WO2019126706A1 - Agents chimio-répulsifs utilisés dans le traitement d'affections cutanées d'origine immunitaire - Google Patents

Agents chimio-répulsifs utilisés dans le traitement d'affections cutanées d'origine immunitaire Download PDF

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Publication number
WO2019126706A1
WO2019126706A1 PCT/US2018/067202 US2018067202W WO2019126706A1 WO 2019126706 A1 WO2019126706 A1 WO 2019126706A1 US 2018067202 W US2018067202 W US 2018067202W WO 2019126706 A1 WO2019126706 A1 WO 2019126706A1
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Prior art keywords
composition
agent
chemorepellent
site
reaction
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PCT/US2018/067202
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English (en)
Inventor
Mark C. Poznansky
Fabrizio Vianello
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The General Hospital Corporation
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Publication of WO2019126706A1 publication Critical patent/WO2019126706A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/195—Chemokines, e.g. RANTES
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer

Definitions

  • the present invention is directed to skin-penetrating compositions for the treatment of a localized immune- or inflammation-related disorders and/or reactions, the compositions comprising an effective amount of a chemorepellent agent to treat the disorder and/or reaction when applied to the subject and a penetration enhancer.
  • Psoriasis is an autoimmune disease characterized by abnormally rapid growth of the skin, which creates patches of skin that are typically itchy, scaly and red. It is believed to be caused by an inflammatory cascade due to secretion of cytokines by white blood cells in the dermis.
  • Eczema also called dermatitis or atopic dermatitis
  • dermatitis is caused by inflammation of the skin. It is characterized by itchy, erythematous, vesicular, weeping, and crusting patches on the skin.
  • Contact dermatitis may be caused by irritants or allergens.
  • Poisonous plants such as poison ivy, poison oak, and poison sumac, as well as other allergens can cause allergic contact dermatitis as a result of inflammation of the dermis and epidermis. This results in burning, itchy rashes that may take several days to weeks to resolve.
  • Other dermatological disorders that are caused by an undesired immune or inflammatory response include immune and autoimmune disease, including scleroderma, dermatomyositis, epidermolysis bullosa acquisita, bullous pemphigoid; dermatitis; vasculitis; and diaper rash.
  • the present invention relates to skin-penetrating compositions for treating an immune- or inflammation-related skin disorder in a subject in need thereof and methods of use thereof.
  • This disclosure is predicated on the discovery that chemorepellent agents (e.g., CXCL12 and other CXCR4- or CXCR7-binding molecules) (e.g., when targeted to a subdermal region) can reduce or prevent the occurrence/recurrence of immune- or inflammation-related skin disorders at a site in a subject.
  • chemorepellent agents e.g., CXCL12 and other CXCR4- or CXCR7-binding molecules
  • the immune- or inflammation related skin disorders to be treated as described herein are believed to occur as a result of an abnormality in immune responsiveness, function and trafficking resulting in the accumulation of inflammatory cells (granulocytes and macrophages) and immune cells (lymphocytes and dendritic cells) in the skin. Without being bound by theory, it is believed that reducing the inflammatory response by a subject’s immune system at a site with or prone to psoriasis, eczema, or other immune- or inflammation-related skin disorders reduces the occurrence or severity of the disorder.
  • Chemorepellent agents can repel and modify the function of effector T-cells while recruiting immune- suppressive regulatory T-cells to an anatomic site in/on a subject. This action allows for a down-regulation of immune activity in, for example, a localized area.
  • Chemorepellent agents are agents that have migratory cell (e.g., immune cell) repellent activity (i.e., chemorepellent effect). Some chemokines are chemorepellent at high concentrations, whereas at low concentrations they may exhibit chemoattractant activity.
  • chemorepellent agents may inhibit or attenuate the inflammatory response in the skin that results from psoriasis, eczema, allergic contact dermatitis, or other immune- or inflammation-related skin disorders.
  • a chemorepellent agent may be a CXCR4-binding molecule or CXCR7 -binding molecule.
  • a chemorepellent may be IL-8 or CXCL12 (also called SDF-1), or a chemorepellent active fragment thereof or a homologue of a fragment thereof.
  • a chemorepellent agent may be CXCL12. Additional chemorepellent agents are described, for example, in U.S. Patent No. 6,448,054, which is incorporated herein by reference in its entirety.
  • a chemorepellent agent may be present in a topical formulation in an amount to deliver about 500 nanograms per milliliter per day (ng/mL/day) to about 5 micrograms/mL/day (pg/mL/day).
  • a skin-penetrating composition may comprise between about 500 ng/mL and about 5 pg/mL of the
  • a skin-penetrating composition for the treatment of an immune- or inflammation-related skin disorder comprising a chemorepellent agent and a penetration enhancer.
  • the skin-penetrating composition is in a formulation that may be, but is not limited to, a cream, a lotion, an ointment, a gel, a solution, a spray, a foam, or a transdermal patch.
  • a skin-penetrating composition comprises an effective amount of a chemorepellent agent to treat the disorder when applied to the subject.
  • the skin disorder may be psoriasis. In some embodiments, the skin disorder may be eczema. In some embodiments, the skin disorder may be allergic contact dermatitis. In some embodiments, the allergic contact dermatitis may be caused by a plant toxin, such as from poison ivy, poison oak, and/or poison sumac ( e.g ., urushiol). In some embodiments, the skin disorder may be, but is not limited to, scleroderma,
  • a skin-penetrating composition for treatment of a localized immune-related disorder and/or reaction in a subject comprising an effective amount of a chemorepellent agent to treat the disorder and/or reaction when applied to the subject, and a penetration enhancer.
  • a localized immune-related disorder and/or reaction may be psoriasis, eczema, allergic contact dermatitis, scleroderma, dermatomyositis, epidermolysis bullosa acquisita, bullous pemphigoid, dermatitis, vasculitis, and/or diaper rash.
  • a penetration enhancer may be a biphasic lipid vesicle, a surfactant, l-dodecylazacycloheptan-2-one (laurocapram) (AZONE ® ), a pyrrolidone, a fatty acid, an essential oil, an oxazolidinone, a transkarbam, an analog of each thereof, or any combination thereof.
  • a composition may further comprise an effective amount of at least one additional agent to treat the disorder and/or reaction, and/or a symptom thereof, when applied to the subject.
