Uses of plasminogen activator inhibitor 1 (PAI-1) inhibitors

Abstract

To provide methods for the treatment and / or prevention of certain types of hair loss (also known as alopecia), including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia.SOLUTION: A method for treating a subject comprises providing a composition that includes or delivers a plasminogen activator inhibitor-1 (PAI-1) inhibitor, and administering the composition to a site of the subject such that the PAI-1 inhibitor is delivered to the subject, wherein the site comprises or has comprised a plurality of hair follicles each optionally containing a hair therein, and wherein the subject has one or more treatable conditions selected from the group consisting of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia.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 September 13, 2018, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Hair loss or alopecia often causes great anxiety. Many people are willing to go to great lengths to regrow hair, especially when hair loss occurs prematurely. Previously available treatments have proven largely inadequate, and therefore new treatment options are needed. Summary of the Invention [Problem to be solved by the invention]

[0003] The present disclosure provides, among other things, novel technologies (e.g., methods, kits, compositions, etc.) for the treatment and / or prevention of certain types of alopecia (hair loss). Among other things, the present disclosure provides insight that plasminogen activator inhibitor 1 (PAI-1) inhibitors may only be useful for the treatment and / or prevention of certain types of alopecia, and may not be useful for other types of alopecia. In particular, the present disclosure provides, in some embodiments, novel technologies (e.g., methods, kits, compositions, etc.) that may be particularly useful for the treatment and / or prevention of certain types of alopecia (or hair loss), including male pattern baldness (also known as androgenetic alopecia), alopecia areata, frontal fibrosing alopecia, and senile alopecia. Furthermore, the present disclosure provides insight that novel technologies may not be particularly useful for the treatment and / or prevention of other types of alopecia, such as radiation-induced alopecia, chemotherapy-induced alopecia, and alopecia caused by chronic discoid lupus erythematosus.

[0004] Those skilled in the art will 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 surprising insight that PAI-1 may also be associated with only certain types of hair loss.The present disclosure provides the surprising insight that the provided novel technology (for example, method, kit, composition, etc.) is effective for the treatment and / or prevention of certain types of hair loss, including male pattern baldness, alopecia areata, frontal fibrosing alopecia, and senile alopecia.Alternatively or additionally, in some embodiments, the present disclosure provides the surprising insight that the provided novel technology utilizing PAI-1 inhibitors may not be effective for the treatment and / or prevention of certain other types of hair loss, such as radiation-induced alopecia, chemotherapy-induced alopecia, and alopecia caused by chronic discoid lupus erythematosus. Furthermore, in some embodiments, the present disclosure provides the surprising insight that the provided novel technologies utilizing PAI-1 inhibitors may be effective in regrowing hair in subjects with androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and age-related alopecia. [Means for solving the problem]

[0005] In some embodiments, the present disclosure provides a method of treating a subject, the method comprising providing a composition comprising or delivering a plasminogen activator inhibitor 1 (PAI-1) inhibitor; administering the composition to a site on the subject such that the PAI-1 inhibitor is delivered to the subject, wherein the site contains or has contained a plurality of hair follicles, each of which may have a hair located therein, and the subject is suffering from one or more treatable conditions, wherein the one or more treatable conditions are selected from the group consisting of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and age-related alopecia.

[0006] In some embodiments, the present disclosure provides methods of treating a subject, the method comprising providing a composition comprising or delivering a plasminogen activator inhibitor 1 (PAI-1) inhibitor; administering the composition to the subject such that the PAI-1 inhibitor is delivered to the subject, wherein the subject's area contains or has contained multiple hair follicles, each of which may have a hair located therein, and the subject is suffering from one or more treatable conditions, wherein the one or more treatable conditions are selected from the group consisting of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and age-related alopecia.

[0007] In some embodiments, the disclosure provides a method for preventing the occurrence or progression of one or more conditions in a subject, the method comprising: (a) providing a composition comprising or delivering a plasminogen activator inhibitor-1 (PAI-1) inhibitor; (b) topically administering the composition to a site on the subject, wherein the site is a skin surface that contains or has contained multiple hair follicles, each of which may have a hair located therein, and the one or more conditions are selected from the group consisting of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, age-related alopecia, and combinations thereof; and (c) leaving the composition at the site for a period of time such that the PAI-1 inhibitor is delivered to the subject.

[0008] In some embodiments, the present disclosure provides a method of regenerating hair in a subject, the method comprising providing a composition comprising or delivering a plasminogen activator inhibitor 1 (PAI-1) inhibitor; administering the composition to a site in the subject such that the PAI-1 inhibitor is delivered to the subject, wherein the site contains or has contained multiple hair follicles, each of which may or may not be active, and the subject is afflicted with one or more treatable conditions, wherein the one or more treatable conditions are selected from the group consisting of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and age-related alopecia.

[0009] In some embodiments, the present disclosure provides novel techniques for treating and / or preventing the occurrence or progression of certain types of alopecia. In some embodiments, the alopecia is or includes androgenetic alopecia. In some embodiments, the alopecia is or includes alopecia areata. In some embodiments, the alopecia is or includes frontal fibrosing alopecia. In some embodiments, the alopecia is or includes age-related alopecia. In some embodiments, the alopecia is not radiation-induced alopecia. In some embodiments, the alopecia is not chemotherapy-induced alopecia. In some embodiments, the alopecia is not alopecia due to chronic discoid lupus erythematosus.

[0010] In some embodiments, the present disclosure provides novel techniques for hair restoration in subjects with certain types of alopecia. In some embodiments, the alopecia is or includes androgenetic alopecia. In some embodiments, the alopecia is or includes alopecia areata. In some embodiments, the alopecia is or includes frontal fibrosing alopecia. In some embodiments, the alopecia is or includes age-related alopecia. In some embodiments, the alopecia is not radiation-induced alopecia. In some embodiments, the alopecia is not chemotherapy-induced alopecia. In some embodiments, the alopecia is not alopecia due to chronic discoid lupus erythematosus.

[0011] In some embodiments, the present disclosure provides novel compositions comprising and / or delivering a therapeutically effective amount of a PAI-1 inhibitor. In certain embodiments, the present disclosure provides novel compositions comprising and / or delivering a therapeutically effective amount of a PAI-1 inhibitor and a pharmaceutically 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.

[0012] In some embodiments, provided novel compositions are characterized by, when administered to an animal that suffers from or is prone to at least one of the disclosed types of alopecia, (i) achieve at least one of the following: treatment of at least one type of alopecia in animal; (ii) delay, slow or prevent the progression of at least one type of alopecia in animal.In certain detailed embodiments, for example, when certain types of alopecia are or include androgenic alopecia, alopecia areata, frontal fibrosing alopecia, senile alopecia and any combination thereof, provided novel compositions can, when administered to an animal that suffers from or is prone to at least one of the alopecias described herein, achieve at least one of the following: (i) increase the number of hair (for example, at and / or near the administration site), (ii) prevent hair loss (alopecia) (for example, at and / or near the administration site), (iii) delay the onset of hair loss of one or more hairs (for example, at and / or near the administration site), and (iv) increase the number of hair follicles.

[0013] Generally, administration of compositions according to the present disclosure can 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.

[0014] In some embodiments, the administration achieves systemic delivery. In some embodiments, the administration achieves localized delivery.

[0015] 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.

[0016] In some embodiments, the composition is maintained on or at the site for a period of at least 1 minute. In some embodiments, the period is at least 1 hour. In some embodiments, the period is in the range of 1 to 10 minutes. In some embodiments, the period 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.

[0017] In some embodiments, the provided methods of treating certain types of alopecia 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).

[0018] In some embodiments, the site to which a composition according to the present disclosure is administered may be on the surface of the skin. 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 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. 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.

[0019] In some embodiments, the PAI-1 inhibitor used according to 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.

[0020] In some embodiments, the present disclosure provides and / or utilizes compositions comprising and / or delivering a PAI-1 inhibitor. In some embodiments, such compositions are or comprise a suspension. In some embodiments, such compositions are or comprise a foam. In some embodiments, such compositions are or comprise an emulsion, e.g., a nanoemulsion. In some embodiments, such compositions are formulated as a suspension, foam, lotion, cream, gel, oil, powder, plaster, or eye drop.

[0021] In some embodiments, provided methods for treating certain types of alopecia 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 laser treatment.

[0022] In some embodiments, the provided technology aids in the penetration of PAI-1 inhibitors into the administration site. In some embodiments, a provided PAI-1 inhibitor (e.g., in or from a composition described herein) penetrates into the administration site within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, a 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, a 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, a 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.

[0023] In some embodiments, according to the present disclosure, the method for treating and / or preventing certain types of alopecia comprises administering a PAI-1 inhibitor composition two or more times over time.In some embodiments, the administration of the two or more administrations of the composition is separated by a specific period.In some embodiments, according to the present disclosure, the specific period for administering the composition may be longer than the specific period for administering the standard treatment regimen.

