Plasminogen activator inhibitor 1 (PAI-1) inhibitors and uses thereof

Abstract

To provide methods for treatment and / or prevention of certain dermatological conditions, including hair graying, keloids and scleroderma.SOLUTION: A method comprises: providing a composition that comprises or delivers a plasminogen activator inhibitor-1 (PAI-1) inhibitor; and administering the composition to a site in a subject, where the site contains or once contained a plurality of hair follicles, each with a hair positioned therein, so that the PAI-1 inhibitor is delivered to the subject.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 731,076, filed Sep. 13, 2018, which is incorporated by reference in its entirety. [Background technology]

[0002] Graying of hair or other dermatological conditions often fosters great anxiety. Many people go to great lengths to hide the gray hair, especially when the graying appears prematurely. Previously available treatments have proven largely inadequate, and thus new treatment options are needed. Summary of the Invention [Problem to be solved by the invention]

[0003] The present disclosure provides, inter alia, novel technologies (e.g., methods, kits, compositions, etc.) for the treatment and / or prevention of certain dermatological conditions, including, inter alia, hair graying. Among other things, the present disclosure provides the insight that plasminogen activator inhibitor 1 (PAI-1) inhibitors may be useful in the treatment and / or prevention of certain dermatological conditions, such as the treatment and / or prevention of hair graying.

[0004] Those skilled in the art recognize that overexpression of PAI-1 is associated with the inhibition of the conversion of plasminogen to plasmin, which is essential for fibrinolysis, the physiological breakdown of blood clots. The present disclosure provides the insight that PAI-1 may also be associated with certain dermatological conditions. The present disclosure provides novel technologies (e.g., methods, kits, compositions, etc.) for the treatment and / or prevention of certain dermatological conditions, including hair graying. Alternatively or additionally, in some embodiments, the provided technologies may be utilized for the treatment and / or prevention of dermatological conditions, such as keloids, scleroderma, and Raynaud's phenomenon. [Means for solving the problem]

[0005] In some embodiments, the disclosure provides a method of treating a dermatological condition comprising providing a composition that includes or delivers a plasminogen activator inhibitor 1 (PAI-1) inhibitor, administering the composition to a site on a subject such that the PAI-1 inhibitor is delivered to the subject, the site containing or having contained a plurality of hair follicles, each having a hair located therein. Additionally or alternatively, in some embodiments, the disclosure provides a method of treating a dermatological condition comprising administering to a subject a composition that includes or delivers a PAI-1 inhibitor to a site on the subject such that the PAI-1 inhibitor is delivered to the subject, the site containing or having contained a plurality of hair follicles, each having a hair located therein.

[0006] In some embodiments, the disclosure provides a method of preventing the occurrence or progression of a dermatological condition, the method comprising providing a composition that includes or delivers a plasminogen activator inhibitor 1 (PAI-1) inhibitor, topically administering the composition to a site in a subject, where the site is a skin surface that contains or has contained a plurality of hair follicles, each having a hair located therein, and leaving the composition at the site for a period of time such that the PAI-1 inhibitor is delivered to the subject.

[0007] In some embodiments, the present disclosure provides novel techniques for treating and / or preventing the occurrence or progression of dermatological conditions. In some embodiments, the dermatological condition is or includes hair graying. In some embodiments, the dermatological condition is or includes keloids. In some embodiments, the dermatological condition is or includes scleroderma. In some embodiments, the dermatological condition is or includes Raynaud's disease.

[0008] In some embodiments, the disclosure provides novel compositions that include and / or deliver a therapeutically effective amount of a PAI-1 inhibitor. In certain embodiments, the disclosure provides novel compositions that include and / or deliver a therapeutically effective amount of a PAI-1 inhibitor and a pharma- ceutically acceptable carrier. In some embodiments, the therapeutically effective amount w / w is about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, about 0.1% to about 20%, or about 1% to about 5%. In some embodiments, the therapeutically effective amount is about 10 mg / day to about 100 mg / day, about 10 mg / day to about 200 mg / day, about 10 mg / day to about 300 mg / day, about 10 mg / day to about 400 mg / day, about 10 mg / day to about 500 mg / day, about 10 mg / day to about 600 mg / day, about 10 mg / day to about 700 mg / day, about 10 mg / day to about 800 mg / day, about 10 mg / day to about 900 mg / day, or about 10 mg / day to about 1000 mg / day.

[0009] In some embodiments, the novel compositions provided are characterized in that when administered to an animal suffering from or susceptible to at least one dermatological condition, they achieve at least one of: (i) treating at least one dermatological condition in the animal; (ii) delaying, slowing or preventing the progression of at least one dermatological condition in the animal. In certain detailed embodiments, for example when the dermatological condition is or includes hair graying, the novel compositions provided may be characterized in that when administered to an animal suffering from or susceptible to such hair graying, they achieve at least one of: (i) reducing the number of gray hairs (e.g., present at and / or near the administration site); (ii) preventing graying of one or more non-gray hairs (e.g., present at and / or near the administration site); and (iii) delaying the onset of graying of one or more non-gray hairs (e.g., present at and / or near the administration site).

[0010] Generally, administration of compositions according to the present disclosure may be by any of a variety of routes. In some embodiments, administration is topical. In some embodiments, administration is by injection. In some embodiments, administration is oral.

[0011] In some embodiments, the administration achieves systemic delivery. In some embodiments, the administration achieves localized delivery.

[0012] In some embodiments, administering is or includes maintaining the composition at or on the site for a period of time, hi some embodiments, administering is or includes rubbing the composition into the site.

[0013] In some embodiments, the composition is maintained at or on the site for a period of at least 1 minute. In some embodiments, the period of time is at least 1 hour. In some embodiments, the period of time is in the range of 1 to 10 minutes. In some embodiments, the period of time is in the range of about 1 to about 10 minutes, about 5 to about 60 minutes, about 5 to about 12 minutes, about 5 to about 15 minutes, or about 15 to about 30 minutes, about 1 to about 12 hours, about 8 to about 12 hours, or 12 to about 24 hours.

[0014] In some embodiments, the provided methods of treating a dermatological condition may include removing the administered composition from the site of its administration (e.g., removing any composition that may remain after a period of time). In some embodiments, such removing is or includes rinsing or wiping (e.g., using a wipe, which in some embodiments may be wet or in some embodiments may be dry).

[0015] In some embodiments, the site to which a composition according to the present disclosure is administered may be on a skin surface. In some embodiments, the site is or comprises a hair follicle. In some embodiments, the site comprises hair. In some embodiments, the site is or comprises skin overlying a muscle or muscle group. In some embodiments, the site is hairless. In some embodiments, the site is on the torso. In some embodiments, the site is on the back. In some embodiments, the site is on the chest. In some embodiments, the site is on the buttocks. In some embodiments, the site is on the crotch. In some embodiments, the site is on the groin. In some embodiments, the site is on the head. In some embodiments, the site is on the scalp. In some embodiments, the site is on the face. In some embodiments, the site is on the neck. In some embodiments, the site is on the chest. In some embodiments, the site is in the armpit. In some embodiments, the site is in the armpit. In some embodiments, the site is on the hand. In some embodiments, the site is on the foot. In some embodiments, the site is on the arm. In some embodiments, the site is on the leg. In some embodiments, the site previously had hair or hair follicles but no longer has hair or hair follicles. In some embodiments, the site has hair follicles. In some embodiments, the hair follicles present at the site have normal structure and / or density. In some embodiments, the site has hair. In some embodiments, such hair is white, while in some embodiments, such hair is not white.

[0016] In some embodiments, the PAI-1 inhibitor used by the present disclosure is or comprises a polypeptide, a nucleic acid, a lipid, a carbohydrate, a small molecule, a metal, or a combination thereof. In some embodiments, the PAI-1 inhibitor is or comprises a polymer (e.g., a polypeptide or a polynucleotide). In some embodiments, the PAI-1 inhibitor is or comprises an antibody (e.g., an anti-PAI-1 antibody). In some embodiments, the PAI-1 inhibitor is or comprises a nucleic acid (e.g., an oligonucleotide such as an antisense oligonucleotide, siRNA, etc.). In some embodiments, the PAI-1 inhibitor is or comprises a small molecule. In some embodiments, the PAI-1 inhibitor is or comprises 5-chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid, 5-chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid, a benzopyran compound, butadiene, spironolactone, imidapril, angiotensin-converting enzyme inhibitor (ACEI, e.g., captopril or enalapril), angiotensin II receptor antagonist (AIIRA), defibrotide (polydeoxyribonucleotide), or any combination thereof. In some embodiments, the PAI-1 inhibitor is or comprises 5-chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid.

[0017] In some embodiments, the present disclosure provides and / or utilizes compositions that contain and / or deliver PAI-1 inhibitors. In some embodiments, such compositions are or include suspensions. In some embodiments, such compositions are or include foams. In some embodiments, such compositions are or include emulsions, such as nanoemulsions. In some embodiments, such compositions are formulated as suspensions, foams, lotions, creams, gels, oils, powders, poultices, or drops.

[0018] In some embodiments, the provided methods of treating a dermatological condition include administering a penetrating treatment. In some embodiments, the penetrating treatment is or includes a non-irritating chemical agent. In some embodiments, the penetrating treatment is or includes administration of an electric or magnetic field. In some embodiments, the penetrating treatment is or includes microneedling. In some embodiments, the penetrating treatment is or includes a laser treatment.

[0019] In some embodiments, the provided technology aids in the penetration of the PAI-1 inhibitor into the administration site. In some embodiments, the provided PAI-1 inhibitor (e.g., in or from a composition described herein) penetrates into its administration site within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, the provided PAI-1 inhibitor penetrates into the administration site within about 5 to about 60 minutes, about 5 to about 12 minutes, about 5 to about 15 minutes, or about 15 to about 30 minutes of administration. In some embodiments, the provided PAI-1 inhibitor penetrates into the administration site within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours of administration. In some embodiments, the provided PAI-1 inhibitor penetrates into the administration site within about 1 to about 12 hours, about 8 to about 12 hours, or 12 hours to about 24 hours of administration.

[0020] In some embodiments, according to the present disclosure, the method of treating and / or preventing a dermatological condition comprises two or more administrations of a PAI-1 inhibitor composition over time. In some embodiments, the administration of the two or more administrations of the composition is separated by a specific period of time. In some embodiments, according to the present disclosure, the specific period of time for administering the composition may be longer than the specific period of time for administering a reference treatment regimen.

[0021] In certain embodiments, disclosed herein are kits that include compositions that contain or deliver PAI-1 inhibitors.

[0022] In some embodiments, the provided kit comprises a patch. In some embodiments, the patch is arranged, constructed and / or utilized for administration to cover the administered composition. Alternatively or additionally, in some embodiments, the patch may contain or include a composition that includes and / or delivers a PAI-1 inhibitor. In some embodiments, the patch comprises microneedles.

[0023] In some embodiments, the provided kit includes a device for facilitating penetration of the composition into the area of ​​a subject. In some such embodiments, the provided device may be or may include a brush, comb, patch, roller, pen, etc.

[0024] In some embodiments, the kit provided includes instructions for administering the compositions described herein. In some embodiments, the present disclosure provides insight into administering combination therapies and / or treatments to treat or prevent the occurrence of dermatological conditions. In some embodiments, the combination therapy or treatment includes administering a PAI-1 inhibitor described herein in combination with one or more other active agents. In some embodiments, for example, for hair graying, the one or more other active agents are selected from the group consisting of cinnamidopropyltrimonium chloride, solid lipid nanoparticles, l-cystine, l-methionine, melatonin, and combinations thereof. In some embodiments, for example, for keloids, the one or more other active agents are selected from the group consisting of compression therapy, silicone gel sheeting, intralesional triamcinolone acetonide (TAC), cryosurgery, radiation, laser therapy, IFN, 5-FU, high dose oxygen using hyperbaric oxygen therapy (HBOT), cryotherapy, surgical excision, topical agents, and combinations thereof. In some embodiments, for example, for scleroderma, the one or more other active agents are selected from the group consisting of angiotensin II receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, NSAIDs, COX-2 inhibitors, analgesics, low-dose corticosteroids, anesthetics, antacids, H2 blockers, proton pump inhibitors, prokinetic agents, somatostatin agonists, antibiotics, prostaglandin derivatives, treprostinil, iloprost, endothelin receptor antagonists, IP receptor agonists, phosphodiesterase type 5 (PDE5) inhibitors, antifibrotic agents, tyrosine kinase inhibitors, immunosuppressants, alkylating agents, pilocarpine, and combinations thereof.In some embodiments, e.g., for Raynaud's disease or Raynaud's phenomenon, the one or more other active agents are selected from the group consisting of calcium channel blockers, alpha blockers, nitroglycerin, angiotensin II receptor antagonists, selective serotonin reuptake inhibitors, glyceryl trinitrate, tadalafil, ginkgo biloba extract, SLx-2101, St. John's wort, fasudil, cilostazol, iloprost, relaxin, treprostinil diethanolamine, sildenafil, atorvastatin, imatinib mesylate, treprostinil diethanolamine, and combinations thereof.

[0025] definition In this application, unless otherwise clear from the context, (i) the term "a" may be understood to mean "at least one," (ii) the term "or" may be understood to mean "and / or," (iii) the terms "comprising" and "including" may be understood to include the listed components or steps, whether presented alone or with one or more additional components or steps, and (iv) the terms "about" and "approximately" may be understood to allow for standard variations understood by those of ordinary skill in the art, and (v) when ranges are provided, the endpoints are included.

[0026] About: The term "about", when used herein in reference to a value, refers to a value similar to the value referred to in the context. Generally, a person skilled in the art familiar with the context will recognize the appropriate degree of variation encompassed by "about" in the context. For example, in some embodiments, the term "about" may encompass a range of values ​​within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the referenced value.

[0027] Administration: As used herein, the term "administration" refers to administration of a composition to a subject or system to achieve delivery of an agent that is typically a composition or is included in the composition. Those skilled in the art will recognize various routes that may be utilized in an appropriate environment for administration to a subject, e.g., a human. For example, in some embodiments, administration may be intraocular, oral, parenteral, topical, and the like. In some specific embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (e.g., may be or may include one or more of topical administration to the dermis, intradermal, interdermal, transdermal, and the like), enteral, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, in a particular organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreous, and the like. In some embodiments, administration may include only a single dose. In some embodiments, administration may include application of a certain number of doses. In some embodiments, administration may include dosing that is intermittent (e.g., multiple doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may include continuous dosing (e.g., perfusion) over at least a selected period of time.

[0028] Agent: In general, the term "agent" as used herein may be used to refer to any chemical class of compound or entity, including, for example, polypeptides, nucleic acids, saccharides, lipids, small molecules, metals, or combinations or complexes thereof. In appropriate circumstances, as will be apparent to one of skill in the art from the context, the term may be used to refer to an entity that is or includes a cell or organism, or a fraction, extract, or component thereof. Alternatively or additionally, as will be apparent from the context, the term may be used to refer to a product of nature, in that it is found in nature and / or obtained from nature. In some cases, again as will be apparent from the context, the term may be used to refer to one or more entities that are artificial, in that they are designed, engineered, and / or produced by the act of the human hand, and / or are not found in nature. In some embodiments, the agent may be utilized in an isolated or pure form, and in some embodiments, the agent may be utilized in a crude form. In some embodiments, potential agents may be provided as a collection or library that can be screened, for example, to identify or characterize active agents within their scope. In some cases, the term "agent" may refer to a compound or entity that is or includes a polymer, and in some cases, the term may refer to a compound or entity that includes one or more polymer moieties. In some embodiments, the term "agent" may refer to a compound or entity that is not a polymer and / or is substantially free of any polymer and / or one or more specific polymer moieties. In some embodiments, the term may refer to a compound or entity that lacks or is substantially free of any polymer moieties.

[0029] Agonist: Those skilled in the art will recognize that the term "agonist" may be used to refer to a state or event of an agent whose presence, level, degree, type or form correlates with an increase in the level or activity of another agent (i.e., the agent being agonized). In general, an agonist may be or include any chemical class of agent, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals and / or any other entity that exhibits related activation activity. In some embodiments, an agonist may be direct (where the agonist exerts its effect directly on its target), and in some embodiments, an agonist may be indirect (where the agonist exerts its effect other than by binding to its target, e.g., by interacting with a regulator of the target such that the level or activity of the target is altered).

[0030] Antagonist: Those skilled in the art will recognize that the term "antagonist" as used herein may be used to refer to a state or event of an agent whose presence, level, extent, type or form correlates with a decrease in the level or activity of another agent (i.e., the agent or target being inhibited). In general, an antagonist may be or include any chemical class of agent, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals and / or any other entity that exhibits related inhibitory activity. In some embodiments, an antagonist may be direct (where the antagonist exerts its effect directly on its target), and in some embodiments, an antagonist may be indirect (where the antagonist exerts its effect other than by binding to its target, e.g., by interacting with a regulator of the target, such that the level or activity of the target is altered).

[0031] Animal: As used herein, refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans of either sex and at any stage of development. In some embodiments, "animal" refers to non-human animals at any stage of development. In certain embodiments, the non-human animals are mammals (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cows, primates, and / or pigs). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or parasites. In some embodiments, the animals may be transgenic animals, genetically engineered animals, and / or clones.

[0032] Biologically active agent: As used herein, the phrase "biologically active agent" refers to any substance that has activity in a biological system and / or organism. For example, a substance that has a biological effect on an organism when administered to the organism is considered to be biologically active. In some embodiments, when a substance (e.g., a polypeptide, a nucleic acid, an antibody, etc.) is biologically active, a portion of the substance that shares at least one biological activity of the entire substance is typically referred to as a "biologically active" portion.

[0033] Carrier: as used herein, refers to a diluent, adjuvant, excipient or vehicle with which the composition is administered. In some exemplary embodiments, the carrier may comprise a sterile liquid, such as, for example, water and oil, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or comprises one or more solid ingredients.

[0034] Cosmetic preparation: the term "cosmetic preparation" is used herein to refer to a topically applied composition that contains one or more agents with cosmetic properties.To give some examples, cosmetic preparation may be emollient, nourishing lotion-type emulsion, cleansing lotion, cleansing cream, milk, emollient lotion, massage cream, emollient cream, makeup base, lipstick, face pack or face gel, shampoo, rinse, body cleanser, cleansing preparation such as hair tonic or soap, and / or skin composition such as lotion, ointment, gel, cream, patch, deodorant, antiperspirant and / or spray.

[0035] Composition: Those skilled in the art will recognize that the term "composition" as used herein may be used to refer to a separate physical entity that includes one or more specific components. Generally, unless otherwise specified, a composition may be in any form, such as a gas, gel, liquid, solid, etc.

[0036] Comprising: A composition or method described herein as "comprising" one or more recited elements or steps is open-ended, i.e., the recited elements or steps are essential, but other elements or steps may be added within the composition or method. To avoid redundancy, it is understood that any composition or method described herein as "comprising" (or "comprises") one or more recited elements or steps also describes a corresponding more limited composition or method that "consistes essentially of" (or "consists essentially of") the same recited elements or steps, i.e., the composition or method includes the recited essential elements or steps, and may also include additional elements or steps that do not materially affect the basic and novel characteristics of the composition or method. It is also understood that any composition or method described herein as "comprising" or "consisting essentially of" one or more recited elements or steps also describes a corresponding more limited and restrictive composition or method that "consists of" (or "consists of") the recited elements or steps, excluding any other unrecited elements or steps. In any composition or method disclosed herein, known or disclosed equivalents of any recited essential element or step may be substituted for that element or step.

[0037] Cream: The term "cream" refers to a spreadable composition typically formulated for application to the skin. Creams typically contain an oil and / or fatty acid-based matrix. Creams formulated according to the present invention may contain nanoparticles and may be capable of substantially complete penetration (e.g., of such nanoparticles) through the skin upon topical application. Such creams may also act as carriers for incorporated materials (e.g., for example, one or more known therapeutic agents and / or independently active biologically active agents).

[0038] Dispersion medium: As used herein, the term "dispersion medium" refers to a liquid medium in which particles (e.g., empty nanoparticles and / or nanoparticles containing one or more known therapeutic agents and / or independently active biologically active agents) are dispersed. Generally, a dispersion is formed when at least two immiscible materials are combined. An "oil-in-water" dispersion is one in which oily particles are dispersed in an aqueous dispersion medium. A "water-in-oil" dispersion is one in which aqueous particles are dispersed in an oily dispersion medium. Those skilled in the art will recognize that a dispersion can be formed from any two immiscible media and is not strictly limited to the combination of an aqueous medium and an oily medium. Thus, the term "dispersion medium" applies broadly to any dispersion medium, even though it is common to refer to the "aqueous" and "oil" categories.

[0039] Dosage form or unit dosage form: Those skilled in the art will recognize that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of the active agent. In some embodiments, such quantity is a unit dosage (or a whole fraction thereof) appropriate for administration according to a dosing regimen (i.e., according to a therapeutic dosing regimen) that has been determined to correlate with a desired or beneficial outcome when administered to an appropriate population. Those skilled in the art will recognize that the total amount of a therapeutic composition or agent to be administered to a particular subject will be determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0040] Dosing regimen: Those skilled in the art will recognize that the term "dosing regimen" may be used to refer to a series of unit doses (typically more than one) that are typically separated by a period of time and administered individually to a subject. In some embodiments, a given therapeutic agent has a recommended dosing regimen that may include one or more doses. In some embodiments, the dosing regimen includes multiple doses, each separated in time from the other doses. In some embodiments, the individual doses are separated from each other by the same length of time, and in some embodiments, the dosing regimen includes multiple doses and at least two different periods that separate the individual doses. In some embodiments, all doses in the dosing regimen are of the same unit dosage. In some embodiments, the different doses in the dosing regimen are of different amounts. In some embodiments, the dosing regimen includes a first dose of a first dosage followed by one or more additional doses of a second dosage that is different from the first dosage. In some embodiments, the dosing regimen includes a first dose of a first dosage followed by one or more additional doses of a second dosage that is the same as the first dosage. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered to an appropriate entire population (i.e., is a therapeutic dosing regimen).