  • the at least one additional agent may be a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • the effective amount of a chemorepellent agent in the composition may be a concentration of about 100 ng/mL to about 10 ug/mL (e.g.. 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600,
  • the chemorepellent agent is present in the composition in an amount to deliver from about 500 ng/mL/day to about 5 pg/mL/day of the chemorepellent agent.
  • a composition for treatment of a localized immune-related disorder and/or reaction in a subject comprising nanoparticles comprising a chemorepellent agent, wherein the nanoparticles, when positioned at or proximate to the site of the disorder and/or reaction elute an effective amount of the chemorepellent agent to inhibit immune cell migration to the site.
  • the nanoparticles may be positioned sub-dermally, in hair follicles, sub-epidermally, in the dermis, and/or in the hypodermis.
  • the disorder and/or reaction can include, but is not limited to, psoriasis, eczema, allergic contact dermatitis, scleroderma, dermatomyositis, epidermolysis bullosa acquisita, bullous pemphigoid, dermatitis, vasculitis, or diaper rash, or any combination thereof.
  • a composition for treatment of a localized immune-related disorder and/or reaction in a subject comprising nanoparticles comprising a chemorepellent agent and metallic particles, wherein the nanoparticles, when positioned at or proximate to the site of the disorder and/or reaction elute an effective amount of the chemorepellent agent to inhibit immune cell migration to the site, and further wherein the metallic particles are smaller than the nanoparticles, are integrated into the nanoparticles, and are attracted to magnetic forces.
  • the nanoparticles may be positioned sub-dermally, in hair follicles, sub-epidermally, in the dermis, and/or in the hypodermis.
  • the metallic beads may provide a mechanism for moving or removal of the nanoparticles comprising the chemorepellent agent should moving or removal of the nanoparticles be desirable.
  • the disorder and/or reaction can include, but is not limited to, psoriasis, eczema, allergic contact dermatitis, scleroderma,
  • “Positioned at or proximate to the site of the disorder and/or reaction” as used herein means that the nanoparticles are positioned on the site of the localized immune-related in disorder or within about 1 mm to about 15 m from the site (e.g., about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, orl5 mm, and the like, and any value or range therein).
  • the“site of the disorder and/or reaction” may be the area that is visually symptomatic or it may be an area greater or smaller than the area that is visually symptomatic.
  • the site of the disorder and/or reaction may be 1 mm to 5 mm (e.g., about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 mm, and the like, and any value or range therein) greater or smaller than the area that is visually symptomatic.
  • each nanoparticle may comprise at least one metallic particle which may be encapsulated by a polymer coating that elutes the chemorepellent agent.
  • the polymer may be alginate.
  • alginate polymers and coatings can be found in PCT Publication No. WO 2015/069256, which is incorporated herein by reference in its entirety.
  • the composition comprising nanoparticles may be formulated for application to the skin and may further comprise a penetration enhancer.
  • a penetration enhancer may be, for example, a biphasic lipid vesicle, a surfactant, 1- dodecylazacycloheptan-2-one (laurocapram) (AZONE ® ), a pyrrolidone, a fatty acid, an essential oil, an oxazolidinone, a transkarbam, an analog of each thereof, or any combination thereof.
  • the composition may further comprise an effective amount of at least one additional agent to treat the disorder and/or reaction, and/or a symptom thereof, when applied to the subject.
  • the at least one additional agent may be, for example, a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • the composition comprising nanoparticles may be formulated for injection. In some embodiments, the composition may be formulated for subdermal injection. In some embodiments, the composition may be formulated for injection into the site to be treated.
  • the chemorepellent agent may be a CXCR4-binding molecule or a CXCR7-binding molecule.
  • the chemorepellent agent may be CXCL12 or a CXCL12 peptide (e.g., a variant of CXCL12 having at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% of the activating activity of wild type CXCL12).
  • a transdermal patch may be provided for treatment of a localized immune- or inflammation-related disorder or reaction in a subject, which patch comprises a backing layer and a drug-eluting layer, wherein the drug-eluting layer comprises a composition comprising a chemorepellent agent as described herein and elutes a sufficient amount of the chemorepellent agent to treat the disorder or reaction when applied to the subject.
  • the drug-containing layer is adhesive and further comprises a liner layer adjacent to the drug-containing layer.
  • a formulation comprising a composition
  • the formulation comprising a chemorepellent agent as described herein, which is formulated for use as a lotion, an ointment, a cream, or a gel.
  • the formulation comprises chemorepellent agent-eluting nanoparticles.
  • kits comprising one or more containers each of which comprise a composition or formulation comprising a chemorepellent agent as described herein, and/or one or more transdermal patches as described herein.
  • the kit may further comprise a topical composition comprising one or more agents, including, but not limited to, a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • agents including, but not limited to, a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • a formulation in at least one of the containers of a kit may comprise one or more agents including, but not limited to, a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • the formulation in at least one additional container does not contain the one or more agents.
  • a method for treating a localized immune- or inflammation- related disorder and/or reaction at a site in a subject in need thereof comprising applying a composition, formulation, or transdermal patch comprising a chemorepellent agent to the subject.
  • the composition, formulation, or transdermal patch may be applied at least once per day for at least two days.
  • the composition or formulation comprises a permeation enhancer and is applied to skin at or near the site.
  • a method for treating a localized immune- or inflammation- related disorder or reaction at a site in a subject in need thereof comprising contacting the site with an effective amount of a composition comprising nanoparticles comprising a chemorepellent agent, wherein the nanoparticles elute an effective amount of the chemorepellent agent to inhibit immune cell migration to the site.
  • a method for treating a localized immune- or inflammation- related disorder or reaction at a site in a subject in need thereof comprising contacting the site with an effective amount of a composition comprising nanoparticles comprising a chemorepellent agent and metallic particles, wherein the nanoparticles elute an effective amount of the chemorepellent agent to inhibit immune cell migration to the site and further wherein the metallic particles are smaller than the nanoparticles, are integrated into the nanoparticles, and are attracted to magnetic forces.
  • the method may comprise applying a magnetic force to the site.
  • the magnetic force may be continuously applied to the site for a defined period of time.
  • the composition may further comprise a permeation enhancer and may be applied to skin at or near the site.
  • the composition may be administered via injection at or near the site.
  • a chemorepellent agent may be a CXCR4-binding molecule and/or a CXCR7 -binding molecule. In some embodiments, a chemorepellent agent may be CXCL12 or a CXCL12 peptide.
  • an additional therapeutic agent may be administered to the subject.