[0024] In certain embodiments, disclosed herein are kits that include compositions that contain or deliver PAI-1 inhibitors.

[0025] In some embodiments, the provided kit includes 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 includes microneedles.

[0026] In some embodiments, the provided kit includes a device for facilitating penetration of the composition into the area of ​​interest. In some such embodiments, the provided device may be or include a brush, comb, patch, roller, pen, etc.

[0027] In some embodiments, provided kit comprises instructions for administering the compositions described herein.In some embodiments, the present disclosure provides insight into administering combination therapy and / or treatment for treating or preventing the occurrence of certain types of alopecia (for example, androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, senile alopecia, etc.).In some embodiments, combination therapy or treatment comprises administering the PAI-1 inhibitor described herein in combination with one or more other active agents. In some embodiments, for example, for certain types of hair loss (e.g., androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, age-related alopecia, etc.), the one or more other active agents may be minoxidil, finasteride, dutasteride, platelet-rich plasma, cinnamic acid amidopropyltrimonium chloride, solid lipid nanoparticles, l-cysteine, l-methionine, melatonin, 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, angiotensin II, hydroxybenzoates ... The anti-inflammatory drug is selected from the group consisting of steroids, steroid hormone receptor antagonists, 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.

[0028] 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 encompass 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.

[0029] About: The term "about," when used herein in reference to a value, refers to a value similar to the referenced value in the context. Generally, a person of ordinary skill 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.

[0030] Administration: As used herein, the term "administration" refers to the administration of a composition to a subject or system to achieve delivery of an agent, typically a composition or composition contained therein. Those skilled in the art will recognize various routes that may be utilized in appropriate circumstances for administration to a subject, e.g., a human. For example, in some embodiments, administration may be intraocular, oral, parenteral, topical, etc. In certain embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, cutaneous (e.g., may be or include one or more of topical administration to the dermis, intradermal, transdermal, transdermal, etc.), enteral, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intraspecific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreous, etc. In some embodiments, administration may include only a single dose. In some embodiments, administration may include the application of a 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.

[0031] Agent: Generally, as used herein, the term "agent" 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 also 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 also be used to refer to a natural product, 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 also 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 hand of man and / or are not found in nature. In some embodiments, an agent may be utilized in isolated or pure form, and in some embodiments, an agent may be utilized in 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 that range. 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 that 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.

[0032] Agonist: Those skilled in the art will recognize that the term "agonist" can 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). Generally, an agonist can 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 activating activity. In some embodiments, an agonist can be direct (in which case the agonist exerts its effect directly on its target), and in some embodiments, an agonist can be indirect (in which case the agonist exerts its effect other than by binding to its target, e.g., by interacting with a modulator of the target such that the level or activity of the target is altered).

[0033] Antagonist: Those skilled in the art will recognize that the term "antagonist," as used herein, can be used to refer to a state or event of an agent whose presence, level, degree, type, or form correlates with a decrease in the level or activity of another agent (i.e., the agent or target being inhibited). Generally, an antagonist can 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 can be direct (in which case the antagonist exerts its effect directly on its target), and in some embodiments, the antagonist can be indirect (in which case the antagonist exerts its effect other than by binding to its target, e.g., by interacting with a modulator of the target, such that the level or activity of the target is altered).

[0034] Animal: As used herein, refers to any member of the animal kingdom. In some embodiments, "animal" refers to a human of either sex and at any stage of development. In some embodiments, "animal" refers to a non-human animal at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, and / or pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or parasites. In some embodiments, the animal may be a transgenic animal, a genetically engineered animal, and / or a clone.

[0035] 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, when administered to an organism, has a biological effect on the organism is considered to be biologically active. In some embodiments, when a substance (e.g., a polypeptide, nucleic acid, antibody, etc.) is biologically active, a portion of the substance that shares at least one biological activity of the whole substance is typically referred to as a "biologically active" portion.

[0036] Carrier: As used herein, refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, the carrier may comprise a sterile liquid, such as water, and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or comprises one or more solid ingredients.

[0037] 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, emulsion, emollient lotion, massage cream, emollient cream, makeup base, lipstick, facial pack or facial 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.

[0038] 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.

[0039] Comprising: A composition or method described herein as "comprising" one or more recited elements or steps is open-ended, meaning that 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 "consisting essentially of" (or "consists essentially of") the same recited elements or steps, i.e., that 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 "consisting of" (or "consists of") the recited elements or steps, to the exclusion of 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.

[0040] Cream: The term "cream" typically refers to a spreadable composition 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).

[0041] 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 within an aqueous dispersion medium. A "water-in-oil" dispersion is one in which aqueous particles are dispersed within 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, despite the common reference to the "aqueous" and "oil" categories.

[0042] Dosage form or unit dosage form: Those of skill 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) determined to correlate with a desired or beneficial outcome when administered to an appropriate population. Those of skill 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.

[0043] Dosing regimen: Those skilled in the art will recognize that the term "dosing regimen" can be used to refer to a series of unit doses (typically more than one), 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, which can include one or more doses. In some embodiments, a 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, a dosing regimen includes multiple doses and at least two different time periods separating the individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dosage. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a 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 amount followed by one or more additional doses of a second dosage amount that is the same as the first dosage amount. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered to an appropriate population as a whole (i.e., is a therapeutic dosing regimen).

[0044] Excipient: As used herein, refers to a non-therapeutic agent that may be included in a pharmaceutical composition to, for example, 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.

[0045] 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.

[0046] 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).

[0047] 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 several hundred nanometers to micrometers in size. As understood by those skilled in the art, macroemulsions are characterized by droplets greater than 300 nm in diameter. In some embodiments, the macroemulsion compositions utilized by the present disclosure include one or more large drugs or one or more biologically active agents. In some embodiments, the large drug included in the macroemulsion composition may be a biologically active agent. Those skilled in the art will recognize that the macroemulsion compositions utilized 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 a droplet size distribution between about 301 nm and 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 macroemulsion has a droplet size distribution between about 500 nm and about 5000 μm.

[0048] Nanoemulsion: As used herein, the term "nanoemulsion" refers to an emulsion in which at least some of the droplets have diameters in the nanometer size range. As understood by those skilled in the art, nanoemulsions are characterized by droplets with diameters of 300 nm or less. In some embodiments, the nanoemulsion compositions utilized in accordance with the present disclosure include one or more large drugs or one or more biologically active agents. In some embodiments, the large drug included in the nanoemulsion composition may be a biologically active agent. Those skilled in the art will recognize that the nanoemulsion compositions used in accordance with 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 within the range of about 1 nm to about 300 nm. In some embodiments, the nanoemulsion has a droplet size distribution between about 1 nm and about 300 nm.

[0049] 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.

[0050] Nanoparticle composition: As used herein, the term "nanoparticle composition" refers to any substance containing at least one nanoparticle. In some embodiments, a nanoparticle composition is a homogeneous collection of nanoparticles. In some embodiments, a 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 a dispersion of oily particles (or hydrophobic or non-polar) in an aqueous dispersion medium. A "water-in-oil" dispersion is a dispersion of aqueous (or hydrophilic or polar) particles 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," although commonly referring to the "aqueous" and "oil" categories, applies broadly to any dispersion medium. In some embodiments, a nanoparticle composition is a nanoemulsion. In some embodiments, a nanoparticle composition comprises micelles. In some embodiments, a nanoparticle composition is stable. In some embodiments, the nanoparticle composition comprises one or more biologically active agents delivered in conjunction 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).

[0051] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent is formulated with one or more pharmaceutically 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, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue, parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension or sustained-release formulation, topical application, e.g., as a cream, ointment, or controlled-release patch or spray applied to the skin, lungs, or oral cavity, vaginal or rectal, sublingual, ocular, transdermal, or nasal, pulmonary, and other mucosal surfaces, as a pessary, cream, or foam.

[0052] 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 penetration of a drug of interest across the skin compared to that observed in its absence. In some embodiments, the penetration enhancer is characterized by degrading and / or disrupting skin structure. In some embodiments, the penetration enhancer is or includes a chemical agent (e.g., a chemical or enzyme). For example, chemical agents that may damage, disrupt, and / or degrade 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®; AZONE® derivatives; amines and amides, such as pyrrolidone or pyrrolidone derivatives; terpenes and terpene derivatives; 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, a 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, a penetration enhancer is not an irritant. In some embodiments, a 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 structure. In some embodiments, copeptides, carrier molecules, and carrier peptides may be penetration enhancers that do not damage, destroy, and / or degrade skin structure. In some embodiments, 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 their 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.

[0053] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, that is involved in the delivery 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 pharmaceutically 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.

[0054] Prevent or prophylaxis: As used herein, when used in reference to the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder, and / or condition and / or delaying the onset of one or more characteristics or symptoms of the disease, disorder, or condition. Prevention may be considered complete if the onset of the disease, disorder, or condition has been delayed for a predefined period of time.