[0041] Excipient: as used herein refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example to provide or contribute a desired consistency or stabilizing effect. In some embodiments, suitable pharmaceutical excipients can include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc.

[0042] In vitro: As used herein, the term "in vitro" refers to events that take place in an artificial environment, such as a test tube or reaction vessel, cell culture, etc., rather than within a multicellular organism.

[0043] In vivo: As used herein, refers to events that occur within multicellular organisms, such as humans and non-human animals. In the context of cell-based systems, the term may also be used to refer to events that occur within living cells (as opposed to, e.g., in vitro systems).

[0044] Macroemulsion: As used herein, the term "macroemulsion" refers to an emulsion in which at least some of the droplets have diameters in the range of hundreds of nanometers to micrometers in size. As will be appreciated by those of skill in the art, macroemulsions are characterized by droplets with diameters greater than 300 nm. In some embodiments, the macroemulsion compositions utilized by the present disclosure include one or more large agents or one or more biologically active agents. In some embodiments, the large agents included in the macroemulsion composition may be biologically active agents. Those of skill in the art will recognize that the macroemulsion compositions used by the present disclosure may be prepared by any available means, including, for example, chemical or mechanical means. In some embodiments, the droplets in the macroemulsion have a size in the range of about 301 nm to about 1000 μm. In some embodiments, the macroemulsion has droplets with a size distribution between about 301 nm to about 1000 μm. In some embodiments, the droplets in the macroemulsion have a size in the range of about 500 nm to about 5000 μm. In some embodiments, the macroemulsions have a droplet size distribution between about 500 nm and about 5000 μm.

[0045] Nanoemulsion: The term "nanoemulsion" as used herein refers to an emulsion in which at least some of the droplets have diameters in the nanometer size range. As will be understood by those of skill in the art, nanoemulsions are characterized by droplets with diameters of 300 nm or less. In some embodiments, the nanoemulsion compositions utilized by the present disclosure include one or more large drugs or one or more biologically active agents. In some embodiments, the large drugs included in the nanoemulsion composition may be biologically active agents. Those of skill in the art will recognize that the nanoemulsion compositions used by the present disclosure may be prepared by any available means, including, for example, chemical or mechanical means. In some embodiments, the droplets in the nanoemulsion have a size in the range of about 1 nm to about 300 nm. In some embodiments, the nanoemulsion has droplets with a size distribution between about 1 nm to about 300 nm.

[0046] Nanoparticle: As used herein, the term "nanoparticle" refers to a solid particle having a diameter of less than 300 nm as defined by the National Science Foundation. In some embodiments, a nanoparticle has a diameter of less than 100 nm as defined by the National Institutes of Health.

[0047] Nanoparticle composition: As used herein, the term "nanoparticle composition" refers to any material that contains at least one nanoparticle. In some embodiments, the nanoparticle composition is a homogenous collection of nanoparticles. In some embodiments, the nanoparticle composition is a dispersion or emulsion. Generally, a dispersion or emulsion is formed when at least two immiscible materials are combined. An "oil-in-water" dispersion is one in which oily particles (or hydrophobic or non-polar) are dispersed in an aqueous dispersion medium. A "water-in-oil" dispersion is one in which aqueous (or hydrophilic or polar) particles are dispersed in an oily dispersion medium. Those skilled in the art will recognize that a dispersion can be formed from any two immiscible media and is not strictly limited to a combination of an aqueous medium and an oily medium. Thus, the term "dispersion medium" applies broadly to any dispersion medium, even though it is common to refer to the "aqueous" and "oil" categories. In some embodiments, the nanoparticle composition is a nanoemulsion. In some embodiments, the nanoparticle composition includes micelles. In some embodiments, the nanoparticle composition is stable. In some embodiments, the nanoparticle composition comprises one or more biologically active agents delivered in association with the nanoparticles, hi some embodiments, the nanoparticle composition is an empty nanoparticle composition (e.g., does not contain any known therapeutic agents and / or independently active biologically active agents).

[0048] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent is formulated with one or more pharma- ceutically acceptable carriers. In some embodiments, the active agent is present in a unit dosage suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to an appropriate population. In some embodiments, the pharmaceutical composition may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, such as those targeted for buccal, sublingual and systemic absorption, boluses, powders, granules, pastes for application to the tongue, parenteral administration, such as by subcutaneous, intramuscular, intravenous or epidural injection, such as sterile solutions or suspensions or sustained release formulations, topical application, such as creams, ointments or controlled release patches or sprays applied to the skin, lungs or oral cavity, vaginally or rectally, sublingually, intraocularly, transdermally or to the nasal, pulmonary and other mucosal surfaces, as pessaries, creams or foams.

[0049] Penetration enhancer or permeation treatment: As used herein, the term "permeation enhancer" or "permeation treatment" refers to an agent whose presence or level correlates with increased permeation of an agent of interest through the skin compared to that observed in its absence. In some embodiments, the permeation enhancer is characterized by degrading and / or destroying skin structure. In some embodiments, the permeation enhancer is or includes a chemical agent (e.g., a chemical or enzyme). For example, chemical agents that may damage, destroy and / or degrade one or more stratum corneum components may include alcohols, such as short chain alcohols, long chain alcohols or polyalcohols, urea, amino acids or their esters, amides, AZONE®, derivatives of AZONE®, amines and amides, such as pyrrolidone or derivatives of pyrrolidone, terpenes and derivatives of terpenes, fatty acids and their esters, macrocycles, surfactants, such as tensides or sulfoxides (e.g., dimethyl sulfoxide (DMSO), decyl methyl sulfoxide, etc.), anionic, cationic and nonionic surfactants, polyols, essential oils and / or hyaluronidase. In some embodiments, the penetration enhancer may be an irritant in that an inflammatory and / or allergic reaction occurs when the agent is applied to the skin. In some embodiments, the penetration enhancer is not an irritant. In some embodiments, the penetration enhancer may be or include a chemical agent whose presence or level correlates with increased penetration of the agent of interest across the skin compared to that observed in its absence, yet does not damage, destroy or degrade skin structures. In some embodiments, the copeptides, carrier molecules and carrier peptides may be penetration enhancers that do not damage, destroy and / or degrade skin structures. In some embodiments, the copeptides, carrier molecules and carrier peptides may be penetration enhancers that do not irritate the skin. The term "penetration enhancer" does not encompass mechanical devices (e.g., needles, scalpels, etc.) or equivalents (e.g., other damaging procedures).Those skilled in the art will also recognize that structures such as nanoparticles or emulsions are not chemical agents and therefore are not chemical penetration enhancers, even if their presence correlates with enhanced skin penetration of an agent of interest that may be associated with the structure.

[0050] Pharmaceutically acceptable carrier: As used herein, the term "pharmacologically acceptable carrier" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, that is involved in the carrying or transport of a compound of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, pH buffers, polyesters, polycarbonates and / or polyanhydrides and other non-toxic compatible substances utilized in pharmaceutical formulations.

[0051] Prevent or prophylaxis: As used herein, when used in relation to the occurrence of a disease, disorder and / or condition, refers to reducing the risk of developing a disease, disorder and / or condition and / or delaying the onset of one or more characteristics or symptoms of a disease, disorder or condition. Prevention may be considered complete if the onset of a disease, disorder or condition is delayed for a predefined period of time.

[0052] Self-administration: The term "self-administration" as used herein refers to a situation in which a subject has the ability to administer a composition to themselves without the need for medical supervision. In some embodiments of the present invention, self-administration may be performed outside of a clinical setting. By way of example only, in some embodiments of the present invention, a cosmetic facial cream may be administered by a subject at home.

[0053] Small molecule: As used herein, the term "small molecule" refers to a low molecular weight organic and / or inorganic compound. Generally, a "small molecule" is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, 2 kD, or 1 kD. In some embodiments, a small molecule is less than about 800 Daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, about 1500 g / mol, about 1000 g / mol, about 800 g / mol, or about 500 g / mol. In some embodiments, a small molecule is not a polymer. In some embodiments, a small molecule does not include a polymer moiety. In some embodiments, a small molecule is not and / or does not include a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, the small molecule is not and / or does not include a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, the small molecule is not and / or does not include a polysaccharide, e.g., in some embodiments, the small molecule is not a glycoprotein, proteoglycan, glycolipid, etc. In some embodiments, the small molecule is not a lipid. In some embodiments, the small molecule is a modulator (e.g., is an inhibitory agent or an activator). In some embodiments, the small molecule is biologically active. In some embodiments, the small molecule is detectable (e.g., includes at least one detectable moiety). In some embodiments, the small molecule is a therapeutic agent. Those of skill in the art reading this disclosure will recognize that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms, such as, for example, crystalline forms, salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc. Those of skill in the art will recognize that certain small molecule compounds have structures that may exist in one or more stereoisomeric forms. In some embodiments, such small molecules may be utilized by the present disclosure in the form of an individual enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers.In some embodiments, such small molecules may be utilized by the present disclosure in the form of a racemic mixture. Those skilled in the art will recognize that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such small molecules may be utilized by the present disclosure in the form of individual tautomers, or forms that interconvert between tautomeric forms. Those skilled in the art will recognize that certain small molecule compounds may be utilized in the form of individual tautomers, or forms that interconvert between tautomeric forms. 2 H or 3 H, for 12C 11 C. 13 C or 14 C, for 14N 13 N or 15 For N, 16O 17 O or 18 For O, XXC 36 Cl, XXF 18It will be appreciated that such small molecules may have structures that allow for one or more isotopically modified forms or mixtures thereof. In some embodiments, reference to a particular small molecule compound may refer to a particular form of that compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in a salt form (e.g., an acid addition or base addition salt form, depending on the compound). In some such embodiments, the salt form may be a pharma- ceutically acceptable salt form. In some embodiments, when a small molecule compound is naturally occurring or found, the compound may be provided and / or utilized by the present disclosure in a form that is different from the one in which it is naturally occurring or found. One of skill in the art will appreciate that in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound or a particular form thereof that is different from the absolute or relative (e.g., relative to another component of the preparation that contains another form of the compound) amount of the compound or form present in a reference preparation of interest (e.g., in a primary sample from a source of interest, such as a biological or environmental source) will be significantly different from the compound as present in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a distinct form of the compound from a racemic mixture of the compound, a particular salt of a small molecule compound may be considered to be a distinct form of the compound from another salt form of the compound, a preparation that contains only a form of the compound that contains one conformer of the double bond ((Z) or (E)) may be considered to be a distinct form of the compound from one that contains the other conformer of the double bond ((E) or (Z)), a preparation in which one or more atoms are isotopes different from those present in a reference preparation may be considered to be a distinct form, etc.

[0054] Subject: As used herein, the term "subject" refers to an organism, typically a mammal (e.g., a human, including in some embodiments prenatal human forms). In some embodiments, the subject suffers from the relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to the disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject does not exhibit symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject is one who has one or more characteristic features of risk for or susceptibility to a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual to whom and / or to whom a diagnosis and / or treatment is administered.

[0055] Symptoms are reduced: As used herein, the term "symptoms are reduced" refers to when the magnitude (e.g., intensity, severity, etc.) and / or frequency of one or more symptoms of a particular disease, disorder, or condition is reduced. For clarity, delaying the onset of a particular symptom is considered a form of reducing the frequency of that symptom.

[0056] Therapeutic Agent: As used herein, the term "therapeutic agent" refers to any agent that has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect when administered to a subject.

[0057] Therapeutically effective amount: as used herein, refers to an amount that produces a desired effect for which it is administered. In some embodiments, the term refers to an amount sufficient to treat a disease, disorder, and / or condition when administered to a population suffering from or susceptible to the disease, disorder, and / or condition by a therapeutic dosing regimen. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and / or severity and / or delays the onset of one or more symptoms of a disease, disorder, and / or condition. Those skilled in the art will recognize that the term "therapeutically effective amount" does not actually require that successful treatment is achieved in a particular individual. Rather, a therapeutically effective amount may be an amount that, when administered to a patient in need of such treatment, results in a particular desired pharmacological response in a significant number of subjects. In some embodiments, reference to a therapeutically effective amount may be a reference to an amount measured in one or more particular tissues (e.g., tissues affected by a disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). Those skilled in the art will recognize that in some embodiments, a therapeutically effective amount of a particular agent or treatment may be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective agent may be formulated and / or administered in multiple doses, for example as part of a dosing regimen.

[0058] Treatment: As used herein, the term "treatment" (also "treat" or "treating") refers to any administration of a therapy that partially or completely alleviates, improves, alleviates, inhibits, delays, reduces the severity and / or reduces the incidence of one or more symptoms, features and / or causes of a particular disease, disorder and / or condition. In some embodiments, such treatment may be of subjects who do not show signs of the associated disease, disorder and / or condition and / or of subjects who show only early signs of the disease, disorder and / or condition. Alternatively or in addition, such treatment may be of subjects who show one or more established signs of the associated disease, disorder and / or condition. In some embodiments, treatment may be of subjects who have been diagnosed with the associated disease, disorder and / or condition. In some embodiments, treatment may be of subjects who are known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the associated disease, disorder and / or condition. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0059] Plasminogen activator inhibitor 1 (PAI-1) Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (serpin) protein encoded by the SERPINE1 gene. PAI-1 was initially known for its involvement in maintaining the body's homeostasis, as it is the primary inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA). Elevated PAI-1 has also been reported to be associated with organ fibrosis and disease in multiple organ systems (e.g., heart, lung, liver, kidney, and skin).

[0060] In some embodiments, the present disclosure encompasses the recognition that PAI-1 inhibitors may be particularly useful in the treatment and / or prevention of dermatological conditions such as hair graying, scleroderma, keloids, etc. Although hair growth cycles and physiology are well known and understood, there are currently no effective prevention or treatment techniques for hair graying. In some embodiments, the provided methods and / or compositions provide targeted therapy. For example, in some embodiments, the provided methods and compositions provide surprisingly effective treatments that include one or more PAI-1 inhibitors. Without wishing to be bound by any particular theory, in some embodiments, it is proposed that administration of the PAI-1 inhibitors described herein may stimulate hair follicle stem cells (HFSCs), and such stimulation may contribute to the treatment or prevention of hair graying.

[0061] In some embodiments, the methods, kits and compositions provided may be or include an emulsion. In some embodiments, the methods, kits and compositions provided may be or include a macroemulsion. In some embodiments, the methods, kits and compositions provided may be or include a nanoemulsion. In some embodiments, the methods, kits and compositions provided include combination therapy or treatment, e.g., in some embodiments, the compositions provided may be administered in combination with one or more additional treatments. In some embodiments, the one or more additional treatments are or include other active agents and / or therapies, such as known therapeutic agents and / or independently active biologically active agents (e.g., one or more PAI-1 inhibitors or other agents).

[0062] Diseases, Disorders and Conditions The present invention provides techniques for treating and / or preventing certain skin diseases, disorders and / or conditions. In some embodiments, the present invention provides techniques for treating and / or preventing diseases, disorders or conditions associated with the epidermal and / or dermal levels of the skin.

[0063] In some embodiments, the present invention provides techniques for treating and / or preventing one or more of hair graying, keloids, scleroderma, Raynaud's disease (or Raynaud's phenomenon) and / or combinations thereof. In some embodiments, the present invention provides techniques for treating and / or preventing hair graying.

[0064] Graying of hair In some embodiments, the present invention provides techniques for treating and / or preventing dermatological conditions. In some embodiments, the present invention provides techniques for treating and / or preventing hair graying.

[0065] Current treatments for hair graying include, but are not limited to, photoprotective agents such as cinnamidopropyltrimonium chloride and solid lipid nanoparticles as carriers of UV blockers, oral supplementation with l-cystine and l-methionine, and topical melatonin.The most commonly used treatment or solution for premature hair graying is the use of temporary hair colorants.The pharmaceutical composition according to the present invention may be administered for the treatment of hair graying, alone and / or in combination with these treatments used to treat the symptoms and / or causes of hair graying.

[0066] In some embodiments, the compositions provided for the treatment and / or prevention of hair graying are formulated into a suspension.

[0067] In some embodiments, the compositions disclosed herein for the treatment and / or prevention of hair graying are formulated into suspensions, foams, creams, poultices, lotions, gels, shampoos, conditioners, and the like.

[0068] In some embodiments, the compositions disclosed herein for the treatment and / or prevention of hair graying are administered locally to the affected area (e.g., scalp, hair follicles, face, neck, back, arms, chest, etc.).

[0069] Administration of the disclosed compositions and / or formulations may be by any one of a number of routes. In some embodiments, administration is topical. In some embodiments, administration is oral. In some embodiments, administration is by injection.

[0070] In some embodiments, the administration achieves systemic delivery. In some embodiments, the administration achieves localized delivery.

[0071] In some embodiments, the present invention provides a method for treating hair loss by administering to a subject a composition comprising the steps of: (a) administering to a subject a composition comprising at least one of the following: a ... The method includes administering at least one therapeutic agent (e.g., a PAI-1 inhibitor) in a suspension in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying by about 4%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.

[0072] In some embodiments, the present invention provides a method for treating hair loss by administering a compound or compounding agent to a subject in need thereof, in an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of hair graying of at least about 25%, and in some embodiments, a reduction in the severity and / or prevalence of one or more symptoms of hair graying of at least about 30%, and in some embodiments, a reduction in the severity and / or prevalence of one or more symptoms of hair graying of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106 The method comprises administering at least one therapeutic agent (e.g., a PAI-1 inhibitor) in a nanoparticle composition or a nanoemulsion composition or an emulsion composition or a foam formulation or a cream formulation or an oil or lotion formulation or a gel or a shampoo or a conditioner in an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of hair graying of 3%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.

[0073] keloid Keloids are proliferative scar tissue that form at the site of skin injury. In certain embodiments, the site of skin injury is a surgical incision or trauma site. Unlike hypertrophic scars, which are raised scars, keloids grow beyond the borders of the original wound. Keloids arise from the overgrowth of granulation tissue or type 3 collagen at the site of skin injury. Keloids can be tough, rubbery lesions. In some embodiments, keloids can be shiny, fibrous nodules. Keloids are benign tumors and not contagious, but they can be painful, itchy, and affect skin movement. An estimated 15% of African-Americans and Latinos have keloids.

[0074] Although there is no effective treatment, current treatments for keloids include compression therapy, silicone gel sheeting, intralesional triamcinolone acetonide (TAC), cryosurgery, radiation, laser therapy, IFN, 5-FU, high dose oxygen using hyperbaric oxygen therapy (HBOT), cryotherapy and surgical excision, as well as a number of extracts and topical agents.Currently, the most common form of treatment is surgical excision.However, the best treatment is prevention in patients with known predisposition.The pharmaceutical composition according to the present invention may be administered for the treatment of keloids, alone and / or in combination with these treatments used to treat the symptoms and / or causes of keloids.

[0075] In some embodiments, the compositions provided for the treatment and / or prevention of keloids are formulated into a suspension.

[0076] In some embodiments, compositions provided for the treatment and / or prevention of keloids are formulated into suspensions, foams, creams, poultices, lotions, gels, shampoos, conditioners, and the like.

[0077] In some embodiments, compositions provided for the treatment and / or prevention of keloids are administered locally to the affected area (e.g., scalp, hair follicles, face, neck, back, arms, chest, etc.).

[0078] Administration of the disclosed compositions and / or formulations may be by any one of a number of routes. In some embodiments, administration is topical. In some embodiments, administration is oral. In some embodiments, administration is by injection.

[0079] In some embodiments, the administration achieves systemic delivery. In some embodiments, the administration achieves localized delivery.

[0080] In some embodiments, the present invention provides a method for treating keloids comprising administering to a subject an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of a keloid of at least about 25%, and in some embodiments, at least about 30%, and in some embodiments, at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about %, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more reduction in the extent and / or prevalence of one or more symptoms of a keloid.

[0081] In some embodiments, the present invention provides a method for treating keloids comprising administering to a subject an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of a keloid of at least about 25%, and in some embodiments, an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of a keloid of at least about 30%, and in some embodiments, an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of a keloid of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about %, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more reduction in the severity and / or prevalence of one or more symptoms of keloids.

[0082] Scleroderma Scleroderma, or systemic sclerosis, is generally considered a chronic, systemic autoimmune disease characterized by, among other things, fibrosis or sclerosis, vascular degeneration, and autoantibodies.

[0083] In some embodiments, scleroderma is also considered a connective tissue disease generally characterized by excessive accumulation of extracellular matrix proteins in the skin and internal organs, vascular injury, and immune abnormalities.

[0084] Many of the clinical findings of the disease are thought to involve misregulation of vascular remodeling. One of the earliest symptoms of scleroderma is microvascular injury. This microvascular injury is thought to increase endothelial cell activation. Activated endothelial cells express adhesion molecules that alter capillary permeability and allow inflammatory cells to migrate through the endothelium and become trapped in the vessel wall. Immune activation is thought to contribute to the sustained endothelial activation that leads to endothelial cell collapse. This process is thought to contribute to the loss of vascular elasticity and narrowing commonly observed in scleroderma patients. In addition, microvascular injury is thought to contribute to fibroblast activation and perivascular infiltration of mononuclear cells in the dermis, which is thought to contribute to many of the associated hallmark symptoms of scleroderma. As fibrosis increases, permeability decreases. As a result, it becomes more difficult for antibodies to penetrate the affected tissue. Thus, the affinity of anti-CCL2 antibodies becomes particularly important to maintain the localization of the antibodies.