  • the additional therapeutic agent may be in a topical formulation.
  • the additional therapeutic agent may be a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • the disorder and/or reaction may be, but is not limited to, psoriasis, eczema, allergic contact dermatitis, scleroderma, dermatomyositis, epidermolysis bullosa acquisita, bullous pemphigoid, dermatitis, vasculitis, diaper rash, or any combination thereof.
  • ranges can be expressed as from“about” one particular value, and/or to“about” another particular value. It is understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. [0048] “Optional” or“optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
  • the terms“subject,”“patient,”“individual,” and the like are used interchangeably t herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
  • the patient, subject, or individual may be a mammal.
  • the mammal may be a mouse, a rat, a guinea pig, a nonhuman primate, a dog, a cat, or a domesticated animal ( e.g ., horse, cow, pig, goat, sheep).
  • the, subject, patient, or individual may be a human.
  • the term“treating” or“treatment” covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i. e. , causing regression of the disorder; (iii) slowing progression of the disorder (i.e., delay in progression or onset); and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder.
  • administering or“administration” of an agent or drug to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including, but not limited to orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), topically and/or subdermally. In some embodiments, the agents or drugs described herein are administered transdermally or parenterally. Administration includes self-administration and the administration by another.
  • the term“inhibit” or“reduce” or grammatical variations thereof as used herein refers to a decrease or diminishment in the specified level or activity by at least about 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more. In some embodiments, the inhibition or reduction results in little or essentially no detectible activity (at most, an insignificant amount, e.g., less than about 10% or even 5%).
  • the present invention provides a method for decreasing immune cell migration to a site of a disorder or reaction in a subject wherein the migration of the cells into the site is decreased by least about 10%, 15%, 25%, 50%, 75%, 100%, 150%, 200%, 300%, 400%, 500% or more as compared to a control (a control being a site of a disorder or reaction in a subject not treated with the compositions, formulations, patches of the present invention.
  • therapeutic means a treatment, prophylaxis and/or reduction in the risk of developing a disease or disorder.
  • a therapeutic effect is obtained by suppression, remission, or eradication of a disease state.
  • an“therapeutically effective amount” or“effective amount” refers to an amount of an agent (e.g., a chemorepellent agent) that, when administered, is sufficient to provide some improvement or benefit to the subject.
  • an“effective,” “prophylactically effective,” or“therapeutically effective” amount is an amount that will provide some delay, alleviation, mitigation, or decrease in at least one clinical symptom in the subject.
  • an effective amount of a chemorepellent agent may be an amount sufficient to have an inhibitory effect on a migratory cell such as an immune cell.
  • compositions can also be administered in combination with one or more additional therapeutic compounds.
  • the therapeutic compounds may be administered to a subject having one or more signs or symptoms of a disease or disorder.
  • Cytokine is a generic term for non-antibody, soluble proteins which are released from one cell subpopulation and which act as intercellular mediators, for example, in the generation or regulation of an immune response. See Human Cytokines: Handbook for Basic & Clinical Research (Aggrawal, et al. eds., Blackwell Scientific, Boston, Mass. 1991) (which is hereby incorporated by reference in its entirety for all purposes).
  • “Chemorepellent activity” refers to the ability of an agent to repel (or chemorepel) a eukaryotic cell with migratory capacity (i. e. , a cell that can move away from a repellent stimulus). Accordingly, an agent with chemorepellent activity is a“chemorepellent agent.” Such activity may be detected using any of a variety of systems well known in the art (see, e.g ., U.S. Pat. No. 5,514,555 and U.S. Patent Application Pub. No. 2008/0300165, each of which is incorporated by reference herein in its entirety). A system for detection is described in U.S. Patent 6,448,054, which is incorporated herein by reference in its entirety.
  • the term“chemorepellent effect” refers to the chemorepellent effect of a chemokine secreted by a cell. Usually, the chemorepellent effect is present in an area around the cell wherein the concentration of the chemokine is sufficient to provide the chemorepellent effect.
  • Some chemokines including interleukin 8 (IL-8) and CXCL12, may exert chemorepellent activity at high concentrations (e.g., over about 100 nM), whereas lower concentrations exhibit no chemorepellent effect and may even be chemoattractant.
  • Immune cells are cells of hematopoietic origin that are involved in the specific recognition of antigens. Immune cells include antigen presenting cells (APCs), such as dendritic cells or macrophages, B cells, T cells, etc.
  • APCs antigen presenting cells
  • the term“immunorepellent” refers to an ability to repel immune cells from a given site.
  • penetration enhancer and“permeation enhancer” as used herein refer to compounds and compositions that penetrate into skin to reversibly decrease the barrier resistance of the outer skin layers and increase diffusion of agents, such as the
  • skin-penetrating when referring to a composition or formulation described herein refers to the ability of the composition or formulation (or at least one component of the composition or formulation) to penetrate through the outer skin layers and into the subcutaneous layer.
  • compositions Comprising a CXCL12 signaling inhibitor
  • the skin- penetrating composition may be for the treatment of immune- or inflammation-related skin diseases.
  • diseases include, without limitation, psoriasis, eczema, allergic contact dermatitis, scleroderma, dermatomyositis, epidermolysis bullosa acquisita, bullous pemphigoid, dermatitis, vasculitis, diaper rash, or any combination thereof
  • compositions comprising nanoparticles that elute a chemorepellent agent.
  • the nanoparticles also contain a particle(s) that is attracted to a magnetic force, e.g., a ferromagnetic particle.
  • the ferromagnetic particle may be metallic.
  • the ferromagnetic particle may comprise iron, nickel, cobalt, lodestone, an alloy of rare earth metals, or a combination thereof.
  • the nanoparticle may comprise a biocompatible material that elutes the chemorepellent agent.
  • the biocompatible material may be a coating on the ferromagnetic particle.
  • the biocompatible material may be a biocompatible polymer.
  • the biocompatible material may be alginate.
  • Chemorepellent agents are described, for example, in U.S. Patent No. 6,448,054 (which is incorporated herein by reference in its entirety) and include CXCR4-binding molecules and CXCR7-binding molecules.
  • CXCR4-binding molecules include, but are not limited to, CXCL12, a CXCL12 polypeptide (e.g., a variant of CXCL12 having at least 20% of the activating activity of wild type CXCL12 (e.g., at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% of the activating activity of wild type CXCL12)), an antibody to CXCR4, or any other ligand for CXCR4.