[0055] 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 the subject at home.

[0056] 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 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), 600 D, 500 D, 400 D, 300 D, 200 D, or 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer. In some embodiments, a small molecule does not comprise a polymer moiety. In some embodiments, a small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, the small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, the small molecule is not and / or does not comprise 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., 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., comprises 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 can 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 of skill 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 individual tautomeric forms, or in forms that interconvert between tautomeric forms. Those of skill in the art will recognize that certain small molecule compounds may contain isotopic substitutions (e.g., H to H). 2 H or 3 H, relative to 12C 11 C. 13 C or 14 C, for 14N 13 N or 15 For N, 16O 17 O or 18 O, XXC 36 Cl, XXF 18It will be recognized that small molecules have structures that tolerate isotopically modified forms (e.g., 131I for F, XXXI, etc.). In some embodiments, such small molecules may be utilized by the present disclosure in one or more isotopically modified forms or mixtures thereof. In some embodiments, a 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 pharmaceutically acceptable salt form. In some embodiments, if 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 recognize that in some embodiments, a preparation of a particular small molecule compound containing an absolute or relative amount of the compound, or a particular form thereof, that differs from the absolute or relative (e.g., relative to other components of the preparation that contain 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 different form of the compound from a racemic mixture of the compound, a particular salt of a small molecule compound may be considered a different form of the compound from another salt form of the compound, a preparation containing only a form of the compound that contains one conformer of the double bond ((Z) or (E)) may be considered a different 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 a different form, etc.

[0057] 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 predisposed 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 has one or more distinctive characteristics of risk for or susceptibility to the 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.

[0058] 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.

[0059] 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.

[0060] Therapeutically effective amount: As used herein, refers to an amount that produces the 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 via 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 the disease, disorder, and / or condition. Those skilled in the art will recognize that the term "therapeutically effective amount" does not require that successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be an amount that, when administered to patients in need of such treatment, results in a specific desired pharmacological response in a significant number of subjects. In some embodiments, reference to a therapeutically effective amount may be a reference to the amount measured in one or more specific 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.

[0061] 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 the onset of, reduces the severity of, 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 exhibit signs of the associated disease, disorder, and / or condition and / or who exhibit only early signs of the disease, disorder, and / or condition. Alternatively, or in addition, such treatment may be of subjects who exhibit 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 known to have one or more susceptibility factors that statistically correlate with an increased risk of developing the associated disease, disorder, and / or condition. DETAILED DESCRIPTION OF THE INVENTION

[0062] 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 bodily 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 diseases in multiple organ systems (e.g., heart, lung, liver, kidney, and skin).

[0063] In some embodiments, the present disclosure provides the surprising insight that PAI-1 inhibitors are effective in treating and / or preventing some types of alopecia, but not in treating and / or preventing other types of alopecia. In some embodiments, the present disclosure encompasses the surprising insight and realization that PAI-1 inhibitors may be particularly useful for treating and / or preventing certain types of alopecia (or baldness), including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senile alopecia. Furthermore, surprisingly, in some embodiments, the present disclosure provides the insight that new techniques may not be particularly useful for treating and / or preventing other types of alopecia, such as radiation-induced alopecia, chemotherapy-induced alopecia, and alopecia caused by chronic discoid lupus erythematosus. Although the hair growth cycle and physiology are well known and understood, there are currently no highly effective prevention or treatment techniques for hair loss, particularly for certain types of hair loss (or baldness), including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senile alopecia. 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, it is proposed that in some embodiments, 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 loss.

[0064] In some embodiments, the provided methods, kits, and compositions may be or include emulsions. In some embodiments, the provided methods, kits, and compositions may be or include macroemulsions. In some embodiments, the provided methods, kits, and compositions may be or include nanoemulsions. In some embodiments, the provided methods, kits, and compositions include combination therapies or treatments; for example, in some embodiments, 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-1 inhibitors or other agents).

[0065] Diseases, Disorders and Conditions The present invention provides a technique for treating and / or preventing certain types of alopecia.In some embodiments, the present invention provides a technique for treating and / or preventing diseases, disorders or conditions associated with the epidermis and / or dermis level of skin.In some embodiments, the present invention provides a technique for treating and / or preventing any one or combination of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia and senile alopecia.In some embodiments, the present disclosure provides a novel technique that may not be particularly useful for treating and / or preventing other types of alopecia, such as radiation-induced alopecia, chemotherapy-induced alopecia and alopecia caused by chronic discoid lupus erythematosus.

[0066] In some embodiments, the present invention provides techniques for treating and / or preventing one or more specific types of hair loss (or alopecia), including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia and senile alopecia, and / or combinations thereof.In some embodiments, the present invention provides techniques for treating and / or preventing specific types of hair loss (or alopecia), including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia and senile alopecia, but not treating or preventing other types of alopecia, such as radiation-induced alopecia, chemotherapy-induced alopecia and alopecia caused by chronic discoid lupus erythematosus.

[0067] Hair removal In some embodiments, provided technology is useful for treating and / or preventing hair loss.Baldness includes the condition of hair loss in areas where hair usually grows, especially on the head.The most common form of baldness is a progressive hair loss condition called androgenetic alopecia or "male pattern baldness" that occurs in adult male humans and other species.The amount and type of baldness can vary widely, ranging from male and female "pattern baldness" (also called androgenetic alopecia, male pattern baldness or androgen-type baldness), "alopecia areata" with partial hair loss from the head, "alopecia totalis" with all hair loss on the head, and in the most extreme form, "alopecia universalis" with all hair loss on the head and body.Frontal fibrosing alopecia (FFA) is characterized by slowly progressive hair loss and scarring, mainly around the forehead. In some cases, the hair loss in this type of alopecia may include eyebrows, eyelashes and / or other parts of body.Senile alopecia, also known as regression alopecia, is the hair loss caused by aging.Other types of alopecia include but are not limited to radiation-induced alopecia, chemotherapy-induced alopecia, chronic discoid lupus erythematosus alopecia, postpartum alopecia and telogen effluvium.

[0068] Current therapies used to treat hair loss include, but are not limited to, botulinum toxin, azasteroids such as finasteride (PROPECIA®, PROSCAR®, etc.) or dutasteride (AVODART®), topically administered minoxidil, vasodilators (ROGAINE®), antiandrogens (e.g., ketoconazole, fluconazole, spironolactone, etc.), platelet-rich plasma, saw palmetto, caffeine, copper peptides, nitroxide spin labels TEMPO and TEMPOL, unsaturated fatty acids (e.g., gamma-linolenic acid), hedgehog agonists, azelaic acid and zinc combinations, Polygonum multiflorum, pumpkin seed, spironolactone, tretinoin, zinc, nettle, and / or combinations thereof. Pharmaceutical compositions according to the present invention may be administered for the treatment of hair loss alone and / or in combination with these therapies used to treat the symptoms and / or causes of hair loss.

[0069] In some embodiments, the compositions provided for the treatment and / or prevention of hair loss are formulated into a suspension.

[0070] In some embodiments, compositions provided for the treatment and / or prevention of hair loss are formulated into suspensions, foams, creams, patches, lotions, gels, shampoos, conditioners, and the like.

[0071] In some embodiments, compositions provided for the treatment and / or prevention of hair loss are administered locally to the affected area (e.g., scalp, hair follicles, face, neck, back, arms, chest, etc.).

[0072] Administration of the disclosed compositions and / or formulations may be by any one of a number of routes. In some embodiments, compositions provided for the treatment and / or prevention of hair loss are administered systemically (e.g., orally). In some embodiments, administration is topical. In some embodiments, administration is oral. In some embodiments, administration is by injection.

[0073] In some embodiments, the present invention provides a method for treating hair loss in an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of hair loss by 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%, 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 hair loss.

[0074] In some embodiments, the present invention provides a method for treating hair loss in an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of hair loss by 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%, or 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 hair loss.

[0075] 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 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.

[0076] 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.

[0077] [Table 1]

[0078] 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, provided compositions may be formulated for topical and / or transdermal delivery (e.g., as lotions, creams, patches, ointments, powders, gels, eye drops, etc.). In some embodiments, provided compositions may be or include nanoemulsions. In some embodiments, provided compositions may be or include macroemulsions.

[0079] The nanoparticle compositions are useful in a variety of contexts and have proven particularly useful and / or effective in the context of medical applications involving the 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 topical 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). See US09 / 48972, the entire contents of which are incorporated herein by reference).

[0080] In some embodiments, provided nanoparticle compositions have the specific components and / or relative amounts of components described herein. In some embodiments, 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 commonly been associated with nanoparticle compositions are described in the following paragraphs. In some embodiments, provided nanoparticle compositions have one or more of these attributes. In some embodiments, provided nanoparticle compositions have none of these attributes.

