathed.
  • the elastomeric patch 400 will usually be disposed on the opposite side of the involuted balloon 12 from the needle 14.
  • Actuation of the balloon 12 occurs with positive pressurization.
  • pressure (+APi) is added, which begins to deform the flexible but relatively non-distensible structure, causing the balloon involution to begin its reversal toward the lower energy state of a round pressure vessel.
  • the flexible but relatively non-distensible balloon material has reached its rounded shape and the elastomeric patch has begun to stretch.
  • FIG. 10D at still higher pressure +AP 3 , the elastomeric patch has stretched out to accommodate the full lumen diameter, providing an opposing force to the needle tip and sliding the needle through the lumen wall and into the adventitia.
  • Typical dimensions for the body lumens contemplated in this figure are between 0.1 mm and 50 mm, more often between 0.5 mm and 20 mm, and most often between 1 mm and 10 mm.
  • the thickness of the tissue between the lumen and adventitia is typically between 0.001 mm and 5 mm, more often between 0.01 mm and 2 mm and most often between 0.05 mm and 1 mm.
  • the pressure + ⁇ useful to cause actuation of the balloon is typically in the range from 0.1 atmospheres to 20 atmospheres, more typically in the range from 0.5 to 20 atmospheres, and often in the range from 1 to 10 atmospheres.
  • the dual modulus structure formed herein provides for low-pressure (i.e., below pressures that may damage body tissues) actuation of an intraluminal medical device to place working elements such as needles in contact with or through lumen walls.
  • low-pressure i.e., below pressures that may damage body tissues
  • an intraluminal medical device By inflation of a constant pressure, and the elastomeric material will conform to the lumen diameter to provide full apposition.
  • Dual modulus balloon 12 is inflated to a pressure + ⁇ 3 in three different lumen diameters in FIGS. 11 A, 11B, and 11C. for the progressively larger inflation of patch 400 provides optimal apposition of the needle through the vessel wall regardless of diameter.
  • variable diameter system in which the same catheter often is employed in lumens throughout the body that are within a range of diameters. This is useful because most medical products are limited to very tight constraints (typically within 0.5 mm) in which lumens may be used.
  • a system as described in this disclosure in some cases accommodates several millimeters of variability in the luminal diameters for which they are useful.
  • FIGS. 12A-12F show schematics of an exemplary treating of vascular disease in a subject.
  • FIG. 12A shows a blood vessel 1210 in the lower limb that is affected by
  • FIG. 12B shows the affected blood vessel 1210 after a revascularization procedure such as angioplasty or atherectomy to increase the lumen diameter of the blood vessel.
  • the target region of the tissue surrounding the affected blood vessel in some cases has had a revascularization procedure previously.
  • FIG. 12C shows the delivery of the treatment catheter 10 into the target region through the vasculature of the subject.
  • FIG. 12D shows the expansion of the expandable element 12 of the treatment catheter to puncture into the target tissue 1260 surrounding the blood vessel with the needle 14 of the treatment catheter.
  • the expandable element 12 often is also known as an actuator.
  • FIG. 12E shows the delivery of the pharmaceutical composition comprising temsirolimus, dexamethasone, paclitaxel, or a combination thereof 1270 into the target tissue surrounding the blood vessel 1260.
  • FIG. 12F shows the withdrawal of the treatment catheter 10 after the collapse of the expandable element 12 and withdrawal of the needle 14 from the target tissue 1260 surrounding the blood vessel.
  • FIG. 13 shows a flow chart of a method 1300 of treating vascular disease in a subject.
  • a subject suitable for treating a vascular disease is identified.
  • the vascular disease in some instances is any vascular disease described above and herein.
  • exemplary vascular disease described above and herein.
  • the vascular disease is post-angioplasty restenosis.
  • a blood vessel or blood vessels in the subject to target for treatment often is identified.
  • the blood vessel is any blood vessel described above and herein, such as a femoral artery.