  • CXCR7-binding molecules include, but are not limited to, CXCL12, a CXCL12 polypeptide, an antibody to CXCR7, or any other ligand for CXCR7.
  • the chemorepellent agent may be CXCL12.
  • a CXCL12 polypeptide useful with this invention may be any CXCL12 polypeptide that activates the CXCL12/CXCR4 and/or CXCL12/CXCR7 pathway (e.g., having at least 20% of the activating activity of wild type CXCL12, e.g., at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,
  • Activators of the CXCL12/CXCR4 and/or CXCL12/CXCR7 pathway useful with the invention may include, but are not limited to, wild-type CXCL12 or CXCL12 mutants, fusion
  • the CXCL12 proteins/genes, truncations and/or analogues.
  • the CXCL12 the CXCL12
  • polypeptide is wild-type CXCL12 (e.g., mammalian CXCL12, e.g., human CXCL12) or an active fragment thereof, e.g., a CXCL12 polypeptide containing a N-terminal and/or C- terminal truncation and/or internal deletion.
  • CXCL12 truncation variants that can activate CXCR4 or CXCR7 include CXCL12[22-89] and CXCL12[22-88] (Richter et al. Stem Cells Dev. 23(16): 1959-1974 (2014)).
  • the CXCL12 polypeptide is one having one or more mutations (e.g ., additions, deletions, and/or substitutions) that retains at least a portion of the biological activity of wild-type CXCL12.
  • CXCL12 mutants that may be useful as activators of CXCR4 include S-SDF-l(S4V) (Segers et al. Circulation: ]. 16(5): 1683-1692 (2007) and Segers et al. Circulation 123: 1306-1315 (2011)) and AAV-[S4V]-SDF-la and V-[S4V]-SDF-la
  • CXCL12 fusion proteins/genes that may be useful as activators of CXCL4 or CXCR7 include CXCL12-GL (CXCL12 fused to Gaussia luciferase) (Luker et al. Biotechniques 47(l):625- 632 (2009)), SDF1-GPVI protein (SDF-1 -glycoprotein VI)(Ziegler et al. Circulation 125(5):685-696 (2012)), SDF-1/HOXB4 (Chen et al. Am. J. Transl.
  • CXCL12 analogues that may be useful as activators of CXCR4 or CXCR7 include lactam analogues of CXCL12, CTCE 0021 and CTCE 0214 (Patrussi et al. Curr. Med. Chem.
  • modified CXCL12 sequences for activation of the CXCL12/CXCR4 and/or CXCL12/CXCR7 pathway include, without limitation, sequences disclosed in US Patent Nos. 7,696,309 (protease resistant sequences); 7,999,067 (protease resistant sequences); 9,308,277 (protease resistant sequences); 9,631,005 (protease resistant sequences); 7,776,564 (splice variants); 8,058,403 (splice variants);
  • a CXCL12 polypeptide sequence useful with the invention may be any isoform of CXCL12.
  • CXCL12 polypeptides are known in the art. See, for example, Poznansky et al., Nature Medicine 2000, 6:543-8. Note that the terms CXCL12 and SDF-1 may be used interchangeably.
  • Exemplary CXCL12 isoforms are provided in Table 1.
  • a CXCL12 polypeptide has at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to any one of the isoforms listed in Table 1.
  • the sequences may be the same isoform (e.g. , two CXCL12- a isoforms) or different isoforms. Table 1. CXCL12 isoforms
  • 1 to 5 of the first consecutive amino acid residues of the CXCL12 polypeptide sequence are deleted relative to the wild-type CXCL12 sequence.
  • Reference to the first five consecutive amino acid residues of the CXCL12 polypeptide sequence refers to the sequence KPVSL in mature human CXCL12 and the corresponding residues from CXCL12 of other species.
  • 1, 2, 3, 4, or 5 of the first consecutive amino acid residues of the CXCL12 polypeptide sequence are deleted.
  • the recombinant CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:7.
  • the sixth amino acid residue of the CXCL12 polypeptide sequence is substituted relative to the wild-type CXCL12 sequence.
  • the sixth amino acid residue in human CXCL12 is a serine.
  • the residue may be substituted with a conservative substitution.
  • the residue is substituted with alanine.
  • the recombinant CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:8. MNAKVVVVLVLYLTALCLSDGKPVSLAYRCPCRFFESHYARANVKHLKILNTPNCA LQIVARLK NNRQV CIDPKLKWIQEYLEKALNK (SEQ ID NO:8)
  • the deletion of 1 to 5 of the first consecutive amino acid residues of the CXCL12 polypeptide sequence is combined with the substitution of the sixth residue.
  • the modified CXCL12 polypeptide may have 1, 2, 3, 4, or 5 of the first consecutive amino acid residues deleted in combination with substitution of the sixth residue, e.g., to alanine.
  • the CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:9.
  • the CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:10.
  • the CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 11.
  • the CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 12.
  • Conservative amino acid substitutions in the CXCL12 polypeptides of the invention may be based on any characteristic known in the art, including the relative similarity or differences of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like.
  • the hydropathic index of amino acids may be considered.
  • the importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art (see, Kyte and Doolittle, J. Mol Biol, 157: 105 (1982); incorporated herein by reference in its entirety). It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like.
  • Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics (Kyte and Doolittle, id), these are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5);
  • aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).
  • the hydropathic index of the amino acid may be considered when modifying the peptides specifically disclosed herein for use as a chemorepellent agent.
  • threonine (-0.4); proline (-0.5 ⁇ I); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); tryptophan (-3.4).
  • hydrophilicity of the amino acid may be considered when identifying additional peptides beyond those specifically disclosed herein.
  • a CXCL12 polypeptide may have at least about 85%, 90%,
  • a CXCL12 polypeptide is a biologically active fragment or analog of a wild-type CXCL12 polypeptide.
  • the skin-penetrating composition or nanoparticle composition may comprise about 100 ng/mL to about 10 qg/mL of a chemorepellent agent (e.g., about 100,
  • a skin-penetrating composition or nanoparticle composition of the invention may comprise a chemorepellent agent in a range of about 100 ng/mL to about 500 ng/mL,
  • the amount of a chemorepellent agent in a composition of the invention may be in a range of about 100 ng/mL to about 500 ng/mL,
  • the skin-penetrating composition or nanoparticle composition further comprises at least one additional therapeutic agent.
  • the at least one additional therapeutic agent may be a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • the at least one additional therapeutic agent may be an antibiotic.