[0081] Generally, a nanoparticle composition is any composition comprising at least one nanoparticle. In some embodiments, the nanoparticle composition comprises at least one known therapeutic agent and / or independently active biologically active agent (e.g., a 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, associated with the interface of the nanoparticle, and / or 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 adsorptive forces. In some embodiments, the nanoparticle composition comprises empty nanoparticles (e.g., nanoparticles that do not contain any known therapeutic agent and / or independently active biologically active agent).

[0082] In some embodiments, the nanoparticle composition is stable. In some embodiments, the nanoparticle composition is uniform. For example, in some embodiments, the difference between the minimum diameter and the maximum diameter of the nanoparticles in the nanoparticle composition is not more than 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, or about 100 nm, about 90 nm, about 80 nm, about 70 nm, about 60 nm, about 50 nm or less.

[0083] 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.

[0084] 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.

[0085] In some embodiments, the entire particle distribution falls within a particular particle size range. In some embodiments, less than 50%, 25%, 10%, 5%, or 1% of the entire particle distribution falls outside a particular particle size range. In some embodiments, less than 1% of the entire particle distribution falls outside a particular particle size range. 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 has a diameter greater than 300 nm, 250 nm, 200 nm, 150 nm, 120 nm, 100 nm, 75 nm, 50 nm, or 25 nm.

[0086] 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 nm, 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.

[0087] 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, a majority 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.

[0088] 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.

[0089] In some embodiments, the nanoparticle composition is substantially free of particles having a diameter greater than 500 nm. Specifically, 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] In some embodiments, about 50% of the nanoparticles in a 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 a 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 a 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 a 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 a 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 a provided composition have a diameter (e.g., average and / or median diameter) between 10 nm and 150 nm.

[0098] 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 a provided composition comprises or consists of nanoparticles having a diameter between 10 nm and 150 nm.

[0099] 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 within an aqueous dispersion medium). In some embodiments, the nanoparticle composition is a "water-in-oil" dispersion (i.e., a dispersion of aqueous particles within an oily dispersion medium).

[0100] 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.

[0101] 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 non-homogeneous, utilize one or more toxic (e.g., organic) solvents, and / or utilize one or more polymers.

[0102] 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., the percentage of particles above a specified size and / or outside a specified size range) 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 a stated range (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.

[0103] As described herein, the provided compositions 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 one skilled in the art for the disease, disorder, or condition of interest. In some embodiments, routes may be utilized, including oral (PO), intravenous (IV), intramuscular (IM), intraarterial, intramedullary, intrathecal, subcutaneous (SQ), intracerebroventricular, transdermal, intracutaneous, intradermal, rectal (PR), vaginal, intraperitoneal (IP), intragastric (IG), topical and / or transdermal (e.g., via lotions, creams, powders, ointments, poultices, gels, eye drops, etc.), mucosal, intranasal, buccal, enteral, intravitreal, and / or sublingual administration, intratracheal instillation, bronchial instillation, and / or inhalation, as oral spray, nasal spray, and / or aerosol, and / or via a portal vein catheter, and / or any combination of the foregoing. In most embodiments, administration is topical, parenteral, or oral, as described herein.

[0104] Formulations of the provided compositions may be prepared by any suitable method known in the art. Generally, such preparation methods include bringing the provided compositions into association with one or more excipients, and then, if necessary and / or desired, shaping and / or packaging them into a form suitable for administration, such as a single or multiple dose unit or in these units.

[0105] 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 typically administered to a subject, and / or a convenient fraction of such dosage, such as, for example, half or one-third of such dosage.

[0106] In some embodiments, suitable excipients for use in a composition (e.g., a pharmaceutically and / or cosmetically suitable composition) may include, for example, one or more excipients such as solvents, dispersion media, granulation media, diluents or other liquid vehicles, dispersing or suspending aids, surface active agents and / or emulsifiers, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, disintegrants, binding agents, preservatives, buffers, etc., appropriate for the particular dosage form desired. In some embodiments, excipients such as cocoa butter and / or suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and / or fragrances may be utilized. See Remington's The Science and Practice of Pharmacy, 21 st Edition, A.R. 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.

[0107] In some embodiments, suitable excipients (e.g., pharmaceutically 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.

[0108] In some embodiments, provided compositions are formulated as cream, plaster, ointment, oil, foam, spray, lotion, liquid, powder, thickened lotion or gel (for example, formulated for transdermal delivery as described herein).Certain exemplary formulations of this type can be prepared as cosmetic formulation products, such as emollient, nourishing lotion-type emulsion, cleansing lotion, cleansing cream, emulsion, emollient lotion, massage cream, emollient cream, makeup base, facial pack or facial gel, shampoo, rinse, body cleanser, hair tonic or soap, or skin composition, such as lotion, ointment, gel, cream, plaster, patch, deodorant or spray.

[0109] The present disclosure embraces the recognition that emulsion technology can provide stabilization advantages for target drugs, including the PAI-1 inhibitors described herein.Furthermore, both macro- and nano-emulsions can be used to prepare formulations for administering PAI-1 inhibitors as treatments for treating and / or preventing any one or a combination of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senile alopecia.In some embodiments, the present disclosure provides a novel technology that may not be particularly useful for treating and / or preventing other types of alopecia, such as radiation-induced alopecia, chemotherapy-induced alopecia, and alopecia caused by chronic discoid lupus erythematosus.In some specific embodiments, the formulation can be a topical formulation.In some specific embodiments, the formulation can be an injectable formulation.In some specific embodiments, the formulation can be an oral formulation.

[0110] In some embodiments, provided compositions comprise provided nanoemulsion compositions. In some embodiments, provided compositions are cream and / or lotion formulations. In some embodiments, provided cream and / or lotion formulations comprise nanoemulsion compositions. In some embodiments, compositions comprise provided nanoemulsion compositions but are not cream and / or lotion formulations. In some embodiments, suitable compositions are formulated into creams and / or lotions but do not comprise nanoemulsion compositions.

[0111] In some embodiments, provided compositions comprise a mixture of a provided nanoemulsion composition and one or more pharmaceutically acceptable excipients, for example, for topical and / or transdermal administration (e.g., via lotion, cream, powder, ointment, plaster, gel, eye drops, etc.).

[0112] emulsion In some embodiments, the present disclosure provides a surprisingly effective technique for administering and delivering PAI-1 inhibitor.In some embodiments, the present disclosure teaches topical, oral and / or injectable formulations and compositions of such PAI-1 inhibitor for hair growth and / or hair regeneration for the subjects who suffer from or have a predisposition to, or are in the early stage of, androgenetic alopecia, alopecia areata, frontal fibrosing alopecia and senile alopecia.In some embodiments, the present disclosure teaches the method for treating and / or preventing one or more conditions of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia and senile alopecia by administering PAI-1 inhibitor formulations and / or compositions to the subjects who need it.In some embodiments, formulations and / or compositions comprise emulsions.

[0113] Furthermore, this 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 Nos. 2012 / 0328701, 2012 / 0328702, 8,318,181, and 8,658,391, the entire disclosures of which are incorporated herein by reference. These liquid nanoemulsions are far superior to solid nanoparticle drug delivery, particularly transdermal drug delivery, where solid nanoparticles cannot penetrate the skin and only accumulate in hair follicles, as described by Gomaa. These liquid nanoemulsions are also stable for at least 34 months, making them commercially viable.

[0114] Macroemulsion In some embodiments, the present invention utilizes macroemulsion compositions comprising PAI-1 inhibitors that are particularly effective and / or useful for treating certain types of hair loss, including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senile alopecia. 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 composition may be comprised of one or more PAI-1 inhibitors.

[0115] 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 eye drops.

[0116] 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.

[0117] In some embodiments, provided compositions comprise a mixture of a provided macroemulsion composition and one or more pharmaceutically acceptable excipients. In some embodiments, cream and / or lotion formulations comprise a mixture of a provided macroemulsion composition and / or saline.

[0118] In some embodiments, provided compositions comprise a macroemulsion composition comprising one or more PAI-1 inhibitors. In some embodiments, provided compositions are cream and / or lotion formulations. In some embodiments, provided cream and / or lotion formulations comprise a macroemulsion composition. In some embodiments, a composition comprises a provided macroemulsion composition but is not a cream and / or lotion formulation. In some embodiments, suitable compositions are formulated into creams and / or lotions but do not comprise a macroemulsion composition.

[0119] In some embodiments, provided compositions comprise a mixture of a provided macroemulsion composition and one or more pharmaceutically acceptable excipients, for example, for topical and / or transdermal administration (e.g., via lotions, creams, powders, ointments, patches, gels, eye drops, etc.).

[0120] 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, plaster, gel, or eye drops. In some embodiments, the macroemulsion may be formulated into an injectable composition. In some embodiments, the injectable composition may be sterile.

[0121] Macroemulsion formulations can act to stabilize active agents and / or therapeutic agents, such as PAI-1 inhibitors. While 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 can be provided by incorporation into macroemulsion compositions achieves a synergistic enhancement of transdermal delivery.