[0085] Many of the clinical manifestations of the disease are generally thought to involve misregulation of fibroblasts. The main function of fibroblasts is to maintain the structural integrity of connective tissues by continuously secreting precursors of the extracellular matrix. Fibroblasts provide the structural framework (stroma) of many tissues, play a key role in wound healing, and are the most common cells of animal connective tissues. Fibroblasts are morphologically heterogeneous, with diverse appearances depending on their location and activity.

[0086] There are two main forms of scleroderma: localized systemic sclerosis / scleroderma and diffuse systemic sclerosis / scleroderma. In localized cutaneous scleroderma, fibrosis of the skin is typically localized to the area. Patients with localized cutaneous scleroderma typically experience vascular dysfunction. In patients with localized scleroderma, skin and organ fibrosis typically progresses slowly. Patients with diffuse scleroderma typically experience more rapidly progressing skin and organ fibrosis and / or widespread inflammation and / or more severe visceral involvement than that seen in localized scleroderma.

[0087] Interstitial lung disease, which causes pulmonary fibrosis, is generally considered to be the leading cause of scleroderma-related death (Ludwicka-Bradley, A., et al. Coagulation and autoimmunity in scleroderma interstitial lung disease. Semin Arthritis Rheum, 41(2), 212-22, 2011). Additional complications that cause scleroderma-related death include, but are not limited to, cancer, heart failure, pulmonary hypertension, renal failure and malabsorption, or any combination thereof.

[0088] Scleroderma is most commonly diagnosed by examining the skin symptoms. Diagnostic tests include, but are not limited to, visual and / or manual examination of the skin, blood pressure test, chest x-ray, lung CT, echocardiogram, urinalysis, skin biopsy, and blood tests including antinuclear antibody test, antitopoisomerase antibody test, anticentromere antibody test, anti-U3 antibody test, anti-RNA antibody test, other types of antibody test, erythrocyte sedimentation test, and rheumatoid factor. There is currently no known cure for scleroderma. The treatment administered is designed to treat the symptoms of the disease. Treatments include angiotensin II receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors, NSAIDs, COX-2 inhibitors, analgesics, low-dose corticosteroids, anesthetics, antacids, H2 blockers, proton pump inhibitors, prokinetic agents, somatostatin agonists, antibiotics, prostaglandin derivatives, treprostinil, iloprost, endothelin receptor antagonists, IP receptor agonists, phosphodiesterase type 5 (PDE5) inhibitors, antifibrotic agents, tyrosine kinase inhibitors, immunosuppressants, alkylating agents, pilocarpine, and combinations thereof.

[0089] In some embodiments, the compositions provided for the treatment and / or prevention of scleroderma are formulated into a suspension.

[0090] In some embodiments, compositions provided for the treatment and / or prevention of scleroderma are formulated into suspensions, foams, creams, patches, lotions, gels, shampoos, conditioners, and the like.

[0091] In some embodiments, compositions provided for the treatment and / or prevention of scleroderma are administered locally to the affected area (e.g., scalp, hair follicles, face, neck, back, arms, chest, etc.).

[0092] Administration of the disclosed compositions and / or formulations may be by any one of a number of routes. In some embodiments, administration is topical. In some embodiments, administration is oral. In some embodiments, administration is by injection.

[0093] In some embodiments, the administration achieves systemic delivery. In some embodiments, the administration achieves localized delivery.

[0094] In some embodiments, the present invention provides an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of scleroderma by at least about 25%, and in some embodiments, an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of scleroderma by at least about 30%, and in some embodiments, at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, or about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more reduction in the severity and / or prevalence of one or more symptoms of scleroderma.

[0095] In some embodiments, the present invention provides an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of scleroderma by at least about 25%, and in some embodiments, an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of scleroderma by at least about 30%, and in some embodiments, an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of scleroderma by at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 1 %, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more reduction in the severity and / or prevalence of one or more symptoms of scleroderma.

[0096] Raynaud's phenomenon Raynaud's phenomenon or Raynaud's disease is a vasospastic condition of the fingers and toes. The skin of the fingers typically becomes discolored (often in that order: white, blue, and / or red) and painful in response to cold or emotional stress. Severe Raynaud's phenomenon can cause necrosis of the skin and ultimately of the fingers and / or toes, resulting in "spontaneous shedding." The nails of Raynaud's phenomenon sufferers can become brittle. The condition is often associated with connective tissue diseases such as scleroderma and / or rheumatoid arthritis.

[0097] The pharmaceutical compositions according to the present invention may be administered for the treatment of Raynaud's phenomenon, alone and / or in combination with other agents used to treat the symptoms and / or causes of Raynaud's phenomenon. In some embodiments, such agents include calcium channel blockers (such as nifedipine), alpha blockers (such as hydralazine), nitroglycerin, angiotensin II receptor antagonists (such as losartan), selective serotonin reuptake inhibitors (such as fluoxetine), glyceryl trinitrate, tadalafil, ginkgo biloba extract, SLx-2101, St. John's wort, fasudil, cilostazol, iloprost, relaxin, treprostinil diethanolamine, sildenafil, atorvastatin, imatinib mesylate, treprostinil diethanolamine, and / or combinations thereof.

[0098] In some embodiments, compositions provided for the treatment and / or prevention of Raynaud's disease are formulated into a suspension.

[0099] In some embodiments, the compositions disclosed herein for the treatment and / or prevention of Raynaud's disease are formulated into suspensions, foams, creams, patches, lotions, gels, shampoos, conditioners, and the like.

[0100] In some embodiments, the compositions disclosed herein for the treatment and / or prevention of Raynaud's disease are administered locally to the affected area (e.g., nose, lips, ears, nipples, fingers, toes, scalp, face, neck, back, arms, chest, etc.).

[0101] Administration of the disclosed compositions and / or formulations may be by any one of a number of routes. In some embodiments, administration is topical. In some embodiments, administration is oral. In some embodiments, administration is by injection.

[0102] In some embodiments, the administration achieves systemic delivery. In some embodiments, the administration achieves localized delivery.

[0103] In some embodiments, the present invention provides a method for treating Raynaud's phenomenon comprising administering to a subject a therapeutically effective amount of at least one of the following: a) ... The present invention includes administration of at least one therapeutic agent (e.g., a PAI-1 inhibitor) in a suspension in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of Raynaud's phenomenon by about 4%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.

[0104] In some embodiments, the present invention provides a method for treating Raynaud's phenomenon comprising administering to a subject a therapeutically effective amount of at least one of the following: a) administering to a subject a therapeutically effective amount of at least one of the following: a) administering to a subject a therapeutically effective amount of at least one of the following: a) administering to a subject a therapeutically effective amount of at least one of the following: a) administering to a subject a therapeutically effective amount of at least one of the following: a) administering to a subject a therapeutically effective amount of at least one of the following: a) administering to a subject a therapeutically effective amount of at least one of the following: a) administering to a subject a therapeutically effective amount of at least one of the following: a) administering to a subject a therapeutically effective amount of at least one of the following: The method comprises administering at least one therapeutic agent (e.g., a PAI-1 inhibitor) in a nanoparticle composition or nanoemulsion composition or emulsion composition or foam formulation or cream formulation or oil or lotion formulation or gel or shampoo or conditioner in an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of Raynaud's phenomenon by 3%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.

[0105] PAI-1 inhibitors PAI-1 inhibitors can be used to treat or prevent medical conditions or diseases associated with overexpression of PAI-1. PAI-1 inhibitors can be antibodies, peptides, polypeptides, proteins, nucleic acids, lipids, carbohydrates, small molecules, metals, polymers, therapeutic antibodies, or any combination thereof. In some embodiments, the PAI-1 inhibitor is an siRNA. In some embodiments, the PAI-1 inhibitor is a benzopyran compound, butadiene, spironolactone, imidapril, angiotensin-converting enzyme inhibitors (ACEI, captopril or enalapril), angiotensin II receptor antagonists (AIIRA), defibrotide (polydeoxyribonucleotide), and any combination thereof. In some embodiments, the PAI-1 inhibitor is a benzopyran compound.

[0106] In some embodiments, the PAI-1 inhibitor may be a small molecule. For example, the PAI-1 inhibitor is 5-chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid. In another example, the PAI-1 inhibitor is 5-chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid. Exemplary PAI-1 inhibitors are listed in Table 1 below.

[0107] [Table 1]

[0108] Compositions and Formulations As described herein, the present invention provides and / or utilizes compositions comprising one or more PAI-1 inhibitors for administration. In some embodiments, administration is in combination with microneedle skin conditioning (MSC). In some embodiments, the provided compositions may be formulated for topical and / or transdermal delivery (e.g., as a lotion, cream, poultice, ointment, powder, gel, drops, etc.). In some embodiments, the provided compositions may be or include a nanoemulsion. In some embodiments, the provided compositions may be or include a macroemulsion.

[0109] The nanoparticle compositions are useful in a variety of contexts, and may prove to be particularly useful and / or effective in the context of medical applications involving administration of therapeutic agents (e.g., PAI-1 inhibitors) to patients in need thereof. Nanoparticle compositions have proven particularly useful and / or effective in the context of localized administration of therapeutic agents (see, e.g., PCT Patent Application No. PCT US06 / 46236, filed December 1, 2006, entitled "BOTULINUM NANOEMULSIONS," published April 17, 2008 as WO08 / 045107, PCT Patent Application No. PCT US07 / 86018, filed November 30, 2007, entitled "AMPHIPHILIC ENTITY NANOPARTICLES," published June 12, 2008 as WO08 / 070538, and / or PCT Patent Application No. PCT US07 / 86018, filed June 26, 2009, entitled "DERMAL DELIVERY," published December 30, 2009 as WO09 / 158687, and / or PCT Patent Application No. PCT US07 / 158687, filed June 26, 2009, entitled "DERMAL DELIVERY"). See US09 / 48972, the entire contents of which are incorporated herein by reference.

[0110] In some embodiments, the provided nanoparticle compositions have the specific components and / or relative amounts of components described herein. In some embodiments, the provided nanoparticle compositions have specific structural and / or functional attributes that distinguish and / or define them. In some embodiments, exemplary attributes (e.g., physical, structural and / or functional attributes) that have been commonly associated with nanoparticle compositions are described in the following paragraphs. In some embodiments, the provided nanoparticle compositions have one or more of these attributes. In some embodiments, the provided nanoparticle compositions have none of these attributes.

[0111] Generally, a nanoparticle composition is any composition that includes at least one nanoparticle. In some embodiments, the nanoparticle composition includes at least one known therapeutic agent and / or independently active biologically active agent (e.g., PAI-1 inhibitor). The known therapeutic agent and / or independently active biologically active agent may be encapsulated or completely surrounded by one or more nanoparticles, may be associated with the interface of the nanoparticle, and / or may be adsorbed to the outer surface of one or more nanoparticles. The known therapeutic agent and / or independently active biologically active agent may or may not be covalently bound to the nanoparticle and / or nanoparticle composition, and the known therapeutic agent and / or independently active biologically active agent may or may not be attached to the nanoparticle and / or nanoparticle composition by adsorption forces. In some embodiments, the nanoparticle composition includes empty nanoparticles (e.g., nanoparticles that do not contain any known therapeutic agent and / or independently active biologically active agent).

[0112] In some embodiments, the nanoparticle composition is stable.In some embodiments, the nanoparticle composition is homogeneous.For example, in some embodiments, the difference between the minimum diameter and the maximum diameter of the nanoparticle in the nanoparticle composition is not more than about 600nm, about 550nm, about 500nm, about 450nm, about 400nm, about 350nm, about 300nm, about 250nm, about 200nm, about 150nm or about 100nm, about 90nm, about 80nm, about 70nm, about 60nm, about 50nm or less.

[0113] In some embodiments, the particles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) of less than about 1000 nm, about 600 nm, about 550 nm, about 500 nm, about 450 nm, about 400 nm, about 350 nm, about 300 nm, about 250 nm, about 200 nm, about 150 nm, about 130 nm, about 120 nm, about 115 nm, about 110 nm, about 100 nm, about 90 nm, about 80 nm, about 50 nm or less.

[0114] In some embodiments, the particles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) ranging from about 10 nm to about 600 nm. In some embodiments, the particles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) ranging from about 10 nm to about 300 nm, about 10 nm to about 200 nm, about 10 nm to about 150 nm, about 10 nm to about 130 nm, about 10 nm to about 120 nm, about 10 nm to about 115 nm, about 10 nm to about 110 nm, about 10 nm to about 100 nm, or about 10 nm to about 90 nm. In some embodiments, the particles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) in the range of 1 nm to 1000 nm, 1 nm to 600 nm, 1 nm to 500 nm, 1 nm to 400 nm, 1 nm to 300 nm, 1 nm to 200 nm, 1 nm to 150 nm, 1 nm to 120 nm, 1 nm to 100 nm, 1 nm to 75 nm, 1 nm to 50 nm, or 1 nm to 25 nm. In some embodiments, the particles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) in the range of 1 nm to 15 nm, 15 nm to 200 nm, 25 nm to 200 nm, 50 nm to 200 nm, or 75 nm to 200 nm.

[0115] In some embodiments, the entire particle distribution falls within a particular range of particle sizes. In some embodiments, less than 50%, 25%, 10%, 5% or 1% of the entire particle distribution is outside of a particular range of particle sizes. In some embodiments, less than 1% of the entire particle distribution is outside of a particular range of particle sizes. In certain embodiments, the nanoparticle composition is substantially free of particles having a diameter greater than 300 nm, 250 nm, 200 nm, 150 nm, 120 nm, 100 nm, 75 nm, 50 nm or 25 nm. In some embodiments, less than 50%, 25%, 10%, 5% or 1% of the entire particle distribution is greater than 300 nm, 250 nm, 200 nm, 150 nm, 120 nm, 100 nm, 75 nm, 50 nm or 25 nm.

[0116] In some embodiments, the particles in the nanoparticle composition have an average particle size of about 600 nm, about 550 nm, about 500 nm, about 450 nm, about 400 nm, about 350 nm, about 300 nm, about 250 nm, about 200 nm, about 150 nm, about 130 nm, about 120 nm, about 115 nm, about 110 nm, about 100 nm, about 90 nm, or less than about 50 nm. In some embodiments, the average particle size is within the range of about 10 nm to about 300 nm, about 50 nm to about 250, about 60 nm to about 200 nm, about 65 nm to about 150 nm, or about 70 nm to about 130 nm. In some embodiments, the average particle size is about 80 nm and about 110 nm. In some embodiments, the average particle size is about 90 nm and about 100 nm.

[0117] In some embodiments, a majority of the particles in a nanoparticle composition have diameters less than a particular size or within a particular range, in some embodiments, the majority is greater than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or more of the particles in the composition.

[0118] In some embodiments, the nanoparticle composition is substantially free of particles having a diameter greater than 600 nm. In particular, in some embodiments, less than 50% of the nanoparticles in the nanoparticle composition have a diameter greater than 600 nm. In some embodiments, less than 25% of the particles have a diameter greater than 600 nm. In some embodiments, less than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or less of the particles have a diameter greater than 600 nm. Furthermore, in some embodiments, the nanoparticles in the nanoparticle composition have a diameter within the range of 10 nm to 600 nm.

[0119] In some embodiments, the nanoparticle composition is substantially free of particles having a diameter greater than 500 nm. In particular, in some embodiments, less than 50% of the nanoparticles in the nanoparticle composition have a diameter greater than 500 nm. In some embodiments, less than 25% of the particles have a diameter greater than 500 nm. In some embodiments, less than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or less of the particles have a diameter greater than 500 nm. Furthermore, in some embodiments, the nanoparticles in the nanoparticle composition have a diameter within the range of 10 nm to 500 nm.

[0120] In some embodiments, the nanoparticle composition is substantially free of particles having a diameter greater than 400 nm. In particular, in some embodiments, less than 50% of the nanoparticles in the nanoparticle composition have a diameter greater than 400 nm. In some embodiments, less than 25% of the particles have a diameter greater than 400 nm. In some embodiments, less than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or less of the particles have a diameter greater than 400 nm. Furthermore, in some embodiments, the nanoparticles in the nanoparticle composition have a diameter within the range of 10 nm to 400 nm.

[0121] In some embodiments, the nanoparticle composition is substantially free of particles having a diameter greater than 300 nm. In particular, in some embodiments, less than 50% of the nanoparticles in the nanoparticle composition have a diameter greater than 300 nm. In some embodiments, less than 25% of the particles have a diameter greater than 300 nm. In some embodiments, less than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or less of the particles have a diameter greater than 300 nm. Furthermore, in some embodiments, the nanoparticles in the nanoparticle composition have a diameter within the range of 10 nm to 300 nm.

[0122] In some embodiments, the nanoparticle composition is substantially free of particles having a diameter greater than 200 nm. In particular, in some embodiments, less than 50% of the nanoparticles in the nanoparticle composition have a diameter greater than 200 nm. In some embodiments, less than 25% of the particles have a diameter greater than 200 nm. In some embodiments, less than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or less of the particles have a diameter greater than 200 nm. Furthermore, in some embodiments, the nanoparticles in the nanoparticle composition have a diameter within the range of 10 nm to 200 nm.

[0123] In some embodiments, the provided compositions are substantially free of particles having a diameter greater than 150 nm. In particular, in some embodiments, less than 50% of the nanoparticles in the provided compositions have a diameter greater than 150 nm. In some embodiments, less than 25% of the particles have a diameter greater than 150 nm. In some embodiments, less than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or less of the particles have a diameter greater than 150 nm. Furthermore, in some embodiments, the nanoparticles in the provided compositions have a diameter within the range of 10 nm to 150 nm.

[0124] In some embodiments, the nanoparticle composition is substantially free of particles having a diameter greater than 120 nm. In particular, in some embodiments, less than 50% of the nanoparticles in the nanoparticle composition have a diameter greater than 120 nm. In some embodiments, less than 25% of the particles have a diameter greater than 120 nm. In some embodiments, less than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or less of the particles have a diameter greater than 120 nm. Furthermore, in some embodiments, the nanoparticles in the nanoparticle composition have a diameter within the range of 10 nm to 120 nm.

[0125] In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 10 nm and 150 nm. In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 10 nm and 120 nm. In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 20 nm and 120 nm. In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 20 nm and 110 nm. In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 20 nm and 100 nm. In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 20 nm and 90 nm. In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 20 nm and 80 nm. In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 20 nm and 70 nm. In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 20 nm and 60 nm. In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 20 nm and 50 nm. In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 20 nm and 40 nm. In some embodiments, the majority of the particles in the provided compositions have a diameter (e.g., average and / or median diameter) between 20 nm and 30 nm.

[0126] In some embodiments, the majority of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 10 nm and 120 nm. In some embodiments, the majority of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 20 nm and 120 nm. In some embodiments, the majority of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 20 nm and 110 nm. In some embodiments, the majority of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 20 nm and 100 nm. In some embodiments, the majority of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 20 nm and 90 nm. In some embodiments, the majority of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 20 nm and 80 nm. In some embodiments, the majority of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 20 nm and 70 nm. In some embodiments, the majority of the nanoparticles in a nanoparticle composition have a diameter (e.g., average and / or median diameter) between 20 nm and 60 nm. In some embodiments, the majority of the nanoparticles in a nanoparticle composition have a diameter (e.g., average and / or median diameter) between 20 nm and 50 nm. In some embodiments, the majority of the nanoparticles in a nanoparticle composition have a diameter (e.g., average and / or median diameter) between 20 nm and 40 nm. In some embodiments, the majority of the nanoparticles in a nanoparticle composition have a diameter (e.g., average and / or median diameter) between 20 nm and 30 nm.

[0127] In some embodiments, about 50% of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 10 nm and 40 nm. In some embodiments, about 90% of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 10 nm and 80 nm. In some embodiments, about 90% of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 10 nm and 90 nm. In some embodiments, about 95% of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 10 nm and 110 nm. In some embodiments, about 95% of the nanoparticles in the nanoparticle composition have a diameter (e.g., average and / or median diameter) between 10 nm and 120 nm. In some embodiments, about 95% of the particles in the provided composition have a diameter (e.g., average and / or median diameter) between 10 nm and 150 nm.

[0128] In some embodiments, about 50% of the total volume of all nanoparticles in the nanoparticle composition comprises or consists of nanoparticles having a diameter between 10 nm and 40 nm. In some embodiments, about 90% of the total volume of all nanoparticles in the nanoparticle composition comprises or consists of nanoparticles having a diameter between 10 nm and 80 nm. In some embodiments, about 95% of the total volume of all nanoparticles in the nanoparticle composition comprises or consists of nanoparticles having a diameter between 10 nm and 110 nm. In some embodiments, about 95% of the total volume of all nanoparticles in the nanoparticle composition comprises or consists of nanoparticles having a diameter between 10 nm and 120 nm. In some embodiments, about 95% of the total volume of all particles in the provided composition comprises or consists of nanoparticles having a diameter between 10 nm and 150 nm.

[0129] In some embodiments, the nanoparticle composition is or comprises an emulsion or dispersion. In some embodiments, the nanoparticle composition is an "oil-in-water" dispersion (i.e., a dispersion of oily particles dispersed within an aqueous dispersion medium). In some embodiments, the nanoparticle composition is a "water-in-oil" dispersion (i.e., a dispersion of aqueous particles dispersed within an oily dispersion medium).