  • a treatment catheter often is prepared with a pharmaceutical composition comprising temsirolimus and dexamethasone, although temsirolimus, dexamethasone, paclitaxel, contrast media or combinations thereof may be used as the therapeutic agent of choice.
  • Alternative pharmaceutical compositions often are used as well, and the treatment catheter often comprises any of the drug injection and infusion devices described herein and above.
  • the catheter In a step 1320, the catheter often is advanced through the vasculature of the subject to the target region(s), such as target region(s) in the blood vessel where plaque has been compressed by angioplasty. In a step 1325, the catheter often is positioned at or near the target region(s) of the blood vessel. In a step 1330, an expandable element of the catheter often is expanded to puncture the target region with a needle on the balloon. The expandable element often is an expandable segment, an expandable section, or a balloon of the treatment catheter. The needle often is a microneedle. In a step 1335, the needle of the treatment catheter often is positioned into the tissue surrounding the blood vessel so that the aperture of the needle often is positioned at the target tissue. In a step 1340, a therapeutic amount of the pharmaceutical composition comprising temsirolimus and
  • dexamethasone (or other combinations of agents as previously described) often is injected into the target tissue surrounding the blood vessel.
  • the target tissue often is adventitial tissue, perivascular tissue, or connective tissue surrounding a blood vessel.
  • the needle often is withdrawn from the tissue and the expandable element often is collapsed.
  • the treatment catheter with the collapsed expandable element and the needle often is removed from the vasculature of the subject.
  • Example 1 Metabolic activity of VSMCs in the presence of select drugs.
  • FIG. 14A shows the percent inhibition of metabolic activity and proliferation in the presence of sirolimus or sirolimus + dexamethasone.
  • FIG. 14B shows the percent inhibition of metabolic activity and proliferation in the presence of temsirolimus or temsirolimus + dexamethasone.
  • 14C shows the percent inhibition of metabolic activity and proliferation in the presence of paclitaxel or paclitaxel + dexamethasone. Data represent the average of 9 replicate wells per condition and error bars represent the standard deviation of the 9 replicates. [0171] In the presence of PDGF, conversion of MTT substrate into colorimetric product should occur to a significantly higher degree, as compared to media controls. Indeed, in FIG. 14A
  • VSMCs stimulated with 10 ng/mL PDGF showed increased accumulation of metabolite compared to vehicle control (5% DMSO (v/v) in saline) and cytotoxic control (the transcription inhibitor actinomycin D at 100 ng/mL).
  • Drug, specifically, temsirolimus, sirolimus and paclitaxel at higher concentrations had inhibitory activity in the MTT assay (FIGS. 14A-C).
  • FIG 19 A cultured human aortic VSMCs (4xl0 5 cells/mL) were grown in complete DMEM in 96 well plates and stimulated with PDGF at 10 ng/mL (Peprotech).
  • Single drug titrations of temsirolimus (TEM), paclitaxel (PAC) or dexamethasone (DEX) were administered (0, 10, 50, 500 nM), or fixed high-dose paclitaxel or temsirolimus were administered in combination with dexamethasone titrations (10, 50, 500 nM).
  • FIG 19A presents the percent of inhibition that was identified in the presence of single or combination drugs. Low doses of all drugs, administered individually, had minimal inhibitory properties, as compared to high dose of each drug. Addition of dexamethasone to high-dose paclitaxel or temsirolimus increased the anti-proliferative effect in each case.
  • Example 2 VSMC TNFa cytokine production in the presence of select drugs.
  • FIG. 15A shows TNFa production in the presence of increasing concentrations of sirolimus or sirolimus + 50 nM dexamethasone.
  • FIG. 15B shows TNFa production in the presence of increasing concentrations of temsirolimus or temsirolimus + 50 nM dexamethasone.
  • FIG. 15C shows TNFa production in the presence of increasing concentrations of paclitaxel or paclitaxel + 50 nM dexamethasone.
  • Data represent the average of 9 replicate wells per condition and error bars represent the standard deviation of the 9 replicates.