[0122] Nanoemulsion In some embodiments, the present invention utilizes nanoemulsion compositions comprising PAI-1 inhibitors that are particularly effective and / or useful for treating certain types of hair loss, including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and age-related alopecia. 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.

[0123] In some embodiments, provided nanoemulsion compositions comprise an oil and surfactant in a ratio ranging from about 0.1:1 to about 2:1. In some embodiments, provided nanoemulsion compositions comprise an oil and surfactant in a ratio of about 0.1:1 to about 1:1. In some embodiments, provided nanoemulsion compositions comprise an oil and surfactant in a ratio of about 0.5:1 to about 1:1. In some embodiments, provided nanoemulsion compositions comprise an oil and surfactant in a ratio of about 0.5:1 to 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.

[0124] In some embodiments, the aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) and 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 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 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 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.

[0125] 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 in the 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.

[0126] In some embodiments, the entire droplet distribution falls within a specified range of droplet diameter sizes. In some embodiments, less than 50%, 25%, 10%, 5%, or 1% of the entire droplet distribution falls outside a specified range of droplet diameter sizes. In some embodiments, less than 1% of the entire droplet distribution falls outside a specified range of droplet diameter sizes. 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.

[0127] 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 nm, 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.

[0128]

[0159] In some embodiments, the nanoemulsion droplets have a zeta potential ranging from -80 mV to +80 mV. In some embodiments, the nanoemulsion droplets have a zeta potential ranging from -50 mV to +50 mV. In some embodiments, the nanoemulsion droplets have a zeta potential ranging from -25 mV to +25 mV. In some embodiments, the nanoemulsion droplets have a zeta potential ranging from -10 mV to +10 mV. In some embodiments, the nanoemulsion droplets have a zeta potential of about -80 mV, about -70 mV, about -60 mV, 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 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.

[0129] In some embodiments, the aqueous dispersion medium and surfactant are utilized in a ratio ranging from about 8:1 to 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.

[0130] In some embodiments, the aqueous dispersion medium and oil are utilized in a ratio ranging from about 12:1 to about 14:1. In some embodiments, the aqueous dispersion medium and 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 surfactant are utilized in a ratio of about 13.1:1.

[0131] In some embodiments, the percent oil in the nanoemulsion ranges between 0% and 50%. In some embodiments, the percent oil in the nanoemulsion ranges between 0% and 40%. In some embodiments, the percent oil in the nanoemulsion ranges between 0% and 30%. In some embodiments, the percent oil in the nanoemulsion ranges between 0% and 20%. In some embodiments, the percent oil in the nanoemulsion ranges between 0% and 10%. In some embodiments, the percent oil in the nanoemulsion ranges between 0% and 5%. In some embodiments, the percent 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 percent 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 percent oil in the nanoemulsion ranges between 20% and 30%, between 20% and 40%, or between 20% and 50%. In some embodiments, the percent oil in the nanoemulsion ranges between 30% and 40%, or between 30% and 50%. In some embodiments, the percent oil in the nanoemulsion ranges between 40% and 50%.

[0132] 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%.

[0133] 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.

[0134] 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 eye drops. In some embodiments, the nanoemulsions may be formulated into injectable compositions. In some embodiments, the injectable compositions may be sterile.

[0135] These compositions are particularly useful in that they can be used to deliver drugs to a subject in need thereof by topical and / or transdermal administration (e.g., via lotions, creams, powders, ointments, poultices, gels, eye drops, etc.). In some embodiments, provided cream and / or lotion formulations may be administered to a subject in need thereof by topical and / or transdermal administration (e.g., via lotions, creams, powders, ointments, poultices, gels, eye drops, etc.). In some embodiments, provided nanoemulsion compositions may be formulated into cream and / or lotion formulations. In some embodiments, provided cream and / or lotion formulations comprising a nanoemulsion composition may be useful and / or effective for topical administration to a subject. In some embodiments, 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) to prepare a pharmaceutical composition.

[0136] 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 provided cream and / or lotion formulations may be particularly useful for formulating emulsions, such as those described herein, for administration to a subject.

[0137] Topical preparations The compositions described herein are particularly useful in that they can be used to deliver PAI-1 inhibitors to a subject in need thereof by topical and / or transdermal administration (e.g., via lotions, creams, powders, ointments, patches, gels, eye drops, etc.). In some embodiments, provided cream and / or lotion formulations comprising PAI-1 inhibitors are administered to a subject in need thereof by topical administration (e.g., via lotions, creams, powders, ointments, patches, gels, eye drops, etc.). In some embodiments, the topical formulation comprises a macroemulsion described herein. In some embodiments, the topical formulation comprises a nanoemulsion described herein.

[0138] 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.

[0139] In some embodiments, the present invention provides certain cream and / or lotion formulations 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.

[0140] In some embodiments, the cream and / or lotion formulations may be useful for topical and / or transdermal administration. The present invention encompasses the recognition that, in some embodiments, the provided cream and / or lotion formulations may be particularly useful for delivering PAI-1 inhibitors to, for example, hair follicles located at the administration site. In some embodiments, the treated area includes areas that previously had hair or hair follicles but no longer have hair or hair follicles. In some embodiments, the provided cream and / or lotion formulations are formulated for topical delivery to a subject in need thereof. In some embodiments, the provided cream and / or lotion formulations are administered to a subject in need thereof by topical delivery.

[0141] In some embodiments, the provided compositions are formulated with cosmetically acceptable ingredients. For example, in some embodiments, the provided compositions are formulated with water and any cosmetically acceptable solvent, particularly 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 90% by weight of the total composition.

[0142] 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 whom the composition is administered (e.g., a matte appearance, which may be particularly desirable or suitable for administration to subjects with oily skin).

[0143] In some embodiments, provided compositions are formulated with at least one cosmetically acceptable filler material to achieve a matte product, which may be particularly desirable, for example, for individuals with oily skin.

[0144] 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, provided compositions may be formulated and delivered in combination with microneedle skin conditioning (MSC) to achieve systemic delivery. In some embodiments, provided compositions may be formulated and / or delivered to achieve local, but not systemic, delivery.

[0145] In some embodiments, compositions suitable for topical formulations include a penetration enhancer. In some embodiments, the penetration enhancer degrades, destroys, and / or damages skin structure and / or skin. In some embodiments, the penetration enhancer does not degrade, destroy, and / or damage skin structure and / or skin. In some embodiments, the penetration enhancer is an irritant. In some embodiments, the penetration enhancer is not an irritant.

[0146] 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 readily 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 applied to the skin.

[0147] Those skilled in the art will recognize that the provided compositions may be incorporated into a device such as a patch. Various 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.

[0148] In some embodiments, the transdermal patch comprises an adhesive. Some examples of adhesive patches are well 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 patient's skin, a depot or reservoir for holding the provided composition, and an outer surface that prevents the provided composition from leaking from the reservoir. The outer surface of the patch may be non-adhesive.

[0149] According to the present invention, the provided composition is incorporated into a 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 from the matrix and the patch. The provided composition may also be incorporated into an adhesive layer of the patch so that the provided composition can diffuse through the skin when the patch is applied to the skin. In some embodiments, the adhesive layer may be heat-activated, where the adhesive gradually liquefies at a temperature of about 37°C so that the agent can diffuse through the skin. The adhesive can remain adhesive when stored below 37°C, and when applied to the skin, the adhesive liquefies and loses its adhesiveness.

[0150] In some embodiments, the provided composition can be provided in a reservoir of the patch, so that the provided composition can be guided out of the patch through the microneedle and the stratum corneum by the pressure applied to the patch.The exemplary embodiment of the microneedle is described above.Suitable devices for 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.The intradermal composition can be administered by a device that limits the effective penetration length of the needle into the skin, such as those described in PCT Publication WO99 / 34850 and its functional equivalents.

[0151] In some embodiments, it may be desirable to slow 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 may 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 properties of the specific polymer used.Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).

[0152] Injectable preparations Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated by known techniques using suitable dispersants, wetting agents, and / or suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, and / or emulsions in non-toxic parenterally acceptable diluents and / or solvents, for example, solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include 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 also be used in the preparation of injectables.

[0153] 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.

[0154] To prolong the effect of a provided composition, it may be desirable to slow the absorption of the provided composition from subcutaneous or intramuscular injection. This can be achieved 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 depends on the dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered provided composition form can be achieved 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. The release rate of the provided composition can be controlled depending on the ratio of the provided composition to polymer and the nature of the particular polymer employed. 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.

[0155] Oral formulation Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, provided compositions are mixed with at least one inert pharmaceutically acceptable excipient and / or filler or extender such as sodium citrate or dicalcium phosphate (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid), binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia), humectants (e.g., glycerol), disintegrating agents (e.g., agar, calcium carbonate, potato starch, tapioca starch, alginic acid, certain silicates, and sodium carbonate), solution inhibitors (e.g., paraffin), absorption accelerators (e.g., quaternary ammonium compounds), humectants (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 form may also comprise buffering agents.