[0130] In some embodiments, the provided compositions do not require a toxic solvent. In contrast, many conventional strategies for inducing the formation of nanoparticles in a composition utilize toxic (typically organic) solvents. In some embodiments, the provided compositions do not require a polymer. In contrast, many conventional strategies for preparing compositions containing nanoparticle structures require a polymer.

[0131] In some embodiments, provided compositions have better tissue absorption and / or better biocompatibility than other nanoparticle compositions. For example, in some embodiments, provided compositions have better tissue absorption and / or better biocompatibility than nanoparticle compositions that are not homogeneous, utilize one or more toxic (e.g., organic) solvents, and / or utilize one or more polymers.

[0132] In some embodiments, the nanoparticle composition is stable. In some embodiments, a stable nanoparticle composition is one in which the mean particle size, maximum particle size, particle size range, and / or particle size distribution (i.e., percentage of particles above a specified size and / or outside a specified range of sizes) are maintained for a period of time. In some embodiments, the period of time is at least about 1 hour, and in some embodiments, the period of time is about 5 hours, about 10 hours, about 1 day, about 1 week, about 2 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 12 months, about 24 months, or more. In some embodiments, the period of time is within a range of about 1 day to about 24 months, about 2 weeks to about 12 months, about 2 months to about 5 months, etc. For example, a nanoparticle composition is stable if a population of nanoemulsion particles is subjected to long-term storage, temperature changes, and / or pH changes, and the majority of the nanoparticles in the population maintain diameters within the stated ranges (i.e., between about 10 nm and about 120 nm, for example). In some such populations, a majority is greater than about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or greater than about 99.9% pure. In some embodiments, when a nanoparticle composition comprises at least one known therapeutic agent and / or independently active biologically active agent, the nanoparticle composition is considered stable if the concentration of the known therapeutic agent and / or independently active biologically active agent (e.g., a PAI-1 inhibitor) is maintained in the composition under a specified set of conditions and for a specified period of time.

[0133] As described herein, the compositions provided are useful for various cosmetic and / or medical applications. Such compositions may be administered to a subject by any suitable route, as can be easily determined by those skilled in the art for the disease, disorder or condition of interest. In some embodiments, the routes that may be utilized may include one or more of oral (PO), intravenous (IV), intramuscular (IM), intra-arterial, intramedullary, intrathecal, subcutaneous (SQ), intracerebroventricular, transdermal, intradermal, intradermal, rectal (PR), vaginal, intraperitoneal (IP), intragastric (IG), topical and / or transdermal (e.g., by lotion, cream, powder, ointment, poultice, gel, drops, etc.), mucosal, intranasal, buccal, enteral, vitreous and / or sublingual administration, intratracheal instillation, bronchial instillation and / or inhalation, as oral spray, nasal spray and / or aerosol, and / or by portal vein catheter, and / or any combination of the above. In most embodiments, administration will be topical, parenteral or oral, as described herein.

[0134] The formulation of the provided composition may be prepared by any suitable method as understood in the art.In general, such preparation method includes the step of bringing the provided composition into association with one or more excipients, and then forming and / or packaging it, as necessary and / or desired, into a suitable form for administration, for example, as or in a single or multiple dose unit.

[0135] In some embodiments, the composition may be prepared, packaged and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses.As used herein, a "unit dose" is a discrete amount of pharmaceutical composition that contains a predetermined amount of the provided composition.The amount of the provided composition is equal to the dosage of the provided composition that is generally administered to a subject, and / or a convenient fraction of such dosage, such as, for example, a half or a third of such dosage.

[0136] In some embodiments, suitable excipients for use in a composition (e.g., a pharma- ceutically and / or cosmetically suitable composition) may include, for example, one or more excipients, such as a solvent, dispersion medium, granulation medium, diluent or other liquid medium, dispersion or suspension aid, surface active agent and / or emulsifier, isotonicity agent, thickening or emulsifying agent, preservative, solid binder, lubricant, disintegrant, binding agent, preservative, buffering agent, etc., appropriate for the particular dosage form desired. In some embodiments, excipients such as cocoa butter and / or suppository wax, coloring agents, coating agents, sweetening agents, flavoring agents and / or aromatic agents may be utilized. Remington's The Science and Practice of Pharmacy, 21 st Edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2005; incorporated herein by reference) discloses various excipients used in formulating pharmaceutical compositions and known techniques for their preparation.

[0137] In some embodiments, suitable excipients (e.g., pharma- ceutically and / or cosmetically acceptable excipients) are at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some embodiments, the excipients are approved by the U.S. Food and Drug Administration. In some embodiments, the excipients are pharmaceutical grade. In some embodiments, the excipients meet the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and / or other international pharmacopoeias.

[0138] In some embodiments, provided compositions are formulated as cream, poultice, ointment, oil, foam, spray, lotion, liquid, powder, thickened lotion or gel (e.g., formulated for transdermal delivery as described herein).Particular exemplary such formulations can be prepared as cosmetic formulation products, such as skin softener, nourishing lotion-type emulsion, cleansing lotion, cleansing cream, milk, emollient lotion, massage cream, emollient cream, makeup base, facial pack or facial gel, shampoo, rinse, body cleanser, cleansing formulation such as hair tonic or soap, or skin composition such as lotion, ointment, gel, cream, poultice, patch, deodorant or spray.

[0139] The present disclosure encompasses the recognition that emulsion technology may provide stabilization advantages for agents of interest, including for the PAI-1 inhibitors described herein. Additionally, both macro- and nano-emulsions may be used to prepare formulations for administration of PAI-1 inhibitors as treatments for dermatological conditions. In certain embodiments, the formulation may be a topical formulation. In certain embodiments, the formulation may be an injectable formulation. In certain embodiments, the formulation may be an oral formulation.

[0140] In some embodiments, the compositions provided comprise a nanoemulsion composition. In some embodiments, the compositions provided are cream and / or lotion formulations. In some embodiments, the cream and / or lotion formulations provided comprise a nanoemulsion composition. In some embodiments, the compositions comprise a nanoemulsion composition provided but are not cream and / or lotion formulations. In some embodiments, suitable compositions are formulated into creams and / or lotions but do not comprise a nanoemulsion composition.

[0141] In some embodiments, provided compositions comprise a mixture of a provided nanoemulsion composition and one or more pharma- ceutically acceptable excipients, e.g., for topical and / or transdermal administration (e.g., via lotion, cream, powder, ointment, poultice, gel, drops, etc.).

[0142] Emulsions In some embodiments, a surprisingly effective technique for administration and delivery of PAI-1 inhibitors is provided herein. In some embodiments, the present disclosure teaches topical, oral and / or injectable formulations and compositions of such PAI-1 inhibitors for various dermatological conditions, including hair graying. In some embodiments, the present disclosure teaches methods of treating and / or preventing one or more dermatological conditions by administration of a PAI-1 inhibitor formulation and / or composition to a subject in need thereof. In some embodiments, the formulation and / or composition comprises an emulsion.

[0143] Furthermore, the present disclosure recognizes that certain liquid nanoemulsion technologies have been demonstrated to provide significant transdermal delivery properties even for very large molecules such as botulinum and / or antibody drugs. See, for example, U.S. Patent Publication No. 2012 / 0328701, U.S. Patent Publication No. 2012 / 0328702, U.S. Patent No. 8,318,181, and U.S. Patent No. 8,658,391, the disclosures of which are incorporated herein by reference in their entirety. These liquid nanoemulsions are far superior to solid nanoparticle drug delivery, particularly transdermal drug delivery where, as described by Gomaa, solid nanoparticles are unable to penetrate the skin and only accumulate in hair follicles. These liquid nanoemulsions are also stable for at least 34 months, making them commercially viable in this respect.

[0144] Macro Emulsion In some embodiments, the present invention utilizes macroemulsion compositions comprising PAI-1 inhibitors that are particularly effective and / or useful for the treatment of dermatological conditions, such as hair graying. In some embodiments, certain macroemulsion compositions are particularly effective and / or useful for topical, oral and / or injectable administration of PAI-1 inhibitors to subjects in need thereof. In some embodiments, the macroemulsion compositions may be comprised of one or more PAI-1 inhibitors.

[0145] In some embodiments, the macroemulsions may be formulated into compositions suitable for topical administration to the skin, hi some embodiments, compositions suitable for topical administration may be lotions, creams, powders, ointments, patches, gels or drops.

[0146] In some embodiments, the macroemulsion formulation comprises water, medium chain triglycerides, Span 65, polysorbate 80, methylparaben and propylparaben. In some embodiments, the macroemulsion formulation comprises water, medium chain triglycerides, Span 65 and polysorbate 80.

[0147] In some embodiments, provided compositions comprise a mixture of a provided macroemulsion composition and one or more pharma- ceutically acceptable excipients. In some embodiments, cream and / or lotion formulations comprise a mixture of a provided macroemulsion composition and / or saline.

[0148] In some embodiments, the compositions provided comprise a macroemulsion composition comprising one or more PAI-1 inhibitors. In some embodiments, the compositions provided are cream and / or lotion formulations. In some embodiments, the cream and / or lotion formulations provided comprise a macroemulsion composition. In some embodiments, the compositions comprise a macroemulsion composition provided but are not cream and / or lotion formulations. In some embodiments, suitable compositions are formulated into creams and / or lotions but do not comprise a macroemulsion composition.

[0149] In some embodiments, provided compositions comprise a mixture of a provided macroemulsion composition and one or more pharma- ceutically acceptable excipients, e.g., for topical and / or transdermal administration (e.g., via lotions, creams, powders, ointments, poultices, gels, drops, etc.).

[0150] In some embodiments, the macroemulsion may be formulated into a composition suitable for topical administration. In some embodiments, the composition suitable for topical administration may be a lotion, cream, powder, ointment, poultice, gel or liquid drop. In some embodiments, the macroemulsion may be formulated into an injectable composition. In some embodiments, the injectable composition may be sterile.

[0151] Macroemulsion formulations can act to stabilize active agents and / or therapeutic agents, such as PAI-1 inhibitors. Although macroemulsion formulations are not necessarily expected to achieve transdermal delivery of active agents in or by themselves, the present disclosure encompasses that, when combined with the microneedle technology described herein, the improved stabilization that may be provided by incorporation into the macroemulsion composition achieves a synergistic enhancement of transdermal delivery.

[0152] Nanoemulsion In some embodiments, the present invention utilizes nanoemulsion compositions comprising PAI-1 inhibitors that are particularly effective and / or useful for the treatment of dermatological conditions, such as hair graying. In some embodiments, certain nanoemulsion compositions are particularly effective and / or useful for topical, oral and / or injectable administration of PAI-1 inhibitors to a subject in need thereof. In some embodiments, a nanoemulsion composition may be comprised of one or more PAI-1 inhibitors.

[0153] In some embodiments, provided nanoemulsion compositions include oil and surfactant in a ratio ranging between about 0.1:1 and about 2:1. In some embodiments, provided nanoemulsion compositions include oil and surfactant in a ratio of about 0.1:1 and about 1:1. In some embodiments, provided nanoemulsion compositions include oil and surfactant in a ratio of about 0.5:1 and about 1:1. In some embodiments, provided nanoemulsion compositions include oil and surfactant in a ratio of about 0.5:1 and about 1:1.5. In some embodiments, provided nanoemulsion compositions comprise an oil and surfactant in a ratio of about 0.1:1, about 0.15:1, about 0.2:1, about 0.25:1, about 0.3:1, about 0.35:1, about 0.4:1, about 0.45:1, about 0.5:1, about 0.5:1, about 0.55:1, about 0.6:1, about 0.65:1, about 0.7:1, about 0.75:1, about 0.8:1, about 0.85:1, about 0.9:1, about 0.95:1, or about 1:1. In some embodiments, provided nanoemulsion compositions comprise an oil and surfactant in a ratio of about 0.67:1.

[0154] In some embodiments, the aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) and the surfactant are utilized in a ratio ranging between 0.01 and 20. In some embodiments, the aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) and the surfactant are utilized in a ratio ranging between 0.1 and 20. In some embodiments, the aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) and the surfactant are utilized in a ratio ranging between 0.5 and 10. In some embodiments, the aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) and the surfactant are utilized in a ratio ranging between 0.5 and 1. In some embodiments, the ratio of aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) to surfactant is about 0.01:1, about 0.02:1, about 0.03:1, about 0.04:1, about 0.05:1, about 0.06:1, about 0.07:1, about 0.08:1, about 0.0:1, about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1. In some embodiments, the ratio of surfactant to water is about 0.5:1, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, or about 20:1. In some embodiments, the aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) and surfactant are utilized in a ratio ranging between 0.5 and 2. In some embodiments, the ratio of aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) to surfactant is about 0.5-1, about 1:1, or about 2:1. In some embodiments, the ratio of surfactant to aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) is about 0.5 to 1, about 1:1, or about 2:1. In some embodiments, the ratio of aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) to surfactant is about 1:1.In some embodiments, compositions utilizing such ratios of aqueous dispersion medium (eg, water, buffer, saline, etc.) to surfactant include water-in-oil emulsions.

[0155] In some embodiments, the droplets in the nanoemulsion composition have a diameter (e.g., average and / or median diameter) within the range of about 10 nm to about 300 nm, about 10 nm to about 200 nm, about 10 nm to about 150 nm, about 10 nm to about 130 nm, about 10 nm to about 120 nm, about 10 nm to about 115 nm, about 10 nm to about 110 nm, about 10 nm to about 100 nm, or about 10 nm to about 90 nm. In some embodiments, the droplets in the nanoemulsion composition have a diameter (e.g., average and / or median diameter) within the range of 1 nm to 300 nm, 1 nm to 200 nm, 1 nm to 150 nm, 1 nm to 120 nm, 1 nm to 100 nm, 1 nm to 75 nm, 1 nm to 50 nm, or 1 nm to 25 nm. In some embodiments, the droplets within a nanoemulsion composition have a diameter (e.g., average and / or median diameter) of 1 nm to 15 nm, 15 nm to 200 nm, 25 nm to 200 nm, 50 nm to 200 nm, or 75 nm to 200 nm.

[0156] In some embodiments, the entire droplet distribution falls within a particular range of droplet size. In some embodiments, less than 50%, 25%, 10%, 5% or 1% of the entire droplet distribution falls outside of a particular range of droplet size. In some embodiments, less than 1% of the entire droplet distribution falls outside of a particular range of droplet size. In some embodiments, the nanoemulsion composition is substantially free of droplets having a diameter greater than 300 nm, 250 nm, 200 nm, 150 nm, 120 nm, 100 nm, 75 nm, 50 nm or 25 nm. In some embodiments, less than 50%, 25%, 10%, 5% or 1% of the entire droplet distribution has a diameter greater than 300 nm, 250 nm, 200 nm, 150 nm, 120 nm, 100 nm, 75 nm, 50 nm or 25 nm.

[0157] In some embodiments, the droplets in the nanoemulsion composition have an average droplet size of less than about 300 nm, about 250 nm, about 200 nm, about 150 nm, about 130 nm, about 120 nm, about 115 nm, about 110 nm, about 100 nm, about 90 nm, or about 50 nm. In some embodiments, the average droplet size is within the range of about 10 nm to about 300 nm, about 50 nm to about 250, about 60 nm to about 200 nm, about 65 nm to about 150 nm, or about 70 nm to about 130 nm. In some embodiments, the average droplet size is about 80 nm and about 110 nm. In some embodiments, the average droplet size is about 90 nm and about 100 nm.

[0158]

[0159] In some embodiments, the nanoemulsion droplets have a zeta potential ranging between -80mV and +80mV. In some embodiments, the nanoemulsion droplets have a zeta potential ranging between -50mV and +50mV. In some embodiments, the nanoemulsion droplets have a zeta potential ranging between -25mV and +25mV. In some embodiments, the nanoemulsion droplets have a zeta potential ranging between -10mV and +10mV. In some embodiments, the nanoemulsion droplets have a zeta potential of about -80mV, about -70mV, about -60mV, about 50mV, about -40mV, about -30mV, about -25mV, about -20mV, about -15mV, about -10mV, or about -5mV. In some embodiments, the nanoemulsion droplets have a zeta potential of about +50 mV, about +40 mV, about +30 mV, about +25 mV, about +20 mV, about +15 mV, about +10 mV, or about +5 mV. In some embodiments, the nanoemulsion droplets have a zeta potential that is about 0 mV.

[0159] In some embodiments, the aqueous dispersion medium and surfactant are utilized in a ratio ranging between about 8:1 and about 9:1. In some embodiments, the aqueous dispersion medium and surfactant are utilized in a ratio of about 8:1, about 8.1:1, about 8.2:1, about 8.3:1, about 8.4:1, about 8.5:1, about 8.6:1, about 8.7:1, about 8.8:1, about 8.9:1, about 9:1, etc. In some embodiments, the aqueous dispersion medium and surfactant are utilized in a ratio of about 8.7:1. In some embodiments, the aqueous dispersion medium and surfactant are utilized in a ratio of about 8.8:1.

[0160] In some embodiments, the aqueous dispersion medium and the oil are utilized in a ratio ranging between about 12:1 and about 14:1. In some embodiments, the aqueous dispersion medium and the surfactant are utilized in a ratio of about 12:1, about 12.1:1, about 12.2:1, about 12.3:1, about 12.4:1, about 12.5:1, about 12.6:1, about 12.7:1, about 12.8:1, about 12.9:1, about 13:1, about 13.1:1, about 13.2:1, about 13.3:1, about 13.4:1, about 13.5:1, about 13.6:1, about 13.7:1, about 13.8:1, about 13.9:1, about 14:1, etc. In some embodiments, the aqueous dispersion medium and the surfactant are utilized in a ratio of about 13.1:1.

[0161] In some embodiments, the percentage of oil in the nanoemulsion ranges between 0% and 50%. In some embodiments, the percentage of oil in the nanoemulsion ranges between 0% and 40%. In some embodiments, the percentage of oil in the nanoemulsion ranges between 0% and 30%. In some embodiments, the percentage of oil in the nanoemulsion ranges between 0% and 20%. In some embodiments, the percentage of oil in the nanoemulsion ranges between 0% and 10%. In some embodiments, the percentage of oil in the nanoemulsion ranges between 0% and 5%. In some embodiments, the percentage of oil in the nanoemulsion ranges between 5% and 10%, between 10% and 15%, between 15% and 20%, between 20% and 25%, between 25% and 30%, between 35% and 40%, or between 45% and 50%. In some embodiments, the percentage of oil in the nanoemulsion ranges between 10% and 20%, between 10% and 30%, between 10% and 40%, or between 10% and 50%. In some embodiments, the percentage of oil in the nanoemulsion ranges between 20% and 30%, between 20% and 40%, or between 20% and 50%. In some embodiments, the percentage of oil in the nanoemulsion ranges between 30% and 40%, or between 30% and 50%. In some embodiments, the percentage of oil in the nanoemulsion ranges between 40% and 50%.

[0162] In some embodiments, the percentage of oil is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49% or about 50%. In some embodiments, the oil percentage is approximately 10%. In some embodiments, the oil percentage is approximately 9%. In some embodiments, the oil percentage is approximately 8%. In some embodiments, the oil percentage is approximately 7%. In some embodiments, the oil percentage is approximately 6%. In some embodiments, the oil percentage is approximately 5%. In some embodiments, the oil percentage is approximately 4%. In some embodiments, the oil percentage is approximately 3%. In some embodiments, the oil percentage is approximately 2%. In some embodiments, the oil percentage is approximately 1%.

[0163] In some embodiments, the nanoemulsion formulation comprises water, a medium chain triglyceride, polysorbate 80, methylparaben, and propylparaben. In some embodiments, the nanoemulsion formulation comprises water, a medium chain triglyceride, and polysorbate 80.

[0164] In some embodiments, the nanoemulsions may be formulated into compositions suitable for topical administration. In some embodiments, compositions suitable for topical administration may be lotions, creams, powders, ointments, patches, gels, or drops. In some embodiments, the nanoemulsions may be formulated into injectable compositions. In some embodiments, the injectable compositions may be sterile.

[0165] These compositions are particularly useful in that they may be used to deliver a drug to a subject in need thereof by topical and / or transdermal (e.g., by lotion, cream, powder, ointment, poultice, gel, drops, etc.) administration. In some embodiments, the provided cream and / or lotion formulations may be administered to a subject in need thereof by topical and / or transdermal (e.g., by lotion, cream, powder, ointment, poultice, gel, drops, etc.) administration. In some embodiments, the provided nanoemulsion compositions may be formulated into cream and / or lotion formulations. In some embodiments, the provided cream and / or lotion formulations comprising the nanoemulsion compositions may be useful and / or effective for topical administration to a subject. In some embodiments, the provided nanoemulsion compositions may be combined with one or more cream ingredients and / or saline in a cream formulation (e.g., a provided cream formulation) for the preparation of a pharmaceutical composition.

[0166] The present invention encompasses the recognition that emulsion compositions (e.g., macroemulsion and nanoemulsion compositions) may be formulated into cream and / or lotion formulations for administration to a subject. The present invention encompasses the recognition that the cream and / or lotion formulations provided may be particularly useful for formulating emulsions for administration to a subject, such as those described herein.