  • mTOR inhibitors decreased T Fa production at higher doses and the presence of dexamethasone decreased TNFa production when combined with mTOR inhibitors.
  • Dexamethasone alone strongly decreased TNFa production in a dose-dependent manner.
  • paclitaxel activated pro-inflammatory cytokine expression, which was ameliorated by the addition of 50 nM dexamethasone.
  • FIG. 19E cultured human aortic VSMCs (4xl0 5 cells/mL) were grown in complete DMEM in 96 well plates (Corning) and stimulated with PDGF at 10 ng/mL (Peprotech).
  • Single drug titrations of temsirolimus (TEM), paclitaxel (PAC) or dexamethasone (DEX) were administered (0, 10, 50, 500 nM), or fixed high-dose paclitaxel or temsirolimus were administered in combination with dexamethasone titrations (10, 50, 500 nM).
  • TEM temsirolimus
  • PAC paclitaxel
  • DEX dexamethasone
  • Example 3 VSMC IL6 cytokine production in the presence of select drugs.
  • FIG. 16A shows IL6 production in the presence of increasing concentrations of sirolimus or sirolimus + 50 nM dexamethasone.
  • FIG. 16B shows IL6 production in the presence of increasing concentrations of temsirolimus or temsirolimus + 50 nM dexamethasone.
  • FIG. 16C shows IL6 production in the presence of increasing concentrations of paclitaxel or paclitaxel + 50 nM dexamethasone. Data represent the average of 9 replicate wells per condition and error bars represent the standard deviation of the 9 replicates.
  • FIGS. 16A-C The percent change in T Fa and IL6 levels compared to vehicle control levels (set as baseline) were also analyzed and are presented in FIGS. 15A-C and FIGS. 16A-C, respectively.
  • the mTOR inhibitors each decreased TNFa levels when present at 50-500 nM.
  • Paclitaxel induced IL6 and TNFa production by SMCs at all doses tested.
  • TNFa levels increased steadily as paclitaxel concentrations increased with no significant change in IL6 levels between 50 and 500 nM drug.
  • Dexamethasone ameliorated paclitaxel -induced TNFa and IL6 production in VSMCs. Also very noteworthy was the unexpected finding that mTOR inhibitors alone decreased IL6 production in a dose-dependent manner and similar to dexamethasone. mTOR inhibitor + dexamethasone showed an enhanced ability to inhibit IL6 production by VSMCs.
  • FIG. 19D cultured human aortic VSMCs (4xl0 5 cells/mL) were grown in complete DMEM in 96 well plates (Corning) and stimulated with PDGF at 10 ng/mL (Peprotech).
  • Single drug titrations of temsirolimus (TEM), paclitaxel (PAC) or dexamethasone (DEX) were administered (0, 10, 50, 500 nM), or fixed high-dose paclitaxel or temsirolimus were administered in combination with dexamethasone titrations (10, 50, 500 nM).
  • IL6 levels were measured by ELISA (Peprotech). Absorbance readings were taken using a microtiter plate reader (Tecan). Data represent the average absorbance readings. Error bars represent the standard deviation amongst triplicate wells of triplicate plates.
  • paclitaxel induced a dose-dependent upregulation of the proinflammatory cytokines IL6, while temsirolimus and dexamethasone, administered individually, induced a dose-dependent reduction in the same cytokine. Dexamethasone similarly
  • IL6 expression levels are highest; addition of dexamethasone at any dose (10, 50, 500 nM) significantly reduced pro-inflammatory cytokine production of paclitaxel.
  • Example 4 Apoptosis in drug-treated VSMCs.
  • FIG. 17A shows Caspase 3 activation in the presence of increasing concentrations of sirolimus or sirolimus + 50 nM dexamethasone.
  • FIG. 17B shows Caspase 3 activation in the presence of increasing concentrations of temsirolimus or temsirolimus + 50 nM dexamethasone.
  • FIG. 17C shows Caspase 3 activation in the presence of increasing concentrations of paclitaxel or paclitaxel + 50 nM dexamethasone.