  • the antibiotic may be sodium sulfacetamide, gentamycin, clindamycin, doxycycline, tetracycline, erythromycin, or any combination thereof.
  • the at least one additional agent may be a retinoid.
  • the retinoid may be tretinoin, adapalene, retinol, tazarotene, or any combination thereof.
  • the at least one additional agent may be a calcineurin inhibitor.
  • the calcineurin inhibitor may be cyclosporin, tacrolimus, sirolimus, or any combination thereof.
  • the at least one additional agent may be a steroid.
  • the steroid may be diflorasone diacetate, halobetasol propionate, fluocinonide, desoximetasone, desonide, fluocinolone acetonide, fluticasone, alclometasone, prednicarbate, clobetasol propionate, betamethasone dipropionate, betamethasone valerate, diflucortolone valerate, hydrocortisone 17-butyrate, mometasone furoate, methylprednisolone aceponate, clobetasone butyrate, triamcinolone acetonide, amcinonide, halcinonide, clocortolone pivalate, hydrocortisone, hydrocortisone acetate, or any combination thereof.
  • skin-penetrating compositions comprising a chemorepellent agent and a skin penetration enhancer are provided.
  • Skin penetration enhancers are well-known in the art and include, without limitation, biphasic lipid vesicles, surfactants, 1- dodecylazacycloheptan-2-one (laurocapram) (AZONE ® ), pyrrolidones, fatty acids, essential oils, oxazolidinones, transkarbams, and analogs of any of these, as well as combinations thereof. Additional non-limiting examples can be found in U.S. Patent Publication No. 2009/0053290 and U.S. Patent Nos. 6,818,226; 5,066,648; 6,958,153; and 4,847,250; each of which is incorporated herein by reference in its entirety.
  • a skin-penetrating composition for treatment of a localized immune- or inflammation-related disorder and/or reaction in a subject, the composition comprising an effective amount of a chemorepellent agent to treat the disorder and/or reaction when applied to the subject and a penetration enhancer.
  • the disorder and/or reaction may include, but is not limited to, psoriasis, eczema, allergic contact dermatitis, scleroderma, dermatomyositis, epidermolysis bullosa acquisita, bullous pemphigoid, dermatitis, vasculitis, diaper rash, or any combination thereof.
  • the penetration enhancer may be a biphasic lipid vesicle, a surfactant, l-dodecylazacycloheptan-2-one (laurocapram) (AZONE ® ), a pyrrolidone, a fatty acid, an essential oil, an oxazolidinone, a transkarbam, an analog of each thereof, or any combination thereof.
  • a composition of the invention may farther comprise an effective amount of at least one additional agent to treat the disorder and/or a symptom thereof when applied to the subject.
  • the at least one additional agent may include, but is not limited to, a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • a composition for treatment of a localized immune- or inflammation-related disorder and/or reaction in a subject, the composition comprising nanoparticles comprising a chemorepellent agent, wherein the nanoparticles, when positioned proximate to the site of the disorder and/or reaction, elute an effective amount of the chemorepellent agent to inhibit immune cell migration to the site.
  • the nanoparticles are positioned sub-dermally, in hair follicles, sub-epidermally, in the dermis, and/or in the hypodermis.
  • the disorder and/or reaction may include, but is not limited to, psoriasis, eczema, allergic contact dermatitis, scleroderma,
  • a composition for treatment of a localized immune- or inflammation-related disorder and/or reaction in a subject, the composition comprising nanoparticles comprising a chemorepellent agent and metallic particles, wherein the nanoparticles, when positioned proximate to the site of the disorder and/or reaction, elute an effective amount of the chemorepellent agent to inhibit immune cell migration to the site and further wherein the metallic particles are smaller than the nanoparticles, are integrated into the nanoparticles, and are attracted to magnetic forces.
  • the nanoparticles are positioned sub-dermally, in hair follicles, sub-epidermally, in the dermis, and/or in the hypodermis.
  • the disorder and/or reaction may include, but is not limited to, psoriasis, eczema, allergic contact dermatitis, scleroderma,
  • each nanoparticle may comprise at least one metallic particle encapsulated by a polymer coating that elutes the chemorepellent agent.
  • the polymer may be alginate.
  • the composition comprising nanoparticles may be formulated for application to the skin and may further comprise a penetration enhancer.
  • the penetration enhancer may include, but is not limited to, a biphasic lipid vesicle, a surfactant, l-dodecylazacycloheptan-2-one (laurocapram) (AZONE ® ), a pyrrolidone, a fatty acid, an essential oil, an oxazolidinone, a transkarbam, an analog of each thereof, or any combination thereof.
  • the composition may further comprise an effective amount of at least one additional agent to treat the disorder and/or reaction, and/or a symptom thereof, when applied to the subject.
  • the at least one additional agent is a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • composition comprising nanoparticles may be formulated for injection.
  • the chemorepellent agent may be a CXCR4-binding molecule or a CXCR7-binding molecule , In some embodiments, the chemorepellent agent may be CXCL12 or a CXCL12 polypeptide.
  • this disclosure relates to a transdermal patch comprising a chemorepellent agent and a skin penetration enhancer as described herein.
  • the chemorepellent agent may be a CXCR4-binding molecule or a CXCR7- binding molecule.
  • the transdermal patch may be for treatment of an immune- or inflammation-related skin disorder and/or reaction, and/or symptom thereof, in a subj ect in need thereof.
  • Transdermal patches and methods of making are well-known in the art, and non limiting examples can be found in tl.S. Patent Nos. 5,948,433; 5,965,154; 5,262,165; and 8,911,782; and U.S. Patent App. Pub. Nos. 2008/0008747; and 2012/0265158; each of which is incorporated herein by reference in its entirety.
  • a transdermal patch for treatment of a localized immune- or inflammation-related disorder or reaction in a subject, which patch comprises a backing layer and a drug-eluting layer, wherein the drug-eluting layer comprises a composition comprising a chemorepellent agent as described herein and elutes an effective amount of the chemorepellent agent to treat the disorder and/or reaction, and/or symptom thereof, when applied to the subject.
  • the drug-containing layer may be adhesive and in some embodiments, may further comprise a liner layer adjacent to the drug-containing layer.
  • the drug-eluting layer may comprise a skin penetration enhancer.
  • a skin-penetrating composition as described herein may be formulated for application to the skin.
  • the skin-penetrating composition may be formulated as a lotion, an ointment, a cream, a gel, a solution, a spray, a foam, a skin masque, or a skin peel.