[0167] Topical preparations The compositions described herein are particularly useful in that they may be used to deliver a PAI-1 inhibitor to a subject in need thereof by topical and / or transdermal (e.g., by lotion, cream, powder, ointment, poultice, gel, drops, etc.) administration. In some embodiments, the provided cream and / or lotion formulations comprising a PAI-1 inhibitor are administered to a subject in need thereof by topical (e.g., by lotion, cream, powder, ointment, poultice, gel, drops, etc.) administration. In some embodiments, the topical formulation comprises a macroemulsion as described herein. In some embodiments, the topical formulation comprises a nanoemulsion as described herein.

[0168] In some embodiments, the cream and / or lotion formulation comprises purified water, methylparaben, mineral oil, isopropyl myristate, white petrolatum, emulsifying wax, and propylparaben. In some embodiments, the cream and / or lotion formulation comprises purified water, mineral oil, isopropyl myristate, white petrolatum, and emulsifying wax.

[0169] In some embodiments, the present invention provides certain cream and / or lotion formulations as described herein. In some embodiments, the provided cream and / or lotion formulations include water. In some embodiments, the provided cream and / or lotion formulations include methylparaben. In some embodiments, the provided cream and / or lotion formulations include mineral oil. In some embodiments, the provided cream and / or lotion formulations include isopropyl myristate. In some embodiments, the provided cream and / or lotion formulations include white petrolatum. In some embodiments, the provided cream and / or lotion formulations include emulsifying wax. In some embodiments, the provided cream and / or lotion formulations include propylparaben. In some embodiments, the provided cream and / or lotion formulations are paraben-free. In some embodiments, the provided cream and / or lotion formulations are methylparaben-free. In some embodiments, the provided cream and / or lotion formulations are propylparaben-free.

[0170] In some embodiments, the cream and / or lotion formulation may be useful for topical and / or transdermal administration. The present invention encompasses the recognition that in some embodiments, the cream and / or lotion formulation provided may be particularly useful for delivery of PAI-1 inhibitors to, for example, hair follicles located at the administration site. In some embodiments, the treated site includes one that previously had hair or hair follicles but no longer has hair or hair follicles. In some embodiments, the cream and / or lotion formulation provided is formulated for topical delivery to a subject in need thereof. In some embodiments, the cream and / or lotion formulation provided is administered to a subject in need thereof by topical delivery.

[0171] In some embodiments, the provided compositions are formulated with cosmetically acceptable ingredients. For example, in some embodiments, the provided compositions are formulated with water, as well as any cosmetically acceptable solvent, in particular monoalcohols such as alkanols having 1 to 8 carbon atoms (such as ethanol, isopropanol, benzyl alcohol and phenylethyl alcohol), polyalcohols such as alkylene glycols (such as glycerin, ethylene glycol and propylene glycol) and glycol ethers such as mono-, di- and triethylene glycol monoalkyl ethers, for example ethylene glycol monomethyl ether and diethylene glycol monomethyl ether, used alone or in mixtures. Such ingredients may be present, for example, in proportions of up to 60%, 70%, 80% or even 90% by weight based on the weight of the total composition.

[0172] In some embodiments, provided compositions for topical administration include one or more cosmetically acceptable ingredients that impart a desirable or suitable appearance attribute to the subject to which the composition is administered (e.g., a matte appearance, which may be particularly desirable or suitable for administration to subjects with oily skin).

[0173] In some embodiments, provided compositions are formulated with at least one cosmetically acceptable filler material to obtain a matte product, which may be particularly desirable for individuals with, for example, oily skin.

[0174] In some embodiments, one or more PAI-1 inhibitors are formulated into a composition suitable for topical administration. Exemplary PAI-1 inhibitors include those described herein. In some embodiments, the provided compositions may be formulated and delivered in combination with microneedle skin conditioning (MSC) to achieve systemic delivery. In some embodiments, the provided compositions may be formulated and / or delivered to achieve local but not systemic delivery.

[0175] In some embodiments, the composition suitable for topical formulation comprises a penetration enhancer. In some embodiments, the penetration enhancer degrades, destroys and / or damages the skin structure and / or skin. In some embodiments, the penetration enhancer does not degrade, destroy and / or damage the skin structure and / or skin. In some embodiments, the penetration enhancer is an irritant. In some embodiments, the penetration enhancer is not an irritant.

[0176] In some embodiments, the provided compositions may be incorporated into a device, such as a patch. A variety of transdermal patch structures are known in the art, and those skilled in the art will recognize that the provided compositions may be easily incorporated into any of a variety of such structures. In some embodiments, the transdermal patch may include multiple needles extending from one side of the patch that is administered to the skin.

[0177] Those skilled in the art will recognize that the provided compositions may be incorporated into devices such as patches. A variety of transdermal patch structures are known in the art, and those skilled in the art will recognize that the provided compositions may be easily incorporated into any of a variety of such structures. In some embodiments, the transdermal patch may include multiple needles extending from one side of the patch that is administered to the skin, the needles extending from the patch and protruding through the stratum corneum of the skin. In some embodiments, the needles do not rupture blood vessels. In some embodiments, the needles do not penetrate deep enough to reach nerves in the dermis of the skin.

[0178] In some embodiments, the transdermal patch comprises an adhesive. Some examples of adhesive patches are known (see, for example, U.S. Design Patent 296,006 and U.S. Patents 6,010,715, 5,591,767, 5,008,110, 5,683,712, 5,948,433 and 5,965,154, all of which are incorporated herein by reference). Adhesive patches are generally characterized by having an adhesive layer that is applied to the skin of a patient, a depot or reservoir for holding the composition provided, and an outer surface that prevents leakage of the composition provided from the reservoir. The outer surface of the patch may be non-adhesive.

[0179] According to the present invention, the provided composition is incorporated into the patch so that it remains stable for a long period of time. For example, in some embodiments, the provided composition may be incorporated into a polymer matrix that stabilizes the active agent and allows the agent to diffuse out of the matrix and the patch. The provided composition may also be incorporated into the adhesive layer of the patch so that the provided composition can diffuse through the skin when the patch is administered to the skin. In some embodiments, the adhesive layer may be heat-activated, where the adhesive is gradually liquefied by a temperature of about 37°C so that the agent diffuses through the skin. The adhesive can remain sticky when stored below 37°C, and when administered to the skin, the adhesive liquefies and loses its sticky properties.

[0180] In some embodiments, the provided composition may be provided in a reservoir of the patch, so that the provided composition is directed out of the patch through the microneedle and the stratum corneum by the pressure applied to the patch.Exemplary embodiments of the microneedle are described above.Suitable devices for use in intradermal administration of the provided composition include those described in U.S. Patent Nos. 4,886,499, 5,190,521, 5,328,483, 5,527,288, 4,270,537, 5,015,235, 5,141,496 and 5,417,662.Intradermal compositions may be administered by devices that limit the effective penetration length of the needle into the skin, such as those described in PCT Publication WO99 / 34850 and its functional equivalents.

[0181] In some embodiments, it may be desirable to slow down the absorption of the provided composition into the skin, for example to prolong the effect of the provided composition.In some embodiments, this can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility.In this case, the absorption rate of the provided composition depends on the dissolution rate, which in turn can depend on the crystal size and crystalline form.In some embodiments, the release rate of the provided composition can be controlled depending on the ratio of the provided composition to the polymer and the nature of the specific polymer used.Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).

[0182] Injectable preparations Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated by known techniques using suitable dispersing agents, wetting agents and / or suspending agents. Sterile injectable preparations may be as sterile injectable solutions, suspensions and / or emulsions in non-toxic parenterally acceptable diluents and / or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP and isotonic sodium chloride solution. Sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid, may be used in the preparation of injectables.

[0183] The injectable preparations may be sterilized, for example, by filtration through a bacterial-retaining filter, and / or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0184] To prolong the effect of the provided composition, it may be desirable to slow the absorption of the provided composition from subcutaneous or intramuscular injection. In some embodiments, administration achieves systemic delivery. In some embodiments, administration achieves localized delivery. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the rate of absorption of the provided composition will depend on the rate of dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered provided composition form is accomplished by dissolving or suspending the provided composition in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the provided composition in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the provided composition to polymer and the nature of the particular polymer employed, the release rate of the provided composition can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are prepared by entrapping the provided composition in liposomes or microemulsions that are compatible with body tissues.

[0185] Oral Formulations Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compositions provided are mixed with at least one inert pharma- ceutically acceptable excipient, such as sodium citrate or dicalcium phosphate, and / or fillers or extenders (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid), binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia), humectants (e.g., glycerol), disintegrants (e.g., agar-agar, calcium carbonate, potato starch, tapioca starch, alginic acid, certain silicates, and sodium carbonate), dissolution inhibitors (e.g., paraffin), absorption accelerators (e.g., quaternary ammonium compounds), wetting agents (e.g., cetyl alcohol and glycerol monostearate), absorbents (e.g., kaolin and bentonite clay), and lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0186] Similar types of solid compositions may be used as fillers for soft and / or hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. These may contain opacifying agents and may be of a composition that releases the provided composition only, or preferentially in a certain part of the intestinal tract, in a suitably delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions may be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0187] Administration The present invention provides techniques for treating dermatological conditions or disorders, including hair graying, using any of the provided compositions described herein (e.g., provided emulsion compositions, cream and / or lotion formulations, combinations of provided emulsion compositions with cream and / or lotion formulations, etc.). In some embodiments, the provided compositions are administered in combination with MSCs.

[0188] As described herein, the present invention provides methods of administering provided compositions to a subject for various uses, including, for example, cosmetic and / or medical uses. In some embodiments, the present invention provides methods of treating and / or preventing diseases, disorders and / or conditions associated with activity of epidermal and / or dermal structures (e.g., sweat glands, sebaceous glands, hair follicles, etc.) by administering provided compositions to a subject in need thereof.

[0189] part In accordance with the present disclosure, a PAI-1 inhibitor may be administered to a site of interest for the treatment and / or prevention of a dermatological condition at the site.

[0190] The technology of the present invention is suitable for both human and veterinary use. In some embodiments, subjects suffering from any of the dermatological disorders described herein that would benefit from topical, oral and / or injectable administration of a PAI-1 inhibitor may be treated with the disclosed technology.

[0191] Any suitable site for MSCs is a suitable administration site. In some embodiments, the administration site is the skin overlying a muscle or muscle group of the subject. In some embodiments, the site is hairless. In some embodiments, the site is on the torso. In some embodiments, the site is on the back. In some embodiments, the site is on the chest. In some embodiments, the site is on the buttocks. In some embodiments, the site is on the crotch. In some embodiments, the site is on the groin. In some embodiments, the site is on the head. In some embodiments, the site is on the scalp. In some embodiments, the site is on the face. In some embodiments, the site is on the neck. In some embodiments, the site is on the chest. In some embodiments, the site is in the armpit. In some embodiments, the site is in the armpit. In some embodiments, the site is on the hand. In some embodiments, the site is on the foot. In some embodiments, the site is on the arm. In some embodiments, the site is on the leg. In some embodiments, the site previously had hair or hair follicles but no longer has hair or hair follicles.

[0192] In some embodiments, the site of interest has hair follicles. In some embodiments, the hair follicles have normal structure and / or density. In some embodiments, the hair follicles do not contain hair. In some embodiments, the hair follicles contain hair. In some embodiments, the percentage of hair follicles having hair is about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%. , about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.

[0193] In some embodiments, the hairs in the hair follicles are not gray. In some embodiments, the hairs in the hair follicles are gray. In some embodiments, the percentage of gray hairs is about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 109%, about 109%, about 108%, about 109%, about 109%, about 109%, about 109%, about 109%, about 109%, about 110%, 9%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.

[0194] In some embodiments, the site is affected by a skin condition.

[0195] In some embodiments, the length of the microneedles used for the MSCs is adjusted based on the thickness of the skin at the treatment site.

[0196] In some embodiments, the MSCs comprise one press of a microneedle (MN) or MN array. In some embodiments, the MSCs comprise two presses of a MN or MN array. In some embodiments, the MSCs comprise three presses of a MN or MN array. In some embodiments, the MSCs comprise four presses of a MN or MN array. In some embodiments, the MSCs comprise five presses of a MN or MN array. In some embodiments, the MSCs comprise six presses of a MN or MN array. In some embodiments, the MSCs comprise seven presses of a MN or MN array. In some embodiments, the MSCs comprise eight presses of a MN or MN array. In some embodiments, the MSCs comprise nine presses of a MN or MN array. In some embodiments, the MSCs comprise ten presses of a MN or MN array. In some embodiments, the MSCs comprise eleven presses of a MN or MN array. In some embodiments, the MSCs comprise twelve presses of a MN or MN array. In some embodiments, the MSCs comprise thirteen presses of a MN or MN array. In some embodiments, the MSCs comprise 14 presses of the MN or MN array. In some embodiments, the MSCs comprise 15 presses of the MN or MN array. In some embodiments, the MSCs comprise 16 presses of the MN or MN array. In some embodiments, the MSCs comprise 17 presses of the MN or MN array. In some embodiments, the MSCs comprise 18 presses of the MN or MN array. In some embodiments, the MSCs comprise 19 presses of the MN or MN array. In some embodiments, the MSCs comprise 20 presses of the MN or MN array. In some embodiments, the MSCs comprise rotating the MN or MN array on the skin one or more times. In some embodiments, the MN array is rotated during pressing. In some embodiments, the MN array is not rotated during pressing. In some embodiments, the pressing is performed at the same site. In some embodiments, the pressing is performed at overlapping sites. In some embodiments, the pressing is performed at different sites. In some embodiments, the pressing is performed by stamping the MN array. In some embodiments, the pressure is applied by rolling a microneedle roller over the site one or more times.In accordance with established MN practice, in some embodiments, the pressure of the MN array against the skin lasts for less than 1 second, or alternatively in some embodiments, the pressure may last for longer than 1 second, e.g., 30 seconds or more, 60 seconds or more, 2 minutes or more, 5 minutes or more, 10 minutes or more, 30 minutes or more, etc.

[0197] subject Generally, the subject is an organism, typically a mammal (e.g., a human, including in some embodiments, prenatal human forms). In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is human. In certain embodiments, the human subject is at least 10 years old. In some embodiments, the subject does not have hair. In some embodiments, the subject has hair. In some embodiments, the subject has low hair follicle density. In some embodiments, the subject has high hair follicle density. In some embodiments, the subject has colored hair. In some embodiments, the subject suffers from an associated disease, disorder, or condition (e.g., a dermatological condition, such as hair graying, etc.). In some embodiments, the subject is predisposed to a disease, disorder, or condition (e.g., a dermatological condition, such as hair graying, etc.). In some embodiments, the subject exhibits one or more symptoms or characteristics of a disease, disorder, or condition (e.g., a dermatological condition, such as hair graying, etc.). In some embodiments, the subject does not exhibit a symptom or characteristic of a disease, disorder, or condition (e.g., a dermatological condition, such as hair graying, etc.). In some embodiments, the subject is one who has one or more specific characteristics or risks of susceptibility to a disease, disorder or condition (e.g., a dermatological condition such as hair graying).In some embodiments, the subject is a patient.In some embodiments, the subject is an individual to whom and / or to whom a diagnosis and / or treatment is administered.

[0198] The technology of the present invention is suitable for both human and veterinary use. In some embodiments, subjects suffering from any of the dermatological disorders described herein that would benefit from topical, oral and / or injectable administration of a PAI-1 inhibitor may be treated with the disclosed technology.

[0199] route In general, the route is selected to achieve delivery of a therapeutically effective amount to the appropriate site of action. Without wishing to be bound by any particular theory, in some embodiments, the site of action may be or may include a site containing hair follicles. In some embodiments, the administration site is the skin overlying a muscle or muscle group of the subject. In some embodiments, the site is hairless. In some embodiments, the site is on the torso. In some embodiments, the site is on the back. In some embodiments, the site is on the chest. In some embodiments, the site is on the buttocks. In some embodiments, the site is on the crotch. In some embodiments, the site is on the groin. In some embodiments, the site is on the head. In some embodiments, the site is on the scalp. In some embodiments, the site is on the face. In some embodiments, the site is on the neck. In some embodiments, the site is on the chest. In some embodiments, the site is in the armpit. In some embodiments, the site is in the axilla. In some embodiments, the site is on the hand. In some embodiments, the site is on the foot. In some embodiments, the site is on the arm. In some embodiments, the site is on the leg.

[0200] In some embodiments, the present invention provides methods of administering a composition provided by any delivery route, including, but not limited to, oral (PO), intravenous (IV), intramuscular (IM), intra-arterial, intramedullary, intrathecal, subcutaneous (SQ), intracerebroventricular, transdermal, intercutaneous, intradermal, rectal (PR), vaginal, intraperitoneal (IP), intragastric (IG), topical and / or transdermal (e.g., by lotion, cream, poultice, ointment, powder, gel, drops, etc.), mucosal, intranasal, buccal, enteral, intravitreal and / or sublingual administration, intratracheal instillation, bronchial instillation and / or by inhalation, as an oral spray, nasal spray and / or aerosol, and / or by portal vein catheter, and / or combinations thereof.

[0201] In some embodiments, provided methods include topical, transdermal, or intradermal administration of a provided composition to the skin of a subject. In some embodiments, such routes achieve localized delivery.

[0202] In certain embodiments, the methods provided include topical administration of an emulsion composition comprising a PAI-1 inhibitor. In certain embodiments, the emulsion composition is a macroemulsion. In certain embodiments, the emulsion composition is a nanoemulsion. In certain embodiments, topical administration by or in combination with MSCs.

[0203] In some embodiments, the active agent or biologically active agent (e.g., a PAI-1 inhibitor) penetrates the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, the biologically active agent penetrates the skin within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates the skin within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates the skin within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates the skin within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates the skin within about 1 hour of administration. In some embodiments, the biologically active agent penetrates the skin within about 2 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 3 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 4 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 5 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 6 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 7 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 8 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 12 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 24 hours of administration.

[0204] In some embodiments, the biologically active agent (e.g., a PAI-1 inhibitor) penetrates into the layers of the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 1 hour of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 2 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 3 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 4 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 5 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 6 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 7 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 8 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 12 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 24 hours of administration.

[0205] In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 1 hour of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 2 hours of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 3 hours of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 4 hours of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 5 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 6 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 7 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 8 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 12 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 24 hours of administration.

[0206] In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 1 hour of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 2 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 3 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 4 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 5 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 6 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 7 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 8 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 12 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 24 hours of administration.

[0207] Regimen In general, the regimen is selected to achieve delivery of a therapeutically effective amount to the appropriate site of action. In some embodiments, the compositions and formulations described herein may be administered to a subject in need thereof in a single dose to the appropriate site of action. In some embodiments, the compositions and formulations described herein may be administered to a subject in need thereof in multiple doses to the appropriate site of action. For example, the compositions and formulations described herein may be administered by any one of multiple administration routes (e.g., topically, orally, by injection) described herein sufficient to achieve delivery of an effective amount of biologically active agent (e.g., PAI-1 inhibitor).

[0208] In some embodiments, the dosing regimen of a particular active agent (e.g., one or more PAI-1 inhibitors) may involve intermittent or continuous (e.g., by perfusion or other sustained release system) administration, e.g., to achieve a particular desired pharmacokinetic profile or other pattern of exposure in one or more tissues or fluids of interest in the subject being treated.

[0209] In some embodiments, different agents administered in a combination may be administered by different delivery routes and / or according to different schedules. Alternatively or in addition, in some embodiments, one or more doses of a first active agent are administered substantially simultaneously with one or more other active agents, and in some embodiments by a common route and / or as part of a single composition.

[0210] Factors to be considered when optimizing the route and / or dosing schedule of a given treatment regimen may include, for example, the particular indication being treated, the clinical condition of the subject (e.g., age, general health, previous treatments and / or response thereto), the site of delivery of the agent, the nature of the agent (e.g., an antibody or other polypeptide-based compound), the mode and / or route of administration of the agent, the presence or absence of concomitant therapy, and other factors known to medical practitioners. For example, in the treatment of cancer, relevant features of the indication being treated may include, for example, one or more of the type, stage, location of the cancer.

[0211] In some embodiments, one or more features of a particular pharmaceutical composition and / or the dosing regimen utilized may be modified over time (e.g., increasing or decreasing the amount of active agent in any individual dose, lengthening or shortening the time interval between doses) to optimize, for example, the desired therapeutic effect or response (e.g., inhibition of the PAI-1 gene or gene product).

[0212] In general, the type, amount and frequency of administration of the active agent according to the present invention are dictated by the safety and efficacy requirements that apply when one or more suitable agents are administered to a mammal, preferably a human. In general, such characteristics of administration are selected to provide a specific, and typically detectable, therapeutic response compared to that observed in the absence of treatment. In the context of the present invention, exemplary desirable therapeutic responses may include, but are not limited to, inhibition of PAI-1 gene and / or gene product, inhibition and / or reduction of the severity and / or prevalence of the associated dermatological condition.For example, the dermatological condition is one described herein.In a particular example, the dermatological condition is hair graying.Such criteria can be easily evaluated by any of a variety of immunological, cytological and other methods disclosed in the literature.

[0213] In some embodiments, the effective amount (and / or unit dose) of the active agent may be at least about 0.01 ng / kg body weight, at least about 0.01 μg / kg body weight, at least about 0.05 μg / kg body weight, at least about 0.1 μg / kg body weight, at least about 1 μg / kg body weight, at least about 2.5 μg / kg body weight, at least about 5 μg / kg body weight, at least about 10 μg / kg body weight, at least about 100 μg / kg body weight, at least about 1 mg / kg body weight, at least about 10 mg / kg body weight, at least about 100 mg / kg body weight, at least about 200 mg / kg body weight, at least about 300 mg / kg body weight, at least about 400 mg / kg body weight, and up to about 500 mg / kg body weight. Those skilled in the art will appreciate that in some embodiments, such guidelines may be adjusted depending on the molecular weight of the active agent. Dosages may also vary depending on the route of administration, treatment cycles, or as a result of dose escalation protocols that may be used to determine the maximum tolerated dose and dose-limiting toxicities (if any) associated with administration of increasing doses of the PAI-1 antagonist and / or additional therapeutic agent. As a result, the relative amounts of each agent within the pharmaceutical composition may vary, e.g., each composition may contain between 0.001% and 100% (w / w) of the corresponding agent.