  • Data represent the average of 9 replicate wells per condition and error bars represent the standard deviation of the 9 replicates.
  • Baseline levels of VSMC apoptosis were obtained using vehicle controls and values were set to zero. The percent change in apoptosis in the presence of drug was determined from baseline (FIG. 17A-C).
  • Apoptosis was observed to be induced in a dose-dependent manner for all mTOR inhibitors and paclitaxel, with paclitaxel inducing up to a 173% average increase in apoptosis under the test conditions.
  • dexamethasone did not induce significant apoptosis.
  • FIG. 19B In yet another experiment (FIG. 19B) cultured human aortic VSMCs (4xl0 5 cells/mL) were grown in complete DMEM in 96 well plates (Corning) and stimulated with PDGF at 10 ng/mL (Peprotech). Single drug titrations of temsirolimus (TEM), paclitaxel (PAC) or dexamethasone (DEX) were administered (0, 10, 50, 500 nM), or fixed high-dose paclitaxel or temsirolimus were administered in combination with dexamethasone titrations (10, 50, 500 nM). Cells were then incubated for 12 hours. At harvest, plates were centrifuged at 800 rpm in a clinical centrifuge, and supernatant was carefully removed. Cells were then fixed and
  • FIG. 19B presents the amount of apoptosis inhibited compared to vehicle control.
  • paclitaxel at all doses tested, was shown to promote apoptosis (lack of inhibition), which was rescued by the addition of dexamethasone.
  • Example 5 Necrotic LDH measurements in drug-treated VSMCs.
  • Temsirolimus, sirolimus, paclitaxel and dexamethasone were also assessed for toxicity using the LDH release assay to measure necrosis and cytolysis in PDGF-treated VSMCs (FIG. 18A-C).
  • Data in FIG. 18A represent the LDH release in the presence of increasing concentrations of sirolimus or sirolimus + 50 nM dexamethasone.
  • FIG. 18B shows LDH release in the presence of increasing concentrations of temsirolimus or temsirolimus + 50 nM dexamethasone.
  • FIG. 18C shows LDH release in the presence of increasing concentrations of paclitaxel or paclitaxel + 50 nM dexamethasone.
  • FIG. 19C cultured human aortic VSMCs (4xl0 5 cells/mL) were grown in complete DMEM in 96 well plates (Corning) and stimulated with PDGF at 10 ng/mL (Peprotech).
  • Single drug titrations of temsirolimus (TEM), paclitaxel (PAC) or dexamethasone (DEX) were administered (0, 10, 50, 500 nM), or fixed high-dose paclitaxel or temsirolimus were administered in combination with dexamethasone titrations (10, 50, 500 nM). Treated cells were then incubated for 12 hours.
  • TEM temsirolimus
  • PAC paclitaxel
  • DEX dexamethasone
  • Porcine vascular anatomy is similar to human anatomy, allowing the study of medical equipment intended for use in humans. Porcine vascular pathology allows for the development of stenotic arteries for the study of anti-stenotic or anti-restenotic therapies intended for use in humans.
  • the femoral artery in each leg is injured by angioplasty overstretch and followed with either temsirolimus, dexamethasone, combination of both drugs, or control saline injection, for bilateral injury and injection.
  • the angioplasty balloon is selected to be 40-60% larger than the reference diameter of the artery to be injured and is delivered by a catheter to the target injury site by carotid artery access.
  • the angioplasty balloon is inflated to 10-20 atmosphere of pressure three times for 30 seconds each inflation at the target injury site.
  • the Mercator MedSystems Bullfrog® Micro-Infusion Device microneedle catheter is used to deliver either temsirolimus, dexamethasone, combination of both drugs, or control saline by injection into the adventitia and perivascular tissue around the injured artery at the center of each target injury site.
  • the injections are administered under and verified by fluoroscopy.
  • the animals are monitored before, during, and after the procedure, ensuring that all animals survive without adverse incidents until sacrifice.