  • the composition or formulation may comprise nanoparticles that elute the chemorepellent agent.
  • the nanoparticles may contain a ferromagnetic material.
  • the composition may be in a formulation that hides or masks the immune- or inflammation-related disorder and/or reaction, and/or symptom thereof.
  • the formulation may be tinted or colored, and/or form a layer over the site of application that hides the disorder and/or reaction, and/or symptom thereof.
  • tintings/colorings are known in the art.
  • the formulation may include one or more additional agents that are suitable for dermatological/cosmetic use.
  • agents include, but are not limited to, film-forming polymers, carriers, solvents, preservatives, stabilizers, antioxidants, thickening agents, surfactants, pigments, colorants, fragrances, emulsifiers, and/or other adjuvants.
  • water-soluble film-forming polymers include: proteins, for instance, proteins of plant origin such as wheat proteins and soybean proteins; proteins of animal origin such as keratins, for example keratin hydrolysates and sulfonic keratins; anionic, cationic, amphoteric or nonionic chitin or chitosan polymers; polymers of celluloses such as hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, ethylhydroxyethylcellulose and carboxymethylcellulose, and quaternized cellulose derivatives; acrylic polymers or copolymers, such as polyacrylates or polymethacrylates; vinyl polymers, for instance polyvinylpyrrolidones, copolymers of methyl vinyl ether and of malic anhydride, the copolymer of vinyl acetate and of crotonic acid, copolymers of vinylpyrrolidone and of vinyl acetate; copolymers of vinylpyrrolidone and of cap
  • Non-limiting examples of carriers that may be used in the formulations as described herein include dermatologically acceptable liquid solvents, preferably in which the chemorepellent agent, penetration enhancer, and/or additional agents are soluble at relevant concentrations.
  • dermatologically acceptable liquid solvents is intended to mean those solvents which can safely be used on the skin in the formulations of this invention, i.e., solvents which do not provoke a severe reaction and which are not toxic when contacted with the skin for relatively short periods of time.
  • Solvents may be organic solvents that are relatively volatile, to facilitate evaporation of the solvent after application of a coating of the skin-penetrating composition onto the skin. Volatile solvents with moderate flash points, e.g., above 30°C, may be useful for safety reasons, to minimize flammability risks.
  • solvents include, but are not limited to, alkylene glycols such as propylene glycol, polyethylene glycol, and/or aqueous alcohol, e.g., ethanol and/or isopropanol.
  • alkylene glycols such as propylene glycol, polyethylene glycol, and/or aqueous alcohol, e.g., ethanol and/or isopropanol.
  • Other useful solvents include methanol, acetone and/or ether (diethyl ether). Mixtures containing one or more of these solvents or other solvents are included.
  • Other useful carriers herein may include the various dermatological and cosmetic carriers such as gels, emulsions, creams, waxes, compacts, etc.
  • the skin-penetrating compositions of the invention may comprise other components, such as preservatives, stabilizers, antioxidants, thickening agents, surfactants, pigments, colorants, fragrances and other adjuvants.
  • Such components may be dermatologically acceptable.
  • the additional components do not interfere with the efficacy or impose any negative influence upon the efficacy of the skin-penetrating composition.
  • Such additives may further include, for example, an aromatic, a surfactant, a preservative, an anti-oxidant, a moisturizing agent, and so on.
  • vitamin A acid, an alkyl acrylatemethacrylate copolymer, etc. maybe added.
  • the additional components may be present individually or in combination, and their concentrations are not limited. For example, the concentration of the additional components may be from about 0.01 to about 5 wt%, based on the weight of the formulation.
  • the formulation may include one or more surfactants and/or emulsifiers.
  • Surfactants or surface-active substances that may be present include anionic, non-ionic, cationic and/or amphoteric surfactants.
  • anionic surfactants include, but are not limited to, soaps, alkylbenzenesulfonates, alkanesulfonates, olefin sulfonates, alkyl ether sulfonates, glycerol ether sulfonates, a-methyl ester sulfonates, sulfo fatty acids, alkyl sulphates, fatty alcohol ether sulphates, glycerol ether sulphates, fatty acid ether sulphates, hydroxy mixed ether sulphates, monoglyceride (ether) sulphates, fatty acid amide (ether) sulphates, mono- and dialkyl sulfosuccinates, mono- and dialkyl sulfosuccinamates, sul fb triglycerides, amide soaps, ether carboxylic acids and salts thereof, fatty acid isethionates, fatty acid sarcos thereof
  • non-ionic surfactants include, but are not limited to, fatty alcohol polyglycol ethers, alkylphenol polyglycol ethers, fatty acid polyglycol esters, fatty acid amide polyglycol ethers, fatty amine polyglycol ethers, alkoxylated triglycerides, mixed ethers or mixed formals, optionally partially oxidized alk(en)yl oligoglycosides or glucoro ic acid derivatives, fatty acid N-alkylglucamides, protein hydrolysates (in particular wheat- based vegetable products), polyol fatty acid esters, sugar esters, sorbitan esters, polysorbates and/or amine oxides.
  • amphoteric or zwitterionic surfactants include, but are not limited to, alkylbetaines, alkylamidobetaines, aminopropionates, aminoglycinates, imidazolinium-betaines and/or sulfobetaines.
  • a surfactant can include, but is not limited, to fatty alcohol polyglycol ether sulphates, monoglyceride sulphates, mono- and/or dialkyl sulfosuccinates, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, fatty acid glutamates, alpha- olefmsulfonates, ether carboxylic acids, alkyl oligoglucosides, fatty acid glucamides, alkylamidobetaines, amphoacetals and/or protein fatty acid condensates.
  • zwitterionic surfactants include, but are not limited to, betaines, such as N-alkyl-N,N-dimethylammonium glycinates, for example cocoalkyldimethylammonium glycinate, N ⁇ acylaminopropyl-N,N-dimethylammonium glycinates, for example
  • cocoacylaminopropyldimethylammonium glycinate and 2-alkyl-3-carboxymethyl-3- hydroxyethylimidazolines having in each case 8 to 18 carbon atoms in the alkyl or acyl group, and/or cocoacylaminoethylhydroxyethyl-carboxymethyl glycinate.