[0214] In some embodiments, a "therapeutically effective amount" or a "therapeutically effective dose" is an amount of a PAI-1 antagonist, or a combination of two or more PAI-1 antagonists, or a combination of a PAI-1 antagonist and one or more additional therapeutic agents, that completely or partially inhibits the progression of a condition or at least partially relieves one or more symptoms of a condition. In some embodiments, a therapeutically effective amount may be a prophylactically effective amount. In some embodiments, a therapeutically effective amount may depend on the size and / or sex of the patient, the condition being treated, the severity of the condition, and / or the outcome desired. In some embodiments, a therapeutically effective amount refers to an amount of a PAI-1 antagonist that results in the improvement of at least one symptom of the patient. In some embodiments, for a given patient, a therapeutically effective amount may be determined by methods known to those skilled in the art.

[0215] In some embodiments, the toxicity and / or therapeutic efficacy of the PAI-1 antagonist can be evaluated, e.g., by measuring the maximum tolerated dose (MTD) and ED 50 The therapeutic index may be determined by standard pharmaceutical procedures in cell cultures or experimental animals to determine the effective dose (the dose that produces 50% of the maximum response). Typically, the dose ratio between the toxic and therapeutic effects is the therapeutic index. In some embodiments, this ratio is the MTD and ED 50 The data obtained from such cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.

[0216] In some embodiments, dosage may be guided by monitoring the effect of the PAI-1 antagonist on one or more pharmacodynamic markers of inhibition in diseased or alternative tissues. For example, cell culture or animal studies may be used to determine the relationship between the dose required for change in the pharmacodynamic marker, and the dose required for therapeutic efficacy may be determined in cell culture or animal studies or early phase clinical trials. In some embodiments, the dosage of the PAI-1 antagonist is preferably determined to be ED with little or no toxicity. 50 In some embodiments, the dosage may vary within such ranges, depending, for example, on the dosage form used and / or the route of administration utilized. The exact formulation, route of administration and dosage can be selected by the individual physician in view of the patient's condition. Treatment of acute episodes or severe conditions may require administration of a dosage close to the MTD to obtain a rapid response.

[0217] In some embodiments, dosage and / or interval may be individually adjusted, for example, to provide plasma levels of the active moiety sufficient to maintain the desired effect or minimal effective concentration (MEC) for the period required to achieve therapeutic efficacy. In some embodiments, the MEC of a particular PAI-1 antagonist may be estimated, for example, from in vitro data and / or animal studies. The dosage required to achieve the MEC depends on individual characteristics and route of administration. In some embodiments, plasma concentrations may be determined using high performance liquid chromatography (HPLC) assays or bioassays.

[0218] In some embodiments, dosing intervals may be determined using the MEC value. In certain embodiments, the PAI-1 antagonist should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably 30-90%, and most preferably 50-90% of the time, until the desired improvement in symptoms is achieved. In other embodiments, different MEC plasma levels are maintained for different lengths of time. In cases of localized administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0219] Those skilled in the art will appreciate that a variety of dosage regimens may be selected from, and that the effective amount of a particular PAI-1 antagonist will depend on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration, and / or the judgment of the prescribing physician.

[0220] In some embodiments, the present invention provides a method for treating or preventing dermatological conditions by administering a dosing regimen sufficient to achieve a reduction in the severity and / or prevalence of the associated dermatological condition by at least about 20%, in some embodiments by administering at least about 25%, in some embodiments by administering at least about 30%, in some embodiments by administering at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, or by administering at least about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about The present invention includes administration of at least one provided composition administered with a dosing regimen sufficient to achieve about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more reduction.

[0221] In some embodiments, the present invention provides a method for treating or preventing dermatological conditions by administering a dosing regimen sufficient to achieve a reduction in the severity and / or prevalence of the associated dermatological condition by at least about 20%, in some embodiments by administering at least about 25%, in some embodiments by administering at least about 30%, in some embodiments by administering at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or by administering at least about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about The present invention includes administration of at least one provided composition administered in combination with MSCs in a dosing regimen sufficient to achieve about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more reduction.

[0222] In some embodiments, the present invention provides a method for treating or preventing dermatological conditions by administering a dosing regimen sufficient to achieve a reduction in the severity and / or prevalence of the relevant dermatological condition by at least about 20% in a particular percentage of the patient population to which the composition is administered, in some embodiments, by administering a dosing regimen sufficient to achieve at least about 25% in a particular percentage of the patient population to which the composition is administered, in some embodiments, by administering a dosing regimen sufficient to achieve at least about 30% in a particular percentage of the patient population to which the composition is administered, in some embodiments, by administering a dosing regimen sufficient to achieve at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99 8%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about The present invention includes administration of at least one provided composition, which may be administered in combination with MSCs, with a dosing regimen sufficient to achieve a reduction of 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more. In some embodiments, the particular percentage of the patient population to which the composition is administered is at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 100%. To give some illustrative examples, in some embodiments, the invention involves administration of at least one provided composition with a dosing regimen sufficient to achieve a reduction in the severity and / or prevalence of the associated dermatological condition by at least about 20% in at least about 50% of a population of patients to whom the composition is administered.In some embodiments, the invention involves administration of at least one provided composition with a dosing regimen sufficient to achieve a reduction in the severity and / or prevalence of the relevant dermatological condition by at least about 30% in at least about 50% of a population of patients to whom the composition is administered.

[0223] The present invention provides techniques for treating a condition or disorder by administering to a patient a provided composition as described herein, optionally in combination with MSCs (e.g., provided emulsion compositions, cream and / or lotion formulations, combinations of provided emulsion compositions and cream and / or lotion formulations, etc.). In some embodiments, the present invention provides techniques for treating a condition or disorder by topically administering to a patient a composition containing a provided emulsion composition as described herein, optionally in combination with MSCs.

[0224] In some embodiments, the active agent or biologically active agent (e.g., a PAI-1 inhibitor) penetrates the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, the biologically active agent penetrates the skin within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates the skin within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates the skin within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates the skin within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates the skin within about 1 hour of administration. In some embodiments, the biologically active agent penetrates the skin within about 2 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 3 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 4 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 5 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 6 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 7 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 8 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 12 hours of administration. In some embodiments, the biologically active agent penetrates the skin within about 24 hours of administration.

[0225] In some embodiments, the biologically active agent (e.g., a PAI-1 inhibitor) penetrates into the layers of the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 1 hour of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 2 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 3 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 4 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 5 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 6 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 7 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 8 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 12 hours of administration. In some embodiments, the biologically active agent penetrates into the layers of the skin within about 24 hours of administration.

[0226] In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 1 hour of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 2 hours of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 3 hours of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 4 hours of administration. In some embodiments, the biologically active agent penetrates the upper layer of the skin within about 5 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 6 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 7 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 8 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 12 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 24 hours of administration.

[0227] In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 1 hour of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 2 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 3 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 4 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 5 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 6 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 7 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 8 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 12 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin, including the stratum corneum, skin pores, hair follicles, and / or sebaceous glands, within about 24 hours of administration.

[0228] Penetration enhancement procedures According to the present invention, in some embodiments, the provided compositions may be administered in combination with one or more penetration enhancing treatments, such as known penetration enhancers and / or penetration enhancing treatment methods (e.g., chemical agents, laser treatment, microneedling, body massage, etc.), to facilitate penetration of, for example, the PAI-1 inhibitor across a biological barrier (e.g., skin). In some embodiments, the provided compositions include one or more such other penetration enhancers. In some embodiments, such other penetration enhancers are provided as part of a separate composition. In some embodiments, the penetration enhancing treatment includes simultaneous administration of two or more different penetration enhancing treatments and / or penetration enhancing treatment methods. In some embodiments, the penetration enhancing treatment includes simultaneous exposure to two or more different penetration enhancing treatments and / or penetration enhancing treatment methods, for example, by simultaneous administration of a laser treatment and a composition.

[0229] In some embodiments, the penetration enhancer is or includes a chemical agent. For example, chemical agents that can damage, destroy and / or decompose one or more stratum corneum components can include alcohols, such as short-chain alcohols, long-chain alcohols or polyalcohols, urea, amino acids or their esters, amides, AZONE®, derivatives of AZONE®, amines and amides, such as pyrrolidone or derivatives of pyrrolidone, terpenes and derivatives of terpenes, fatty acids and their esters, macrocycles, tensides or sulfoxides (e.g., dimethyl sulfoxide (DMSO), decyl methyl sulfoxide, etc.), surfactants, such as anionic, cationic and nonionic surfactants, polyols, essential oils and / or hyaluronidase. In some embodiments, the penetration enhancer can be an irritant in that it causes inflammatory and / or allergic reactions when the agent is administered to the skin. In some embodiments, the penetration enhancer is not an irritant. In some embodiments, the penetration enhancer may be or include a chemical agent that does not damage, destroy or degrade skin structures, yet whose presence or level correlates with increased penetration of the agent of interest through the skin compared to that observed in its absence. In some embodiments, the copeptides, carrier molecules and carrier peptides may be penetration enhancers that do not damage, destroy and / or degrade skin structures. In some embodiments, the copeptides, carrier molecules and carrier peptides may be penetration enhancers that do not irritate the skin. The term "penetration enhancer" does not include mechanical devices (e.g., needles, scalpels, etc.) or their equivalents (e.g., other damaging treatments). In addition, those skilled in the art will recognize that structures such as nanoparticles or emulsions are not chemical agents and therefore are not chemical penetration enhancers, even if their presence correlates with increased skin penetration of the agent of interest that may be associated with the structure. In some embodiments, the penetration enhancer is or includes an alcohol.

[0230] In some embodiments, the penetration enhancing treatment is or includes microneedling. In some embodiments, the penetration enhancing treatment is or includes laser treatment. In some embodiments, the penetration enhancing treatment is or includes body massage. For example, in some embodiments, the composition may be administered before or after performing laser treatment on the site. In some embodiments, the penetration enhancing treatment is or includes administering an electric or magnetic field.

[0231] Microneedling: In some specific embodiments, the microneedle (MN) array used by the present disclosure is or shares features with a minimally invasive system developed to overcome some of the disadvantages commonly associated with the use of subcutaneous tissue and subcutaneous needles and to improve patient comfort and compliance. Such disadvantages include, for example, the possibility of misplacement of the needle tip with subcutaneous tissue needles due to the medical professional being unable to visualize the exact destination of the needle, which can lead to adverse reactions when injected incorrectly. MNs are less likely to cause such problems. Other advantages of MNs are that they do not cause bleeding, minimize the introduction of pathogens through holes created by MNs, and may eliminate the variability of transdermal dosing. Other advantages are that they allow for self-administration, reduce the risk of needlestick injury accidents, reduce the risk of transmitted infections, and are easy to dispose of. In some embodiments, MNs are multiple microprojections assembled on one side of a support such as a patch or device (e.g., stamp, roller, array, applicator, pen).

[0232] In some embodiments, the MNs used by the present disclosure may be designed and / or constructed in an array to improve skin contact and facilitate penetration into the skin. In some embodiments, the MNs utilized are of suitable length, width and shape to minimize contact with nerves when inserted into the skin while still creating an efficient pathway for drug delivery. Alkilani, AZ, et al., "Transdermal drug delivery: Innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum." Pharmaceutics. 7:438-470 (2015).

[0233] In some embodiments, suitable MNs may be solid, coated, porous, dissolving, hollow or hydrogel MNs. Solid MNs create micropores in the skin, thereby increasing the transport of drug formulations (e.g., the "poke and patch" method). Coated MNs allow for rapid dissolution of the coated drug into the skin (e.g., the "coat and poke" method). Dissolving MNs allow for rapid and / or controlled release of drugs incorporated within the microneedles. Hollow MNs allow for puncturing the skin and release of the composition following active infusion or diffusion of the formulation through the holes in the microneedles (e.g., the "poke and flow" method). In the case of dissolving MNs, the MNs act as drug reservoirs and can hold the drug composition until released by dissolution in the case of dissolving MNs or by swelling in the case of hydrogel MNs (e.g., the "poke and release" method). However, as previously described herein, in many embodiments, the active agent is not delivered by injection through one or more microneedles. That is, in many embodiments, any microneedles utilized by such embodiments are not coated, loaded, or fabricated with a biologically active agent in any manner that achieves delivery of the biologically active agent. Alternatively, in some embodiments, MNs (whether MSCs or otherwise) utilized by the present disclosure as described herein may contain and / or deliver a biologically active agent when the biologically active agent is formulated in a macro- or nanoemulsion composition as described herein. Thus, as will be recognized by those of skill in the art upon reading the present specification, treatment of the skin with microneedles that deliver a biologically active agent (e.g., by injection from the microneedle, by release of a microneedle coating, or by release from a dissolving microneedle) is not microneedle skin conditioning.

[0234] In some embodiments, the microneedle has a consistent diameter throughout the length of the microneedle. In some embodiments, the diameter of the microneedle is longest at the base end of the microneedle. In some embodiments, the microneedle tapers to a small diameter at the distal end of the base of the microneedle. In some embodiments, the microneedle may be solid. In some embodiments, the microneedle may be hollow. In some embodiments, the microneedle may be tubular. In some embodiments, the microneedle may be sealed at one end. In some embodiments, the microneedle is part of a microneedle array. In some embodiments, the microneedle may have a length between about 1 μm and about 4,000 μm. In some embodiments, the microneedle may have a length between about 1 μm and about 2,000 μm. In some embodiments, the microneedle may have a length between about 50 μm and about 400 μm. In some embodiments, the microneedle may have a length between about 800 μm and about 1500 μm.

[0235] In some embodiments, the MNs used by the present disclosure may be fabricated from a variety of materials using techniques including, but not limited to, micromolding processes or lasers. In some embodiments, the MNs may be manufactured using various types of biocompatible materials including polymers, metals, ceramics, semiconductors, organics, composites, or silicon. In some embodiments, unless designed to detach and dissolve into the skin, the microneedles have the mechanical strength to remain intact while being inserted into the skin and / or removed from the skin after insertion, and to deliver drugs or collect biological fluids. In some embodiments, the MNs can remain in place for up to several days before removal intact. In some embodiments, the microneedles may be sterilizable using standard techniques. In some embodiments, the MNs are biodegradable. In some embodiments, the MNs comprise polymeric materials. In some embodiments, the polymeric material comprises poly-L-lactic acid, polyglycolic acid, polycarbonate, polylactic-co-glycolic acid (PLGA), polydimethylsiloxane, polyvinylpyrrolidone (PVP), copolymers of methyl vinyl ether and maleic anhydride, sodium hyaluronate, carboxymethylcellulose, maltose, dextrin, galactose, starch, gelatin, or combinations thereof.

[0236] Suitable MN array and MSC devices for use in combination with compositions containing biologically active agents for transdermal delivery of the biologically active agent include devices such as those described in US Patents 6,334,856, 6,503,231, 6,908,453, 8,257,324 and 9,144,671.

[0237] Combination Therapies or Procedures According to the present invention, the provided compositions may be administered in combination with one or more additional treatments. In some embodiments, the one or more additional treatments are or include other active agents and / or therapies, such as known therapeutic agents and / or independently active biologically active agents (e.g., one or more PAI-inhibitors or other agents). In some embodiments, for example, the provided compositions include one or more such other active agents. In some embodiments, such other active agents are provided as part of a separate composition. In some embodiments, the combination therapy includes the simultaneous administration of one or more doses or units of two or more other active agents and / or therapies. In some embodiments, the combination therapy includes simultaneous exposure to two or more other active agents and / or therapies, for example, by overlapping dosing regimens.

[0238] In some embodiments, provided compositions include or are administered in combination with one or more other active agents useful in the treatment of associated dermatological or other diseases, disorders and / or conditions, e.g., as discussed herein in the context of associated diseases, disorders and / or conditions.

[0239] kit In some embodiments, the present invention provides a pharmaceutical pack or kit comprising one or more emulsion compositions comprising one or more PAI-1 inhibitors according to the present invention, and / or one or more microneedle devices. In some embodiments, the pharmaceutical pack or kit comprises a preparation or pharmaceutical composition containing the provided composition in one or more containers that may be filled with one or more additional ingredients of the pharmaceutical composition. In some embodiments, the pharmaceutical pack or kit comprises an additional approved therapeutic agent for use in combination therapy. In some embodiments, such container may be accompanied by a notice reflecting that it has been approved by a government agency for manufacture, use, or sale for human administration in a form prescribed by the agency regulating the manufacture, use, or sale of pharmaceutical products.

[0240] Kits are provided that include therapeutic reagents and / or active agents, such as PAI-1 inhibitors.As just one non-limiting example, the compositions provided may be provided as topical formulations and administered as treatment.Their pharmaceutical dosages or instructions may be provided in the kit for administration to individuals suffering from or at risk of a condition or disorder, such as those associated with the dermal level of the skin.

[0241] In some embodiments, the kit may include (i) a provided composition, and (ii) at least one pharma- ceutically acceptable excipient, and optionally (iii) at least one syringe, spatula, swab for administration to the skin, and (iv) instructions for use.

[0242] In some embodiments, the kit may include (i) a provided composition, and (ii) at least one pharma- ceutically acceptable excipient, and optionally (iii) an injection device (e.g., a syringe and needle, a microneedle array, a hair brush, etc.), and (iv) instructions for use.

[0243] Those skilled in the art will recognize that the compositions of the present invention for topical administration may have cosmetic formulations such as emollients, nourishing lotion-type emulsions, cleansing lotions, cleansing creams, milks, emollient lotions, massage creams, emollient creams, makeup bases, facial packs or gels, cleansing formulations such as shampoos, rinses, body cleansers, hair tonics or soaps, or skin compositions such as lotions, ointments, gels, creams, patches or sprays. In some embodiments, the compositions for topical administration are not formulated for administration to mucosa (e.g., are not suitable for administration to mucosa and / or are not formulated to deliver a suitable amount of large amount of drug to or across mucosa). EXAMPLES

[0244] Example 1: Effect of a topical PAI-1 inhibitor formulation on hair graying A topical study of a topical PAI-1 inhibitor formulation is conducted in men following topical administration of a topical formulation of a PAI-1 inhibitor (see, e.g., Table 1). The study is designed to test whether a topical formulation of a PAI-1 inhibitor significantly reduces hair graying in humans by measuring changes in hair color following topical treatment with a PAI-1 inhibitor.

[0245] The study includes two groups of 25 human subjects each. Both groups have subjects with various levels of hair follicle density and various numbers and / or densities of gray hair. The scalp of each subject in the second group is treated topically twice daily for six months with a volume of a PAI-1 inhibitor formulation at a fixed concentration of PAI-1 inhibitor. The concentration of PAI-1 inhibitor in the formulation is 5% w / w. Administration of the topical preparation to the scalp takes approximately 5 minutes, after which the suspension is left on the site for approximately 8-12 hours. The scalp of subjects in the first group is treated topically twice daily for six months with a blank formulation, which serves as a control.

[0246] The expected effect of such treatment is a reduction in the density of gray hair at the site of treatment with the PAI-1 inhibitor formulation. The number of gray hairs at the treatment site is measured by two methods: 1) taking a photograph of the treated area and observing the change in hair color, or 2) a gray hair density test that measures the number of gray hairs in a small area of ​​each subject's scalp. The small area of ​​the scalp is selected before the start of the study.

[0247] Photographs and gray hair density test methods are utilized at baseline before PAI-1 inhibitor treatment. Following this, photographs of each subject's scalp are obtained every 4 weeks after treatment starts, and at the end of the 6-month study. Gray hair density test is also performed every 4 weeks after treatment starts, and at the end of the 6-month study. The study finds that at baseline, the average amount of gray hairs counted by either gray hair density test or by observing from photographs is approximately equivalent in the control group and the treatment group. Photographs of the scalp of subjects in the treatment group show a visible reduction in the total number of gray hairs, on average, every 4 weeks. Gray hair density test also shows a reduction in the number of gray hairs in selected areas of the scalp of each subject belonging to the treatment group, on average, every 4 weeks. In contrast, subjects in the control group do not show a visible reduction in gray hairs in treatment areas or a reduction in the density of gray hairs in selected areas of the scalp.

[0248] This study establishes that topical administration of a topical formulation of a PAI-1 inhibitor reduces the number of gray hairs and reverses hair graying in humans.

[0249] [Example 2] Effect of oral PAI-1 inhibitor preparation on hair graying A study of oral administration of an oral formulation of a PAI-1 inhibitor in men is conducted. The study is designed to test whether an oral formulation of a PAI-1 inhibitor significantly reduces hair graying in humans by measuring changes in hair color after oral treatment with a PAI-1 inhibitor.

[0250] The study includes two groups of 25 human subjects each. Both groups have subjects with different levels of hair follicle density and different numbers and / or densities of gray hair. Each subject in the second group is administered an oral preparation of PAI-1 inhibitor formulated as a 75mg capsule three times a day for six months. Each subject in the first group is administered an empty oral preparation formulated as a 75mg capsule three times a day for six months, which serves as control.