[0156] 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. Solid dosage forms such as 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 formulating 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 an appropriately 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.

[0157] Administration The present invention provides techniques for treating certain types of hair loss, including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia and senile alopecia, using any of the provided compositions described herein (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, provided compositions are administered in combination with MSCs.

[0158] 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 a provided composition to a subject in need thereof.

[0159] part According to the present disclosure, PAI-1 inhibitors may be administered to target areas for the treatment and / or prevention of any one or combination of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senile alopecia.In some embodiments, PAI-1 inhibitors may not be particularly useful for the treatment and / or prevention of other types of alopecia, such as radiation-induced alopecia, chemotherapy-induced alopecia, and alopecia caused by chronic discoid lupus erythematosus.

[0160] The technology of the present invention is suitable for both human and veterinary use.In some embodiments, the subject suffering from any one or combination of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia and senile alopecia, which can be benefited from topical, oral and / or injectable administration of PAI-1 inhibitor, can be treated by the technology disclosed.In some embodiments, the subject suffering from any one or combination of other types of alopecia, such as radiation-induced alopecia, chemotherapy-induced alopecia and alopecia caused by chronic discoid lupus erythematosus, which can not be benefited from topical, oral and / or injectable administration of PAI-1 inhibitor, can not be treated by the technology disclosed.

[0161] 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 a 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 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. In some embodiments, the site previously had hair or hair follicles but no longer has hair or hair follicles.

[0162] 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-bearing follicles 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%, or 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.

[0163] In some embodiments, the hair in the hair follicle is not gray. In some embodiments, the hair in the hair follicle is gray. In some embodiments, the percentage of gray 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%, 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 115%, about 116%, about 117%, about 118%, about 119%, about 1 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.

[0164] In some embodiments, the site is affected by a skin condition.

[0165] 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.

[0166] 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 MNs or MN arrays. In some embodiments, the MSCs comprise 15 presses of MNs or MN arrays. In some embodiments, the MSCs comprise 16 presses of MNs or MN arrays. In some embodiments, the MSCs comprise 17 presses of MNs or MN arrays. In some embodiments, the MSCs comprise 18 presses of MNs or MN arrays. In some embodiments, the MSCs comprise 19 presses of MNs or MN arrays. In some embodiments, the MSCs comprise 20 presses of MNs or MN arrays. In some embodiments, the MSCs comprise rotating the MNs or MN arrays on the skin one or more times. In some embodiments, the MN array is rotated between presses. In some embodiments, the MN array is not rotated between presses. In some embodiments, the presses are performed at the same site. In some embodiments, the presses are performed at overlapping sites. In some embodiments, the presses are performed at different sites. In some embodiments, the presses are performed by stamping the MN array. In some embodiments, the pressure is applied by rolling the microneedle roller over the site one or more times.According to 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, such as 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.

[0167] 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 particular type of alopecia disclosed herein). In some embodiments, the subject is predisposed to a disease, disorder, or condition (e.g., a particular type of alopecia disclosed herein). In some embodiments, the subject exhibits one or more symptoms or characteristics of a disease, disorder, or condition (e.g., a particular type of alopecia disclosed herein). In some embodiments, the subject does not exhibit symptoms or characteristics of a disease, disorder, or condition (e.g., a particular type of alopecia disclosed herein). In some embodiments, the subject has one or more specific characteristics or risk of being susceptible to disease, disorder or condition (for example, the specific type of alopecia disclosed herein).In some embodiments, the subject is a patient.In some embodiments, the subject is the individual who is administered and / or has been administered diagnosis and / or treatment.

[0168] The technology of the present invention is suitable for both human and veterinary use.In some embodiments, the subject suffering from any one or combination of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia and senile alopecia, which can be benefited from topical, oral and / or injectable administration of PAI-1 inhibitor, can be treated by the technology disclosed.In some embodiments, the subject suffering from any one or combination of other types of alopecia, such as radiation-induced alopecia, chemotherapy-induced alopecia and alopecia caused by chronic discoid lupus erythematosus, which can not be benefited from topical, oral and / or injectable administration of PAI-1 inhibitor, can not be treated by the technology disclosed.

[0169] 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 skin overlying a muscle or muscle group of a 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 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.

[0170] In some embodiments, the present invention provides methods of administering a provided composition by any delivery route, including, but not limited to, oral (PO), intravenous (IV), intramuscular (IM), intra-arterial, intramedullary, intrathecal, subcutaneous (SQ), intracerebroventricular, transdermal, transcutaneous, intradermal, rectal (PR), vaginal, intraperitoneal (IP), intragastric (IG), topical and / or transdermal (e.g., by lotion, cream, plaster, ointment, powder, gel, eye 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.

[0171] In some embodiments, provided methods involve topical, transdermal, or intradermal administration of a provided composition to the skin of a subject. In some embodiments, such routes achieve localized delivery.

[0172] In certain embodiments, provided methods 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.

[0173] 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.

[0174] In some embodiments, the biologically active agent (e.g., a PAI-1 inhibitor) penetrates into the skin layers 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 skin layers within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 1 hour of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 2 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 3 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 4 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 5 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 6 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 7 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 8 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 12 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 24 hours of administration.

[0175] In some embodiments, the biologically active agent penetrates into the upper 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 upper layers of the skin within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 1 hour of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 2 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 3 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 4 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers 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.

[0176] 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.

[0177] Regimen Generally, 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 the multiple administration routes described herein (e.g., topically, orally, by injection) sufficient to achieve delivery of an effective amount of the biologically active agent (e.g., a PAI-1 inhibitor).

[0178] In some embodiments, the dosing regimen for a particular active agent (e.g., one or more PAI-1 inhibitors) may involve intermittent or continuous (e.g., via 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.

[0179] In some embodiments, different agents administered in a combination may be administered by different delivery routes and / or according to different schedules. Alternatively or additionally, 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.

[0180] 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., 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 professionals. 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, and location of the cancer.

[0181] 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, for example, optimize a desired therapeutic effect or response (e.g., inhibition of the PAI-1 gene or gene product).

[0182] Generally, the type, amount, and frequency of administration of an active agent according to the present invention are dictated by the safety and efficacy requirements applicable when one or more appropriate agents are administered to a mammal, preferably a human. Generally, such characteristics of administration are selected to produce 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 the PAI-1 gene and / or gene product, inhibition and / or reduction of the severity and / or prevalence of associated alopecia, including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senile alopecia. Such criteria may be readily assessed by any of a variety of immunological, cytological, and other methods disclosed in the literature.

[0183] In some embodiments, an effective amount (and / or unit dose) of an 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 cycle, or as a result of dose escalation protocols that can be used to determine the maximum tolerated dose and dose-limiting toxicities (if any) associated with administering increasing doses of the PAI-1 antagonist and / or additional therapeutic agent. Consequently, the relative amounts of each agent within the pharmaceutical composition may vary; for example, each composition may contain between 0.001% and 100% (w / w) of the corresponding agent.

[0184] In some embodiments, a "therapeutically effective amount" or "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 alleviates one or more symptoms of a condition. In some embodiments, a therapeutically effective amount may also 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 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 of skill in the art.

[0185] In some embodiments, the toxicity and / or therapeutic efficacy of a PAI-1 antagonist can be assessed using, for example, 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 toxic and therapeutic effects is the therapeutic index. In some embodiments, this ratio is the MTD / 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.

[0186] 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 affected or alternative tissues. For example, cell culture or animal studies may be used to determine the relationship between the dose required for changes in pharmacodynamic markers, 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 at an ED level with little or no toxicity. 50 In some embodiments, the dosage may vary within such a range, 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 consideration 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.

[0187] In some embodiments, dosage and / or interval may be individually adjusted, for example, to produce plasma levels of the active moiety sufficient to maintain the desired effect or minimum 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 the route of administration. In some embodiments, plasma concentrations may be determined using high-performance liquid chromatography (HPLC) assays or bioassays.

[0188] In some embodiments, dosing intervals can 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% of the time, and most preferably 50-90% of the time, until the desired symptomatic improvement 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 plasma concentration.

[0189] 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, the subject's weight, the severity of the affliction, the manner of administration, and / or the judgment of the prescribing physician.

[0190] In some embodiments, the present invention provides a method for treating hair loss by administering a dosing regimen sufficient to achieve a reduction in the severity and / or prevalence of the specific type of hair loss involved (e.g., androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and age-related alopecia) of at least about 20%, and in some embodiments, by administering a dosing regimen sufficient to achieve a reduction of at least about 25%, and in some embodiments, by administering a dosing regimen sufficient to achieve a reduction of at least about 30%, and in some embodiments, by administering a dosing regimen sufficient to achieve a reduction 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% ,approximately 45%,approximately 46%,approximately 47%,approximately 48%,approximately 49%,approximately 50%,approximately 51%,approximately 52%,approximately 53%,approximately 54%,approximately 55%,approximately 56%,approximately 57%,approximately 58%,approximately 59%,approximately 60%,approximately 61%,approximately 62%,approximately 63%,approximately 64%,approximately 65%,approximately 66%,approximately 67%,approximately 68%,approximately 69%,approximately 70%,approximately 71%,approximately 72%, This includes administration of at least one provided composition administered in a dosing regimen sufficient to achieve about a 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 greater reduction.