  • an emulsifier can be a nonionogenic surfactant selected from the following: the addition products of from 2 to 30 mole of ethylene oxide and/or 0 to 5 mole of propylene oxide onto linear fatty alcohols having 8 to 22 carbon atoms, onto fatty acids having 12 to 22 carbon atoms, onto alkylphenols having 8 to 15 carbon atoms in the alkyl group, or onto alkylamines having 8 to 22 carbon atoms in the alkyl radical; alkyl and/or alkenyl oligoglycosides having 8 to 22 carbon atoms in the alk(en)yl radical and the ethoxylated analogs thereof; the addition products of from 1 to 15 mole of ethylene oxide onto castor oil and/or hydrogenated castor oil; the addition products of from 15 to 60 mole of ethylene oxide onto castor oil and/or hydrogenated castor oil; partial esters of glycerol and/or sorbitan with unsaturated, linear or
  • an emulsifier may be a polyalkylene glycol such as, for example, polyethylene glycol and/or polypropylene glycol.
  • an emulsifier may be polyethylene glycol having a molecular weight of 100 Da to 5,000 Da, 200 Da to 2,500 Da, 300 Da to 1,000 Da, 400 Da to 750 Da, 550 Da to 650 Da, or about 600 Da.
  • an emulsifier may be a poloxamer.
  • an emulsifier may be composed of one or more fatty alcohols.
  • the fatty alcohol may be a linear or branched C 6 to C35 fatty alcohol.
  • fatty alcohols include, but are not limited to, capryl alcohol (1-octanol), 2-ethyl hexanol, pelargonic alcohol (1-nonanol), capric alcohol (1-decanol, decyl alcohol), undecyl alcohol (1-undecanol, undecanol, hendecanol), lauryl alcohol (dodecanol, 1- dodecanol), tridecyl alcohol (1-tridecanol, tridecanol, isotridecanol), myristyl alcohol (1- tetradecanol), pentadecyl alcohol (1-pentadecanol, pentadecanol), cetyl alcohol (1- hexadecanol), palmitoleyl
  • the formulations of the invention may also include additional components suitable in such compositions.
  • the formulation may include one or more of the following components: fats, waxes, pearlescent waxes, bodying agents, thickeners, superfatting agents, stabilizers, polymers, silicone compounds, lecithins, phospholipids, biogenic active ingredients, deodorants, antimicrobial agents, antiperspirants, swelling agents, insect repellents, hydrotropes, solubilizers, preservatives, perfume oils and/or dyes. Examples of each of these components are disclosed in U.S. Patent No. 8,067,044, which is incorporated by reference with respect these components.
  • agents set forth herein are intended as examples only, and are not intended to be limiting. Additional agents which may be included in the formulations described herein can be found, for example, in U.S. Patent Nos. 8,945,594; 6,379,702; 6,296,840; 5,747,022; 5,716,599; 5,599,546; 4,640,932; 5,139,771 ; 5,026,552; 5,194,253; and 5,690,945; and U.S. Patent Publication No. 2004/0161435; each of which is incorporated herein by reference in its entirety.
  • the present invention relates to nanoparticle compositions comprising nanoparticles that elute chemorepellent agents.
  • the nanoparticles comprise a biocompatible material that elutes the chemorepellent agent.
  • the nanoparticles comprise a ferromagnetic particle.
  • the nanoparticles are attracted to a magnetic force.
  • the nanoparticles comprise a ferromagnetic particle(s) encased in or coated with a biocompatible material that elutes the chemorepellent agent.
  • nanoparticles useful with this invention may be small enough to move within the sub-dermal region, in hair follicles, sub-epidermal region, in the dermis, and/or in the hypodermis without causing damage (or significant damage) to the region.
  • the biocompatible material may be a biocompatible polymer.
  • the biocompatible polymer can be carbohydrate-based, protein-based, and/or synthetic, e.g., PLA (polylactic acid).
  • Biocompatable materials suitable for use herein include, but are not limited to, poly-dimethyl-siloxane (PDMS), poly-glycerolsebacate (PGS), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), polyglycolide, polyglycolic acid (PGA), polylactide-co-glycolide (PLGA), polydioxanone, polygluconate, polylactic acid-polyethylene oxide copolymers, modified cellulose, collagen, polyhydroxybutyrate, polyhydroxpriopionic acid, polyphosphoester, poly( alpha-hydroxy acid), polycaprolactone, polycarbonates, polyamides, polyanhydrides, polyamino acids, polyorthoesters, polyacetal
  • the biocompatible polymer is alginate. In one embodiment, the biocompatible polymer is not alginate, Non-limiting examples of chemorepellent agent-eluting polymers can be found in PCT Publication No.
  • the ferromagnetic particle may be metallic. In one embodiment,
  • the ferromagnetic particle may comprise iron, nickel, cobalt, lodestone, an alloy of rare earth metals, or a combination thereof.
  • the nanoparticle composition may be formulated for application to the skin.
  • the nanoparticle composition may comprise a skin-penetrating agent.
  • the nanoparticle composition may be formulated for injection.
  • kits containing one or more containers containing a skin-penetrating composition comprising a chemorepellent agent and a penetration enhancer, as described herein.
  • kits comprising one or more containers comprising a composition or formulation comprising a chemorepellent agent as described herein, and/or one or more transdermal patches as described herein.
  • the kit may further contain a topical composition comprising one or more agents including, but not limited to, a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • a formulation in at least one of the containers may comprise one or more agents including, but not limited to, a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • the formulation in at least one container does not contain the one or more additional agents.
  • a kit containing a plurality (e.g. , 2, 3, 4, or more) of containers which contain a skin-penetrating composition, nanoparticle composition, or formulation as described herein.
  • the formulation in at least one of the containers may comprise one or more additional agents.
  • the one or more additional agents may be a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or a combination thereof.
  • the formulation in at least one additional container does not contain the one or more additional agents.
  • the kit contains one or a plurality of transdermal patches as described herein.
  • a first subset of the plurality of transdermal patches may comprise one or more additional agents.
  • a second subset of the plurality of transdermal patches does not comprise the one or more additional agents.
  • at least one subset of the plurality of transdermal patches is labeled so as to distinguish it from the other subset.
  • the kit may contain a sufficient number of transdermal patches for two weeks of treatment of a patient, wherein during the first week the patient uses the transdermal patches including the one or more additional agents and during the second week the patient uses the transdermal patches without the one or more additional agents.
  • a kit may further comprise a topical composition.
  • the topical composition may comprise at least one additional therapeutic agent.
  • the at least one additional therapeutic agent may include, but is not limited to, a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or a combination thereof.