[0251] The expected effect of such treatment is a reduction in the density of gray hair due to the PAI-1 inhibitor formulation treatment. The number of gray hairs on the subject's scalp is measured by two methods: 1) taking a photograph of the scalp and observing the change in hair color, or 2) a gray hair density test that measures the number of gray hairs in a small area of ​​each subject's scalp. The small area of ​​the scalp is selected before the start of the study.

[0252] Photographs and gray hair density test methods are utilized at baseline before PAI-1 inhibitor treatment. Following this, photographs of each subject's scalp are obtained every 4 weeks after treatment starts, and at the end of the 6-month study. Gray hair density test is also performed every 4 weeks after treatment starts, and at the end of the 6-month study. The study finds that at baseline, the average amount of gray hairs counted by either gray hair density test or by observing from photographs is approximately equivalent in the control group and the treatment group. Photographs of the scalp of subjects in the treatment group show a visible reduction in the total number of gray hairs, on average, every 4 weeks. Gray hair density test also shows a reduction in the number of gray hairs in selected areas of the scalp of each subject belonging to the treatment group, on average, every 4 weeks. In contrast, subjects in the control group do not show a visible reduction in gray hairs in treatment areas or a reduction in the density of gray hairs in selected areas of the scalp.

[0253] This study establishes that oral administration of an oral formulation of a PAI-1 inhibitor reduces the number of gray hairs and reverses hair graying in humans.

[0254] [Example 3] Effect of an injectable PAI-1 inhibitor preparation on hair graying A study of the injectable PAI-1 inhibitor formulation is conducted in humans after administration by injection of a sterile injectable formulation of the PAI-1 inhibitor (e.g., see Table 1). The study is designed to test whether the injectable formulation of the PAI-1 inhibitor significantly reduces hair graying in humans by measuring the change in hair color after treatment with the PAI-1 inhibitor.

[0255] The study includes two groups of 25 human subjects each. Both groups have subjects with various levels of hair follicle density and various numbers and / or densities of gray hair. The scalp of each subject in the second group is treated twice daily for six months with a volume of a PAI-1 inhibitor injectable formulation at a fixed concentration of PAI-1 inhibitor. The concentration of PAI-1 inhibitor in the formulation is 5% w / w. Administration of the injectable preparation to the scalp takes about 5-10 minutes, after which the suspension is left on the site for about 8-12 hours. The scalp of the subjects in the first group is treated twice daily for six months with an empty injectable formulation, which serves as a control.

[0256] The expected effect of such treatment is a reduction in the density of gray hair due to the PAI-1 inhibitor formulation treatment. The number of gray hairs in the treatment area is measured by two methods: 1) taking a photograph of the treated area and observing the change in hair color, or 2) a gray hair density test that measures the number of gray hairs in a small area of ​​each subject's scalp. The small area of ​​the scalp is selected before the start of the study.

[0257] Photographs and gray hair density test methods are utilized at baseline before PAI-1 inhibitor treatment. Following this, photographs of each subject's scalp are obtained every 4 weeks after treatment starts, and at the end of the 6-month study. Gray hair density test is also performed every 4 weeks after treatment starts, and at the end of the 6-month study. The study finds that at baseline, the average amount of gray hairs counted by either gray hair density test or by observing from photographs is approximately equivalent in the control group and the treatment group. Photographs of the scalp of subjects in the treatment group show a visible reduction in the total number of gray hairs, on average, every 4 weeks. Gray hair density test also shows a reduction in the number of gray hairs in selected areas of the scalp of each subject belonging to the treatment group, on average, every 4 weeks. In contrast, subjects in the control group do not show a visible reduction in gray hairs in treatment areas or a reduction in the density of gray hairs in selected areas of the scalp.

[0258] This study establishes that the administration of an injectable formulation of a PAI-1 inhibitor by injection reduces the number of gray hairs and reverses hair graying in humans.

[0259] [Example 4] Effect of topical PAI-1 inhibitor formulation on keloids A topical study of a topical PAI-1 inhibitor formulation is conducted in humans after topical administration of a topical formulation of a PAI-1 inhibitor (e.g., see Table 1). The study is designed to test whether a topical formulation of a PAI-1 inhibitor significantly reduces keloids in humans by measuring the change in size of the keloid after topical treatment with a PAI-1 inhibitor.

[0260] The study includes two groups of 25 human subjects each. Both groups have subjects with keloids of various sizes and various numbers. The keloid sites of each subject in the second group are treated topically twice daily for six months with a volume of a PAI-1 inhibitor formulation with a fixed concentration of PAI-1 inhibitor. The concentration of PAI-1 inhibitor in the formulation is 5% w / w. Application of the topical preparation to the scalp takes about 5 minutes, after which the suspension is left on the site for about 8-12 hours. The keloid sites of subjects in the first group are treated topically twice daily for six months with a blank formulation, which serves as a control.

[0261] The expected effect of such treatment is a reduction in the size of the keloid at the site of the PAI-1 inhibitor formulation treatment and / or a reduction in the perceived pain. The reduction in the size of the keloid at the treatment site is measured and photographs of the treated area are taken to observe the change in the size of the keloid. The patient is also asked to score the perceived pain on a pain scale of 1 to 5 (1-no pain, 2-mild pain, 3-moderate pain, 4-severe pain, 5-extremely severe pain).

[0262] Photograph and pain scoring test methods are utilized at baseline before PAI-1 inhibitor treatment. Following this, photographs of keloid sites of each subject are obtained every 4 weeks after treatment starts, and at the end of the 6-month study. Pain score test is also performed every 4 weeks after treatment starts, and at the end of the 6-month study. The study finds that at baseline, the average size of keloids measured or observed from photographs is approximately equivalent in the control group and the treatment group. Photographs of the keloid sites of subjects in the treatment group show a visible reduction in keloid size on average every 4 weeks. Pain score test also shows a reduction in the perceived pain at the site of each subject belonging to the treatment group on average every 4 weeks. In contrast, subjects in the control group do not show a visible reduction in keloid size or a reduction in perceived pain at the treatment site.

[0263] This study establishes that topical administration of a topical formulation of a PAI-1 inhibitor treats keloids in humans and reduces the size of and the pain perceived by the keloids.

[0264] [Example 5] Effect of oral PAI-1 inhibitor preparation on keloids An oral administration study of an oral formulation of a PAI-1 inhibitor in humans is conducted. The study is designed to test whether an oral formulation of a PAI-1 inhibitor significantly reduces keloids in humans by measuring the change in size of keloids after oral treatment with a PAI-1 inhibitor.

[0265] The study includes two groups of 25 human subjects each. Each group has subjects with keloids of various sizes and various numbers. Each subject in the second group is administered an oral preparation of PAI-1 inhibitor formulated as a 75mg capsule three times a day for six months at the keloid site. Each subject in the first group is administered an empty oral preparation formulated as a 75mg capsule three times a day for six months, which serves as a control.

[0266] The expected effect of such treatment is a reduction in the size of the keloid and / or a reduction in the perceived pain due to administration of the PAI-1 inhibitor formulation treatment. The reduction in the size of the keloid is measured and photographs of the treated area are taken to observe the change in the size of the keloid. Also, the patient is asked to score the perceived pain on a pain scale of 1 to 5 (1-no pain, 2-mild pain, 3-moderate pain, 4-severe pain, 5-extremely severe pain).

[0267] Photograph and pain scoring test methods are utilized at baseline before PAI-1 inhibitor treatment. Following this, photographs of keloid sites of each subject are obtained every 4 weeks after treatment starts, and at the end of the 6-month study. Pain score test is also performed every 4 weeks after treatment starts, and at the end of the 6-month study. The study finds that at baseline, the average size of keloids measured or observed from photographs is approximately equivalent in the control group and the treatment group. Photographs of the keloid sites of subjects in the treatment group show a visible reduction in keloid size on average every 4 weeks. Pain score test also shows a reduction in the perceived pain at the site of each subject belonging to the treatment group on average every 4 weeks. In contrast, subjects in the control group do not show a visible reduction in keloid size or a reduction in perceived pain.

[0268] This study establishes that oral administration of an oral formulation of a PAI-1 inhibitor treats keloids in humans and reduces the size of and the pain perceived by the keloid.

[0269] [Example 6] Effect of injectable PAI-1 inhibitor preparation on keloids A study is conducted in humans administering an injectable formulation of a PAI-1 inhibitor. The study is designed to test whether an injectable formulation of a PAI-1 inhibitor significantly reduces keloids in humans by measuring the change in size of keloids after injection treatment with a PAI-1 inhibitor.

[0270] The study includes two groups of 25 human subjects each. Both groups have subjects with keloids of various sizes and various numbers. The keloid sites of each subject in the second group are treated twice daily for six months with a fixed volume of a PAI-1 inhibitor injectable formulation with a fixed concentration of PAI-1 inhibitor. The concentration of PAI-1 inhibitor in the formulation is 5% w / w. Administration of the injectable preparation to the keloid site takes about 5 minutes, after which the suspension is left on the site for about 8-12 hours. The keloid sites of the subjects in the first group are treated twice daily for six months with an empty injectable formulation, which serves as a control.

[0271] The expected effect of such treatment is a reduction in the size of the keloid and / or a reduction in the perceived pain due to the PAI-1 inhibitor preparation treatment. The reduction in the size of the keloid at the treatment site is measured, and the treated area is photographed to observe the change in the size of the keloid. Also, the patient is asked to score the perceived pain on a pain scale of 1 to 5 (1-no pain, 2-mild pain, 3-moderate pain, 4-severe pain, 5-extremely severe pain).

[0272] Photograph and pain scoring test methods are utilized at baseline before PAI-1 inhibitor treatment. Following this, photographs of keloid sites of each subject are obtained every 4 weeks after treatment starts, and at the end of the 6-month study. Pain score test is also performed every 4 weeks after treatment starts, and at the end of the 6-month study. The study finds that at baseline, the average size of keloids measured or observed from photographs is approximately equivalent in the control group and the treatment group. Photographs of the keloid sites of subjects in the treatment group show a visible reduction in keloid size on average every 4 weeks. Pain score test also shows a reduction in the perceived pain at the site of each subject belonging to the treatment group on average every 4 weeks. In contrast, subjects in the control group do not show a visible reduction in keloid size or a reduction in perceived pain at the treatment site.

[0273] This study establishes that administration of an injectable formulation of a PAI-1 inhibitor treats keloids in humans and reduces the size of and the pain perceived by the keloid.

[0274] [Example 7] Effect of topical PAI-1 inhibitor formulation on scleroderma A topical study of a topical PAI-1 inhibitor formulation is conducted in humans following topical administration of a topical formulation of a PAI-1 inhibitor (see, e.g., Table 1). The study is designed to test whether a topical formulation of a PAI-1 inhibitor significantly reduces one or more symptoms of cutaneous scleroderma (on the arms and legs) in humans by measuring the number of square centimeters (area) of scleroderma lesions following topical treatment with a PAI-1 inhibitor.

[0275] The study includes two groups of 25 human subjects each. Both groups have subjects with various levels of cutaneous scleroderma (on the arms and legs) and various numbers and / or densities of scleroderma lesions. The scleroderma lesions of each subject in the second group are treated topically twice daily for six months with a volume of a PAI-1 inhibitor formulation at a fixed concentration of PAI-1 inhibitor. The concentration of PAI-1 inhibitor in the formulation is 5% w / w. Application of the topical preparation to the lesion takes approximately 5 minutes, after which the suspension is left on the site for approximately 8-12 hours. The sites of subjects in the first group are treated topically with a blank formulation twice daily for six months, which serve as controls.

[0276] The expected effect of such treatment is a reduction in the number of square centimeters of scleroderma lesions at the site of treatment with the PAI-1 inhibitor formulation. The number of square centimeters of scleroderma lesions at the treatment site is measured by two methods: 1) taking a photograph of the treated area and observing the change in the number of lesions or the size of the lesions, or 2) a lesion area test that measures the number of square centimeters of scleroderma lesions at a selected site of each subject. The sites to be measured on the subjects are selected before the start of the study.

[0277] Photographs and lesion area testing methods are utilized at baseline before PAI-1 inhibitor treatment. Following this, photographs of each subject's lesioned site are obtained every 4 weeks after treatment starts, and at the end of the 6-month study. Lesion area testing is also performed every 4 weeks after treatment starts, and at the end of the 6-month study. The study finds that at baseline, the average amount of lesions observed from photographs or the average area of ​​lesions measured by lesion area testing is approximately equivalent in the control group and the treatment group. Photographs of the treatment group subjects' sites show a visible reduction in the area of ​​lesions on average every 4 weeks. Lesion area testing also shows a reduction in the square centimeters of scleroderma lesions on selected sites on average every 4 weeks for each subject belonging to the treatment group. In contrast, the control group subjects do not show a visible reduction in lesions on treatment sites or a reduction in the square centimeters of scleroderma lesions on selected sites.

[0278] This study establishes that topical administration of a topical formulation of a PAI-1 inhibitor reduces one or more symptoms of cutaneous scleroderma (of the arms and legs) in humans.

[0279] [Example 8] Effect of oral PAI-1 inhibitor preparation on scleroderma An oral administration study of an oral formulation of a PAI-1 inhibitor in humans is conducted. The study is designed to test whether an oral formulation of a PAI-1 inhibitor significantly reduces one or more symptoms of cutaneous scleroderma (on the arms and legs) in humans by measuring the number of square centimeters (area) of scleroderma lesions after oral treatment with a PAI-1 inhibitor.

[0280] The study includes two groups of 25 human subjects each. Both groups have subjects with different levels of cutaneous scleroderma (on arms and legs) and different numbers and / or densities of scleroderma lesions. Each subject in the second group is administered an oral preparation of PAI-1 inhibitor formulated as a 75mg capsule three times a day for six months. Each subject in the first group is administered an empty oral preparation formulated as a 75mg capsule three times a day for six months, which serves as control.

[0281] The expected effect of such treatment is a reduction in the number of square centimeters of scleroderma lesions at the sites of treatment with the PAI-1 inhibitor formulation. The number of square centimeters of scleroderma lesions at the treatment sites is measured by two methods: 1) taking photographs of the scalp and observing changes in the number of lesions or size of the lesions, or 2) a lesion area test that measures the number of square centimeters of scleroderma lesions at selected sites on each subject. The sites to be measured on the subjects are selected prior to the start of the study.

[0282] Photographs and lesion area testing methods are utilized at baseline before PAI-1 inhibitor treatment. Following this, photographs of each subject's lesioned site are obtained every 4 weeks after treatment starts, and at the end of the 6-month study. Lesion area testing is also performed every 4 weeks after treatment starts, and at the end of the 6-month study. The study finds that at baseline, the average amount of lesions observed from photographs or the average area of ​​lesions measured by lesion area testing is approximately equivalent in the control group and the treatment group. Photographs of the treatment group subjects' sites show a visible reduction in the area of ​​lesions on average every 4 weeks. Lesion area testing also shows a reduction in the square centimeters of scleroderma lesions on selected sites on average every 4 weeks for each subject belonging to the treatment group. In contrast, the control group subjects do not show a visible reduction in lesions on treatment sites or a reduction in the square centimeters of scleroderma lesions on selected sites.

[0283] This study establishes that oral administration of an oral formulation of a PAI-1 inhibitor reduces one or more symptoms of cutaneous scleroderma (of the arms and legs) in humans.

[0284] [Example 9] Effect of injectable PAI-1 inhibitor preparation on scleroderma A study of the injectable PAI-1 inhibitor formulation is conducted in humans following administration by injection of a sterile injectable formulation of the PAI-1 inhibitor (e.g., see Table 1). The study is designed to test whether the injectable formulation of the PAI-1 inhibitor significantly reduces one or more symptoms of cutaneous scleroderma (of the arms and legs) in humans, as measured by the number of square centimeters (area) of scleroderma lesions following treatment with the PAI-1 inhibitor.

[0285] The study includes two groups of 25 human subjects each. Both groups have subjects with various levels of cutaneous scleroderma (on the arms and legs) and various numbers and / or densities of scleroderma lesions. The scleroderma lesions of each subject in the second group are treated twice daily for six months with a volume of a PAI-1 inhibitor injectable formulation at a fixed concentration of PAI-1 inhibitor. The concentration of PAI-1 inhibitor in the formulation is 5% w / w. Administration of the injectable preparation to the scalp takes about 5-10 minutes, after which the suspension is left on the site for about 8-12 hours. The sites of subjects in the first group are treated topically with a blank formulation twice daily for six months, which serve as controls.

[0286] The expected effect of such treatment is a reduction in the number of square centimeters of scleroderma lesions at the site of treatment with the PAI-1 inhibitor formulation. The number of square centimeters of scleroderma lesions at the treatment site is measured by two methods: 1) taking a photograph of the treated area and observing the change in the number of lesions or the size of the lesions, or 2) a lesion area test that measures the number of square centimeters of scleroderma lesions at a selected site of each subject. The sites to be measured on the subjects are selected before the start of the study.

[0287] Photographs and lesion area testing methods are utilized at baseline before PAI-1 inhibitor treatment. Following this, photographs of each subject's lesioned site are obtained every 4 weeks after treatment starts, and at the end of the 6-month study. Lesion area testing is also performed every 4 weeks after treatment starts, and at the end of the 6-month study. The study finds that at baseline, the average amount of lesions observed from photographs or the average area of ​​lesions measured by lesion area testing is approximately equivalent in the control group and the treatment group. Photographs of the treatment group subjects' sites show a visible reduction in the area of ​​lesions on average every 4 weeks. Lesion area testing also shows a reduction in the square centimeters of scleroderma lesions on selected sites on average every 4 weeks for each subject belonging to the treatment group. In contrast, the control group subjects do not show a visible reduction in lesions on treatment sites or a reduction in the square centimeters of scleroderma lesions on selected sites.

[0288] This study establishes that administration of an injectable formulation of a PAI-1 inhibitor by injection reduces one or more symptoms of cutaneous scleroderma (of the arms and legs) in humans.

[0289] [Example 10] Effect of topical PAI-1 inhibitor formulation on Raynaud's phenomenon A topical study of a topical PAI-1 inhibitor formulation is conducted in humans following topical administration of a topical formulation of a PAI-1 inhibitor (e.g., see Table 1). The study is designed to test whether a topical formulation of a PAI-1 inhibitor significantly reduces the overall pain associated with Raynaud's disease and the number of Raynaud's pain episodes in humans by measuring the overall pain associated with Raynaud's disease since the last clinic visit and the number of Raynaud's pain episodes since the last clinic visit following topical treatment with a PAI-1 inhibitor.

[0290] The study includes two groups of 25 human subjects each. Both groups have subjects with various levels of overall pain associated with Raynaud's disease and number of Raynaud's pain episodes. The sites affected by Raynaud's disease of each subject in the second group are treated topically twice daily for six months with a volume of a PAI-1 inhibitor formulation at a fixed concentration of PAI-1 inhibitor. The concentration of PAI-1 inhibitor in the formulation is 5% w / w. Administration of the topical preparation to the affected site takes approximately 5 minutes, after which the suspension is left on the site for approximately 8-12 hours. The affected sites of the subjects in the first group are treated topically twice daily for six months with a blank formulation, which serves as a control.

[0291] The expected effect of such treatment is a reduction in overall Raynaud's pain since the last visit at the site of treatment with the PAI-1 inhibitor formulation and the number of Raynaud's pain episodes since the last visit. Overall Raynaud's pain since the last visit and the number of Raynaud's pain episodes since the last visit at the treatment site are measured by 1) a pain scale of 1 to 5 (1-no pain, 2-mild pain, 3-moderate pain, 4-severe pain, 5-extremely severe pain) and / or 2) the number of Raynaud's pain episodes at the treatment site for each subject.

[0292] At baseline before PAI-1 inhibitor treatment, subjects record the overall Raynaud's pain and the number of Raynaud's pain episodes experienced over the past 4 weeks. The overall Raynaud's pain and the number of Raynaud's pain episodes since the last visit of each subsequent subject are obtained every 4 weeks after treatment starts and at the end of the study in 6 months. The study finds that at baseline, the average amount of overall Raynaud's pain and the number of Raynaud's pain episodes are approximately equal in the control group and the treatment group. The subjects in the treatment group observe a reduction in the overall Raynaud's pain score and the number of Raynaud's pain episodes since the last visit on average every 4 weeks. In contrast, the subjects in the control group do not show a reduction in the overall pain score since the last visit or the number of Raynaud's pain episodes since the last visit.

[0293] This study establishes that topical administration of a topical formulation of a PAI-1 inhibitor reduces the overall pain associated with Raynaud's disease and the number of Raynaud's pain episodes in humans.

[0294] [Example 11] Effect of oral PAI-1 inhibitor preparation on Raynaud's phenomenon An oral administration study of an oral formulation of a PAI-1 inhibitor in humans is conducted. The study is designed to test whether the oral formulation of a PAI-1 inhibitor significantly reduces the overall pain associated with Raynaud's disease and the number of Raynaud's pain episodes in humans by measuring the overall pain associated with Raynaud's disease since the last clinic visit and the number of Raynaud's pain episodes since the last clinic visit after oral treatment with a PAI-1 inhibitor.

[0295] The study includes two groups of 25 human subjects each. Both groups have subjects with various levels of Raynaud's overall pain and number of Raynaud's pain episodes. Each subject in the second group is administered an oral preparation of PAI-1 inhibitor formulated as a 75mg capsule three times a day for six months. Each subject in the first group is administered an empty oral preparation formulated as a 75mg capsule three times a day for six months, which serve as controls.