  • Temsirolimus preparation The 25 mg/mL of Torisel® (temsirolimus) is diluted to 10 mg/ml with the supplied diluent and further diluted to 1.0 mg/mL in 0.9% sodium chloride solution. Then, the 1.0 mg/mL temsirolimus is diluted in a ratio of 4 parts temsirolimus to 2 parts contrast medium, IsoVUE 370, and 4 parts 0.9% sodium chloride solution, for a final temsirolimus concentration of 400 ⁇ g/ml. This temsirolimus preparation is subsequently administered in temsirolimus-treated group pigs. Similarly, a control solution is prepared by mixing 0.9% sodium chloride solution at 4: 1 ratio with a contrast medium, Isovue-370. This control solution is administered in control group pigs.
  • Dexamethasone preparation A 10 mg/mL solution of dexamethasone is diluted to 5 mg/mL in 0.9% sodium chloride solution. Then, the 5 mg/mL dexamethasone is mixed at 4: 1 ratio with a contrast medium, Isovue-370, for a final dexamethasone concentration of 4 mg/mL. This dexamethasone preparation is subsequently administered in dexamethasone -treated group pigs.
  • Temsirolimus/dexamethasone combination preparation The 1.0 mg/mL temsirolimus and the 10 mg/mL dexamethasone solutions are mixed at a 2:2: 1 ratio with a contrast medium, Isovue-370, for a final temsirolimus concentration of 0.4 mg/mL, and a final dexamethasone concentration of 4.0 mg/mL.
  • This temsirolimus/dexamethasone preparation is subsequently administered in temsirolimus/dexamethasone-treated group pigs.
  • Temsirolimus-treated group Six pigs receive a single dose of temsirolimus (1.5 mL of 400 ⁇ g/mL temsirolimus) in the tissue around each 3-cm injured femoral artery segment, for a total of two doses per animal. In each case, all temsirolimus treated animals undergo
  • Dexamethasone-treated group Six pigs receive a single dose of dexamethasone (1.5 mL of 4.0 mg/mL dexamethasone) in the tissue around each injured femoral artery, for a total of two doses per animal. In each case, all dexamethasone treated animals undergo perivascular infusion into the femoral artery adventitia. Two pigs are sacrificed at each time point of 3 days, 7 days, and 28 days post-procedure, and each pig is analyzed for histopathology, pharmacokinetics, and safety evaluation.
  • Temsirolimus/Dexamethasone combination-treated group Six pigs receive a single dose of the temsirolimus/dexamethasone composition (1.5 ml of 400 ⁇ g/mL temsirolimus/4.0 mg/mL dexamethasone) in the tissue around each injured femoral artery, for a total of two doses per animal. In each case, all temsirolimus treated animals undergo perivascular infusion into the femoral artery adventitia. Two pigs are sacrificed at each time point of 3 days, 7 days, and 28 days post-procedure, and each pig is analyzed for histopathology, pharmacokinetics, and safety evaluation.
  • Control group Six pigs serve as control animals. Each pig receives 2 injury sites in femoral arteries, for a total of 12 injury sites among the 6 pigs. Each injury site receives 1.5 ml of 0.9% sodium chloride (saline) diluted 4: 1 ratio with contrast medium (Isovue-370). Two pigs are sacrificed at each time point of 3 days, 7 days, and 28 days post-procedure, and each pig is analyzed for histopathology, pharmacokinetics, and safety evaluation.
  • All treatment and control group animals will successfully receive their respective injection administered directly to the adventitia and perivascular tissues of the femoral arteries. All injection sites except the two control sites will have complete or partial circumferential and longitudinal coverage of the target site by the injection.
  • Example 9 Porcine Model of Femoral Vessel Injury with Paclitaxel
  • Example 7 The general method of Example 7 is followed, with the modification that the researcher replaces temsirolimus with paclitaxel, in dosages described herein. Outcomes are evaluated in a similar manner.
  • Example 10 Porcine Model of Femoral Vessel Injury with Sequential Paclitaxel
  • Example 8 The general method of Example 8 is followed, with the modification that the researcher replaces temsirolimus with paclitaxel, in dosages described herein. Outcomes are evaluated in a similar manner, and the effect of sequential treatment is ascertained.