  • a topical formulation of the invention may be in the form of a gel, cream, lotion, ointment, spray, foam, solution, or the like.
  • kits may further comprise instructions for use of the skin- penetrating composition, patch, nanoparticle composition, and/or topical
  • composition/formulation in the treatment of an immune- or inflammation-related skin disease, disorder, reaction or condition.
  • compositions Comprising a Chemorepellent Agent
  • the invention relates to methods of using skin-penetrating compositions and kits as described herein. In some embodiments, the invention relates to a method of treating a subject in need thereof with a skin-penetrating composition as described herein.
  • a skin-penetrating composition, formulation, or transdermal patch of the invention may be applied at least once per day for at least two days.
  • an additional therapeutic agent may be administered to the patient.
  • the additional therapeutic agent may be in a topical formulation.
  • the additional therapeutic agent may include, but is not limited to, a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or a combination thereof.
  • the skin-penetrating composition may be applied for a period of time between about 5 minutes to about 12 hours or to about 24 hours.
  • the period of time is at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, or at least 12 hours.
  • the period of time may be overnight. Contemplated periods of time may include any value or subrange between any of the recited values, including endpoints.
  • the skin-penetrating composition may be removed after the period of time.
  • the skin-penetrating composition is not actively removed.
  • a skin-penetrating composition may be applied every day, every two days, every three days, every four days, every five days, every six days, or every week. In some embodiments, a skin-penetrating composition is applied every 1 hour to every 24 hours. Contemplated periods of time include any value or subrange between any of the recited values,
  • a skin-penetrating composition may be applied periodically for a period of time.
  • a skin-penetrating composition may be applied one time per day, multiple times (e.g., 2, 3, 4, or 5 times) per day, every other day, etc.
  • the skin- penetrating composition may be applied for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more days.
  • a transdermal patch will not be reused for more than a single application. However, reusable patches are contemplated by the current invention.
  • a skin-penetrating composition comprising the
  • chemorepellent agent with an additional therapeutic agent may be applied periodically for a period of time, followed by (and/or preceded by) application of a skin-penetrating composition without the additional therapeutic agent for a period of time.
  • a skin-penetrating composition without the additional therapeutic agent for a period of time.
  • an additional therapeutic agent may be administered to the patient.
  • the additional therapeutic agent may be in a topical formulation.
  • the additional therapeutic agent may include, but is not limited to, a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or a combination thereof.
  • a method for treating a localized immune- or inflammation-related disorder or reaction at a site in a subject in need thereof comprising applying a composition, formulation, or transdermal patch comprising a chemorepellent agent to the subject.
  • the composition, formulation, or transdermal patch may be applied at least once per day for at least two days.
  • a composition or formulation may comprise a permeation enhancer and may be applied to skin at or near the site.
  • a method for treating a localized immune- or inflammation-related disorder or reaction at a site in a subject in need thereof, the method comprising contacting the site with an effective amount of a composition comprising nanoparticles comprising a chemorepellent agent and metallic particles, wherein the nanoparticles elute a sufficient amount of the chemorepellent agent to inhibit immune cell migration to the site and further wherein the metallic particles are smaller than the nanoparticles, are integrated into the nanoparticles, and are attracted to magnetic forces.
  • the method may comprise applying a magnetic force to the site.
  • the magnetic force may be continuously applied to the site for a defined period of time.
  • the composition further comprises a permeation enhancer and is applied to skin at or near the site.
  • the composition may be administered via injection at or near the site.
  • the chemorepellent agent may be a CXCR4-binding molecule or a CXCR7-binding molecule.
  • the chemorepellent agent may be a CXCL12 or a CXCL12 polypeptide.
  • an additional therapeutic agent may be administered to the patient.
  • the additional therapeutic agent may be present in a topical formulation.
  • the additional therapeutic agent may include, but is not limited to, a steroid, a vitamin D analogue, anthralin, a retinoid, a calcineurin inhibitor, an antibiotic, salicylic acid, coal tar, a moisturizer, or any combination thereof.
  • an immune- or inflammation-related disorder or reaction includes, but is not limited to, psoriasis, eczema, allergic contact dermatitis, scleroderma, dermatomyositis, epidermolysis bullosa acquisita, bullous pemphigoid, dermatitis, vasculitis, diaper rash or any combination thereof.

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Abstract

La présente invention concerne des compositions pénétrant la peau comprenant un agent chimiorépulsif et un promoteur de pénétration, éventuellement en association avec un agent thérapeutique supplémentaire, ainsi que des formulations, des timbres transdermiques et un kit comprenant les compositions. L'invention concerne en outre des méthodes d'utilisation des compositions pour le traitement de maladies et/ou réactions cutanées d'origine immunitaire ou inflammatoire.
PCT/US2018/067202 2017-12-21 2018-12-21 Agents chimio-répulsifs utilisés dans le traitement d'affections cutanées d'origine immunitaire WO2019126706A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100203087A1 (en) * 2006-10-06 2010-08-12 Celtaxsys, Inc. Chemorepulsion of cells
US20100298214A1 (en) * 2007-08-31 2010-11-25 Massachusetts Institute Of Technology Treatment of autoimmune disease
WO2014145236A2 (fr) * 2013-03-15 2014-09-18 Juventas Therapeutics, Inc. Utilisation de sdf-1 d'atténuation de formation de cicatrice
WO2015069256A1 (fr) * 2013-11-07 2015-05-14 The General Hospital Corporation Matrice d'elution et utilisations associees
US20170304400A1 (en) * 2016-04-25 2017-10-26 ViCapsys.Inc Methods for preventing fibrosis using cxcr4 and/or cxcr7 binding agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100203087A1 (en) * 2006-10-06 2010-08-12 Celtaxsys, Inc. Chemorepulsion of cells
US20100298214A1 (en) * 2007-08-31 2010-11-25 Massachusetts Institute Of Technology Treatment of autoimmune disease
WO2014145236A2 (fr) * 2013-03-15 2014-09-18 Juventas Therapeutics, Inc. Utilisation de sdf-1 d'atténuation de formation de cicatrice
WO2015069256A1 (fr) * 2013-11-07 2015-05-14 The General Hospital Corporation Matrice d'elution et utilisations associees
US20170304400A1 (en) * 2016-04-25 2017-10-26 ViCapsys.Inc Methods for preventing fibrosis using cxcr4 and/or cxcr7 binding agents

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