[0191] In some embodiments, the present invention provides a method for treating hair loss by administering a dosing regimen sufficient to achieve a reduction in the severity and / or prevalence of the specific type of hair loss involved (e.g., androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and age-related alopecia) of at least about 20%, and in some embodiments, by administering a dosing regimen sufficient to achieve a reduction of at least about 25%, and in some embodiments, by administering a dosing regimen sufficient to achieve a reduction of at least about 30%, and in some embodiments, by administering a dosing regimen sufficient to achieve a reduction 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%. ,approximately 46%,approximately 47%,approximately 48%,approximately 49%,approximately 50%,approximately 51%,approximately 52%,approximately 53%,approximately 54%,approximately 55%,approximately 56%,approximately 57%,approximately 58%,approximately 59%,approximately 60%,approximately 61%,approximately 62%,approximately 63%,approximately 64%,approximately 65%,approximately 66%,approximately 67%,approximately 68%,approximately 69%,approximately 70%,approximately 71%,approximately 72%,approximately 73%,approximately 74 The present invention includes administering at least one provided composition in combination with MSCs in a dosing regimen sufficient to achieve a reduction of 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.

[0192] In some embodiments, the present invention provides a method for treating hair loss by administering a dosing regimen sufficient to achieve a reduction in the extent and / or prevalence of the particular type of hair loss (e.g., androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and age-related alopecia) of 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 a reduction of 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 a reduction of 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 a reduction 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 9 34%, approximately 35%, approximately 36%, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, The invention includes administering at least one provided composition, optionally in combination with MSCs, in a dosing regimen sufficient to achieve 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 greater reduction. 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 present invention comprises the administration of at least one provided composition in a dosage regimen sufficient to achieve a reduction in the severity and / or prevalence of the relevant specific type of hair loss (e.g., androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senile alopecia) by at least about 20% in at least about 50% of the patient population to which the composition is administered. In some embodiments, the present invention comprises the administration of at least one provided composition in a dosage regimen sufficient to achieve a reduction in the severity and / or prevalence of the relevant specific type of hair loss (e.g., androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senile alopecia) by at least about 30% in at least about 50% of the patient population to which the composition is administered.

[0193] The present invention provides techniques for treating a condition or disorder by administering to a patient a provided composition described herein (e.g., provided emulsion compositions, cream and / or lotion formulations, combinations of provided emulsion compositions and cream and / or lotion formulations, etc.), optionally in combination with MSCs. 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 described herein, optionally in combination with MSCs.

[0194] 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.

[0195] In some embodiments, the biologically active agent (e.g., a PAI-1 inhibitor) penetrates into the skin layers 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 skin layers within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 1 hour of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 2 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 3 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 4 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 5 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 6 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 7 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 8 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 12 hours of administration. In some embodiments, the biologically active agent penetrates into the skin layers within about 24 hours of administration.

[0196] In some embodiments, the biologically active agent penetrates into the upper 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 upper layers of the skin within about 5 to about 60 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 5 to about 12 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 5 to about 15 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 15 to about 30 minutes of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 1 hour of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 2 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 3 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers of the skin within about 4 hours of administration. In some embodiments, the biologically active agent penetrates into the upper layers 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.

[0197] 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.

[0198] Penetration enhancement treatment According to the present invention, in some embodiments, 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, a PAI-1 inhibitor across a biological barrier (e.g., skin). In some embodiments, 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 comprises simultaneous administration of two or more different penetration enhancing treatments and / or penetration enhancing treatment methods. In some embodiments, the penetration enhancing treatment comprises simultaneous exposure to two or more different penetration enhancing treatments and / or penetration enhancing treatment methods, for example, by simultaneous administration of laser treatment and the composition.

[0199] 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, for example, alcohols such as short-chain alcohols, long-chain alcohols, or polyalcohols, urea, amino acids or their esters, amides, AZONE®, AZONE® derivatives, amines and amides such as pyrrolidone or pyrrolidone derivatives, terpenes and terpene derivatives, 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 can cause inflammatory and / or allergic reactions when administered to the skin. In some embodiments, the penetration enhancer is not an irritant. In some embodiments, a 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 a target agent through the skin compared to that observed in its absence. In some embodiments, copeptides, carrier molecules, and carrier peptides may be penetration enhancers that do not damage, destroy, and / or degrade skin structures. In some embodiments, 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 their equivalents (e.g., other damaging treatments). Additionally, 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 a target agent that may be associated with the structure. In some embodiments, the penetration enhancer is or includes an alcohol.

[0200] 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.

[0201] Microneedling: In certain 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 hypodermic needles and to improve patient comfort and compliance. Such disadvantages include, for example, the potential for needle tip misplacement associated with hypodermic needles due to the medical professional's inability to visualize the needle's exact destination, which can lead to adverse reactions when injected incorrectly. MNs are less susceptible to such problems. Other advantages of MNs are that they do not cause bleeding, minimize the introduction of pathogens through pores created by MNs, and potentially eliminate the variability of transdermal medication. Other advantages include the ability to self-administer, reduced risk of needlestick injuries, reduced risk of transmitted infections, and easy disposal. In some embodiments, the MNs are multiple microprojections assembled on one side of a support such as a patch or device (e.g., stamp, roller, array, applicator, pen).

[0202] In some embodiments, MNs used according to 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 a length, width, and shape suitable for minimizing 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).

[0203] In some embodiments, suitable MNs may be solid, coated, porous, dissolvable, 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 coated drugs into the skin (e.g., the "coat and poke" method). Dissolvable 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 microneedle holes (e.g., the "poke and flow" method). In the case of dissolvable MNs, the MNs can act as a drug reservoir, retaining the drug composition until released by dissolution in the case of dissolvable MNs or 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 with, loaded with, or fabricated with a biologically active agent in any manner that achieves delivery of the biologically active agent. Alternatively, in some embodiments, as described herein, MNs (whether MSCs or otherwise) utilized by the present disclosure may contain and / or deliver a biologically active agent when the biologically active agent is formulated in a macro- or nanoemulsion composition described herein. Thus, as will be recognized by those skilled 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 microneedles, by release of a microneedle coating, or by release from a dissolving microneedle) is not microneedle skin conditioning.

[0204] In some embodiments, the microneedle has a consistent diameter throughout its length. In some embodiments, the diameter of the microneedle is greatest at the proximal end of the microneedle. In some embodiments, the microneedle tapers to a narrow point distal to 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 1,500 μm.

[0205] In some embodiments, MNs used in accordance with 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, MNs may be fabricated using various types of biocompatible materials, including polymers, metals, ceramics, semiconductors, organics, composites, or silicon. In some embodiments, unless designed to detach and dissolve within the skin, the microneedles have the mechanical strength to remain intact during insertion into and / or removal from the skin after insertion, and to deliver drugs or collect biological fluids. In some embodiments, 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), copolymer of methyl vinyl ether and maleic anhydride, sodium hyaluronate, carboxymethylcellulose, maltose, dextrin, galactose, starch, gelatin, or a combination thereof.

[0206] Suitable MN array and MSC devices for use in combination with compositions containing biologically active agents for transdermal delivery of biologically active agents include devices such as those described in U.S. Patents 6,334,856, 6,503,231, 6,908,453, 8,257,324, and 9,144,671.

[0207] Combination Therapies or Procedures According to the present invention, 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, 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, combination therapy involves simultaneous administration of one or more doses or units of two or more other active agents and / or therapies. In some embodiments, combination therapy involves simultaneous exposure to two or more other active agents and / or therapies, for example, by overlapping dosing regimens.

[0208] In some embodiments, provided compositions comprise or are administered in combination with one or more other active agents useful in treating certain types of associated hair loss (e.g., androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and age-related alopecia), e.g., as discussed herein in the context of associated diseases, disorders, and / or conditions.

[0209] kit In some embodiments, the present invention provides pharmaceutical packs or kits 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 packs or kits comprise preparations or pharmaceutical compositions containing the provided compositions in one or more containers, which may be filled with one or more additional ingredients of the pharmaceutical composition. In some embodiments, the pharmaceutical packs or kits comprise an additional approved therapeutic agent for use in combination therapy. In some embodiments, such containers may be accompanied by a notice reflecting approval by the government agency regulating the manufacture, use, or sale of pharmaceutical products for human administration, in a form prescribed by the agency.

[0210] Kits are provided that include therapeutic reagents and / or active agents, such as PAI-1 inhibitors. As just one non-limiting example, the provided compositions may be provided as topical formulations and administered as a treatment. Pharmaceutical dosages or instructions for administration to individuals suffering from or at risk of a condition or disorder, such as one associated with the dermal level of the skin, may be provided within the kit.