  • Cultured human aortic VSMCs (4xl0 5 cells/mL) were grown in complete DMEM in 96 well plates and stimulated with PDGF at 10 ng/mL (Peprotech).
  • a range of concentrations of drug SIR, sirolimus; TEM, temsirolimus; PAC, paclitaxel; DEX, dexamethasone
  • ACT D actinomycin D
  • PDGF receptors such as VSMCs and ECs up-regulate their cellular metabolism to support growth and proliferation.
  • VSMCs stimulated with 10 ng/mL PDGF showed increased accumulation of metabolite compared to media control and cytotoxic control (the transcription inhibitor actinomycin D at 100 ng/mL).
  • Vehicle control 5% DMSO (v/v) in saline) did not interfere with metabolic activity.
  • a carotid artery access was utilized for all interventional procedures. In each case, all
  • the injury model was angioplasty overstretch 40-60%), at least 10 atm, 3 inflations of 30 sec each and 30 sec flow.
  • Integrationitial delivery was made directly after overstretch injuries.
  • Whole blood samples were taken following each infusion at 5 minutes, 20 minutes, 1 hour, and then 24 hours and upon sacrifice.
  • Whole blood samples were analyzed for circulating temsirolimus and sirolimus concentrations.
  • Arteries were perfused with Lactated Ringers Solution (LRS), extracted, and cut into serial 5 mm sections with every other section fixed in formalin (not perfusion fixed) for immunohistochemical analysis and every other section was frozen for LC/MS/MS analysis of both temsirolimus and sirolimus levels. Histopathology and histomorphometry endpoints were used to determine efficacy of the rapamycin therapy.
  • the total dose given to each treatment animal was 714 ⁇ g.
  • the mean whole blood baseline temsirolimus levels were below the limits of quantitation (0.200 ng/ml for sirolimus and 0.500 ng/ml for temsirolimus) in all swine prior to dosing.
  • the mean temsirolimus levels were highest at 1 hour after the first injection (32.1 ⁇ 11.0 ng/mL) and decreased to 2.4 ⁇ 1.0 ng/mL within 24 hours. Concentrations continued to decrease to almost non-detectable levels by the third day and by day 7 onwards, all blood analyzed for sirolimus and temsirolimus was found to be below the limits of quantitation.
  • the treated vessels were fully or nearly fully healed as early as Day 7, generally showing a normal wall and occasionally displaying minimal to mild perivascular or adventitial fibrosis and low severity nonspecific and localized mural inflammation considered to be of no pathological significance. There was complete or near complete re-endothelialization and no or minimal to mild and non-stenosing neointima formation. Ki67 staining indicated cellular proliferation in the control vessel wall peaking on Day 7. Quantitative analysis of Ki67 positive nuclei showed a treatment-related decrease in average proliferation values at Day 3, Day 7 and Day 28. The decrease was substantial and consistent along the vessel length.
  • SMA smooth muscle actin
  • Endpoint 1 Overall Animal Health. All animals were generally healthy and gained weight for the duration of the study. No adverse treatment related clinical observations were noted. All physical exams were normal throughout the study duration.
  • Endpoint 2 Tissue Response to the Drug. There was no mortality or significant abnormalities noted in the treated arteries at necropsy. Histologically, all arteries were patent and there were no luminal thrombi or occlusions present in any of the sections examined in the test groups. There were no histological remarkable differences in all graded parameters in the treated vessels between the test groups and the control group at either treatment location. There were thin neointimal formation, medial SMC loss, and medial fibrosis present in the treated coronary and femoral arteries in the control and test groups which most likely were caused by balloon overstretching injury in this animal model. The morphometric measured and calculated parameters were comparable between the control and test groups.
  • Endpoint 3 Whole Blood Temsirolimus and Sirolimus Levels. The blood levels for all treated animals peaked at early time points, declined over time to Day 7, and were below LLOQ at 28 days and at termination. In general, observed concentrations were proportional to dose.