[0296] The expected effect of such treatment is a reduction in the overall Raynaud's pain since last visit and the number of Raynaud's pain episodes since last visit in the subject following treatment with the PAI-1 inhibitor formulation. The overall Raynaud's pain since last visit and the number of Raynaud's pain episodes since last visit at the treatment site are measured by 1) a pain scale of 1 to 5 (1-no pain, 2-mild pain, 3-moderate pain, 4-severe pain, 5-extremely severe pain) and / or 2) the number of Raynaud's pain episodes at the treatment site for each subject.

[0297] At baseline before PAI-1 inhibitor treatment, subjects record the overall Raynaud's pain and the number of Raynaud's pain episodes experienced over the past 4 weeks. The overall Raynaud's pain and the number of Raynaud's pain episodes since the last visit of each subsequent subject are obtained every 4 weeks after treatment starts and at the end of the study in 6 months. The study finds that at baseline, the average amount of overall Raynaud's pain and the number of Raynaud's pain episodes are approximately equal in the control group and the treatment group. The subjects in the treatment group observe a reduction in the overall Raynaud's pain score and the number of Raynaud's pain episodes since the last visit on average every 4 weeks. In contrast, the subjects in the control group do not show a reduction in the overall pain score since the last visit or the number of Raynaud's pain episodes since the last visit.

[0298] This study establishes that oral administration of an oral formulation of a PAI-1 inhibitor reduces the overall pain associated with Raynaud's disease and the number of Raynaud's pain episodes in humans.

[0299] [Example 12] Effect of injectable PAI-1 inhibitor preparation on Raynaud's phenomenon A study of the injectable PAI-1 inhibitor formulation is conducted in humans after administration by injection of a sterile injectable formulation of the PAI-1 inhibitor (e.g., see Table 1). The study is designed to test whether the injectable formulation of the PAI-1 inhibitor significantly reduces the overall pain associated with Raynaud's disease and the number of Raynaud's pain episodes in humans by measuring the overall pain associated with Raynaud's disease since the last clinic visit and the number of Raynaud's pain episodes since the last clinic visit after treatment with the PAI-1 inhibitor.

[0300] The study includes two groups of 25 human subjects each. Both groups have subjects with various levels of overall pain associated with Raynaud's disease and number of Raynaud's pain episodes. The sites affected by Raynaud's disease of each subject in the second group are treated twice daily for six months with a volume of an injectable formulation of PAI-1 inhibitor at a fixed concentration of PAI-1 inhibitor. The concentration of PAI-1 inhibitor in the formulation is 5% w / w. Administration of the injectable preparation to the site takes approximately 5-10 minutes, after which the suspension is left on the site for approximately 8-12 hours. The sites of subjects in the first group are treated topically with a blank formulation twice daily for six months, which serve as controls.

[0301] The expected effect of such treatment is a reduction in overall Raynaud's pain since the last visit at the site of treatment with the PAI-1 inhibitor formulation and the number of Raynaud's pain episodes since the last visit. Overall Raynaud's pain since the last visit and the number of Raynaud's pain episodes since the last visit at the treatment site are measured by 1) a pain scale of 1 to 5 (1-no pain, 2-mild pain, 3-moderate pain, 4-severe pain, 5-extremely severe pain) and / or 2) the number of Raynaud's pain episodes at the treatment site for each subject.

[0302] At baseline before PAI-1 inhibitor treatment, subjects record the overall Raynaud's pain and the number of Raynaud's pain episodes experienced over the past 4 weeks. The overall Raynaud's pain and the number of Raynaud's pain episodes since the last visit of each subsequent subject are obtained every 4 weeks after treatment starts and at the end of the study in 6 months. The study finds that at baseline, the average amount of overall Raynaud's pain and the number of Raynaud's pain episodes are approximately equal in the control group and the treatment group. The subjects in the treatment group observe a reduction in the overall Raynaud's pain score and the number of Raynaud's pain episodes since the last visit on average every 4 weeks. In contrast, the subjects in the control group do not show a reduction in the overall pain score since the last visit or the number of Raynaud's pain episodes since the last visit.

[0303] This study establishes that the administration of an injectable formulation of a PAI-1 inhibitor by injection reduces the overall pain associated with Raynaud's disease and the number of Raynaud's pain episodes in humans.

[0304] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the invention is not intended to be limited to the above detailed description, but is as set forth in the following claims.

Claims

1. 1. A method of treating a dermatological condition, comprising: providing a composition that includes or delivers a plasminogen activator inhibitor 1 (PAI-1) inhibitor; administering the composition to a site on the subject such that a PAI-1 inhibitor is delivered to the subject, the site containing or having contained a plurality of hair follicles, each having a hair located therein; A method comprising:

2. 10. The method of claim 1, wherein administering is by topical application to the site on the skin surface.

3. 3. The method of claim 2, wherein administering comprises maintaining the composition on the skin surface for a period of time.

4. 10. The method of claim 1, wherein the administering is by injection.

5. 1. A method of treating a dermatological condition, comprising: providing a composition that includes or delivers a plasminogen activator inhibitor 1 (PAI-1) inhibitor; administering a composition to a subject such that a PAI-1 inhibitor is delivered to the subject, the site on the subject containing or having contained a plurality of hair follicles, each having a hair located therein; A method comprising:

6. 6. The method of claim 5, wherein the administering is by oral administration.

7. 4. The method of claim 3, further comprising removing any remaining composition from the site after a period of time.

8. 8. The method of claim 3, 4 or 7, wherein the step of administering the composition comprises rubbing the composition into the site.

9. The method of claim 3 , wherein the period of time is at least 1 minute.

10. 4. The method of claim 3, wherein the period of time is at least one hour.

11. The method of claim 9, wherein the period of time is in the range of 1 to 10 minutes.

12. 2. The method of any of the preceding claims, wherein the PAI-1 inhibitor is selected from the group consisting of a polypeptide, a nucleic acid, a lipid, a carbohydrate, a small molecule, a metal, a polymer, a therapeutic antibody, and combinations thereof.

13. The method of claim 12, wherein the nucleic acid is or comprises an siRNA.

14. 13. The method of claim 12, wherein the PAI-1 inhibitor is selected from the group consisting of 5-chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid, 5-chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid, benzopyran compounds, butadiene, spironolactone, imidapril, angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril), angiotensin II receptor antagonists (AIIRA), defibrotide (polydeoxyribonucleotide), and any combination thereof.

15. 15. The method of claim 14, wherein the PAI-1 inhibitor is 5-chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid.

16. 13. The method of any one of the preceding claims, wherein the composition comprising the PAI-1 inhibitor is or comprises a suspension.

17. 13. The method of any one of the preceding claims, wherein the composition comprising the PAI-1 inhibitor is or comprises a foam.

18. 13. The method of any one of the preceding claims, wherein the composition comprising the PAI-1 inhibitor comprises an emulsion.

19. 20. The method of claim 18, wherein the emulsion is a nanoemulsion.

20. 20. The method of any one of claims 1-3 or 7-19, further comprising administering an osmotic treatment.

21. 21. The method of claim 20, wherein the permeation treatment is or comprises a non-irritating chemical agent.

22. 21. The method of claim 20, wherein the permeabilization treatment is or comprises the administration of an electric or magnetic field.

23. 21. The method of claim 20, wherein the infiltration treatment is or comprises microneedling.

24. 21. The method of claim 20, wherein the penetration treatment is or comprises a laser treatment.

25. 25. The method of any one of claims 1-3 or 7-24, wherein the PAI-1 inhibitor penetrates the site within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration.

26. 26. The method of any one of claims 1-3 or 7-25, wherein the PAI-1 inhibitor penetrates the site within about 5 to about 60 minutes, about 5 to about 12 minutes, about 5 to about 15 minutes, or about 15 to about 30 minutes of administration.

27. 27. The method of any one of claims 1-3 or 7-26, wherein the PAI-1 inhibitor penetrates the site within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours of administration.

28. 28. The method of any one of claims 1-3 or 7-27, wherein the PAI-1 inhibitor penetrates the site within about 1 to about 12 hours, about 8 to about 12 hours, or 12 to about 24 hours of administration.

29. 13. The method of any one of the preceding claims, comprising more than one administration of the composition over time.

30. 30. The method of claim 29, wherein each administration comprising a PAI-1 inhibitor is separated by a specific period of time.

31. 31. The method of claim 30, wherein the specified time period is longer than the specified time period for administering the reference treatment regimen.

32. 10. A method according to any one of the preceding claims, wherein the dermatological condition is or comprises greying of hair.

33. 10. The method according to any one of the preceding claims, wherein the hair is white hair.

34. The method of any one of claims 1 to 3 or 7 to 33, wherein the composition is formulated as a suspension, foam, lotion, cream, gel, oil, powder, poultice or drops.

35. 1. A method for preventing the occurrence or progression of a dermatological condition, comprising: providing a composition that includes or delivers a plasminogen activator inhibitor 1 (PAI-1) inhibitor; topically administering the composition to a site on a subject, the site being a skin surface that contains or has contained a plurality of hair follicles, each having a hair located therein; and leaving the composition at the site for a period of time such that the PAI-1 inhibitor is delivered to the subject. A method comprising:

36. 36. The method of claim 35, further comprising removing any remaining composition from the site after a period of time.

37. 37. The method of claim 25 or claim 36, wherein the step of administering the composition comprises rubbing the composition into the site.

38. 38. The method of any of claims 35 to 37, wherein the period of time is within the range of about 1 to about 10 minutes, about 5 to about 60 minutes, about 5 to about 12 minutes, about 5 to about 15 minutes, or about 15 to about 30 minutes, about 1 to about 12 hours, about 8 to about 12 hours, or 12 to about 24 hours.

39. The method of any of claims 35 to 37, wherein the PAI-1 inhibitor is selected from the group consisting of a polypeptide, a nucleic acid, a lipid, a carbohydrate, a small molecule, a metal, a polymer, a therapeutic antibody, and combinations thereof.

40. 40. The method of claim 39, wherein the nucleic acid is or comprises an siRNA.

41. 40. The method of claim 39, wherein the PAI-1 inhibitor is selected from the group consisting of 5-chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid, 5-chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid, benzopyran compounds, butadiene, spironolactone, imidapril, angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril), angiotensin II receptor antagonists (AIIRA), defibrotide (polydeoxyribonucleotide), and any combination thereof.

42. 42. The method of claim 41, wherein the PAI-1 inhibitor is 5-chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid.

43. The method of any one of claims 35 to 42, wherein the composition comprising the PAI-1 inhibitor is or comprises a suspension.

44. The method of any one of claims 35 to 42, wherein the composition comprising the PAI-1 inhibitor is or comprises a foam.

45. The method of any one of claims 35 to 42, wherein the composition comprising the PAI-1 inhibitor comprises an emulsion.

46. 46. ​​The method of claim 45, wherein the emulsion is a nanoemulsion.

47. 47. The method of any one of claims 35 to 46, further comprising administering an infiltration treatment.

48. 48. The method of claim 47, wherein the permeation treatment is or comprises a non-irritating chemical agent.

49. 48. The method of claim 47, wherein the permeabilization treatment is or comprises administration of an electric or magnetic field.

50. 48. The method of claim 47, wherein the infiltration treatment is or comprises microneedling.

51. 48. The method of claim 47, wherein the penetration treatment is or comprises a laser treatment.

52. 52. The method of any one of claims 35-51, wherein the PAI-1 inhibitor penetrates the site within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration.

53. 53. The method of any one of claims 35-52, wherein the PAI-1 inhibitor penetrates the site within about 5 to about 60 minutes, about 5 to about 12 minutes, about 5 to about 15 minutes, or about 15 to about 30 minutes of administration.

54. 54. The method of any one of claims 35-53, wherein the PAI-1 inhibitor penetrates the site within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours of administration.

55. 55. The method of any one of claims 35-54, wherein the PAI-1 inhibitor penetrates the site within about 1 to about 12 hours, about 8 to about 12 hours, or 12 to about 24 hours of administration.

56. 56. The method of any one of claims 35 to 55, comprising more than one administration of a composition comprising a PAI-1 inhibitor over time.

57. 57. The method of claim 56, wherein each administration comprising a PAI-1 inhibitor is separated by a specific period of time.

58. 58. The method of claim 57, wherein the specified time period is longer than the specified time period for administering the reference treatment regimen.

59. 59. The method of any one of claims 35 to 58, wherein the dermatological condition is or comprises hair greying.

60. The method of any one of claims 35 to 59, wherein the hair is not gray.

61. The method of any one of claims 35 to 60, wherein the composition is formulated as a suspension, foam, lotion, cream, gel, oil, powder, poultice or drops.

62. A composition comprising a therapeutically effective amount of a PAI-1 inhibitor and a pharma- ceutically acceptable carrier.

63. 63. The composition of claim 62, formulated for topical administration.

64. 64. The composition of claim 63, wherein the therapeutically effective amount is from about 0.1% w / w to about 5% w / w, from about 0.1% to about 10% w / w, from about 0.1% to about 15% w / w, from about 0.1% w / w to about 20% w / w, or from about 1% w / w to about 5% w / w.

65. 63. The composition of claim 62, formulated for oral administration.

66. 66. The composition of claim 65, wherein the therapeutically effective amount is from about 10 mg / day to about 100 mg / day, from about 10 mg / day to about 200 mg / day, from about 10 mg / day to about 300 mg / day, from about 10 mg / day to about 400 mg / day, from about 10 mg / day to about 500 mg / day, from about 10 mg / day to about 600 mg / day, from about 10 mg / day to about 700 mg / day, from about 10 mg / day to about 800 mg / day, from about 10 mg / day to about 900 mg / day, or from about 10 mg / day to about 1000 mg / day.

67. The composition of any one of claims 62 to 66, wherein the PAI-1 inhibitor is selected from the group consisting of a polypeptide, a nucleic acid, a lipid, a carbohydrate, a small molecule, a metal, a polymer, a therapeutic antibody, and combinations thereof.

68. 68. The composition of claim 67, wherein the nucleic acid is or comprises an siRNA.

69. 68. The composition of claim 67, wherein the PAI-1 inhibitor is selected from the group consisting of 5-chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid, 5-chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid, a benzopyran compound, butadiene, spironolactone, imidapril, angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril), angiotensin II receptor antagonists (AIIRA), defibrotide (polydeoxyribonucleotide), and any combination thereof.

70. 70. The composition of claim 69, wherein the PAI-1 inhibitor is 5-chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid.

71. 71. The composition of any one of claims 62 to 70, wherein the composition comprising the PAI-1 inhibitor is or comprises a suspension.

72. 71. The composition of any one of claims 62 to 70, wherein the composition comprising a PAI-1 inhibitor is or comprises a foam.

73. The composition of any one of claims 62 to 70, wherein the composition comprising the PAI-1 inhibitor comprises an emulsion.

74. 74. The composition of claim 73, wherein the emulsion is a nanoemulsion.

75. 75. The composition of any one of claims 62 to 74, wherein the composition comprising the PAI-1 inhibitor is formulated as a suspension, foam, lotion, cream, gel, oil, powder, poultice or drops.

76. A kit comprising a composition comprising a PAI-1 inhibitor and a patch used to cover the composition comprising a PAI-1 inhibitor after administration to a site.

77. 77. The kit of claim 76, wherein the composition comprising the PAI-1 inhibitor is incorporated into a patch.

78. 78. The kit of claim 76 or claim 77, wherein the patch comprises microneedles.

79. 79. The kit of any one of claims 76 to 78, wherein the composition comprising the PAI-1 inhibitor is or comprises a suspension.

80. 79. The kit of any one of claims 76 to 78, wherein the composition comprising the PAI-1 inhibitor is or comprises a foam.

81. The kit of any one of claims 76 to 78, wherein the composition comprising the PAI-1 inhibitor comprises an emulsion.

82. 82. The kit of claim 81, wherein the emulsion is a nanoemulsion.

83. A kit comprising a composition comprising a PAI-1 inhibitor, a device for facilitating penetration of the composition comprising a PAI-1 inhibitor to a site in a subject, and instructions for administering the composition to the site.

84. 84. The kit of claim 83, wherein the composition comprising the PAI-1 inhibitor is or comprises a suspension.

85. 84. The kit of claim 83, wherein the composition comprising the PAI-1 inhibitor is or comprises a foam.

86. 84. The kit of claim 83, wherein the composition comprising the PAI-1 inhibitor is or comprises an emulsion.

87. 87. The kit of claim 86, wherein the emulsion is a nanoemulsion.

88. The kit of any one of claims 83 to 87, wherein the device is a brush or comb.

89. The kit of any one of claims 83 to 88, wherein the device is a patch, roller or pen.

90. The kit of any one of claims 76 to 89, wherein the composition comprising the PAI-1 inhibitor is formulated as a suspension, foam, lotion, cream, powder, ointment, poultice, gel, or drops.

91. 1. A composition comprising a therapeutically effective amount of a PAI-1 inhibitor, wherein the composition, when administered to an animal comprising one or more gray hairs, (i) reducing the number of gray hairs; (ii) preventing the graying of one or more non-gray hairs; and (iii) delaying the onset of graying of one or more non-gray hairs; A composition characterized by achieving at least one of the above.

92. 92. The composition of claim 91, formulated for topical administration.

93. 93. The composition of claim 92, wherein the therapeutically effective amount is from about 0.1% w / w to about 5% w / w, from about 0.1% to about 10% w / w, from about 0.1% to about 15% w / w, from about 0.1% w / w to about 20% w / w, or from about 1% w / w to about 5% w / w.

94. 92. The composition of claim 91, formulated for oral administration.

95. 95. The composition of claim 94, wherein the therapeutically effective amount is from about 10 mg / day to about 100 mg / day, from about 10 mg / day to about 200 mg / day, from about 10 mg / day to about 300 mg / day, from about 10 mg / day to about 400 mg / day, from about 10 mg / day to about 500 mg / day, from about 10 mg / day to about 600 mg / day, from about 10 mg / day to about 700 mg / day, from about 10 mg / day to about 800 mg / day, from about 10 mg / day to about 900 mg / day, or from about 10 mg / day to about 1000 mg / day.

96. The composition of any one of claims 91 to 95, wherein the PAI-1 inhibitor is selected from the group consisting of a polypeptide, a nucleic acid, a lipid, a carbohydrate, a small molecule, a metal, a polymer, a therapeutic antibody, and combinations thereof.

97. 97. The composition of claim 96, wherein the nucleic acid is or comprises an siRNA.

98. 97. The composition of claim 96, wherein the PAI-1 inhibitor is selected from the group consisting of 5-chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid, 5-chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid, a benzopyran compound, butadiene, spironolactone, imidapril, angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril), angiotensin II receptor antagonists (AIIRA), defibrotide (polydeoxyribonucleotide), and any combination thereof.

99. 99. The composition of claim 98, wherein the PAI-1 inhibitor is 5-chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid.

100. 100. The composition of any one of claims 91 to 99, wherein the composition comprising the PAI-1 inhibitor is or comprises a suspension.

101. 100. The composition of any one of claims 91 to 99, wherein the composition comprising a PAI-1 inhibitor is or comprises a foam.

102. 100. The composition of any one of claims 91 to 99, wherein the composition comprising the PAI-1 inhibitor comprises an emulsion.

103. 103. The composition of claim 102, wherein the emulsion is a nanoemulsion.

104. The composition of any one of claims 91 to 103, wherein the composition comprising the PAI-1 inhibitor is formulated as a suspension, foam, lotion, cream, gel, oil, powder, poultice or drops.

105. 62. The method of any one of claims 1 to 61, wherein the dermatological condition is hair greying.

106. 106. The method of claim 105, further comprising administering one or more other active agents, wherein the one or more other active agents are selected from the group consisting of cinnamic acid amidopropyltrimonium chloride, solid lipid nanoparticles, l-cystine, l-methionine, melatonin, and combinations thereof.

107. 62. The method of any one of claims 1 to 61, wherein the dermatological condition is a keloid.

108. 108. The method of claim 107, further comprising administering one or more other active agents, wherein the one or more other active agents are selected from the group consisting of compression therapy, silicone gel sheeting, intralesional triamcinolone acetonide (TAC), cryosurgery, radiation, laser therapy, IFN, 5-FU, high dose oxygen using hyperbaric oxygen therapy (HBOT), cryotherapy, surgical excision, topical agents, and combinations thereof.

109. 62. The method of any one of claims 1 to 61, wherein the dermatological condition is scleroderma.

110. 110. The method of claim 109, further comprising administering one or more other active agents, wherein the one or more other active agents are selected from the group consisting of angiotensin II receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, NSAIDs, COX-2 inhibitors, analgesics, low dose corticosteroids, anesthetics, antacids, H2 blockers, proton pump inhibitors, prokinetic agents, somatostatin agonists, antibiotics, prostaglandin derivatives, treprostinil, iloprost, endothelin receptor antagonists, IP receptor agonists, phosphodiesterase type 5 (PDE5) inhibitors, antifibrotic agents, tyrosine kinase inhibitors, immunosuppressants, alkylating agents, pilocarpine, and combinations thereof.

111. 62. The method of any one of claims 1 to 61, wherein the dermatological condition is Raynaud's phenomenon.

112. 112. The method of claim 111, further comprising administering one or more other active agents, wherein the one or more other active agents are selected from the group consisting of calcium channel blockers, alpha blockers, nitroglycerin, angiotensin II receptor antagonists, selective serotonin reuptake inhibitors, glyceryl trinitrate, tadalafil, ginkgo biloba extract, SLx-2101, St. John's wort, fasudil, cilostazol, iloprost, relaxin, treprostinil diethanolamine, sildenafil, atorvastatin, imatinib mesylate, treprostinil diethanolamine, and combinations thereof.

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