[0211] In some embodiments, the kit may include (i) a provided composition, and (ii) at least one pharmaceutically acceptable excipient, and optionally (iii) at least one syringe, spatula, or swab for administration to the skin, and (iv) instructions for use.

[0212] In some embodiments, the kit may include (i) a provided composition, and (ii) at least one pharmaceutically 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.

[0213] Those skilled in the art will recognize that compositions of the present invention for topical administration can have a cosmetic formulation such as an emollient, a nourishing lotion-type emulsion, a cleansing lotion, a cleansing cream, an emulsion, an emollient lotion, a massage cream, an emollient cream, a makeup base, a facial pack or gel, a cleansing formulation such as a shampoo, a rinse, a body cleanser, a hair tonic or soap, or a dermatological composition such as a lotion, ointment, gel, cream, patch, or spray. In some embodiments, the composition for topical administration is not formulated for administration to a mucosal membrane (e.g., is unsuitable for administration to a mucosal membrane and / or is not formulated to deliver an adequate amount of drug to or across a mucosal membrane). [Example]

[0214] Example 1: Effect of a topical PAI-1 inhibitor formulation on certain types of hair loss (alopecia) A topical study of a topical PAI-1 inhibitor formulation is conducted in men after topical administration of a topical PAI-1 inhibitor formulation (see, for example, Table 1). The study is designed to test whether a topical PAI-1 inhibitor formulation significantly reduces hair loss in men with specific types of alopecia, namely, androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senile alopecia, by measuring hair follicle density after topical treatment with a PAI-1 inhibitor.

[0215] The study included four groups of human subjects. Each of the four groups consisted of a subgroup of 25 human subjects (see Table 2). All groups included subjects with varying levels of hair follicle density and varying hair count and / or density. The scalp of each subject in Groups I and II was topically treated twice daily for six months with a fixed volume of a PAI-1 inhibitor formulation containing a fixed concentration of PAI-1 inhibitor. The concentration of the PAI-1 inhibitor in the formulation was 5% w / w. Application of the topical formulation to the scalp took approximately five minutes, after which the suspension was left on the site for approximately eight to twelve hours. The scalps of subjects in Groups III and IV were topically treated twice daily with an empty formulation for six months and served as controls.

[0216] [Table 2]

[0217] The expected effect of such treatment is an increase in hair density and / or hair follicle density at the site of treatment with the PAI-1 inhibitor formulation. The number and / or density of hair and hair follicle density at the treatment site are measured by two methods: 1) taking photographs of the treated area and observing changes in hair density, or 2) hair follicle density testing, which measures the number of hairs in a small area of ​​each subject's scalp. The small area of ​​scalp is selected before the start of the study.

[0218] Photographs and hair follicle density tests are used at baseline before PAI-1 inhibitor treatment. Following this, photographs of each subject's scalp are taken every 4 weeks after treatment begins, and at the end of the 6-month study. Hair follicle density tests are also conducted every 4 weeks after treatment begins, and at the end of the 6-month study. The study finds that at baseline (i.e., before the start of study, day 0), the average amount of hair counted by hair follicle density tests or by observing from photographs is approximately equal across all control and treatment groups. Photographs of the scalp of subjects in group I of the treatment group show a visible increase in the total number of hairs, on average, every 4 weeks. Hair follicle density tests also show an increase in the number of hair follicles in selected areas of the scalp of each subject belonging to group I of the treatment group, on average, every 4 weeks. In contrast, neither subjects in group II of the treatment group nor the control group show a visible increase in hair in the treatment area or an increase in hair follicle density in selected areas of the scalp.

[0219] This study establishes that topical administration of a topical formulation of PAI-1 inhibitor increases hair count and induces hair regrowth in humans with certain types of alopecia, namely androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senile alopecia, but does not increase hair count or induce hair regrowth in humans with other types of alopecia, such as radiation-induced alopecia, chemotherapy-induced alopecia, and alopecia due to chronic discoid lupus erythematosus.

[0220] Example 2: Effect of oral PAI-1 inhibitor formulations on specific types of hair loss (alopecia) Conduct a study of oral administration of oral formulation of PAI-1 inhibitor in men.The study is designed to test whether oral formulation of PAI-1 inhibitor significantly reduces hair loss in men with specific types of alopecia, namely, male pattern baldness, alopecia areata, frontal fibrosing alopecia and senile alopecia, by measuring hair follicle density after topical treatment with PAI-1 inhibitor.

[0221] The study includes four groups of human subjects. Each of the four groups is composed of a subgroup of 25 human subjects (see Table 2). All groups have subjects with different levels of hair follicle density and different hair numbers and / or densities. Each subject in groups I and II is administered an oral formulation of PAI-1 inhibitor formulated as a 75 mg capsule three times a day for six months. Each subject in groups III and IV is administered an empty oral formulation formulated as a 75 mg capsule three times a day for six months, which serves as a control.

[0222] The expected effect of such treatment is an increase in hair density and / or hair follicle density due to treatment with PAI-1 inhibitor formulation.The number and / or density of hair and hair follicle density in the treatment area are measured by two methods: 1) taking photos of the treated area and observing changes in hair density, or 2) hair follicle density test, which measures the number of hairs in a small area of ​​each subject's scalp.The small area of ​​scalp is selected before the start of the study.

[0223] Photographs and hair follicle density tests are used at baseline before PAI-1 inhibitor treatment. Following this, photographs of each subject's scalp are taken every 4 weeks after treatment begins, and at the end of the 6-month study. Hair follicle density tests are also conducted every 4 weeks after treatment begins, and at the end of the 6-month study. The study finds that at baseline (i.e., before the start of study, day 0), the average amount of hair counted by hair follicle density tests or by observing from photographs is approximately equal across all control and treatment groups. Photographs of the scalp of subjects in group I of the treatment group show a visible increase in the total number of hairs, on average, every 4 weeks. Hair follicle density tests also show an increase in the number of hair follicles in selected areas of the scalp of each subject belonging to group I of the treatment group, on average, every 4 weeks. In contrast, neither subjects in group II of the treatment group nor the control group show a visible increase in hair in the treatment area or an increase in hair follicle density in selected areas of the scalp.

[0224] This study establishes that oral administration of PAI-1 inhibitors increases hair count and induces hair regrowth in humans with certain types of alopecia, namely androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senile alopecia, but does not increase hair count or induce hair regrowth in humans with other types of alopecia, such as radiation-induced alopecia, chemotherapy-induced alopecia, and alopecia due to chronic discoid lupus erythematosus.

[0225] Example 3: Controlled Study of Scalp Grafts Treated with Topical and Oral PAI-1 Inhibitor Formulations in Humans with Male Pattern Baldness Ninety 3-mm full-thickness scalp punch biopsies were obtained from male subjects with androgenetic alopecia rated as moderately severe according to the Hamilton-Norwood Alopecia Scale, Types IV-V (see Classifications of Patterned Hair Loss: A Review, J Cutan Aesthet Surg., 2016, 9(1):3-12). These scalp biopsies were taken from the vertex or frontal regions of the scalp that had previously had normal hair growth but had "moderate vellus baldness" at the time of biopsy, i.e., hair characteristic of vellus and terminal hair.

[0226] Biopsies were implanted into the dorsal skin of 7-week-old SCID beige male mice, with a total of 30 mice receiving three grafts each. The grafts were allowed to grow for 10 days before treatment.

[0227] Ten mice were assigned to Group 1 ("topical vehicle"), which received twice-daily vehicle treatments. Ten mice were assigned to Group 2 ("topical active"), which received twice-daily treatments with a topical formulation described herein (see, e.g., Table 1), containing a plasminogen activator inhibitor 1 ("PAI-1") inhibitor formulation in the same vehicle used for Group 1. Ten mice were assigned to Group 3 ("oral active"), where the mice were allowed to eat ad libitum and were given chow enriched with the same PAI-1 inhibitor formulation used for Group 2.

[0228] Photographs of all grafts were taken immediately prior to the start of treatment ("baseline") and then every four weeks until the completion of 16 weeks of observation. The number of human hairs observed on each graft was counted at the same time intervals, and the mean number of hairs per graft in each treatment group was calculated. The percentage change in the mean number of hairs observed per graft for each treatment group was also calculated. The percentage change in the mean number of hairs observed per graft from baseline to 16 weeks was 80% for the vehicle group, 259% for the topical active group, and 395% for the oral active group.

[0229] In summary, both topical and oral formulations of PAI-1 inhibitors were associated with significantly greater hair growth (eg, about 3 to about 4.5 times greater) than vehicle control.

[0230] It was concluded that PAI-1 inhibitors are an effective treatment for male pattern baldness.

[0231] 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 present invention is not intended to be limited to the above detailed description, but is instead set forth in the following claims.

Claims

[Claim 1] The invention described herein.