  • Endpoint 4 Homogenized Vascular Tissue Temsirolimus and Sirolimus Levels. The tissue levels for all animals were all below LLOQ.
  • Example 14 Porcine Study of Temsirolimus and Dexamethasone in Combination
  • Endpoint 1 Overall animal health. Three of four animals survived for the study duration and were generally healthy throughout. A fourth animal was found deceased. All surviving animals showed a positive weight gain over the course of the study. The deceased animal was lethargic on day 1. Lethargy continued until the animal was found deceased on day 4. On day 2, blood samples were drawn for analysis, though no conclusive results were obtained. Fever and tachycardia were noted on day 3 prior to the animal being found deceased on day 4. No antemortem diagnosis was made. No significant findings in clinical pathology were noted.
  • Endpoint 2 Tissue response to the device. Both test and control animals exhibit none to moderate changes in the vessel wall. Perivascular and skeletal muscle changes also ranged from none to moderate in both test and control animals. Mineralization was not noted in control animal tissues examined. However, as mineralization was not previously seen with a dosage of 4 mg/mL temsirolimus, it is considered likely due to the high ethanol concentration in the solution at this dose.
  • Endpoint 3 Blood temsirolimus and dexamethasone levels (pK assessment).
  • Temsirolimus levels in the blood for all test animals peaked at early time points, declined over time to 7 days and were below the lower limit of quantitation (LLOQ) at termination.
  • the dexamethasone levels in plasma also peaked at early time points and were below LLOQ at the 24-hour time point and after.
  • dexamethasone tissue levels were all ⁇ LLOQ, and low levels of temsirolimus were found in both test animals.
  • Endpoint 4 Homogenized vascular tissue temsirolimus and dexamethasone levels.
  • temsirolimus 50.3 and 97.5 ng/g, equivalent to 48.8 nM and 94.7 nM, respectively) were found in vascular tissue at term for the two animals treated with the test solution; no temsirolimus was found in the control animal vessels.
  • Dexamethasone levels were ⁇ LLOQ (10.0 ng/mL homogenate, equivalent to 100 ng/g in tissue, or 255 nM) in vascular tissue at term for all animals.
  • Endpoint 1 Overall animal health (moribundity). A total of 22 animals were utilized on this study. Two animals either died or were euthanized early. The reason for death or euthanasia in these animals were likely due to anesthesia and surgical intervention, but not test/control article related. While there were some instances of inappetance, no animals were noted to experience clinically significant weight loss. Many rabbits were noted as
  • Endpoint 2 Tissue response to the device.
  • the combination therapy (Tem+Dex) group showed less neointimal thickness (47.40 ⁇ 14.84um) and area (0.19 ⁇ 0.06mm 2 ) versus temsirolimus, dexamethasone, and vehicle group.
  • the %HHF-35 positive intimal/medial area was smaller with combination therapy or temsirolimus alone relative to dexamethasone alone or vehicle group.
  • the number of BrdU and TUNEL positive cells including intima and media showed no statistical difference among these groups.
  • the combination therapy (Tem+Dex) group showed less neointimal thickness (47.40 ⁇ 14.84 ⁇ ) and area (0.19 ⁇ 0.06mm 2 ) versus temsirolimus, dexamethasone, and vehicle group.
  • the % HHF-35 positive intimal/medial area was smaller with combination therapy or temsirolimus alone relative to dexamethasone alone or vehicle group.
  • the number of BrdU and TUNEL positive cells including intima and media showed no statistical difference among these groups.
  • the balloon-only group did not exhibit significant neointima or stenosis, and therefore none of the therapies showed specific benefit over the balloon-only group.
  • the balloon-only group also did not exhibit similar proliferative markers to any of the other groups, suggesting a lack of proliferative injury induction or a different stage of disease in that group of rabbits.

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US20180353488A1 (en) 2018-12-13
US20210236472A1 (en) 2021-08-05
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